Alternatives to Animal Use in Research,

Testing, and Education

February 1986

NTIS order #PB86-183134
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Alternatives to Animal Use in Research,

Testing, and Education (Washington, DC: U.S. Government Printing Office, OTA-BA-273,

February 1986).

Library of Congress Catalog Card Number 85-600621

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, DC 20402
Foreword

With an estimated 17 million to 22 million animals used in laboratories annually in

the United States, public interest in animal welfare has sparked an often emotional debate over such uses of animals. Concerns focus on balancing societal needs for continued

progress in biomedical and behavioral research, for toxicity testing to safeguard the public, and for education in the life sciences with desires to replace, reduce, and refine the

use of laboratory animals. In 1985, Congress enacted three laws that dealt with laboratory animals, including amendments to the Animal Welfare Act.

In this assessment, OTA analyzes the scientific, regulatory, economic, legal, and ethical

considerations involved in alternative technologies in biomedical and behavioral research,

toxicity testing, and education. Included is a detailed examination of Federal, State, and

institutional regulation of animal use, and a review of recent developments in 10 other

countries. The report was requested by Sen. Orrin Hatch, Chairman of the Senate Committee on Labor and Human Resources.

The report illustrates a range of options for congressional action in seven principal

areas of public policy regarding animals: using existing alternatives, developing new alternatives, disseminating research and testing information, restricting animal use, counting the numbers and kinds of animals used, establishing a uniform policy for animal

use within Federal agencies, and amending the Animal Welfare Act.

OTA was assisted in preparing this study by an advisory panel of individuals and

reviewers selected for their expertise and diverse points of view on the issues covered

in the assessment. Advisory panelists and reviewers were drawn from animal welfare

groups, industrial testing laboratories, medical and veterinary schools, Federal regulatory agencies, scientific societies, academia, and the citizenry at large—in short, from

representatives of all parties interested in laboratory-animal use and its alternatives. Written

comments were received from 144 reviewers on the penultimate draft of the assessment. In addition, at the study’s inception, OTA solicited information and opinions from

more than 600 interested groups and individuals.

OTA gratefully acknowledges the contribution of each of these individuals. As with

all OTA reports, responsibility for the content of the assessment is OTA’s alone. The

assessment does not necessarily constitute the consensus or endorsement of the advisory panel or the Technology Assessment Board.

Director

. . . Ill
Advisory Panel

Alternatives to Animal Use in Research, Testing, and Education

Arthur L. Caplan, Panel Chair

The Hastings Center

Hastings-on-Hudson, NY

Perrie M. Adams

The University of

Dallas TX

Melvin W. Balk

Texas Health Science Center

Charles River Breeding Laboratories, Inc.

Wilmington, MA

Earle W. Brauer

Revlon Research Center, Inc.

Edison, NJ

David J. Brusick

Litton Bionetics

Kensington, MD

G. Gilbert Cloyd

Norwich Eaton Pharmaceuticals, Inc.

Norwich, NY

W. Jean Dodds

New York State Department of Health

Albany, NY

Kurt Enslein

Health Designs, Inc.

Rochester, NY

Alan M. Goldberg

The Johns Hopkins School of Public Health

Baltimore, MD

Richard M. Hoar

Findley Research, Inc.

Fall River, MA

Peter Barton Hutt

Covington and Burling

Washington, DC

Connie Kagan

Animal Political Action

Washington, DC

Ronald Lamont-Havers

Massachusetts General

Boston, MA

John E. McArdle

Humane Society of the

Washington, DC

Robert A. Neal

Committee

Hospital

United States

Chemical Industry Institute of Toxicology

Research Triangle Park, NC

J. Wesley Robb

University of Southern California

Los Angeles, CA

Andrew N. Rowan

Tufts University

Boston, MA

Jeri A. Sechzer

The New York Hospital Center

White Plains, NY

Henry Spira

Coalition to Abolish the LD50 and Draize Tests

New York, NY

OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the Advisory Panel members. The views

expressed in this OTA report, however, are the sole responsibility of the Office of Technologv Assessment.

iv
OTA Project Staff

Alternatives to Animal Use in Research, Testing, and Education

Roger C. Herdman, Assistant Director, OTA Health and Life Sciences Division

Gretchen S. Kolsrud, Biological Applications Program Manager

Gary B. Ellis, Project Director and Analyst

Judy K. Kosovich, Principal Analyst

Lisa J. Raines, Legal Analyst

Timothy J. Hart, Project Directorl

Gregory A. Jaffe, Research Assistantz

Marcia D. Brody, Resarch Assistantz

James A. Thomas, Research Assistant3

Thomas M. Bugbee, Research Assistant4

Jeffrey S. Stryker, Research Analyst5

Support Staff

Sharon K. Smith, Administrative Assistant

Elma Rubright, Administrative Assistant3

Linda S. Ray ford, Secretary/Work Processing Specialist

Barbara V. Ketchum, Clerical Assistant

Contractors

Linda Starke (Editor), Washington, DC

Battelle—Columbus Laboratories, Columbus, OH

Leonard M. Chanin, Washington, DC

Eileen M. Cline, Springfield, VA

Paul N. Craig, Shady Side, MD

Arthur H. Flemming, University of Chicago

Gordon G. Gallup, Jr., State University of New York at Albany

Gilbert S. Greenwald, University of Kansas Medical Center

Anne M. Guthrie, Arlington, VA

Health Designs, Inc., Rochester, NY

Henry R. Hertzfeld and Thomas D. Myers, Washington, DC

Meyer, Failer, and Weisman, P.C., Washington, DC

Roland M. Nardone and Lucille Ouellette, Catholic University, Washington, DC

Bennie I. Osburn, University of California, Davis

Stephen P. Push, Washington, DC

‘Through December 1984.

‘Through July 1985,

3

Through August 1984.

4

Through June 1984.

Through January 198.5,
CONTENTS

Chapter Page

1. Summary, Policy Issues, and Options for Congressional Action . . . . . . . , . . . 3

2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

3. Patterns of Animal Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4. Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

5. The Use of Animals in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

6. Ahernatives to Animal Use in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

7.The Use of Animals in Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

8. Ahernatives to Animal Use in Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

9. Animal Use n Education and the Alternatives . . . . . . . . . . . . . . . . . . . . . . . . . 199

10.Information Resources and Computer Systems . . . . . . . . . . . . . . . . . . . . . . . . 219

11. Economic Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . 243

12. Public and Private Funding Toward the Development of Alternatives . . . . . 259

13. Federal Regulation of Animal Use ..., . . . . . . ., . . . . . . . . . . . . . . . . . . . . . . . 275

14. State Regulation of Animal Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

15. Institutional and Self-Regulation of Animal Use . . . . . . . . . . . . . . . . . . . . . . . . 335

16. Regulation of Animal Use in Selected Foreign Countries. . . . . . . . . . . . . . . . . 359

Appendix Page

A. Testing Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

B. Regulation of Animal Use Within Federal Departments and Agencies. . . . . . 386

C. Public Health Service Policy . . . . . . . . . . ..., . . . . . . . . . . . . . . . . . . . . . . . . . . 395

D. Laboratory-Animal Facilities Fully Accredited by the American Association

for Accreditation of Laboratory Animal Care . . . . . . . . . . . . . . . . . . . . . . . . . . 401

E. International Agreements Governing Animal Use . . . . . . . . . . . . . . . . . . . . . . . 412

F. List of Working Papers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418

G. Acknowledgments. ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419

H. Glossary of Acronyms and Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Index . . . . . . . . . . . . . . . . ..., . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . . . . . . . . . . . 433

vii
Chapter I

Summary, Policy Issues,

and options for

Congressional Action
CONTENTS

Page

Definition of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

How Many Animals Are Used? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Alternatives in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Ahernatives infesting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Alternatives in Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Computer Simulation and Information Resources . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Economic Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Funding for the Development of Alternatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Regulation of Animal Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Federal Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

State Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Institutional and Self-Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Regulation Within Federal Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

International Regulation , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Policy Issues and Options for Congressional Action. . . . . . . . . . . . . . . . . . . . . . . . . 17

Issue: Should steps be taken to encourage the use of available alternatives in

research, testing, or education? ., . . . . . . . . . . . . . . ,. . . . . . . . . . . . , . , . . 19

Issue: Should the more rapid development of new alternatives in research,

testing, or education be stimulated? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Issue: Should improvements be made in information resources to reduce any

unintentionally duplicative use of animais in research and testing?. . . . . 23

Issue: Should animal use in research, testing, or education be restricted? . . . . 26

Issue: Should more accurate data be obtained on the kinds and numbers of

animals used in research, testing, and education? . . . , . , . . . . . . . . . . . . . 29

Issue: Should Federal departments and agencies be subject to minimum

standards for animal use? . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . 31

Issue: Should the Animal Welfare Act of 1966 be further amended, or its

enforcement enhanced? . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . 32

List of Tables

Table No. Page

l-l. Animal Use Reported to the U.S. Department of Agriculture, 1983 . . . . . . . . 5

l-2. National Laws for the Protection of Animals in Selected

European Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

l-3. Policy Issues Related to Alternatives to Animal Use and Options

for Congressional Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Figure

Figure No. Page

l-1. Chronological Sequence of Chick Embryo Chorioallantoic

Membrane Assay... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Chapter 1

Summary, Policy Issues, and

Options for Congressional Action

●

●

●

●

●

●

A former high school teacher in New York organizes demonstrations and advertising campaigns

opposing the use of rabbits and rodents in two product-safety tests. Industry responds by giving

several million dollars in grants to university scientists searching for alternatives to animal testing.

Researchers induce seizures in rats, draw their cerebrospinal fluid, and use it to quell seizures

in other rats; the anticonvulsant substance produced during seizures could bear on the understanding and treatment of epilepsy.

Industrial toxicologists in New Jersey adopt refined methods of testing potentially poisonous

chemicals, reducing by 48 percent the number of animals used in acute toxicity studies and

cutting the cost of compliance with government regulations.

A Virginia woman donates $1,250,000 to the University of Pennsylvania to establish the Nation

first endowed professorship in humane ethics and animal welfare. One of the goals of the chair

is to investigate alternatives to animal experiments for medical research.

Members of the Animal Liberation Front break into a biomedical research laboratory in California and remove dogs being used in a cardiac pacemaker experiment.

Veterinary students in Washington study principles of physiology without recourse to the traditional dog dissection. Instead, they use a computer simulation of canine physiology.

These recent events illustrate the complex political, ethical, and economic issues raised by the

use of animals in research, testing, and education.

Concern about the continued use of animals has

led to public calls for development of alternatives.

The popular debate over animal use has been

taken up by proponents holding a wide spectrum

of views, ranging from belief in abolition of animal

use on moral and ethical grounds to belief in free

rein on the use of animals in research, testing, and

education. An increasing number of groups are

taking a middle ground. In the mid-1980s, it is

misleading—and often impossible—to characterize many vocal groups either as simply “pro-animal”

or “pro-research. ”

In light of requests for “a scientific evaluation

of alternative methods to animal research, experimentation, and testing” from the Chairman of the

Senate Committee on Labor and Human Resources,

Senator Orrin G. Hatch (R-UT), and from Senator

Alan Cranston (D-CA), this assessment examines

the reasons for seeking such alternatives and the

prospects for developing them. It describes animal and nonanimal methods used by industry,

academia, and government agencies; explains the

roles and requirements of government regulation

and self-regulation of animal use; and identifies

policy issues and options that the debate over alternatives places before Congress.

The report covers three kinds of animal use:

research in the biomedical and behavioral sciences; testing of products for toxicity; and education of students at all levels, including the

advanced life sciences, and medical and veterinary training. The use of animals in these three

situations—research, testing, and education-differs considerably, and each has different prospects

for development of alternatives.

The assessment excludes examination of the use

of animals in food and fiber production; their use

in obtaining organs, antibodies, and other biological products; and their use for sport, entertainment, and companionship. Such purposes include

numbers of animals generally estimated to be many

multiples greater than the numbers used for purposes described in this report (see ch. 3). Issues

of animal care, such as feeding and maintenance,

are also beyond the scope of this assessment.

3
—

4 ● Alternatives to Animal Use in Research, Testing, and Education

DEFINITION

In this report, animal is defined as any nonhuman member of the five classes of vertebrates: mammals, birds, reptiles, amphibians,

and fish (see ch. 2). Within this group, two kinds

of animals can be distinguished—warm-blooded

animals (mammals and birds) and cold-blooded animals (reptiles, amphibians, and fish). Other creatures customarily included in the animal kingdom,

such as invertebrates (e.g., worms, insects, and

crustaceans), are excluded by this definition. The

use of human subjects is not examined in this

assessment.

The concept of alternatives to animal use has

come to mean more than merely a one-to-one

substitution of nonanimal methods for animal techniques. For alternatives, OTA has chosen a def=

inition characterized by the three Rs: replacement, reduction, and refinement.

Scientists may replace methods that use animals

with those that do not. For example, veterinary

students may use a canine cardiopulmonary -resus -

citation simulator, Resusci-Dog, instead of living

dogs. Cell cultures may replace mice and rats that

are fed new products to discover substances poisonous to humans. In addition, using the preceding definition of animal, an invertebrate (e.g., a

horseshoe crab) could replace a vertebrate (e.g.,

a rabbit) in a testing protocol.

Reduction refers to the use of fewer animals.

For instance, changing practices allow toxicologists to estimate the lethal dose of a chemical with

as few as one-tenth the number of animals used

in traditional tests. In biomedical research, longlived animals, such as primates, may be shared,

assuming sequential protocols are not deemed inhumane or scientifically conflicting. Designing experimental protocols with appropriate attention

to statistical inference can lead to decreases (or

to increases) in the numbers of animals used. Or

several tissues may be simultaneously taken from

a single animal as a result of coordination among

investigators. Reduction can also refer to the minimization of any unintentionally duplicative experOF TERMS

Resusci-Dog, Canine Cardiopulmonary

Resuscitation Simulator

Photo credit: Charles R. Short,

New York State College of Veterinary Medicine,

Cornell University

Resusci-Dog, a plastic mannequin linked to a computer,

can simulate an arterial pulse, and pressure can be

applied to its rib cage for cardiac massage or cardiopulmonary resuscitation. Resusci-Dog has replaced

about 100 dogs per year in the training of veterinary

students at the New York State College

of Veterinary Medicine.

iments, perhaps through improvements in information resources.

Existing procedures may be refined so that animals are subjected to less pain and distress. Refinements include administration of anesthetics to animals undergoing otherwise painful procedures;

administration of tranquilizers for distress; humane destruction prior to recovery from surgical

anesthesia; and careful scrutiny of behavioral indices of pain or distress, followed by cessation of

the procedure or the use of appropriate analgesics.

Refinements also include the enhanced use of noninvasive imaging technologies that allow earlier

detection of tumors, organ deterioration, or metabolic changes and the subsequent early euthanasia of test animals.

Pain is defined as discomfort resulting from injury or disease, while distress results from pain,

anxiety, or fear. Pain may also be psychosomatic,

resulting from emotional distress. Although these

are subjective phenomena, pain and distress can
—.

Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 5

sometimes be identified and quantified by observ- objectives of procedures. Professional ethics reing an animal’s behavior. Pain is relieved with quire scientists to provide relief to animals in pain

analgesics or anesthetics; distress is eased with or distress, unless administering relief would intertranquilizers. Widely accepted ethical standards fere with the objective of the procedure (e.g., when

require that scientists subject animals to as little the objective is a better understanding of the mechpain or distress as is necessary to accomplish the anisms of pain).

HOW MANY ANIMALS ARE USED?

Estimates of the animals used in the United States

each year range from 10 million to upwards of

100 million. OTA scrutinized a variety of surveys

(see ch. 3), including those of the National Research

Council’s Institute for Laboratory Animal Resources

and the Animal and Plant Health Inspection Service (APHIS) of the U.S. Department of Agriculture

(USDA). Indirect estimates of animal use were also

based on data such as Federal funds spent on animal research and sales revenues of the Nation’s

largest commercial breeder of laboratory animals.

All these data are unreliable, No data source exists, for example, to enumerate how many institutions do not report animal use. In addition, nonreporting institutions may not be similar enough

to reporting institutions to justify extrapolation.

Thus every estimate of animal use stands as a rough

approximation. With this caveat in mind, the best

data source available--the USDA/APHIS census

—suggests that at least 17 million to 22 million

animals were used in research and testing in

the United States in 1983. The majority of animals used—between 12 million and 15 million—

were rats and mice. Current data permit no statement about any trends in animal use through recent years. Animal use in medical and veterinary

education amounted to at least 53)

000 animals in

the school year 1983-84.

The Animal Welfare Act of 1966 (Public Law 89-

544), as amended and presently enforced, requires

research and testing facilities to report to USDA

their annual use of dogs, cats, hamsters, rabbits,

guinea pigs, and nonhuman primates (see ch. 13).

(About two-thirds of the reporting institutions also

volunteer the number of rats and mice used ). For

fiscal year 1983, the USDA reporting forms indicate

the facilities used nearly 1.8 million of these six

kinds of animals (see table 1-1).

Table I-l.—Animal Use Reported to the

U.S. Department of Agriculture, 1983a

Number used

Animal in 1983

Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182,425

Cats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55,346

Hamsters . . . . . . . . . . . . . . . . . . . . , . . . . . 454,479

Rabbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509,052

Guinea pigs , . . . . . . . . . . . . . . . . . . . . . . . 521,237

Nonhuman primates . . . . . . . . . . . . . . . . . 59,336

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,781,875

aTotalS do not include rats or mice, two species that together r@ Present the

majority of animals used.

SOURCE” Office of Technology Assessment.

USDA reports are of limited utility because:

●

●

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●

the Department counts only six kinds of animals that together account for an estimated

10 percent of the total animals used (reporting of rats, mice, birds, and fish is not required);

the annual summary report does not tabulate

reports received after December 31st of each

year, resulting in a 10-to 20-percent underestimation of laboratory use of regulated species;

ambiguities in the reporting form ask respondents to add figures in a way that can cause

animals to be counted twice; and

terms on the reporting form are undefined

(e.g., the form has room for voluntary information about “wild animals, ” but does not

specify what animals might be included).

In the absence of a comprehensive animal census,

the USDA reports will continue to provide the best

data. Imprecise as they are, these reports can identify major changes in the numbers of dogs, cats,

hamsters, rabbits, guinea pigs, and nonhuman primates. (It is important to note that any change in

the total number of animals used may reflect not

only the adoption of alternative methods, but

changes in research and testing budgets as well.)
6 ● Alternatives to Animal Use in Research, Testing, and Education

ETHICAL CONSIDERATIONS

At one end of a broad spectrum of ethical concerns about animal use is the belief that humans

may use animals in any way they wish, without

regard for the animals suffering. At the other extreme is the notion--epitomized by the slogan ‘(animals are people, too’’ —that each animal has the

right not to be used for any purpose that does not

benefit it. Each view is anchored in a school of philosophical thought, and people considering this issue can choose from a variety of arguable positions (see ch. 4).

Prominent within the Western philosophic and

religious tradition is the view that humans have

the right to use animals for the benefit of humankind. This view is predicated on the assumption

that human beings have special intrinsic value and

thus may use natural animate and inanimate objects, including animals, for purposes that will enhance the quality of human life. Yet this tradition

suggests that because animals are intelligent and

sentient beings, they should be treated in a humane manner. Current policies and trends within

the scientific community have reinforced this conviction by advocating that pain and suffering be

minimized when animals are used in research, testing, or education.

Advocates of what generally is called animal welfare frequently question the objectives of animal

use, as well as the means. They point out that animals can experience pain, distress, and pleasure.

Drawing on the utilitarian doctrine of providing

the greatest good for the greatest number, some

animal welfare advocates weigh animal interests

against human interests. In this view, it might be

permissible to use animals in research to find a

cure for a fatal human disease, but it would be

unjust to subject animals to pain to develop a product with purely cosmetic value.

ALTERNATIVES

In research, scientists often explore uncharted territory in search of unpredictable

events, a process that inherently involves uncertainty, missteps, and serendipity. Some bio

logical research requires-and in the foresee

Some animal rights advocates carry this concern

a step further and do not balance human and animal rights. They generally invoke the principle of

inalienable individual rights. They believe that animal use is unjustified unless it has the potential

to benefit the particular animal being used. Animal rights advocates refer to the denial of animal

rights as a form of “speciesism,” a moral breach

analogous to racism or sexism. Animals, by this

reasoning, have a right not to be exploited by

people.

People throughout the spectrum find common

ground in the principle of humane treatment,

but they fail to agree on how this principle should

be applied. Society does not apply the principle

of humane treatment equally to all animals. A cat

may evoke more sympathy than a frog, for example, because the cat is a companion species and

possesses apparently greater neurological sophistication than a frog, endowing it with both favored

status and a familiarity that suggests to humans

that they can interpret its behavior. Even within

a species, all individuals are not treated consistently. Pet rabbits in the home and pest rabbits in

the garden, like human friends and strangers, are

treated differently.

The improvements in public health and

safety made possible through the use of animals in research and testing are well known.

But these questions remain” Do these advances

justify animal use? How much of the improve=

ments were actually dependent on the use of

animals? Debate on these and other questions is

bound to continue, but most parties agree that consideration of replacing, reducing, and refining the

use of animals is desirable.

IN RESEARCH

able future will continue to require-the use

of live animals if the study of the complex interactions of the cells, tissues, and organs that

make up an organism is to continue. Knowledge

thus gained is applied to improving the health and
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Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 7

well-being of humans and of animals themselves,

and it may lead to the development of methods

that would obviate the use of some animals.

Some nonanimal methods are becoming available

in biomedical and behavioral research (see ch. 6).

As more develop, animal use in research will likely

become less common. It is important to note, however) that even if animals cannot be replaced

in certain experiments, researchers can attempt to reduce the number used and also to

minimize pain and distress.

Most alternatives to current animal use in research fall into one of four categories:

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Continued, But Modified, Use of Animals.

This includes alleviation of pain and distress,

substitution of cold-blooded for warm-blooded

vertebrates, coordination among investigators, and use of experimental designs that provide reliable information with fewer animals

than were used previously.

Living Systems. These include micro-organisms, invertebrates, and the in vitro culture

of organs, tissues, and cells.

Nonliving Systems. These include epidemiologic databases and chemical and physical systems that mimic biological functions.

Computer Programs. These simulate biological functions and interactions.

The many fields of research—ranging from

anatomy to zoology—use animals differently,

and each thus has different prospects for developing and implementing alternatives. To determine the prevalence of animal and nonanimal

methods in varied disciplines of research, OTA surveyed 6)000 articles published between 1980 and

1983 in 12 biomedical research journals and 3 behavioral research journals (see ch. 5). Research disciplines were distinguished by their characteristic patterns of animal use, as measured by the

percentages of published reports showing animal

use, no animal use, and use of humans. Animal

methods predominated in most of the journals surveyed, including the three behavioral research

journals. The exceptions in the overall survey were

cell biology, which used primarily nonanimal methods, and cardiology, which used primarily human

subjects.

Using alternative methods in biomedical research holds several advantages from scientific,

economic, and humane perspectives, including:

●

●

●

●

●

●

●

●

●

reduction in the number of animals used;

reduction in animal pain, distress, and experimental insult;

reduction in investigator-induced, artifactual

physiological phenomena;

savings in time, with the benefit of obtaining

results more quickly;

the ability to perform replicative protocols on

a routine basis;

reduction in the cost of research;

greater flexibility to alter conditions and vari -

ables of the experimental protocol;

reduction of error stemming from interindividual variability; and

the intrinsic potential of in vitro techniques

to study cellular and molecular mechanisms.

Many of these alternative methods are accompanied by inherent disadvantages, including:

●

●

●

●

●

●

●

●

●

reduced ability to study organismal growth

processes;

reduced ability to study cells, tissues, and organ systems acting in concert;

reduced ability to study integrated biochemical and metabolic pathways;

reduced ability to study behavior;

reduced ability to study the recovery of

damaged tissue;

reduced ability to stud-y interaction between

the organism and its environment;

reduced ability to study idiosyncratic or

species-specific responses;

reduced ability to distinguish between maleand female-specific phenomena; and

a handicap to probing the unknown and phenomena not yet identified.

Behavior encompasses all the movements and

sensations by which living things interact with both

the living and nonliving components of their environment. Since one of the chief goals of behavioral

research is an understanding of human behavior,

there are obvious advantages to the use of human

research subjects. There are also advantages to

using animals, including the following:

● Laboratory research on animals offers a

greater opportunity to control variables such
8 . Alternatives to Animal Use in Research, Testing, and Education

●

●

●

as genetic background, prior experience, and

environmental conditions, all of which affect

behavior and can obscure the influence of the

factor under study.

The short lifespans of certain animals allow

scientists to study behavior as it develops with

age and across generations.

Some animal behavior is less complex than human behavior, facilitating an understanding

of basic elements and principles of behavior.

The behavior of certain animals holds particular interest for humans. These animals include

companion species, farm animals, and agricultural pests.

Although behavior is a biological phenomenon,

behavioral research differs substantially from biomedical research in that researchers have fewer

opportunities to study mechanisms isolated from

living organisms. There is little prospect, for example, of using in vitro cultures to look at aggression, habitat and food selection, exploration patterns, or body maintenance activities—all topics

studied by behavioral scientists. Yet in each of these

disciplines, reduction or refinements of animal use

may be possible. It is the continued, but modified, use of animals that holds the most promise as an alternative in the field of behavioral

research.

ALTERNATIVES IN TESTING

Several million animals are used each year

in testing substances for toxicity and establishing conditions for safe use. The resulting data—

together with information about use and exposure, human epidemiologic data, and other

information—are used in assessing and managing health risks.

As a reduction in the number of animals is a principal alternative, proper statistical design and analysis in testing protocols play an important role (see

ch. 7). The total number of animals needed for statistically significant conclusions depends on the

incidence of toxic effects without administration

of the test substance, the degree of variation from

animal to animal for the biological effect that is

of interest, and the need to determine a quantitative relationship between the size of the dose and

the magnitude of the response. Statistical analysis plays a similarly important role in research.

One of the oldest and, perhaps for that reason,

least sophisticated tests is the LD50 (“lethal dose”

for “50” percent of the test animals). In this shortterm, or acute, test, a group of animals, usually

rats or mice, are exposed to a single substance,

and the measured end point is death (although

other observations may be made). The LD50 is the

dose at which half the test animals can be expected

to die. A range of doses is administered to some

30 to 100 animals and the LD50 is calculated from

the results. Tests providing the same information have recently been developed using as few

as 10 animals, i.e., a 3- to 10-fold reduction,

The LD50 is used to screen substances for their

relative toxicity and mode of toxic action. Scientists and animal welfare advocates have criticized

it in recent years, in part because it cannot be extrapolated reliably to humans, and in part because

the imposition of a highly toxic or lethal dose seems

particularly inhumane.

Another often-criticized acute toxicity assay is

the Draize eye irritancy test. This involves placing a test substance into one eye of four to six rabbits and evaluating its irritating effects. Results are

used to develop precautionary information for situations in which exposure of the human eye to

the substance is possible. Substances with certain

properties-e.g., a caustic pH-could be assumed

to be eye irritants and not tested. Draize procedures may also be modified to reduce pain, and

in vitro methods to test for irritancy are under

development. A promising new bioassay for tissue irritancy makes use of the chorioallantoic membrane of the chick embryo (see fig. 1-1).

Other common tests include those for long-term

chronic effects, carcinogenicity, reproductive and

developmental toxicity, skin irritancy, and neuro -

toxicity. In addition to such descriptive toxicology

(i.e., tests that focus on the response of the organ-
Ch. l—Summary, Policy Issues, and Options for Congressional Action “ 9

Figure l-l.— Chronological Sequence

Embryo Chorioallantoic Membrane

of Chick

Assay

Day O

/

Day 3

Y I

I

i

Day O: Fertile eggs are incubated at 3 7

oC. Day 3: The shell is

penetrated in two places: A window is cut at the top, and 1.5 to 2

milliliters of albumin is removed with a needle and discarded. The

chorioallantoic membrane forms on the floor of the air space, on top

of the embryo. The window is taped. Day 14: A test sample is placed

on the embryonic membrane and contained within a plastic ring. Day

17: The chorioallantoic membrane is evaluated for its response to the

test substance, and the embryo is discarded.

SOURCE J. Leighton, J, Nassauer, and R, Tchao, “The Chick Embryo in Toxicology: An Alternative to the Rabbit Eye,” Food Chem. Toxicol. 23:293-298.

Copyright 1985, Pergamon Press, Ltd.

ism as a whole), testing may also be done to determine the mechanisms by which a substance is

metabolized or excreted, and the chemical reactions by which toxic effects are produced. Such

studies of mechanistic toxicology aid in the selection and design of descriptive tests.

The Federal Government plays a major role

in this area, both through laws that directly or

Chick Embryo Chorioallantoic Membrane Assay

Photo credit: Joseph Leighton, Medical College of Pennsylvania

Typical reaction seen when certain concentrations of

household products are placed on the 14-day-old chorioallantoic membrane and examined 3 days later on 17-day -

old membranes. The thin white plastic ring has an

internal diameter of 10 millimeters (0.4 inch). The area

of injury occupies the entire plastic ring. Damaged blood

vessels appear within the ring as an elaborate branching

structure of pale, white, dead vessels of various sizes.

The severity of the reaction is gauged by measuring

the diameter of the injury, in this instance

spanning the entire ring

indirectly require testing and through guidelines that influence testing procedures. The

greatest amount of testing is done under laws

administered by the Food and Drug Administration (FDA) requiring that products be safe and effective and that labeling claims be substantiated.

The Environmental Protection Agency (EPA) requires testing to support pesticide registrations

and in certain other cases. For substances other

than pesticides, EPA relies largely on published

literature and EPA-sponsored testing. Other agencies that use animal testing data include USDA,

the Consumer Product Safety Commission, the Occupational Safety and Health Administration, the

Department of Transportation, the Federal Trade

Commission, and the Centers for Disease Control.

Although most laws do not explicitly require

animal testing, requirements of safety implicitly require that the best available means

for determining safety be used. Thus, alternatives are not likely to be used widely until they

can be shown to be at least as valid and reliable as the tests being replaced. Meeting these

criteria is probably not overly difficult with some
10 . Alternatives to Animal Use in Research, Testing, and Education

alternatives that involve reduction or refinement,

but it maybe harder to replace whole-animal testing totally with in vitro methods.

Reductions in the number of animals used can

be brought about by using no more animals than

necessary to accomplish the purpose of the test,

by combining tests in such a way that fewer animals are needed, and by retrieving information

that allows any unintentional duplication of earlier

work to be avoided (see chs. 8 and 10). Refinements

include increased use of anesthetics and analgesics

to ameliorate pain and tranquilizers to relieve distress. Replacements may involve human cell cultures obtained from cadavers or in surgery, animal

cell cultures, invertebrates, or micro-organisms.

For example, the use of an invertebrate in place

of a vertebrate, as in the case of substituting horseshoe crabs for rabbits in testing drugs for their

production of fever as a side effect, is increasingly

accepted as a replacement.

The most promising in vitro methods are based

on an understanding of whole-organ or organism

responses that can be related to events at the cellular or subcellular level. Cells manifest a variety

of reactions to toxins, including death, changes

in permeability or metabolic activity, and damage

to genetic material.

ALTERNATIVES IN EDUCATION

Although far fewer animals are used in education than in either research or testing, animal use in the classroom plays an important

role in shaping societal attitudes toward this

subject. As educational goals vary from level to

level, so does the use of animals and therefore the

potential for alternatives (see ch. 9).

In elementary schools, live animals are generally present solely for observation and to acquaint

students with the care and handling of different

species. Although the guidelines set by many school

boards and science teachers’ associations limit the

use of living vertebrates to procedures that neither cause pain or distress nor interfere with the

animals’ health, these guidelines are not observed

in all secondary schools. Science fairs are an additional avenue for students to pursue original research. The Westinghouse Science Fair prohibits

the invasive use of live vertebrates, whereas the

International Science and Engineering Fair has no

such prohibition.

In the college classroom and teaching laboratory,

alternatives are being developed and implemented

because they sometimes offer learning advantages,

are cheaper than animal methods, and satisfy animal welfare concerns. As a student advances, animal use at the postsecondary level becomes increasingly tied to research and skill acquisition.

As graduate education merges with laboratory research and training, animal use becomes largely

Finalist, 1985 Westinghouse Science Talent Search

Photo credit: Gary B. Ellis

Louis C. Paul, age 18, Baldwin Senior High School,

Baldwin, NY, with his research project, “Effect of

Temperature on Facet Number in the Bar-Eyed Mutant

of Drosophila melanogaster. ”

a function of the questions under investigation.

In disciplines such as surgical training in the health

professions, some measure of animal use can be

helpful but is not universally viewed as essential.

Many alternative methods in education are

already accepted practice (see ch. 9). Replacements include computer simulations of physiological phenomena and pharmacologic reactions, cell

culture studies, human and animal cadavers, and

audiovisual materials. Clinical observation and instruction can also replace the use of animals in

some laboratory exercises in medical and veteri-
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 1 1

nary schools. Reduction techniques include the use

of classroom demonstrations in place of individual students’ animal surgery and multiple use of

each animal, although subjecting an animal to multiple recovery procedures may be viewed as inhumane and counter to refined use. Refinements

include the use of analgesics, euthanasia prior to

recovery from surgery, observation of intact animals in the classroom or in their natural habitats,

and the substitution of cold-blooded for warmblooded vertebrates in laboratory exercises.

Humane education aspires to instill positive

attitudes toward life and respect for living animals. Instruction in proper care and handling of

various species may be complemented by exposure

to the principles of animal use in research and testing and to alternative methods. This type of education promotes attitudes conducive to the development and adoption of alternatives.

COMPUTER SIMULATION AND INFORMATION RESOURCES

Recent advances in computer technology

hold some potential for replacing and reducing the use of animals in research, testing, and

education (see chs. 6, 8) 9, and 10). Inmost cases,

however, research with animals will still be

needed to provide basic data for writing computer software, as well as to prove the validity

and reliability of computer alternatives.

In research, scientists are developing computer

simulations of cells, tissues, fluids, organs, and organ systems, Use of such methods enables less use

of some animals. Limitations on the utility of computer simulations are due to a lack of knowledge

of all the parameters involved in the feedback

mechanisms that constitute a living system, which

means the information on which the computer

must depend is incomplete.

In testing, computers allow toxicologists to develop mathematical models and algorithms that

can predict the biological effects of new substances

based on their chemical structure. If a new chemical has a structure similar to a known poison in

certain key aspects, then the new substance also

may be a poison. Such screening can thus preempt

some animal use.

ment and the effects of extraneous variables, helping students concentrate on a lesson’s main point.

Aside from their direct use in research, testing,

and education, computers also could reduce animal use by facilitating the flow of information

about the results of research and testing. Scientists routinely attempt to replicate results of experiments to ensure their accuracy and validity

and the generality of the phenomenon. Unintentional duplication, however, can waste money and

animal lives. To avoid such situations, the scientific community has established various modes of

communication. Research and testing results are

published in journals, summarized by abstracting

services, discussed at conferences, and obtained

through computer databases.

One way any existing unintentional duplication

might be ended, and thus animal use reduced, is

to establish or refine existing computer-based registries of research or testing data. The National Cancer Institute and the National Library of Medicine

(NLM) developed a limited registry in the late 1970s,

but it failed: The Laboratory Animal Data Bank

(LADB) had few users, as it did not serve user needs.

Any new registry should contain descriptions

In education, computer programs simulate class- of the methods of data collection and the labora -

room experiments traditionally performed with tory results for both experimental and control

animals. The most advanced systems are video- groups of animals. Inclusion of negative results

disks that combine visual, auditory, and interac - (which are seldom reported in journals) could 40

tive properties, much as a real classroom experi- reduce animal use, Entries should undergo peer

ment would. Computer simulations can eliminate review before inclusion in the registry; that is,

both the detailed work of conducting an experi- studies should be scrutinized to judge the validity
12 . Alternatives to Animal Use in Research, Testing, and Education

and reliability of the data. A registry along these

lines would probably be 3 to 15 times as complex

and costly as the unsuccessful LADB.

As alternative methods are developed and implemented, a computerized registry of information about these novel techniques might serve to

speed their adoption. In 1985, the NLM incorporated “animal testing alternatives” as a subject heading in its catalogs and databases, which help users

throughout the world find biomedical books, articles, and audiovisual materials. In amending the

Animal Welfare Act in 1985, Congress directed the

National Agricultural Library to establish a service providing information on improved methods

of animal experimentation, including methods that

could reduce or replace animal use and minimize

pain and distress to animals.

ECONOMIC CONSIDERATIONS

The total dollar cost of the acquisition and maintenance of laboratory animals is directly related

to the length of time animals stay in the laboratory. With no accurate source of data on various

species’ length of stay, it is impossible to calculate

the actual total dollar cost of animal use. Reducing the number of animals used can lower acquisition and maintenance costs. Yet, the overall savings will not be proportionate to the smaller

number of animals used, as the overhead costs of

breeding and laboratory animal facilities must still

be met.

Animal use carries with it both great expense

and major economic and health benefits (see

chs. 5, 7, and 11). Nonetheless, it is difficult to express many of the costs and benefits monetarily.

What price does society put on the pain and distress of an animal used in research, for example,

or on the life of a person saved by a new medical

treatment that was made possible by the use of

animals?

In research, there is no way of knowing when

a particular result would have been obtained if

an experiment had not been done. Thus, it is impossible to predict many of the costs related to

the use of alternatives in research. Attempts to

do so are likely to result in economic predictions

with little basis in fact.

The primary reason a company conducts animal tests is to meet its responsibilities to make safe

products under safe conditions. For pharmaceuticals, the need extends to the assurance of product

effectiveness. In testing, animal methods generally are more labor-intensive and time consuming

than nonanimal methods, due to the need, for ex -

ample, to observe animals for toxic effects over

lifetimes or generations. Testing can cause delays

in marketing new products, including drugs and

pesticides, and thus defer a company’s revenue.

Rapid, inexpensive toxicity tests could yield major benefits to public health. There are more than

50,000 chemicals on the market, and 500 to 1)000

new ones are added each year. Not all must be

tested, but toxicologists must expand their knowledge of toxic properties of commercial chemicals

if human health is to be protected to the extent

the public desires. Rapid and economical testing

would facilitate the expansion of that knowledge.

Government regulatory practices can be read

as promoting animal testing although the laws

and practices appear flexible enough to accept

alternatives when such tests become scientifically acceptable. To date, regulatory practices

have not, in fact, provided a basis for companies

to expect that acceptance of alternative methods

will be an expedient process. In addition to responding to regulatory requirements, companies

conduct animal tests to protect themselves from

product liability suits. Here, the necessary tests

can exceed government requirements.

Because of the great expense and long time required for animal research and testing, priority

in research results has considerable value to investigators and testing results bear considerable

proprietary value for industry. Some data are made

public by statute, and various arrangements can

be made for sharing testing costs. Yet many data

are held in confidence, for example, by the company that generated them.
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 1 3

FUNDING FOR THE DEVELOPMENT OF ALTERNATIVES

The Federal Government does not explicitly

fund the development of alternatives to animal

use per se. Because research on and development

of alternatives is founded on a broad base of disciplines, it is difficult to ascertain the dimensions

of the effective level of support. No category of

research funds, for example, distributed by the

National Institutes of Health (NIH) or the National

Science Foundation is earmarked for the development of alternatives. Yet despite this lack of identifiable, targeted funding, Federal dollars do support areas of testing and research that generate

alternatives.

In biomedical and behavioral research, it is not

clear whether targeted funding efforts would produce alternatives faster than they are already being

devised. The research areas most likely to result

in useful alternatives include computer simulation of living systems; cell, tissue, and organ

culture technology; animal care and health;

and mechanisms of pain and pain perception.

Funding to improve animal facilities can result

in healthier, less stressed animals and can free

research from confounding variables bred by

a less well defined or inferior environment.

Some Federal agencies, notably the National Toxicology Program and FDA, conduct in-house research on alternatives to animal testing, as do some

corporations. Industry has also committed funds

to university researchers seeking alternatives. Revlon has given $1.25 million to the Rockefeller

University to support research on alternatives to

the Draize eye irritancy test. The Cosmetic, Toiletry, and Fragrance Association and Bristol Myers

Company have given $2.1 million to the Center for

Alternatives to Animal Testing at The Johns Hopkins University, which funds research into testing alternatives, especially in vitro methods.

Alternatives to animal use in education generally build on techniques developed in research and

funded by research monies. Some Federal support

for research in science education addresses the

development of alternatives, particularly in the

area of computer simulation. In 1985, the enactment of Public Law 99-129 authorized the Secretary of the Department of Health and Human Services to make grants to veterinary schools for the

development of curriculum for training in the care

of animals used in research, the treatment of animals while being used in research, and the development of alternatives to the use of animals in research.

Colleges and universities may offer courses related to humane principles or principles of experimentation. In addition, animal welfare groups are

active sponsors in the areas of humane education

and attitudes about animals.

A number of humane societies and animal welfare

groups fund research on alternatives in research,

testing, or education. Several private foundations,

notably the Geraldine R. Dodge Foundation, designate support for research in animal welfare as

among their funding missions.

REGULATION OF ANIMAL USE

Several Federal and State laws, regulations, Care and Use of Laboratory Animals by Awardee

guidelines, and institutional and professional so- Institutions (revised in 1985; see app. C).

cieties’ policies affect the use of animals in research

and testing (see chs. 13, 14, and 15; app. B). Chief

among these are the Animal Welfare Act, the Health Federal Regulation Research Extension Act of 1985 (Public Law 99-

158), rules on good laboratory practices established Prompted by publicity about pet dogs used in

by FDA and EPA, the NIH Guide for the Care and research, Congress passed the Animal Welfare Act

Use of Laboratory Animals (revised in 1985), and to halt the use of stolen pets in experimentation.

the Public Health Service (PHS) Policy on Humane Enacted in 1966 and amended in 1970, 1976, and
74 ● Alternatives to Animal use in Research, Testing, and Education

1985, the statute also contains provisions for the

care and treatment of certain animals used in experiments. The act defines “animal” as:

. . . any live or dead dog, cat, monkey (nonhuman

primate animal), guinea pig, hamster, rabbit, or

such other warm-blooded animal, as the Secretary [of the Department of Agriculture] may determine is being used, or is intended for use, for

research, testing, experimentation or exhibition

purposes . . .

USDA, empowered to identify other mammals

and birds to be regulated, has done so only for

marine mammals. In fact, in 1977, USDA promulgated a regulation excluding birds, rats, mice, and

horses and other farm animals from coverage by

the Animal Welfare Act. The use of rats and mice,

the most common laboratory animals, is therefore

not regulated.

The act does not cover facilities that use none

of the regulated species. Facilities that use regulated species but that receive no Federal funds and

maintain their own breeding colonies also fall out -

side the act’s coverage.

The Animal Welfare Act regulates housing,

feeding, and other aspects of animal care but bars

USDA from regulating the design or performance

of actual research or testing. A facility need only

report annually that the provisions of the act are

being followed and that professionally acceptable

standards are being followed during actual experimentation. Facilities must also describe procedures

likely to produce animal pain or distress and provide assurances that alternatives to those procedures were considered.

The Food Security Act of 1985 (Public Law 99-

198) amended the Animal Welfare Act (amendments effective December 1986) to strengthen

standards for laboratory animal care, increase enforcement of the Animal Welfare Act, provide for

the dissemination of information to reduce unintended duplication of animal experiments, and

mandate training for personnel who handle animals. For the first time, the Department of Health

and Human Services is brought into the enforcement of the Animal Welfare Act, as the Secretary

of Agriculture is directed to “consult with the Secretary of Health and Human Services prior to the

issuance of regulations” under the act.

Each research facility covered by the Animal

Welfare Act—including Federal facilities—is required to appoint an institutional animal committee that includes at least one doctor of veterinary

medicine and one member not affiliated with the

facility. The committee shall assess animal care,

treatment, and practices in experimental research

and shall inspect all animal study areas at least twice

a year.

Many groups concerned about animal welfare

want the act and its enforcement strengthened,

They criticize USDA’s exclusion of rats and mice,

the level of funding for enforcement, and the choice

of USDA’s Animal and Plant Health Inspection Service as the enforcement agency. Inspectors, whose

primary concern is preventing interstate transport

of disease-carrying livestock and plants, spend

about 6 percent of their time enforcing the research provisions of the Animal Welfare Act. Additional criticism is leveled at the act’s failure to

offer guidance in research practices during experimentation. A 1982 report by the Humane Society

of the United States indicates that USDA regulations and guidelines failed to provide “information

sufficient to demonstrate that researchers have used

pain-relieving drugs ‘appropriately’ and in accordance with ‘professionally acceptable standards ’.”

The Health Research Extension Act of 1985

mandates the establishment of animal care committees at all entities that conduct biomedical and

behavioral research with PHS funds. [t requires

all applicants for NIH funding to submit assurances

that they are in compliance with the law’s provisions for the operation of animal care committees

and that all personnel involved with animals have

available to them training in the humane practice

of animal maintenance and experimentation. The

NIH Director is empowered to suspend or revoke

funding if violations of the act are found and not

corrected. In essence, the act puts the force of

Federal law behind certain elements of the PHS

Policy.

The act also directs the NIH Director to establish a plan for research into methods of biomedical research and experimentation that do not require the use of animals, that reduce the number

of animals used, or that produce less pain and distress in experimental animals than methods currently in use.
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 1 5

FDA and EPA both established rules on good laboratory practices to ensure the quality of toxicity

data submitted by industry in compliance with the

agencies’ regulations. Because proper animal care

is essential to good animal tests, these rules indirectly benefit animals.

The NIH Guide for the Care and Use of Laboratory Animals prescribes detailed standards for animal care, maintenance, and housing. It applies to

all research supported by NIH and is in fact used

by most animal facilities throughout the public and

private sector.

The Department of Defense (DOD) has been criticized for its use of animals in weapons research

and in training for treatment of wounds, In 1973,

Congress prohibited DOD from using dogs for research and development of chemical or biological

weapons. In 1983, publicity caused an uproar

about the use of dogs, pigs, and goats to train military surgeons in the treatment of gunshot wounds.

The furor led to congressional action that prohibited DOD from using dogs and cats in such training during fiscal years 1984 and 1985.

State Regulation

Most State anticruelty statutes forbid both active cruelty and neglect (see ch. 14). Many of these

laws incorporate vague terms, and alleged offenders offer a variety of defenses. Enforcement may

be delegated to humane societies, whose members

are not well trained to build criminal cases skillfully and are underfunded for the task.

Twenty States and the District of Columbia regulate the use of animals in research to some extent. As in the case of the Federal Animal Welfare

Act, most State laws address such matters as

procurement rather than the actual conduct of

experiments.

All 50 States and the District of Columbia allow

some form of pound animal use for research and

training. In some States, laws permitting or requiring research and teaching facilities to purchase

stray dogs and cats from pounds and shelters have

been the targets of repeal efforts. To date, 9 States

prohibit in-State procurement (although not importation from out-of-State) of pound animals for

research and training. Of these, Massachusetts will

in October 1986 prohibit the use of any animal

obtained from a pound.

Institutional and Self-Regulation

Opponents of increased government regulation

of research assert that investigators and their institutions are best suited to determine what constitutes appropriate care and use of animals. To

regulate animal use at this level, the scientific community relies on a variety of policies and administrative structures (see ch. 15).

Taken together, the requirements for institutional animal committees contained in the Animal Welfare Act (as amended), the Health Research Extension Act of 1985, and the PHS

policy bring the overwhelming majority of

experimental-animal users in the United States

under the oversight of a structured, local review committee.

Institutions that receive funds from PHS for research on warm-blooded laboratory animals must

have committees that oversee the housing and routine care of animals. NIH reports that about a quarter of these animal care and use committees currently review research proposals to determine

whether experimental procedures satisfy concerns

about animal welfare. Committees with such responsibility are not unique to research with animals: For 15 years, similar groups have been weighing ethical issues raised by the use of human

research subjects, and these committees have

served as models in the development of animal care

and use committees.

Committees usually have included the institution’s attending veterinarian, a representative of

the institution’s administration, and several users

of research animals. Some committees also have

nonscientist members, or lay members not affiliated with the institution. Nonscientist and lay seats

have been filled by clergy, ethicists, lawyers, humane society officials, and animal rights advocates.

Animal care and use committees at PHS-supported facilities are today required to consist

of not less than five members, and must include

at least:

● one Doctor of Veterinary Medicine with

training or experience in laboratory ani-
76 ● Alternatives to Animal Use in Research, Testing, and Education

mal science or medicine, who has responsibility for activities involving animals at

the institution;

● one practicing scientist experienced in research using animals;

● one member whose primary concerns are

in a nonscientific area; and

● one individual who is not affiliated with

the institution in any way.

The minimum committee structure required by

the PHS policy is thus more rigorous than that mandated by Federal law. The Animal Welfare Act and

the Health Research Extension Act do not require,

for example, that the committee veterinarian be

trained in laboratory-animal medicine. The acts

require a minimum committee of three individuals, whereas the PHS policy requires five.

Institutional regulation generally entails compliance with some type of minimum standards for

an animal facility, usually those of the NIH Guide

for the Care and Use of Laboratory Animals. Compliance can be checked in-house or through accreditation by the American Association for Accreditation of Laboratory Animal Care (AAALAC),

a voluntary private organization. As of April 1985,

a total of 483 institutions had received AAALAC

accreditation, which requires site visits that include

interviews, inspection of facilities, and review of

policies and records. Accredited institutions include hospitals, universities, facilities of the Veterans’ Administration (VA), and pharmaceutical

manufacturers (see app. D).

A number of scientific and professional societies, universities, and corporations have promulgated statements of policy concerning their members’ or employees’ standards of conduct in animal

use. These policies generally require:

●

●

●

●

humane care and use of animals,

minimization of the number of animals used,

alleviation of pain and suffering, and

supervision of animal use by qualified personnel.

Twelve of fifteen such policies reviewed by OTA

encourage or require consideration of the use of

alternatives. But only 3 of the 15 include enforcement provisions or mention sanctions against violators.

Regulation Within Federal Agencies

Six Federal departments and four independent

agencies use laboratory animals intramurally and

account for approximately one-tenth of the animal

use in the United States. Beginning in December

1986, Federal facilities in those departments and

agencies using animals will be required by the 1985

amendments to the Animal Welfare Act to install

institutional animal committees. Each committee

shall report to the head of the Federal agency conducting the experimentation.

Most Federal agencies that use animals in research or testing have formal policies and administrative structures to ensure that the animals receive humane treatment. At the request of the

Executive Office of Science and Technology Policy, the Interagency Research Animal Committee

developed a 450-word policy statement, Principles

for the Utilization and Care of Vertebrate Animals

Used in Testing, Research, and Education, to be

followed by all Federal agencies supporting animal use (see ch. 13).

No one Federal agency policy on animal care

and use has all the characteristics needed toaddress all issues adequately. Combining certain

aspects from each would produce an effective

uniform Federal policy. Almost all policies today

require adherence to the NIH Guide and the Animal Welfare Act. Most agencies also require an

attending veterinarian and an animal care and use

committee at each facility. The committees generally review research protocols to ensure that

animals are not used in excessive numbers, that

adequate provisions are made for animal care and

pain relief, and that alternatives are used whenever possible. Most committees and attending

veterinarians have little enforcement power, and

those who have such power rarely use it.

Some agencies’ policies have features that would

be considered advantageous by animal welfare advocates. NIH and the National Aeronautics and

Space Administration have laypeople on their animal care and use committees. The VA requires all

its animal facilities to acquire AAALAC accreditation. The Department of Defense has a separate

policy and committee for nonhuman primates. The

Air Force has solicited evaluation of its policies by

a panel of independent experts and plans to implement the group’s recommendations.
Ch. l—Summary, Policy Issues, and Options for Congressional Action • 17

International Regulation

OTA surveyed laws controlling use of experimental animals in 10 foreign nations, including

countries of Western Europe (see table 1-2) and

Australia and Canada. Comparative analysis of regulation of animal use abroad can yield lessons from

foreign regulatory experiences, models for regulation, and models for funding of alternatives.

A review of foreign laws, especially those revised

or instituted in the last decade, indicates three

trends of note in government control of animal

research (see ch. 16):

● Attention is shifting away from intentionally

or negligently “cruel” treatment and toward

the avoidance of pain and suffering. This

change in perspective raises the difficulty of

defining prohibited conduct, and disagreement arises over the definition of animal pain

and suffering. Newer statutes rely on authorized reviewers who check experimental plans

in advance and apply their own sensibilities

to satisfy themselves—and thereby the public interest–that pain and suffering are not

being inflicted without justification.

● There is increasing emphasis on finding alternatives. The old method of justifying animal

research by reference to its potential for providing new knowledge is being enhanced by

the greater burden of demonstrating that no

less painful method is available to achieve the

same result. Increasingly, animals are being

viewed as having an interest in not being hurt.

Countries with comprehensive reporting systerns (e.g., the United Kingdom) have found

that fewer animals are now being used in experiments. The data are insufficient to determine the reasons for these reductions or what

the effect may be on the production of new

information.

These trends indicate a growing interest in

Western Europe in replacing, reducing, or refining the use of animals through legislation.

It is not clear whether the tighter control

found in some West European countries can be

applied in the United States. Most West European nations are more homogeneous than is this

country of federated States. In geographical dispersal and size, the research enterprises in those

countries are small—there are fewer than 300 investigators using animals in Denmark, for example. The British system functions well, despite its

complexity, because it has been refined over the

course of a century. New scientists are weaned

on it, and the inspector is a familiar sight in the

laboratory. The British system’s enforcement is

based more on advice and negotiation than on confrontation.

POLICY ISSUES AND OPTIONS FOR CONGRESSIONAL ACTIO N

Seven policy issues related to alternatives to animal use in research, testing, and education were

identified during the course of this assessment.

The first concerns the implementation of alternatives and examines options that might encourage

the research, testing, and education communities

to adopt currently available methods of replacing,

reducing, and refining their use of animals. The

second issue explores options for promoting research and development leading to more and better alternatives. Both recognize that scientifically

valid alternative methods can make positive contributions to research, testing, and education and

might therefore be promoted.

The five additional policy issues examined are:

disseminating information about animal experimentation, restricting animal use, counting animal use, establishing a Federal animal use policy,

and changing the implementation of or amending

the Animal Welfare Act. Although these policy issues do not explicitly address either the implementation or development of alternative methods, they

are inextricably linked to the replacement, reduction, and refinement of animal use.

Associated with each policy issue are several options for congressional action, ranging in each case

from taking no specific steps to making major
Table 1=2.—National Laws for the Protection of Animals in Selected European Countries

Federal Republic

Provisions Denmark of Germany Netherlands Norway Sweden Switzerland United Kingdom

Species protected . . . Vertebrates All animals Vertebrates, native Vertebrates Vertebrates Vertebrates

Distinctions among species . . . Should use lowest Better to use

rank; dogs, cats, invertebrates or coldmonkeys purpose-bred blooded vertebrates

Alternatives must be used

if available . . . . . . . . .Yes

Anesthetics, analgesics, or

approval required for

painful experiments . . . . . . Except for minor or

transient pain

Educational uses. . . . Higher education,

technique

Ban on animal use for more

than one painful experiment .All dogs, cats,

monkeys; most

experiments

License/permit for dealers,

facilities, and investigators ., .All facilities, head

investigators

Review of experiments . . . . . . . Most experiments need

approval by national

Board

Administration. . . . . . Centralized,

government/

nongovernment board

iicensee is

responsible

Animal welfare representation ...3 nominees to

national Board

Reporting . . . . . . . .Annual report

Yes

if pain, suffering, or

injury likely

High school and above

No multiple surgeries

on vertebrates

Dealers, facilities,

investigators

Not needed; proposed

that facility’s animal

welfare officer review

States enforce and

administer (proposed

that facilities have

animal welfare

officer)

Being considered

in-house

recordkeeping

species

Vertebrates better

protected

Vertebrates

If injury or pain likely

University and

vocational

Rarely reused because

of pain requirements

Dealers (dogs and cats),

facilities

Head of institute

reviews

Central enforcement

and reporting;

administration by

institute

Not required, but

facility reports are

public

Annual report

Vertebrates,

crustaceans

Monkeys, dogs, cats

better protected

Yes

if pain is possible

(unless Board

approves)

Professional training

Only one experiment

allowed per animal

Investigators or facilities

licensed

investigator or facility

(licensee) review

Central coordination,

some functions

delegated to licensees

Not required

Annual report

Should use lowest Should use lowest rank

rank; all purpose-bred

Alternatives promoted

Surgery on mammals

unless committee

approves

Allowed, but restricted

Rarely reused because

of pain requirements

Breeders, facilities

Notification/application;

tiered system

Central coordination

with oversight by

facility head and

committee

On all committees;

being reconsidered

Government

recordkeeping

Yes

Slight pain or anxiety;

if too painful, must

forgo

Not allowed

Only reused if pain

was slight

Breeders, facilities

2 State committees

review

Central coordination,

administered by

States

Members of national

commission

in-house

. - recordkeeping

SOURCE: Office of Technology Assessment

Primates, dogs, cats,

equidae preferred; no

stray dogs

Alternatives encouraged

Statute does not specify,

but certificate may

require

Some demonstration; not

for practicing

if anesthetized or

because of pain

requirements

Facilities registered,

investigators licensed

Home Office and

Advisory Committee

Centralized, shared by

Head Office, Advisory

Committee, Royal

Society

Advisory Committee

Annual reports
Ch. l—Summary, Policy Issues, and Options for Congressional Action • 19

changes. The order in which the options are presented should not imply their priority. Furthermore, the options are not, for the most part, mutually exclusive: Adopting one does not necessarily

disqualify others in the same category or within

any other category. A careful combination of options might produce the most desirable effects.

In some cases, an option may suggest alterations

in more than one aspect of alternatives to using

animals, It is important to keep in mind that

changes in one area have repercussions in others.

Some of the options involve direct legislative action. Others are oriented to the actions of the executive branch but involve congressional oversight

or encouragement. Congress can promote alternatives in at least three ways, It can provide incentives through tax policies, grants, or educational

assistance. It can mandate the adoption or development of alternatives by means of appropriations

or legislation. And it can provide encouragement

via oversight or resolutions. Table 1-3 summarizes

the seven policy issues and associated options derived from this assessment.

ISSUE: Should steps be taken to encourage the

use of available alternatives in research,

testing, or education?

Alternatives to animals become accepted practice in the research, testing, and educational communities as methods are developed through research, validated by independent measurements,

gradually accepted by the scientific community,

and implemented as they come to be relied on or

required. Several alternatives to the use of animals

are in the validation or implementation phase today; for the most part, these methods are based

on reductions and refinements. Approaches that

replace the use of animals have generally not been

completely validated and accepted. Instead, these

represent possibilities for the longer term. (An exception may be educational simulations of living

systems where an adequate range of physiological variables is known. ) The processes of validation and gradual implementation are certain to continue, and they could be accelerated.

Analysis of alternatives in research (see ch. 6),

testing (see ch. 8), and education (see ch. 9) demonstrates differing availability both among and

within these three areas. In research, for example, animal methods can be complemented by computer models, and experiments may be designed

to provide the desired information with fewer animals. Dissemination of information within the research community may reduce any instances of

unintentional duplication, thereby lowering the

number of animals used. In testing, the LD50 protocol has in many cases been modified to use fewer

animals. And eye irritancy can be assumed—without testing—for substances exhibiting strong skin

irritation or having a strongly acid or alkaline pH.

In educational settings, exercises not involving animals may be substituted to teach the scientific

method or to introduce biological concepts. In

other instances, animals are destroyed humanely

following a single surgery in a teaching session,

rather than experiencing multiple recovery procedures. Four options address the implementation

of alternatives such as these.

Option I: Take no action.

As alternatives are developed and validated, they

are likely to continue being implemented at an uneven pace, influenced by factors largely external

to Congress. Science and technologies will continue

to evolve, and as nonanimal methods emerge from

research and validation, they may or may not be

accepted and implemented by the scientific community.

This course does not necessarily pass judgment

on the value of adopting alternatives per se. Nor

does it mean that alternatives will not be implemented. It would merely indicate that Congress

has decided against encouraging or forcing the implementation of alternatives beyond its direction

in 1985 to NIH to establish a plan to develop and

assess alternatives in biomedical research (Public

Law 99-158). This option might illustrate the belief that external political, ethical, economic, and

scientific factors are sufficient to govern the implementation of alternatives.

Further congressional action toward implementation might be judged unnecessary because various other sources are already acting to implement

alternatives. For example, EPA has defined circumstances where the LD50 test can be replaced by

a limit test (see ch. 8), and FDA has stated that it

does not require data derived from the LD50 test;

industry is watching to gauge the practical effects
. .

Table 1-3.-Policy Issues Related to Alternatives to Animal Use and Options for Congressional Action

Policy issue

Using existing Developing new Disseminating Restricting Counting animals Establishing a Federal Changing Animal

alternatives alternatives information animal use used animal-use policy Welfare Act

Options for congressional action

Take no action Take no action

Charge a Federal entity charge a Federal

with coordinating the entity with

implementation of coordinating the

alternatives development of

Encourage alternative alternatives

methods in Federal Fund development of

testing requirements alternatives

Ban procedures for which

alternatives are

available

aAnimal and plant Health Inspection ServiCe.

SOURCE: Office of Technology Assessment.

Take no action

Mandate easy access

to federally funded

testing and research

data

Promote greater use

of testing data

submitted to

Federal agencies

Require literature

searches

Create new databases

Translate foreign

literature into

English

Take no action

Restrict use of certain

kinds of animals

Restrict use of certain

protocols

Restrict acquisition of

animals from certain

sources

License animal users

for certain protocols

and/or kinds of

animals

Prohibit animal use

Take no action

Eliminate APHISa

census

Correct inadequacies

in present APHISa

reporting system

Expand APHISa

census to include

rats and mice

Establish independent

census

Take no action

Establish intramural

Federal policy of

minimum standards

Take no action

Eliminate funding for

enforcement

Increase funding for

enforcement

Amend to expand

coverage to include

experimentation

Amend to realign

enforcement authority

Amend to preempt

State and local laws
—

Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 2 1

of these statements. Also, members of the soap

and detergent industry have implemented modifications of the LD50 test. Noteworthy, too, is the

important role of institutional animal care and use

committees in all phases of animal experimentation. In education, medical schools are conducting some laboratory exercises with computer simulations or video demonstrations in lieu of live

animals. Medical students in some instances bypass experiments and training involving animals,

proceeding from cadavers to people. Activities such

as these are likely to continue without new congressional action.

Additional congressional steps may be deemed

inappropriate because implementation of alternatives may be judged unimportant. Some people do

not object to animal use, for example, in toxicological testing. They believe the status quo brings

the comforts and health benefits of new products

and technology and protects them from hazards.

Option 2: Require a new or existing Federal entity to coordinate the validation and implementation of alternatives.

This action is based on the assumption that validation and implementation of alternatives would

occur more rapidly with enhanced Federal coordination. Along this line, an information service at

the National Agricultural Library on improved

methods of animal experimentation was mandated

by Congress in 1985 (Public Law 99-198). A clearinghouse for resources required to implement

alternatives would further hasten their adoption.

This entity might, for example, be a central source

for computer software or cell culture material.

Existing Federal entities that might be assigned

such responsibilities include some component of

the National Institutes of Health (e.g., the Division

of Research Resources), the National Toxicology

Program, or the National Center for Toxicological

Research. Coordinating activities could include

symposia, workshops, newsletters, scholarships,

grants, and the issuance of model protocols or

guidelines. The coordinating body could monitor

both public and private initiatives. In 1985, Congress took a step toward coordination of the use

of alternatives in biomedical research conducted

by or through NIH. It directed NIH to disseminate

information about alternatives found to be valid

and reliable to those involved in animal experimentation (Public Law 99-158).

Educational programs play a central role in this

type of effort. Training scientists in replacement

methods and raising awareness about reductions

and refinements is likely to increase the implementation of alternatives. This type of education is

closely allied with the teaching of principles of humane care and use (see ch. 9).

Animal care and use committees at individual

institutions might function as a relay between Federal coordination efforts and individual investigators (see ch. 15). The institutional animal care and

use committee might be required to suggest alternative methods as part of its review of animal care

and use. Linked in this way to a Federal implementation effort, these committees would both feed

into and draw on the resources of the Federal

entity.

A different type of coordination, particularly in

research, would be the attachment of provisions

to Federal grants regarding the implementation

of alternatives. Research grant applications using

alternative methods could be awarded higher priority scores in the grant evaluation process or be

otherwise favored. This strategy would require

sufficient flexibility to ensure that valuable, stateof-the-art scientific proposals that may not involve

alternatives are not handicapped. Funding mechanisms could also be used to encourage coordination between laboratories. The responsibility for

overseeing the implementation of alternatives via

funding mechanisms could be borne by each source

of Federal funding (see ch. 12).

Option 3: Encourage regulatory agencies to review existing testing guidelines and requirements and to substitute alternatives whenever scientifically feasible.

Through oversight or legislation, Congress could

encourage or require Federal agencies to evaluate existing alternatives in testing, to participate

in their validation, to adopt them where appropriate, and to report to Congress on their progress in implementing alternatives, as the NIH has

been asked to do (Public Law 99-158). Such agency

review would have to be a periodic or continuing

effort, given rapid advances in the state of the art.

Some review of testing guidelines now occurs in

keeping requirements up to date, although the purpose of that review is to improve the science rather

than to protect animals per se. Formal agency review of international testing guidelines, such as
22 ● Altematives to Animal Use in Research, Testing, and Education

those of the Organization for Economic Cooperation and Development, could also be encouraged

(see ch. 7 and app. E). The costs of agency review

should be moderate, entailing input from agency

experts, comment from outside experts, and publication. If Federal laboratories were involved in

the validation of alternative testing methods, additional costs would be incurred. Such a policy

could encourage industry to develop alternatives

because the barriers to acceptance would be

reduced.

Option 4: Ban procedures for which alternatives

are available, or give a Federal agency

authority to ban procedures as valid

alternatives become available.

This option recognizes that prohibitions can be

used to force technological change. Prohibiting

procedures for which scientifically acceptable

alternatives are already available would accelerate the implementation of such alternatives. Existing reductions and refinements in animal use

include the greater use of analgesics in research,

the use of fewer animals in the LD50 and Draize

eye irritancy tests, and reliance on videotaped demonstrations and computer simulations in education.

A ban could not only force implementation of

existing alternatives, but, over time, help focus the

development of new techniques (as discussed in

the next section) and allow considerable flexibility in achieving the desired end. A disadvantage

of banning a specified procedure is that the replacement, or the process of developing one, may be

even more politically unacceptable (e.g., the in vitro

culture of human fetal nerve cells). A prohibition

also takes no account of the question of judging

the scientific acceptability of an alternative.

In pursuing this option or the preceding one,

it is important to appreciate that the swiftest adoption of alternatives may come about if regulatory

agencies avoid mandating specific testing requirements. Requiring specified tests might actually

serve as a strong inhibitor to the implementation

(and development) of alternative methods. Greater

flexibility is achieved when testing requirements

are defined in a manner that allows judgment and

encourages use of alternate methods, Viewed from

this perspective, the adoption of alternatives might

be best stimulated by regulatory requirement for

evaluation of a potential toxic response, such as

mutagenicity, rather than requirement of a specified test for mutagenicity.

ISSUE: Should the more rapid development of

new alternatives in research, testing or

education be stimulated?

Alternatives are currently being developed in

many phases of animal use. It is worth noting that

development of many of these techniques, especially their validation, cannot occur without animals being used (unless humans are used instead).

In addition, many replacement systems will never

be fully divorced from animal research and testing, and therefore they will serve to reduce but

not eliminate animal use.

Certain research and testing methods now being developed, such as in vitro culture of animal

components, bear great promise as alternatives.

Similarly, the growing capabilities of computer

modeling, for example biological simulation (see

ch. 6) and pharmacology (see ch. 8), may reduce

the number of animals needed. Development of

an enhanced ability to detect and relieve pain can

help refine animal use.

Research that spawns alternatives usually takes

place across traditional disciplinary lines—princi -

pally within the life sciences–but also in applied

mathematics, statistics, engineering, physics, and

chemistry. The principal support for such research

comes from Federal funds, predominantly NIH and

the National Science Foundation. In general, there

is little incentive for private investment in methodologies at a stage so remote from commercialization and, in the case of testing, so governed by

regulation. Some private concerns, however, specifically fund research into alternative testing

methods (see ch. 12).

Clearly, research and development require

money. Determining the optimum level of funding, however, and the best way to distribute funds

remains elusive, Nonetheless, the promotion of

such research is likely to increase the number of

alternatives available for implementation; in turn,

increased implementation is likely to spur research

in this area.

Option 1: Take no action.

If Congress takes no specific steps beyond its

recent charge to NIH to establish a plan for the
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 2 3

development of alternatives in biomedical research, the development of alternatives will continue to be a function of ethical, political, economic,

and scientific factors.

That alternatives are being developed in the absence of direct legislation is best illustrated by research centers at Rockefeller University and The

Johns Hopkins University funded by corporate and

private donations (see ch. 12). In addition, corporations are undertaking work in-house or sponsoring it in universities, often in response to scientific, economic, animal welfare, and public relations

considerations.

An uncertain pace of development marks the

chief disadvantage of this option. Although alternatives may emerge, changing research priorities

in both the public and private sectors will affect

the rate of development. From another perspective, this is an advantage: It permits researchers

to respond to changing needs and priorities with

minimal Federal interference.

Option 2: Require a new or existing Federal entity to coordinate the development of

alternatives.

Implementation of this option would have great

symbolic value within the scientific and animal welfare communities and could lead to more rapid

development of alternatives. A central clearinghouse for the development of alternatives could

compile and maintain records of all federally

funded research and development (R&D) on alternatives. Information on R&Din the private sector

would be a valuable component of the coordination effort, though it may prove difficult to obtain.

Coordination could involve identifying research

areas likely to lead to new alternatives and reviewing Federal support for those areas across agency

lines. The latter responsibility might preclude housing this entity within an existing Federal agency

involved in funding R&D on alternatives to avoid

either a real or apparent conflict of interest.

As in the implementation of alternatives (see preceding issue), education plays a central role in the

development of such approaches. Coordination of

efforts aimed at informing investigators and students about animal research (see ch. 9) could be

among the responsibilities of this Federal entity.

Option 3: Provide intramural and extramural Federal funding for the development of

alternatives.

An effective mechanism for encouraging R&D

on alternatives is funding. Small pilot programs

might assess whether or not targeted development

is effective.

Development of alternatives in testing within the

Federal Government is a natural offshoot of and

closely allied with toxicological research. The agencies most likely to produce alternatives in response

to new Federal funding are the National Cancer

Institute and NIH. Because testing is so closely tied

to regulation, funding could also be directed to

FDA, EPA, the Consumer Product Safety Commission, and the National Institute for Occupational

Safety and Health. Regulatory agencies could be

required to develop alternatives to specified tests

or to spend funds generally toward their development.

To stimulate extramural R&D, granting agencies

reviewing applications could be required to assign

priority to those that contain research with promise for the development of new alternatives. Postdoctoral training programs could be established,

along the lines of NIH’s National Research Service

Awards, to ensure a steady supply of young researchers schooled in traditional disciplines, ranging from molecular biology to animal behavior,

with applications in the development of alternatives.

Financial incentives to private groups developing alternatives could take the form of tax incentives—perhaps tax credits in addition to those already in place for R&D. Such groups could also

be eligible for a new program (analogous to the

Small Business Innovation Research program) that

would target the development of alternatives (see

ch. 12).

ISSUE: Should improvements be made in information resources to reduce any unintentionally duplicative use of animals

in research and testing?

Science is able to advance rapidly because information about what has been done is disseminated

(see ch. 10). If attempts to find prior work are inadequate or prior work is not sufficiently accessi -
24 ● Alternatives to Anima/ use in Research, Testing, and Education

ble, unintentional duplication may occur. Such

unnecessary repetition of experiments must be

distinguished from replication of experiments to

demonstrate the reproducibility of a method or

to confirm the validity of results.

The amount of unintentional, largely duplicative research and testing that occurs today is unknown. Investigations into the amount and circumstances of unintentional duplication would be

valuable in determining whether it results in substantial waste of animals or funds. Moreover,

consultations with potential users of any new information resources would be essential in implementing certain options addressing this issue.

Although the storage and retrieval of data are

costly, there are clear benefits to making information that reduces unintentional duplication

readily available. Among these benefits are savings in the expense and time associated with animal research and testing. Other benefits are savings in animal lives and the additional work that

might be done if resources are not wasted (see ch.

11).

Option 1: Take no action.

By making the National Agricultural Library the

focus of a service to provide information on improved methods of animal experimentation (Public Law 99-198), Congress in 1985 indicated its

intention to facilitate the dissemination of information about alternatives and to prevent unintended duplication of animal experimentation.

Even if no further improvements in information

resources are made specifically for the sake of

avoiding unintentionally duplicative animal use,

general improvements in information resources

will proceed as a matter of course. Many resources

already exist. The National Library of Medicine,

the National Toxicology Program, and other Federal entities maintain large databases that contain

information or citations to published sources. Major commercial databases exist as well. National

libraries and information centers provide the full

text of articles and reports. The National Technical Information Service (NTIS) catalogs, stores, and

distributes on request many unpublished Federal

reports. Improvements in these resources can be

expected, either to fill needs for which the benefits justify the costs or to achieve other information policy goals, such as openness in government

or advancement of science.

Option 2: Require that results of all federally

funded research and testing be conveniently accessible.

By means of oversight authority or legislation,

all Federal entities could be required to provide

convenient access to the results of all federally

funded animal research and testing. Implementation could be largely through mechanisms already

available—publishing in the scientific literature;

circulating published reports or depositing them

with NTIS, NLM, the National Agricultural Library,

or other entity; or entering the results in a publicly available database. New databases might also

be established. Requirements that results be made

conveniently accessible could apply to Federal employees, contractors (through contract terms), and

grantees (as a condition of awards). Contractors

and grantees, however, may not be enthusiastic

about assuming the burden of publicizing their

results and responding to requests for information.

This option recognizes that much research and

some testing using animals is federally funded, that

dissemination of research and testing results could

be more comprehensive, and that better dissemination might reduce any unintentional duplication.

Because publication and information dissemination are normally much less costly than obtaining

original data, the benefits of enhanced communication extend beyond saving animal lives.

It is important to note that most federally funded

work, indeed the vast majority of significant work,

is already accessible, although access comes with

different levels of convenience. And the results

of federally funded work (except some grants) are

available under the Freedom of Information Act

(FOIA). Requiring that all results be conveniently

accessible may burden databases and libraries with

inconclusive results or other information that will

not be used.

Option 3: Promote greater use of animal testing

data submitted by industry to Federal

agencies, except where confidentiality

protections apply.

Industry must submit data to regulatory agencies before it can market certain products or sometimes in response to reporting requirements. Statutory and regulatory provisions already exist that

make some of this information publicly available,

thus theoretically avoiding unintentional duplication. In addition, information that is voluntarily
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 2 5

submitted and not claimed as confidential is available under FOIA.

Using oversight authority or legislation, greater

use of nonconfidential information could be promoted, for example, by requiring that it be put

into databases, compiled in reports, or summarized

in newsletters. Industry could bear the cost of information dissemination, and any data submission

to the Federal Government would have to be accompanied by evidence of intent to publish nonconfidential testing data. Industry may be unenthusiastic about such a procedure, because in some

cases nonconfidential data provide direct clues to

confidential data. Nevertheless, greater availability of nonconfidential data could aid in avoiding

unintentionally duplicative testing.

The extent to which researchers who need such

data already know how to obtain them is not

known. The needs of those engaged in animal testing must be carefully gauged prior to consideration of this option. A further consideration is the

willingness of those who generate the data to encourage others to benefit from their investment.

Option 4: Require comprehensive literature searches

to ensure that federally funded research or

testing involving animals is not duplicative.

A literature review is normally conducted by an

investigator in the course of preparing a grant application, contract proposal, or data submission.

In addition, the reviewers of such proposals are

expected to be familiar with work that has already

been done. Implementation of this option would

require proof of a literature search through, for

example, a companion document in any proposal

to conduct federally funded research or testing.

The funding entity would presumably have to

judge the appropriateness of the literature search.

Both the investigator’s act of searching the literature and the funding agency’s certification of the

search may reduce any unintentional duplication.

To make a mandatory literature search palatable

to investigators, free access to some or all of the

necessary information resources may have to be

provided.

An alternative strategy is to require a literature

search by the funding agency, or other entity, prior

to the release of any funds. The disadvantages of

requiring a comprehensive literature search before work could be funded include the delay that

an additional step would cause, the cost of the

search itself to the Federal Government, and possibly part of the cost of developing new information resources.

Option S: Create new databases designed to reduce unintentional duplication of animal use in research and testing.

New computerized databases might play an

important role in reducing any unintentionally

duplicative animal use. There are at least three

types that could contribute to this end:

●

●

●

Unpublished Results, Including Negative

Results. Such a database would disseminate

results that are otherwise distributed narrowly or not at all. The major problem with unpublished information is that its quality is difficult to evaluate because it is rarely subjected

to peer review. Another problem is that the

most useful unpublished data are owned by

industry and would not be disclosed because

of their proprietary value (although provision

could be made for voluntary submissions). A

category of special interest, particularly from

the standpoint of duplicative testing, is negative results (e.g., showing the absence of toxic

effects). Few journals are willing to publish

negative testing results. Dissemination of negative results could spare any unintentional

duplication, direct investigators away from

fruitless paths, or suggest improvements in

methodologies.

Data From Untreated, or Control, Animals.

Data pertaining to the health or behavior of

animals not given a test substance could be

used in choosing the best species for experimentation (e.g., a species most likely to yield

unambiguous results). This information might

obviate the need to use more than one species

or might allow smaller control groups in some

experiments (see ch. 7). Compiling the database could be both difficult and costly because

the necessary data are often not published (see

ch. 10).

Experimental Protocols and Results. This

database could be as narrow as abbreviated

listings of methods and results, perhaps arranged by species, or as comprehensive as the

on-line full text of all published scientific literature. (The full text of a scientific report includes not only protocol and results, but also

discussion and interpretation of the results,

tables, figures, and bibliography. At present,

38-750 0 - 86 - 2
26 ● Alternatives to Animal Use in Research, Testing, and Education

the full text (minus figures and images) of a

few dozen scientific journals is available online.) The greatest obstacle to the successful

creation of a database of this size is catering

to the diverse needs of animal users. In its

fullest incarnation, this would cost hundreds

of millions of dollars to start and maintain.

Most important, the extent to which any of these

databases would be used is unknown. Within the

Federal Government, the NLM has the greatest expertise in establishing and operating large databases, and implementation of any form of this option is likely to build on the experience and existing

resources of that library.

Option 6: Facilitate the use of foreign data by providing translations of foreign journals.

An often-overlooked source of published data

is foreign-language literature, although most important scientific work is routinely published in

or translated into English. The advantages of providing translations of additional work are thought

by many experts to be quite limited and economically unjustifiable. English translation costs for the

four principal languages of science (French, German, Russian, and Japanese) range from $40 to

$88 per thousand words. An estimated $4 billion

to $5 billion would be required, for example, to

translate the current foreign-language holdings of

the NLM into English, with an ongoing yearly translation cost of $150 million (see ch. 10). Copyright

protections might involve costly inconvenience as

well. The impact of this option is uncertain, as English abstracts are today available for most foreign

journals, and translations can be obtained on an

ad hoc basis by those interested in a particular

report.

ISSUE: Should animal use in research, testing,

or education be restricted?

The use of animals for research, testing, and

educational purposes is not closely restricted in

the United States. Only four types of constraints

can be identified. The Animal Welfare Act requires

humane handling, care, and treatment of nonhuman primates, dogs, cats, rabbits, guinea pigs, and

hamsters. However, any regulation of these animals within an actual experimental protocol is specifically excepted by the Animal Welfare Act (see

ch. 13). Second, at the State and local levels, cruelty to animals is generally proscribed, although

such statutes are generally not applied to animal

use during experimentation (see ch. 14). Third, selfregulation takes place at individual institutions and

facilities through the implementation of Federal

policies. These call for assessment of animal care,

treatment, and practices in experimentation by

institutional animal care and use committees.

Fourth, the Department of Defense was prohibited

in fiscal years 1984 and 1985 from expending any

funds for training surgical personnel by treating

in dogs and cats wounds that had been produced

by weapons (see app. B).

The few existing restrictions on animal use illustrate two phenomena. First, they show that primates and pets have a privileged position in public policy. The Animal Welfare Act names only six

kinds of animals, omitting the rats and mice that

together constitute approximately 75 percent of

the animals used in research, testing, and education. It requires exercise for dogs and a physical

environment adequate to promote the psychological well-being of primates. In the case of the DOD

appropriation, dogs and cats were named, while

goats and pigs (also used in surgical wound training) were not.

Second, the restrictions demarcate the longstanding frontier of legislative province over animal use—the laboratory door. The actual conduct

of experiments stands largely outside of any specific mandatory provisions of law. (In contrast, British investigators are licensed to carry out specified procedures using specified animals and face

inspection visits to the laboratory bench by government officials; see ch. 16.) Solely in the case

of the prohibition of DOD expenditures is one use

of two particular species addressed.

Considering the issue of restriction of animal use

may require the resolution of four difficult

questions:

● Are there some kinds of animals on which

experimentation is inherently inappropriate?

● Are some methods or procedures beyond

the realm of societal acceptability?

● Should some sources of animals be deemed

off limits for animal use in research, testing,

or education?

● Should licensed investigators alone be permitted to engage in animal experimentation?

The resolution of these questions turns on science, law, politics, and, to a large degree, ethics.
Ch. I—SummaryJ Policy Issues, and Options for Congressional Action ● 2 7

Six options for congressional action have been identified.

Option 1: Take no action.

In the absence of new restrictions, animal use

in research, testing, and education will continue

to be governed loosely at the Federal level. Like

the American system of education, control of animal use can be largely a local issue, and institutional animal care and use committees stand as

the arbiters of community standards. One drawback of a minimal Federal role is the possible development of conflicting or confusing State and

local policies.

Maintenance of the status quo would reaffirm

that Congress concurs that no methods or procedures are beyond the realm of societal acceptability (except the training of military personnel in surgical techniques on wounded dogs and cats in fiscal

years 1984 and 1985). Maintenance of the status

quo would leave unaffected the acquisition of animals for research, testing, and education: Sources

of animals today include breeders, dealers, pounds,

and in-house breeding. Some States will continue

to bar the acquisition of pound animals for research

(see ch. 14). Finally, in the absence of a licensing

scheme, investigators and their areas of inquiry

will remain wholly a function of available resources

and individual interests.

Option 2: Restrict the use of certain kinds of

animals.

Some people feel it is wrong to use particular

animals in research, testing, or education. This belief may stem from respect for apparent intelligence, and animals most closely related to humans,

such as nonhuman primates, may be considered

off limits for investigation or manipulation. Similarly, attachment to companion animals such as

dogs and cats or to pet species such as hamsters

may lead to a desire for their legislated immunity

from experimentation.

A restriction of this nature is likely to have several consequences. The restricted species would

be protected while investigators faced, at a minimum, an inconvenience until new methods are

developed. Development of new model systems

would likely necessitate the generation of new fundamental data about the characteristics of the

model system, while the existing base of data—

which could be large—about the restricted animal

is set aside because it is no longer useful. In some

cases, new methods would lead to a substitution

of a less favored species for the restricted one. Perhaps the most important consequence would be

that where the restricted species (e.g., monkey or

dog) is the most scientifically appropriate model

for research or testing, a prohibition on the use

of that species may affect the ability to extrapolate results to humans.

Given that few, if any, kinds of animals are exclusively used in testing, research, and education,

a restriction of this nature would be difficult to

impose. How, for example, might a restriction distinguish between primates under behavioral observation in a field colony and those observed by

tourists at a safari-style game preserve? Restriction of the use of particular kinds of animals may

be inconsistent with the popular treatment and

use of those same animals (e.g., circus, zoological

park, sport, hunt, or farm) throughout the United

States. Combining this option with the next one—to

restrict the use of a species in a certain protocol—

would yield a more limited, more practicable form

of restriction than a blanket prohibition on use

of a species.

Option 3: Restrict the use of particular protocols.

Some people feel that it is inhumane to manipulate animals in certain ways, irrespective of the

motivation for the procedure. Such concerns usually focus on procedures that cause the animal pain

or are painful for humans to watch. The Draize

eye irritancy test is such a procedure, as are inflictions of blunt head trauma in neurology research and of bullet wounds in surgical training.

In research, blanket prohibitions either of a particular animal’s use (the preceding option) or of

a specified procedure entail a risk of being overly

inclusive. They could have unintended or unforeseen consequences, especially in the face of

incomplete knowledge about how animals are used

and in what protocols and what the results might

portend. One risk of such a restriction would be

the elimination of the use of animal models that

may be the best available or the sole method of

studying conditions present in humans but that
28 ● Alternatives to Animal Use in Research, Testing, and Education

do not lend themselves to systematic study in humans (see ch. 5).

In testing, procedures like the Draize test and

the LD50 are used in part because investigators believe that Federal regulatory agencies, such as FDA

and EPA, require the results of these tests in data

submissions (see ch. 7). Exercise of oversight authority could induce Federal regulatory agencies

to make explicit their disinterest in data derived

from objectionable tests and to demonstrate their

ready acceptance of data obtained through alternate means. Such oversight action, coupled with

active research into alternative methods, would

probably end most use of the targeted procedures.

It is likely that review of protocols by committee, particularly a committee with expertise in bioethics, laboratory animal science, and anesthesia,

would effectively restrict procedures to those that

are generally accepted as humane. In both research

and testing, banning animal use for a specific purpose would reflect the judgment that knowledge

gained via that procedure could never justify the

cost in animal suffering or lives.

Option 4: Restrict the acquisition of animals from

particular sources.

For several decades, States and municipalities

have wrestled with the issue of the release of dogs

and cats from pounds to research and educational

institutions (see ch. 14). Some people feel that the

release of pound animals for experimentation is

wrong, because the animals are former pets or

are too unhealthy to be proper subjects for study.

In some jurisdictions, research and educational

institutions are barred from acquiring pound animals, while other jurisdictions require that pound

animals be released to researchers after a certain

number of days in captivity.

As pound animals are usually sold at low cost

(see ch. 11), banning their sale would lead to higher

procurement costs as the pound animals were replaced with animals that are purposely bred for

experimentation. (Some animals are already purpose-bred because certain pound animals are not

suitable candidates for experimentation.) The purposeful breeding of such animals for experimentation in parallel with routine euthanasia of pound

animals would probably work out to a net increase

in dogs and cats being killed.

Option 5: License animal users (e.g., for specified

uses or for particular kinds of animals).

Animal users could be granted licenses specifying the procedures they are authorized to perform

or the animals with which they may work. Such

a system is in place in the United Kingdom under

the auspices of the Home Office (see ch. 16). Given

that at least five to six times as many animals are

used in the United States annually (17 million to

22 million) as in the United Kingdom (3 million to

4 million), achieving and maintaining licensure here

would be a considerably larger and more costly

enterprise than now exists in any country.

Implementation of this option would require a

Federal licensing body with inspection and enforcement capability. If the British system is the model,

licenses would be legally enforceable personal documents. A license to perform a particular experiment or a series of experiments or to work with

a particular species would be nontransferable.

Confidentiality would be guaranteed in order to

protect, for example, an investigator’s claim to priority in research results. Comprehensive annual

reporting by licensees and auditing by an oversight body—both integral parts of the British

system—would be necessary. It is noteworthy that

in the United Kingdom this system allows every

animal experiment to be logged (see ch. 16).

The British system works. It relies heavily on

a tradition of cooperation between experimenter

and Home Office inspector. The feasibility of such

a system in the United States is difficult to predict

because the dimensions of animal use are so poorly

characterized. Hence, the number of licensees and

the resources required for monitoring are unknown. perhaps most important, the extent to

which the parties involved would cooperate is uncertain.

Option 6: Prohibit the use of animals in research,

testing, and education.

No other country and no jurisdiction in the

United States has completely banned animal use

in research, testing, or education. In Switzerland,

a binding referendum of this nature was presented

to the public for a vote in December 1985, but it

was defeated (see ch. 16).

Action to ban animal use fully is the most extreme of the six options related to the issue of re-
Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 2 9

striction. It would undeniably provide great impetus towards implementing alternatives. Indeed, the

alternatives of reduction and refinement of animal use would be immediately and completely

achieved. However, the development of many replacements to animal use depends itself on animals. A ban would, for example, eliminate the use

of organ cultures, nonhuman tissue cultures, and

cell cultures, except for those self-perpetuating

ones already in existence. Replacements would

have to be drawn from among human and veterinary patients, micro-organisms, plants, chemical

and physical systems, and simulations of living systems. The development of new computer simulations would faker, with new data from animal systems being unavailable. The ability to verify new

simulations or proposed replacements would also

come to a halt.

Implementation of this option would effectively

arrest most basic biomedical and behavioral research and toxicological testing in the United States.

Education would be affected, too, although perhaps not as severely as research and testing. In

the advanced life sciences and in medical and

veterinary training, students might be handicapped, although not to as great a degree as once

thought. Some medical schools today, for example, use no animals in physiology curricula (see

ch. 9).

The economic and public health consequences

of a ban on animal use are so unpredictable and

speculative that this course of action must be considered dangerous. Caution would demand, for

example, that any new products or processes have

substantial advantages over available ones to merit

the risk of using them without animal testing.

ISSUE: Should more accurate data be obtained

on the kinds and numbers of animals

used in research, testing, and education?

Accurate data on the kinds and numbers of animals used in research, testing, and education in

the United States do not exist (see chs. 3 and 9).

The best numbers now available on the use of certain species (nonhuman primates, dogs, cats, rabbits, guinea pigs, and hamsters) are produced by

the Animal and Plant Health Inspection Service of

the USDA. The APHIS Animal Welfare Enforcement Report submitted to Congress each year is

best viewed as a rough estimate of animal use. It

records approximately 10 percent of all animals

used annually; omitted are rats, mice, birds, fish,

reptiles, and amphibians.

Estimates of animals used yearly in the United

States range to 100 million and more. Although

the development and implementation of alternatives do not require an accurate count, public policy formation would be helped by better data. Regulating animal use, for example, or funding the

development or validation of alternatives to a particular procedure, may depend on how many animals are used and what fraction of the total this

represents. Trends in animal use have similar applications. In the United Kingdom, the exact animal use records kept since 1876 have influenced

policymakers (see ch. 16).

Some animal welfare advocates suggest that the

moral and ethical issues surrounding animal use

are independent of the precise number of animals

used. Others question whether the value of the

data obtained is worth the cost of obtaining accurate numbers. A rough estimate based on minimal data may be all that is necessary to put the

relevant issues into context. Selecting among the

following options will depend, therefore, on judgment of how important it is to know the number

and kinds of animals used, who uses them, and

what trends exist.

Option 1: Take no action.

The primary advantage of this option is that no

additional funding would be required, since nothing within the system would change. Continued

funding of current APHIS activities would keep

yielding rough estimates of the use of six kinds

of animals that account for about 10 percent of

total animal use.

The major disadvantage of maintaining the status quo is that an inaccurate and ambiguous reporting system would be perpetuated, yielding marginally useful analysis of animal use in the United

States, The APHIS counting system is ineffective

because of problems with ambiguous reporting

forms and a failure to audit the forms that are

returned.

Funding for the APHIS survey has been derived

from the approximately $5 million allocated annually in recent years to APHIS to enforce the Animal Welfare Act. Depending on the uses to which
30 . Alternatives to Animal Use in Research, Testing, and Education

data on animal use are put, maintaining the status

quo may be adequate, an unnecessary expense,

or not nearly enough.

Option 2: Eliminate the APHIS reporting system.

If the value of the information obtained by the

APHIS system is not justified by the money allocated for its collection, the APHIS reporting system could be terminated. In adopting this option,

Congress would signal a willingness to rely on estimates produced by nongovernment organizations

and individuals without the benefit of reports or

inspections.

Option 3: Correct inadequacies in the present

APHIS system of reporting use of animals mandated by the Animal Welfare

Act.

To gain a more accurate picture of the use of

nonhuman primates, dogs, cats, rabbits, guinea

pigs, and hamsters in the United States, oversight

authority could be used to require that APHIS alter

its present practices in one or more of the following ways:

●

●

●

●

●

correct its reporting form to eliminate ambiguities;

change the reporting deadline or publication

schedule for the annual Animal Welfare Enforcement Report, so that fewer institutional

reports are excluded;

audit or spot-check the “Annual Report of Research Facility” forms and facilities;

strictly enforce the regulation requiring that

all institutions within the United States using

mandated species register with APHIS and

complete the “Annual Report of Research Facility” forms as required by law; or

allocate more of APHIS’ resources for enforcement of the Animal Welfare Act to reporting.

These changes would require little additional

government funding or expenditure by regulated

entities, although it could affect how they allocate

their resources. Adoption of this option would

bring APHIS closer to delivering the information

it is obliged to deliver under the Animal Welfare

Act.

Option 4: Alter the APHIS system to count additional kinds of animals (e.g., rats and

mice).

Rats and mice account for approximately 75 percent of the animals used in research, testing, and

education in the United States. They go uncounted

because a USDA regulation under the Animal Welfare Act excludes them from its definition of animals. There is, however, some voluntary reporting of the use of these species on the APHIS “Annual

Report of Research Facility” forms.

Data on rats and mice (or other currently unregulated animals) could be obtained in either of

two ways. Congressional oversight of the Secretary of Agriculture could lead to a requirement

that the use of rats and mice be reported. This

would require additional funding for APHIS, because the number of facilities under the act’s regulations would increase. On the other hand, the

counting mechanism is already in place, and only

minor changes would be needed.

Expanding the APHIS animal counting requirement to include rats and mice would raise costs

for some members of the research and testing cornmunities. Accurate counting of these species, including categorization of experiments for pain and

pain relief, is a labor-intensive activity and hence

costly. Such costs will be of exceptional concern

to institutions using large numbers of rats and

mice, and these users can be expected to question

whether accounting needs for policy evaluation

require the extra expense.

A broadening of the APHIS census to include rats

and mice would still leave some uncounted. The

Animal Welfare Act’s definition of research facility covers any institution that uses primates, dogs,

cats, rabbits, guinea pigs, hamsters, or other warmblooded animals, as the Secretary of Agriculture

may determine are used in experimentation, and

that either purchases or transports animals in commerce or receives Federal funds for experiments.

Thus, a facility that breeds all its animals inhouse—most likely rats or mice—falls outside the

scope of the Animal Welfare Act and accompanying USDA regulations. The number of facilities

breeding and using rats and/or mice exclusively

is unknown. Some toxicological testing laboratories

are likely to fall into this group.

Option 5: Establish an independent census of animal use, either on a one-time or periodic basis.
Ch. l—Summary, Policy Issues, and Options for Congressional Action . 31

Fundamental changes could be made in the ways

animals are counted. An animal census could be

periodic-e.g., occurring every 2, 5, or 10 years.

An organization other than APHIS, such as the private Institute for Laboratory Animal Resources

(ILAR) of the National Research Council, could do

the counting. In 1986, ILAR will undertake another

in its series of surveys of laboratory-animal facilities and resources in the United States. (The last

survey was conducted in 1978.) ILAR will survey

the use of two classes of vertebrates—mammals

and birds-at approximately 3,000 facilities.

Another approach to gathering information on

the kinds and numbers of animals used would be

to conduct a comprehensive, one-time study of research, testing, and education. Such a study could

survey all species acquired or bred for research,

testing, and education; count the number of animals actually used in experimentation; record the

length of stay in animals in the facility; and categorize the purposes of the experimental-animal use.

Such a comprehensive survey would not merit

repetition every year—the purposes of animal use

in research, for instance, do not change that

quickly.

A different way to count animals used would

be to obtain figures from breeders on the number of animals bred for experimentation. This

would not take into account the percentage of animals bred that are never used in experimentation,

or animals bred within a laboratory, but it would

yield a valuable index of animal use. Yet another

source of information would be to count the number of facilities or individuals using animals for

specified activities.

It is noteworthy that the revised PHS Policy on

Humane Care and Use of Laboratory Animals by

Awardee Institutions (effective Dec. 31, 1985) requires listing the average daily inventory, by species (with none excepted), of each animal facility,

as part of each institution’s annual report to the

NIH Office for Protection from Research Risks.

Thus, PHS-supported facilities are now required

to report more complete census data to NIH than

facilities covered by the Animal Welfare Act report to APHIS. Consequently, a portion of animal

use in research (e.g., NIH-supported animal research) and testing (e.g., FDA-supported animal

testing) is about to become more closely censused.

The choice among census types under this option will depend on the ways in which the information is to be used, the resources available for

obtaining it, and the utility of the new census required by PHS.

ISSUE: Should Federal departments and agencies be subject to minimum standards

for animal use?

The Federal Government has six cabinet departments and four independent agencies involved in

intramural animal research or testing (see ch. 13

and app. B). These departments and agencies account for at least 1.6 million animals for intramural

research (see ch. 3). Federal agencies have generally followed the existing PHS policy and as of December 1986 will be required to operate institutional animal committees (Public Law 99-198).

Many departments and agencies also follow the

NIH Guide for the Care and Use of Laboratory Animals. Yet there is no stated, detailed policy of minimum standards for animal use within the Federal Government. Therefore, this issue has just two

options: either maintaining the present system or

establishing a minimum policy for intramural animal use. Financial considerations are not a major

factor because funds will be needed either to continue the present system of variable policies or to

implement and enforce a minimum, governmentwide policy.

Option 1: Take no action.

The advantages of the present system are its flexibility and minimal bureaucratic structure, The

policies mentioned previously, along with the Interagency Research Animal Committee’s Principles

for the Utilization and Care of Vertebrate Animals

Used in Testing, Research, and Training, allow each

agency or department to have policies and mechanisms unique to its situation. The disadvantages

are the potential for conflicting policies and the

lack of a neutral enforcement authority.

Option 2: Establish minimum standards for all intramural animal use in Federal departments and agencies.

This option would require that a policy be developed and perhaps that an organizational entity

be established to oversee its implementation and

enforcement. This could be accomplished by an

interagency committee or by a designated agency.
32 Alternatives to Animal Use in Research, Testing, and Education

Setting minimum standards would still give each

agency and department the flexibility to tailor specific policies to unique situations, yet it would establish a Federal model for standards of animal care

in experimentation and ensure humane procedures in Federal facilities.

A Federal intramural policy might incorporate

policies and procedures that address facility accreditation and institutional review of research

proposals. A composite, minimum Federal policy

could reflect the most progressive parts of various current agency standards.

It is noteworthy that this type of action has been

taken to protect human research subjects. A Model

Federal Policy for the Protection of Human Research Subjects involved in research conducted,

supported, or regulated by Federal departments

or agencies is now in draft form. The policy will

be implemented through routine policy and procedural channels of the departments and agencies.

The advantage of minimum standards is that all

concerned parties know the policy and can immediately and permanently put in place the appropriate organizational structure and facilities to

guarantee adherence.

ISSUE: Should the Animal Welfare Act of 1966

be further amended, or its enforcement

enhanced?

One criticism of the Animal Welfare Act is the

lack of coverage of practices other than anesthesia and analgesia during actual experimentation.

Although the most recent amendments to the act,

in 1985, direct institutional animal committees to

assess practices in experimentation and require

that professionally acceptable standards are followed during experimentation, the act at the same

time forbids any regulation related to the design

or performance of experiments. Additional complaints concern the adequacy of resources for its

enforcement, the enforcement structure, the

choice of APHIS as the primary enforcement

agency, and the cumbersome recordkeeping.

In considering whether the act should be strengthened, some related issues must be kept in mind.

First, a change in authority may require funding

for implementation and enforcement. Second, any

change must take into account the present resources of those affected and their ability to achieve

compliance without compromising other objectives. Thus, an important consideration is whether

or not regulated institutions have sufficient institutional and independent veterinary resources to effect meaningful compliance with a strengthened

law and still meet their testing or research objectives. Finally, strengthening the Animal Welfare

Act in the face of differences within the scientific

and animal welfare communities will carry considerable symbolic value.

Option 1: Take no action.

By maintaining the status quo, Congress would

give a strong signal to all concerned parties that

it is satisfied with the present regulatory structure

for animal use in the United States and that no

change is deemed necessary. More specifically,

selection of this option would imply that current

enforcement efforts are sufficient and that it is

not necessary to regulate rats and mice used in

experimentation.

Option 2: Eliminate funding for enforcement of

the Animal Welfare Act.

Elimination of funding for enforcement of the

Animal Welfare Act by APHIS would save the Federal Government approximately $5 million annually. Without these funds, there would be no inspections of facilities (including exhibitors, dealers,

and research institutions) using nonhuman primates, dogs, cats, rabbits, guinea pigs, or hamsters

and no annual census of these six kinds of animals.

Action taken by APHIS against violators would

cease. Therefore, the objective of the Animal Welfare Act—to safeguard the humane care and treatment of certain animals—would no longer be met.

Option 3: Increase funding for enforcement of the

Animal Welfare Act.

Increased funding for the enforcement of the

Animal Welfare Act would bolster enforcement

of the present law. Additional funds could be used

to:

●

●

●

increase the training of inspectors;

increase the number of enforcement agents

in the field, so as to raise the number of inspections;

oversee consistent interpretation of existing

regulation by inspection and enforcement

agents in the field; and/or
Ch. l—Summary, Policy Issues, and Options for Congressional Action . 33

● replace voluntary assurances and simple certifications of compliance with more rigorous

procedures.

Additional funding could help stimulate the present

passive regulatory situation to become a more active, aggressive regulatory environment. Such a

transition would rest on APHIS’ level of enthusiasm

for enforcing the Animal Welfare Act.

Option 4: Expand the jurisdiction of enforcing

agencies to include standards of care,

treatment, and use during the actual

conduct of experimentation.

The Animal Welfare Act exempts the treatment

of animals while they are actually involved in experimentation, except for a requirement for appropriate anesthesia or analgesia and the use of

professionally acceptable standards in the care,

treatment, and use of animals. The original law

exempted actual experimentation because Congress did not want to interfere with the conduct

of the scientific process (see ch. 13). Animal care

and treatment are essentially regulated only before and after a scientific procedure. Implementation of this option would broach the design and

execution of experimental protocols and would

require statutory change. Such action would increase the responsibility of APHIS and its enforcement would require additional funding. A deterrent to implementation of this option is APHIS’ lack

of expertise in reviewing experimental protocols.

Option 5: Realign existing and any new responsibilities for enforcement among Federal

departments and agencies.

APHIS spends little of its resources, either monetary or personnel, enforcing the Animal Welfare

Act (see ch. 13). It was selected by Congress in 1966

to enforce the act because it had some expertise

in animal issues but did not have the conflict of

interest that an entity such as NIH or DHHS might

have.

Enforcement power could be changed by transferring enforcement authority for violations of the

Animal Welfare Act from USDA (APHIS) to DHHS.

This would set up a potential conflict of interest:

A single department would both sponsor animal

experimentation and have oversight authority. In

addition, many of the regulations in the Animal

Welfare Act affect areas in which DHHS has no

expertise (e.g., animal use by exhibitors).

In amending the Animal Welfare Act in 1985,

Congress mandated that the Secretary of Agriculture consult with the Secretary of Health and Human Services prior to issuing regulations under

authority of the act. The implementation of this

provision may lead to DHHS having increased influence on the enforcement of the act,

Option 6: Amend the Animal Welfare Act to preempt State and local laws concerning

animal use in areas not already covered

by the Animal Welfare Act.

Although the Edward Taub case in Maryland (see

ch. 14) did not decide the preemption question,

it did bring up the issue of whether the Animal

Welfare Act could preempt a State statute. Congress may wish to examine its authority to preempt

State anticruelty statutes and may then wish to

specify for the judiciary whether it intended its

law to supersede any State or local laws on this

issue. In doing so, Congress could remove uncertainty in the law by making clear whether it intends the Animal Welfare Act to be a comprehensive, exclusive system of control over the use of

animals in experimental facilities and activities in

interstate and foreign commerce. Without such

clarification, the possibility exists for local criminal prosecution, seizure of animals, injunctions to

close facilities, and cessation of animal investigations.

Current State and local efforts to assure humane

treatment have been criticized for several reasons.

Compliance schemes are overly complex, training

and resources are inadequate, and existing laws

are not specific enough in their standards for care,

treatment, and use. If Federal preemption is not

exercised, then State and local laws will be considered concurrent and complementary to existing Federal laws.

It is important to note that Federal preemption

means that the administrative system for monitoring, including on-site inspection, should be made

adequate to ensure continued compliance with national standards for humane treatment. Otherwise,

State-level organizations with a sincere and reasonable concern about the care of animals will be
34 . Alternatives to Animal Use in Research, Testing, and Education

justified in demanding local enforcement and sur- question of whether the Federal Government has

veillance of research, testing, and education in- the authority to assert itself into areas traditionvolving animals. ally regulated by the States (e.g., pound animal use)

Finally, it should be recognized that if Federal may well land in the courts.

preemption is deemed necessary, the constitutional
Chapter 2

Introduction

Donahue: What doesn’t feel pain? When do you stop feeling pain? Does a frog feel pain?

McArdle: Yes.

Donahue: Frogs feel pain? . . . now what about laboratory high school? You remember, you

had to dissect the frog? . . . Should we eliminate that? How about fishing? . . .

how about baiting a hook with a worm? IS that fair? In other words, where do

we stop?

McArdle: You bring up fishing and I think that's a good point. I used to wonder whether or

not the nonvertebrate animals would feel pain. A few years ago they found endorphins, which are substances that handle chronic pain, in earth worms. So,

earth wvrms may in fact be subject to chronic pain when you’re putting them on

that hook.

Phil Donahue with John E. McArdle, Humane Society of the United States

Donahue (transcript #02065)

February 1985

Although the highest standard of protection must be applied to all animals, we acknowledge that it is right to pay special attention to the companions of man [non-human primates,

cats, dogs, and equidae] for whom there is the greatest public concern.

Scientific Procedures on Living Animals, Command 9521

British Home Office

May 1985
CONTENTS

What is an Animal? . . . . . . . . . . . . . . . .

What is an Alternative? . . . . . . . . . . . . .

Biological Models . . . . . . . . . . . . . . . . . .

Chapter 2 References . . . . . . . . . . . . . . . .

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..,,., 39

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Table

Table No. Page

2-I. Some Types of Living Organisms Used in Research,

Testing, and Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...38
Chapter 2

Introduction

This report assesses the state of the art and the

potential for alternatives to using animals in three

contexts: biomedical and behavioral research, testing of products for toxicity, and education. Distinguishing among these three areas is important

because both the patterns of animal use and the

potential for alternatives vary among them. Research develops new knowledge and new technologies; although prediction of results is one goal,

unpredictable results may prove even more significant. Testing relies on standardized procedures

that have been demonstrated to predict certain

health effects in humans or animals. It entails the

measurement of biological phenomena, such as

the presence or absence of cancer or of skin irritation, or the concentration of certain substances

in tissue or in bodily fluids. Education involves

teaching students in the life sciences, health professionals and preprofessionals, and research scientists, as well as the cultivation of humane attitudes

toward animals at all levels. Alternatives in each

of these three areas consist of procedures that replace animals with nonanimal methods, that reduce the number of animals used, or that refine

existing protocols to make them more humane.

In addition to evaluating alternatives in three

areas, the assessment also examines ethical concerns regarding the use of animals, economic considerations of their use and the alternatives, funding

for the development of alternatives, and current

regulation of animal use, Most important, this report delineates seven major public policy issues

(and associated options for congressional action)

in relation to alternatives (see ch. 1).

With a focus on the prospects for alternatives

to animal use in research, testing, and education,

this assessment necessarily excludes certain related topics and treats others only in brief. The

role of animals in food and fiber production falls

outside the scope of this study, as does the role

of animals in the commercial production of antibodies and other biological materials. In addition,

OTA has not evaluated the use of animals for companionship, sport, or entertainment. Although laboratory

animals are an integral part of this assessment, OTA

did not examine contemporary standards of their

care (e.g., cage size, sanitation, ventilation, feeding,

and watering). Lastly, the use of human subjects is

not considered in this assessment.

WHAT IS AN ANIMAL?

In any biological definition of the word “animal,” Political and scientific discussions often incorall vertebrate and invertebrate organisms are in- porate other subdivisions for the term “animal.”

eluded and plants and unicellular organisms are Although not strictly part of the definition in this

excluded. For the purposes of this report, how- report, the terms “lower” and ‘(higher” are used

ever, an “animal” is defined as any member in many discussions of alternatives that refine ex -

of the five classes of vertebrates (nonhuman isting animal procedures or that replace certain

mammals, birds, reptiles, amphibians, and animal species with other ones. In these contexts,

fish). These five classes of vertebrates can be fur- the substitution of “lower” animals for ‘(higher”

ther divided into two major groups, cold-blooded animals usually refers to using cold-blooded ververtebrates (reptiles, amphibians, and fish) and tebrates instead of warm-blooded vertebrates. In

warm-blooded vertebrates (mammals and birds). addition, within the class of mammals, “lower” is

Invertebrates, therefore, are not discussed as generally used to designate, for example, rodents,

animals. while “higher” refers to primates, companion ani37
38 ● Alternatives to Animal Use in Research, Testing, and Education

mal species (e.g., dogs, cats, or rabbits), and do- and education. It indicates the laboratory species

mestic farm animals (e.g., horses, cattle, or pigs). — falling within this assessment’s definition of an aniTable 2-1 is a classification of the principal liv- mal and the species that can be classified as “alternatives.” ing organisms that are used in research, testing,

Table 2.1.—Some Types of Living Organisms Used in Research, Testing, and Education

Alternatives:

1. Prokaryotes (any living organism without a nuclear

membrane)

A. Bacteria

1. Escherichia coli

2. Salmonella

3. Streptococcus

4. Bacillus

B. Fungi—e.g., yeast

Il. Eukaryotes (any living organism with a nuclear

membrane)

A. Plants

B. Invertebrates

1. Protozoa

a. Paramecium

b. Amoeba

2. Porifera—e.g., sponges

3. Coelenterates—e. g., Hydra and Jellyfish

4. Flatworms—e.g., Planaria

5. Segmented worms

a. Earthworms

b. Leeches

c. Annelids

6. Nematodes—e.g., Caenorhabdiitis elegans

7. Molluscs

a. Gastropods—e.g., snails and Aplysia

b. Pelecypods—e.g., mussels

c. Cephalopods—e.g., squids and octopuses

8. Arthropods

a. Lirnulus (horseshoe crabs)

b. Arachnids

(1) Spiders

(2) Ticks

(3) Mites

(4) Scorpions

c. Crustaceans

(1) Daphnia

(2) Brine shrimp

(3) Crayfish

d. Insects

(1) Crickets

(2) Cockroaches

(3) Drosophila (fruit flies)

(4) Lice

(5) Beetles

(6) Moths

(7) Butterflies

9. Echinoderms

a. Sea urchins

b. Sand dollars

c. Sea cucumbers

Animals:

C. Vertebrates

1. Cold-blooded vertebrates

a. Fish

(1) Jawless fish–e.g., lampreys

SOURCE: Off Ice of Technology Assessment.

(2) Cartilaginous fish–e.g., sharks

(3) Bony fish

b. Amphibians

(1) Frogs—e.g., Rana

(2) Toads–e.g., Xenopus

(3) Salamanders

c. Reptiles

(1) Turtles

(2) Crocodiles

(3) Alligators

(4) Snakes

(5) Lizards

2. Warm-blooded vertebrates

a. Birds

(1) Quail

(2) Chickens

(3) Pigeons

(4) Doves

(5) Ducks

b. Mammals

(1) Bats

(2) Rodents

(a) Mice

(b) Rats

(c) Gerbils

(d) Guinea pigs

(e) Hamsters

(f) Squirrels

(3) Marine mammals

(a) Dolphins

(b) Whales

(c) Seals

(d) Sea lions

(4) Rabbits

(5) Armadillos

(6) Carnivores

(a) Dogs

(b) Cats

(c) Ferrets

(7) Ungulates

(a) Cattle

(b) Sheep

(c) Horses

(d) Pigs

(e) Miniature pigs

(f) Goats

(g) Donkeys

(h) Burros

(8) Primates

(a) Baboons

(b) Capuchins

(c) Chimpanzees

(d) Macaques, Cynomolgous

(e) Macaques, Pig-tailed

(f) Macaques, Rhesus

(g) Marmosets

(h) Squirrel monkeys
Ch. 2—introduction • 39

WHAT IS AN ALTERNATIVE?

Defining the word “alternative” is in a sense always doomed to failure: Regardless of how accommodating or strict the definition, many will fault

it. The term evolved in the political arena, coined

by animal welfare activists and for the most part

nonscientists, and yet it has direct implications for

scientists using laboratory animals. Its meaning

varies greatly, depending on who uses it and the

context in which it is used.

The definition of “alternatives” employed by OTA

obviously affects this entire assessment: It defines

the scope of the study. Too narrow a definition

would dispose of the need for this report, while

too broad a definition would render it unmanageable. Defining alternatives as the nonuse of animals, as some would have it, would restrict the

bounds of the study to the consideration of invertebrate organisms, chemicals, plants, and computers. On the other hand, stretching the definition

to include humans, for example, would create a

whole new series of issues that would be virtually

impossible to address within one assessment. With

these concerns in mind, OTA chose to define

“alternatives” as encompassing any subjects,

protocols, or technologies that ‘(replace the

use of laboratory animals altogether, reduce

the number of animals required, or refine

existing procedures or techniques so as to

minimize the level of stress endured by the

animal” (4; adapted from 5).

Some examples of alternatives under this definition include computer simulations to demonstrate principles of physiology to medical students,

the use of the approximate lethal dose methodology in acute toxicity studies, and the increased use

of anesthetics with pain research subjects. The “reduction” part of the definition indicates that the

increased use of cultured cells, tissues, and organs

instead of whole animals is also an alternative. A

very broad interpretation of alternatives might also

include the substitution of cold-blooded for warmblooded vertebrates.

BIOLOGICAL MODELS

When animals-or alternatives—are used in research, testing, and education, it is because they

possess a simpler or more accessible structure or

mechanism in comparison with the object of primary interest (which is often the human) or are

themselves the object of primary interest, or because certain procedures cannot be carried out

on humans. Viewed from this perspective, both

animals and alternatives stand as models. In the

broadest sense, a biological model is a surrogate,

or substitute, for any processor organism of ultimate interest to the investigator. It is a representation of or analog to some living structure, organism, or process.

In addition to analogy, biology has another analytical tool at its disposal—homology, which is correspondence in structure and function derived

from a common evolutionary origin (i.e., a common gene sequence). The most closely related species are generally presumed to offer the best homologs. Relationships between species are not always

known in detail, however, and unresolved questions about evolutionary events and pathways are

numerous. Care must therefore be used in evaluating the degree of homology and the extent to

which it relates to analogy (3).

Some biological mechanisms, such as the coding of genetic information and the pathways of

metabolism, arose early in evolution. These mechanisms have been highly conserved and are widely

shared by organisms, including humans, at the cellular and molecular levels. Thus, good models for

these fundamental molecular mechanisms in humans can be found in a wide array of organisms,

some of which, such as bacteria, have structures

and functions far less complex than those of mammals (3).

Several characteristics are important in choosing a model for research, testing, or educational

purposes. The most important is the model’s discrimination-the extent to which it reproduces the

particular property in which the investigator is

interested. With greater discrimination, the pre-
40 ● Alternatives to Animal Use in Research, Testing, and Education

dictability between the model and the property

under study increases.

After the discrimination or predictability of a

model, certain other criteria stand out as being

necessary for a good biological model (1)2). A model

should:

●

●

●

●

●

●

●

●

●

●

●

●

accurately reproduce the disease or lesion under study;

be available to multiple investigators;

be exportable from one laboratory to another;

be large enough to yield multiple samples;

fit into available facilities of most laboratories;

be capable of being handled by most investigators;

survive long enough to be usable;

exhibit the phenomenon under study with

relative frequency;

be of defined genetic homogeneity or heterogeneity;

possess unique anatomical, physiological, or

behavioral attributes;

be accompanied by readily available background data; and

be amenable to investigation with available,

sophisticated techniques.

CHAPTER 2

1. Leader R,A,, and Padgett, G.A., “The Genesis and Validation of Animal Models) ’’Azn. J. Pathol. 101:s11-s16,

1980.

2. National Research Council, Mammalian Models for

Research on Agl”ng (Washington, DC: National Academy Press, 1981).

3. National Research Council, Models for Biomedical

Research: A New Perspective (Washington, DC: National Academy Press, 1985).

Depending on the type and needs of the investigation, certain of these criteria might be more important than others. Overall, a model with more

of these characteristics will have higher discrimination and stronger predictive ability,

In research, testing, and education, a small number of species have achieved prominence as experimental tools because they have been extensively

studied from a number of perspectives and thus

provide well-understood paradigms that have been

described in detail in terms of genetics, biochemistry, physiology, and other aspects. These organisms include the laboratory rat, laboratory mouse,

fruit fly, and bacterium Escherichia coli. Yet taxonomic breadth is also required in research and

testing, since it is often impossible to predict what

species will lend themselves particularly well to

the study of specific problems. In biological modeling, concentration on selected species and taxo -

nomic diversity are not mutually exclusive; both

play a role in the establishment of a maximally useful matrix of biological knowledge (3).

REFERENCES

4. Rowan, A. N., Of Mice, Models, & Men: A Critical

Evaluation of Animal Research (Albany, NY: State

University of New York Press, 1984).

5. Russell, W.M.S., and Burch, R. L., Principles of

Humane Experimental Technique (Springfield, IL:

Charles C. Thomas, 1959).
chapter 3

Patterns of Animal Use

Twenty million rats, rabbits, cats, dogs, mice, and monkeys are killed each year in the

name of science. And the number has quadrupled in recent years . . . 150 living creatures

are sacrificed every minute.

Paul Harvey

Radio broadcast of April 30, 1985

Each minute around the clock, 150 creatures are sacrificed ., . a total of 70 million a

year. Included are 25,000 primates . . . and nearly 500,000 dogs and cats.

parade, January 13, 1985

Each year in the United States, almost 100 million animals are used in scientific research.

Nearly a million are dogs and cats.

Ed Bradley

CBS News, 60 MINUTES

October 14, 1984

OTA ignores the fact that more than one-half of all research goes unreported because

unfunded. Secondly, funded researchers consistently understate the number of animals

used for several reasons I won ‘t enumerate. My personal guess is that 120-150 million

animals is the right ballpark figure.

Sidney Gendin

Eastern Michigan University

The Research News 36(3-4):17, 198.5
CONTENTS

Page

The Federal Government’s Use of Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Federal Departments and Agencies Using Animals in Research . . . . . . . . . . . . . 44

Patterns of Federal Animal Use...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Animal Use in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Limitations of Animal-Use Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SO

Critical Evaluation of Animal-Use Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Calculating Rat and Mouse Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Summary and Analysis of Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Future Animal Censuses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Summary and Conclusions . . . . . . . . . . . . . . . ..........+.. . . . . . . . . . . . . . . . . . 65

Chapter p references. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

List of Tables

Table No. Page

3-1. Research-Animal Use in the Federal Government,

by Major Department and Division for Fiscal Year 1983 . . . . . . . . . . . . . . . . . 50

3-2.Total Numbers of Animals Used in Federal Government Facilities

as Reported to Congress in APHIS Animal Welfare

Enforcement Reports, 1978-83 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

3-3.Reliabilityof Various Data Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

3-4. Estimates of Rat and Mouse Usage in laboratories, 1978, 1982, 1983 . . . . . . 59

3-5. Various Estimates of the Number of Animals Used in the United States... . 60

3-6. USDA/APHIS Data, Changes 1982-83 . . . . . . . . . . . . . . . . . . . . . . . . ~ . . . . . . . . . 64

3-7. Animal Use Reported to the U.S. Department of Agriculture,

1982 and 1983 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

List of Figures

Figure No. Page

3-1. USDA/APHIS “Annual Report o fResearch Facility’’ . . . . . . . . . . . . . . . . . . . . . . 48

3-2. Example A of APHIS”Annual Report of Research Facility” . . . . . . . . . . . . . . . 61

3-3. Example B of APHIS ’’Annual Report of Research Facility” . . . . . . . . . . . . . . . 62

3-4.Example C of APHIS ’’Annual Report of Research Facility” . . . . . . . . . . . . . . . 63
Chapter 3

Patterns of Animal Use

Humans “use” animals in several different ways.

In addition to animal use in research, testing, and

education, animals are involved in food and fiber

production, the production of biological products,

sports, and entertainment. Animals can also be kept

as pets for the purpose of companionship. It has

been roughly estimated that 2 billion to 4 billion

animals are used in food and fiber production

every year and that Americans have approximately

75 million dogs and cats as household pets. The

uses not considered in this assessment therefore

account for many times more animals than the estimated 17 million to 22 million animals used annually in research, testing, and education.

There are no easily obtainable data in the United

States allowing an accurate estimate of animal use

for research, testing, and education that satisfies

all interested parties; estimates range over a full

order of magnitude, from approximately 10 million to 100 million animals. These estimates have

all been prepared by different people or institutions with different data sources under different

standards (e.g., different time periods or definitions). Comparison of the various estimates is difficult and, in many cases, impossible.

The issue of numbers is important to any discussion of animal use in research, testing, and education. Most basically, a number is needed from

which to consider arguments to decrease or eliminate animal use. In addition, comparing absolute

numbers in different years would provide some

idea of whether laboratory-animal use is increas -

ing or decreasing in the United States; these numbers are powerful and important to many people.

A high overall total, or high numbers of certain

species (such as nonhuman primates or companion

species), supports the claims of interest groups hoping to restrict or ban such experimentation. On

the other hand, a low number indicates the issue

is not as important as some claim. In addition, a

decreasing trend in animal use supports the position that the present system will lower animal use

on its own.

For this assessment, some idea was needed of

the scope of animal use in terms of both the numbers of particular species used and the different

major users. In addition, an analysis of different

data sources helps put the various estimates of animal use into some comparative perspective. It provides the context in which to discuss alternatives

and how much effect they might have. Although

it is true that the development of alternatives and

alternative methods does not require a perfectly

accurate estimate of usage, the planning of public

policy certainly should be based on firm data.

By looking critically at the different data sources

and coming up with possible estimates of laboratory-animal use in the United States, this assessment attempts to base discussions on a realistic,

factually backed range of figures. Without such

an analysis, any discussion or decisions on policy

issues and possible solutions lack an important perspective.

THE FEDERAL GOVERNMENT’S USE OF ANIMALS

To document the scope and extent of animal use about animal use in each department or agency.

for research by Federal departments and agen- Together, the information illustrates:

cies, information was obtained from the Animal

and Plant Health Inspection Service (APHIS) an- ●

nual reports for Federal research facilities for 1983,

the Animal Welfare Enforcement Reports for fis- ●

cal years 1978 through 1983 (both obtained from

the U.S. Department of Agriculture (USDA)), and ●

personal communications or written material

the extent of animal use in different departments,

the amount and type of animals being used

in the Federal Government,

the experimental conditions under which

most animal experiments are carried out,

43
44 ● Alternatives to Animal Use in Research, Testing, and Education

the general purpose for which animal research and testing is carried out in different

departments and agencies, and

how much research and testing for the Federal Government is conducted intramurally

(i.e., within Federal facilities).

Federal Departments and Agencies

Using Animals in Research

Six departments and four independent Federal

agencies conduct intramural research or testing

involving animals. Uses of animals range from

combat-casualty-care investigations in the Department of the Army, to acute toxicity studies by the

Consumer Product Safety Commission of potentially hazardous substances, to National Aeronautics and Space Administration research on protecting the health of American astronauts. (For

additional information on the use of animals within

the Federal Government, see chs. 7 and 13 and

app. B.)

Department of Agriculture

USDA performs biomedical research using animals under the authority of the Animal Welfare

Act in order to improve animal breeds, food, and

fibers. Most of the research is conducted intramurally by the Agricultural Research Service,

although some extramural research (i.e., research

supported by USDA, but conducted in non-USDA

facilities) is contracted out by the Cooperative State

Research Service. Some of this USDA animal research involves farm animals, however, which are

largely excluded from Government regulatory policies and are exempt from the Animal Welfare Act

and APHIS regulations (44).

Department of Commerce

The Department of Commerce conducts a small

amount of intramural research with animals and

lets some extramural contracts that involve animal studies. There are no specific Commerce guidelines or policies governing the humane treatment

and appropriate veterinary care for laboratory animals (33).

Department of Defense

The divisions within the Department of Defense

(DOD) that conduct experimental research on animals are the Air Force, the Army, the Navy, the

Uniformed Services University of the Health

Sciences, the Defense Nuclear Agency, and the

Armed Forces Institute of Pathology; the first three

of these account for most of the research. Together, all the divisions have approximately 40 research facilities that conduct animal experimentation.

The Aerospace Medical Division (AMD) of the

Air Force accounts for about 95 percent of that

service’s use of animals. Of this, 84 percent is due

to intramural research (9). AMD research and development projects fall within the following areas:

humans in space,

chemical defense and threat countermeasures,

safety and environment,

logistics and technical training,

air combat training,

human components of weapons systems, and

personnel and force management.

The safety and environment program uses the

most animals, while those on human components

of weapons systems and chemical defense also have

some animal use (50).

The Army does medical research to protect the

soldier by the authority in the mission of the US.

Army Medical Research and Development Command. Medical research and development (R&D)

are carried out in five areas: infectious diseases

(tropical disease and biological warfare defense),

combat casualty care, combat systems, dental research (facial injuries), and chemical defense.

About one-third of the research is done in-house

and two-thirds is contracted out (38).

The Navy in fiscal year 1985 allocated $58 million for the life sciences or biomedical research.

Of this, $37 million (64 percent) is for extramural

research while the remainder is for intramural

use. The two main branches of the service doing

research involving animals are the Naval Medical

Research and Development Command and the Of-
Ch. 3—Patterns of Animal Use . 45

fice of Naval Research (ONR). The Naval Medical

Research and Development Command does research in:

● submarine and diving medicine,

● electromagnetic radiation,

● aviation medicine/human performance,

● fleet health care systems,

. infectious diseases, and

● oral and dental health.

ONR conducts research using animals in four major areas: molecular biology, neurophysiology/

physiology, cellular biosystems, and psychological sciences (45).

Department of Energy

The Department of Energy has no intramural

research facilities and so contracts out all its research (47). The primary research objective within

its Office of Health and Environmental Research

is to study the health and environmental effects

of energy technologies and programs. To do this,

in the past, the Department contractor used dogs.

Recently, though, there has been a gradual shift

from whole animals to cellular and molecular research and a much greater emphasis on rodents

as opposed to companion species or primates (12).

Department of Health and

Human Services

Intramural animal research or testing is carried

out by four components of the Department of

Health and Human Services’ Public Health Service: the National Institutes of Health (NIH), the Food

and Drug Administration (FDA), the National Institute on Drug Abuse (NIDA) (a part of the Alcohol, Drug Abuse, and Mental Health Administration), and the National Institute for Occupational

Safety and Health (NIOSH) (a part of the Centers

for Disease Control).

NIH is the largest research institution in the Federal Government and uses more animals than any

other department or agency. The mission of NIH

is to uncover new knowledge that will lead to better health (51). It does this by both intramural and

extramural research. Approximately 88 percent

of the NIH budget is spent on extramural programs

while 10 percent goes to intramural research and

2 percent is used for NIH administration. Some

44 percent of the research awards go to research

involving animals (28).

Research in the FDA is mission-oriented, with

the principal objective being to provide data to support regulatory decisions. Research is conducted

to determine the safety of human and animal foods;

detect contaminants in human and animal foods;

determine the safety and efficacy of human and

animal drugs, biological products, and medical devices; reduce unnecessary exposure to artificial

radiation; and increase fundamental understanding of the toxicological effects of chemicals. Ninety

percent of the dollar budget for FDA research is

allocated to intramural research studies while the

other 10 percent goes to extramural research (5).

Department of the Interior

The Department of the Interior does more than

95 percent of its research in-house (31). Most animal research is performed by the U.S. Fish and

Wildlife Service to support its mission “to provide

the Federal leadership to conserve, protect, and

enhance fish and wildlife and their habitats for

the continuing benefit of people. ” This involves

maintenance of relevant research and education

programs in cooperation with other State and private organizations to enhance fish and wildlife resource management (53).

Department of Transportation

The Department of Transportation conducts animal research under the authority of the Hazardous Transportation Act of 1974 to determine the

level at which substances become Class B poisons

(see ch. 7). Most of the research involving animals

is conducted extramurally (42). The Department

also performs animal research under the authority of the National Traffic and Motor Vehicle Safety

Act of 1966 (10).
46 ● Alternatives to Animal Use in Research, Testing, and Education

Consumer Product Safety Commission

The Consumer Product Safety Commission (CPSC)

both relies on data provided by manufacturers and

conducts its own testing to determine the toxic

potential of consumer products. Animals are used

by CPSC’s Directorate for Health Sciences in determinations of substances’ acute oral toxicity,

their potential for skin and eye irritation, and their

combustion toxicity (16).

Environmental Protection Agency

The Environmental Protection Agency (EPA) performs research involving animals under the statutory and regulatory authority of the Toxic Substances Control Act and the Federal Insecticide,

Fungicide, and Rodenticide Act. The general purpose of this research fits into one of three categories: methods development to assess potential hazards to the environment, dose-response data for

risk assessment, or low dose to high-dose data for

risk assessment. EPA has two major research facilities, one in Cincinnati, OH, and the other in Research Triangle Park, NC. In addition to the intramural research done in these facilities, EPA does

contract extramural research. The amount done

outside the agency varies from year to year and

depends on the program, but it usually does not

exceed 40 percent of total research (48).

National Aeronautics and

Space Administration

The National Aeronautics and Space Administration (NASA) has three facilities that maintain

or conduct research with animals, although approximately 65 percent of NASA’s Life Sciences

research is conducted extramurally. About 12 percent of the life sciences budget was used to fund

animal research in fiscal year 1984 (37).

The general purpose of NASA’s research is to

acquire knowledge that can be used to protect and

ensure the health of American astronauts, both

during their missions in space and after their return to Earth.

National Science Foundation

The National Science Foundation awards grants

for scientific research involving animals but performs no intramural research.

Veterans’ Administration

The Veterans’ Administration (VA) has 174 facilities, 91 of which have the ability and authorization to do animal research. The VA’s mandate

to do research that may involve animals comes

from part of the agency’s defined mission to understand health maladies better, with a special emphasis on those that affect veterans. The VA uses

animals in its research and development divisions

and its education programs, which are located in

many of its local facilities. All research funded by

the VA is done intramurally, and some of the research done by the VA is funded by other agencies, such as NIH (29).

Research and development within the VA has

three elements: the Medical Research Program,

Rehabilitative R&D, and Health Services R&D. The

Medical Research Program includes research basic

to disease and deformities, while Rehabilitative

R&D includes studies on artificial appliances or

substances for use in restoring structure or function of parts of the human body. Finally, Health

Services R&D includes research toward improvement, replacement, or discontinuance of health

care delivery systems (32). Thus, the VA’s mandate for research and development is extremely

broad and holds the potential to use animals in

many programs.

Patterns of Federal Animal Use

APHIS is the agency within the U.S. Department

of Agriculture responsible for administering and

enforcing the Animal Welfare Act of 1966 (Public

Law 89-544) and its amendments (see ch. 13). The

act defines research facility as any individual, institution, organization, or postsecondary school

that uses or intends to use live animals in research,

tests, or experiments and that purchases or transports live animals in commerce or that receives

Federal funds for research, tests, or experiments.

It defines “animal”to include “any live or dead dog,

cat, monkey (nonhuman primate mammal), guinea

pig, hamster, rabbit, or such other warm-blooded

animal, as the Secretary [of the Department of Agriculture] may determine is being used, or is intended

for use, for research, testing, experimentation, or

exhibition purposes, or as a pet .“ The act excludes

horses not used for research purposes and other
Ch. 3—Patterns of Animal Use ● 4 7

Primate Involved in Behavioral Research

i

Photo credit: David Hathcox C), 1935

farm animals intended for use as food or fiber.

Under this definition, dead frogs used in biology

classes or animals killed prior to usage are not included. Rats, mice, and birds were specifically excluded from the act coverage by regulations promulgated in 1977 by the Secretary of Agriculture

(9 C.F.R. 1.l(n); 42 FR 31022); reporting the use

of these animals is voluntary.

The regulations that APHIS enforces require that

each research facility fill out an Annual Report of

Research Facility (see fig. 3-1) by December 1 on

the preceding Federal fiscal year (October 1- September 30). Elementary and secondary schools are

exempt, as are facilities using only exempt species

(rats, mice, or birds). In addition, any facility that

does its own in-house breeding and does not receive Federal funds does not have to file a report.

Although Federal research facilities are not required to register with APHIS, many of them do

fill out the annual reporting forms. Each year,

APHIS reports to Congress on the data collected

from these forms in its Animal Welfare Enforcement Report.

Since 1982, two lines on the Annual Report of

Research Facility have listed rats and mice under

column A, ‘(Animals Covered by the Act” (which

is therefore no longer an accurate heading). Although not legally required, many respondents

who used mandated species filled in the number

of rats and mice anyway, either not realizing that

reporting on these species is voluntary or electing to report their use, Thus, for many institutions

a usage figure for rats and mice is given. In other

cases, though, facilities reporting on mandated species omitted data on rats and mice.

Table 3-1 details the total reported animal use

by research facilities within the Federal Government broken down by departments, major divisions, and agencies for fiscal year 1983. The Annual Report of Research Facility requires not only

that total animals used be reported, but that the

animals used be categorized as being used in research, experiments, or tests: 1) involving no pain

or distress; 2) where appropriate anesthetic, analgesic, or tranquilizer drugs were administered to

avoid pain or distress; or 3) involving pain or distress without administration of appropriate anesthetic, analgesic, or tranquilizer drugs (see fig. 3-1).

Several qualifications are necessary on the numbers reported in table 3-1, which are based on the

annual reports obtained from APHIS:

●

●

●

●

The 131 research reports include only intramural Federal research done at Federal facilities.

The 131 facilities are not all the Federal facilities that might have used animals in 1983; at

least 25 facilities did not file a report for that

year.

The numbers obtained were tabulated from

each report. The reports were checked and

corrected for improper coding of information

and inaccurate addition. In many cases, these

changes reflected substantial differences in

the number of animals used for specific institutions.

The numbers for mice and rats are included

from any institution that reported them voluntarily. Several facilities, however, specifically

mentioned that they were not required to submit these data and did not do so.

In addition to these general limitations on overall numbers, some specific qualifications for individual departments and agencies are also warranted:

● For FDA, table 3-1 does not include its primary

research facility, the National Center for Toxicological Research (NCTR), since no report
48 . Alternatives to Animal Use in Research, Testing, and Education

I I

FORM APPROVE O

OMB NO. 05 79-0036

L -- ——-—- - — — . —

I

5. Dogs I

I

I

I — — — 1 — 1 .

6 Cats

7 Guinea Pigs

8 Hamsters

—

9. Rabbits

10. Primates

*

11. Rats

12, MICe

Wild Animals (specify )

I 3.

. —

I 4. — —

i 5.

CE RTI FIC ATl ON BY ATTENO 1 NG v ETIZR IN AR IAN FOR R EPORTING FA CILI T

Y O R IN ST IT UTi ONA L COMMITTE E

I [w.) hereby certify that the type ● nd ● mount Of ● fU190$lc, anmthetlc, ● nd tranqUlll Zln9 drugs used on Jnlmal$ dUrln9 actual research, t~stln9 Of ● xDeflm6ntatlon Includlnq Oost.oDeratlva and post-procedural care was deemed ● pgroprlate to relieve pain and distress for the subject animal.

16. SIGNATURE OF ATTENDING VETIERINARIAN 17. TITLE

. —

I S. DATE SIGNE D

1 1

t9. SIGNATURE OF COMMIT Tee MEMbe R

-.

20. TITLE 21 DATE SIGNE D

20. SIGNATURE OF COMMITTEE MEMBE R 23. TITLE 24. OATE SIGNED

[ 1

CERTIFICATION BY HEADQUARTERS RESEARCH FACILITY OFFICIAL

I cortlfy that tho ● OOvO Is trUe, Correct, ● nd COmOIOtO ● nd that orofosslonally ● cc.ptablo standardt govefnlng tfse csro, trsatmont, and um of animals Includlng

● PPfOPrlJt* u~ Of ● n*sth*tlc. ● naKf@c. ● nd tranwlll~lm drum durlnif ● ctual research, tostlns, or .xosrlmentatlon Includlng po8t-op4ratlve ● nd post-procedural

are ● ro b.lng follow.d by tho ● bovo rcs.arch faCll RlOS or sites (7 U.S.C. Ssctlon 2143).

X8. SIGNATURE QP RESPONSIBLE OFFICIAL 26. TITLE 27. OATE SIGNED

4

VS FORM 18-23

(AUG 81)

SOURCE: Animal and Plant Health Inspection Service, U.S. Department of Agriculture.
Ch. 3—Patterns of Animal Use ● 4 9

was filed for 1983. This probably excludes a

substantial number of animals since the fiscal year 1984 annual report for NCTR reported

the use of 8 dogs, 334 rabbits, 29 primates,

14)621 rats, and 11,744 mice.

● The VA has 81 facilities accredited by the

American Association for Accreditation of

Laboratory Animal Care (AAALAC) yet only

63 reports were filed for 1983. Therefore,

there is a strong possibility that the numbers

for the VA are underreported.

Bearing in mind all the limitations and qualifications of the data used to generate table 3-1, OTA

estimates that a minimum of 1.6 million animals are used annually by the Federal Government in intramural research. The Department of Defense, the Department of Health

and Human Services, and the Veterans) Administration together account for 96 percent

of reported Federal animal use. DHHS alone

reported 49 percent of the total.

Among the six kind of animals whose inclusion

in annual reporting forms is mandated by the Animal Welfare Act, guinea pigs are used most often—

twice as frequently as hamsters or rabbits (the second and third most used species). Overall, about

the same number of dogs and primates are used,

while far fewer cats are involved in Government

experiments. Finally, table 3-1 suggests that certain agencies do research on specific species. For

example, the VA uses a disproportionately large

number of dogs and the Department of the Interior

is the major user of wild animals.

Reports of Federal facilities indicate that most

animal use falls into the experimental situation

categorized as involving no pain or distress. Sixtythree percent of the animals used were in this category while 32 percent were given drugs to avoid

pain or distress and only 5 percent experienced

pain or distress without receiving anesthetics, analgesics, or tranquilizers. The largest user of drugs

in experiments was the VA (62 percent of the animals in this category), whereas the largest user

of animals experiencing pain or distress was the

Department of Defense (84 percent of the animals

in this category). The latter figure maybe inflated,

however, by the fact that DOD has reported mice

and rats voluntarily under these categories in many

cases and has listed in this column all animals dying in infectious and neoplastic disease studies,

which many Federal agencies may not do (43).

Table 3-2 shows the trends in animal use for Federal agencies as a group from 1978 to 1983, according to the Aninal Welfare Enforcement Reports

submitted by APHIS to Congress (49). As with the

numbers from the 1983 Annual Reports of Research Facilities, these data do not tell the whole

story. Most important, these data do not include

rats and mice, which together make up a majority

of the animals used. Second, only reports that have

been received by December 31 each year (the reports are due December 1) are included (26). It

has been estimated that between 10 percent and

20 percent of the total reporting institutions fail

to report by December 31 and are therefore not

included in the Animal Welfare Enforcement Reports (17). (Thus, the 1983 data are lower in table

3-2 than in 3-1, which included all available annual reports.)

The data are difficult to interpret due to the different numbers of research facilities included each

year. Therefore, no conclusions can be drawn

about whether the trend in animal use is increasing or decreasing. This is also the case for trends

in the use of individual species. The 1983 data do

indicate, however, that no more than 8 percent

of animals used in Federal programs reported here

have experienced pain or distress in an experiment

since 1978. The percentage of animals experiencing no pain or distress has remained between 50

and 60 percent, while drugs have been used to

alleviate pain or distress for 30 to 40 percent of

the animals.

ANIMAL USE IN THE UNITED STATES

OTA surveyed the available data concerning the corrected for methodological deficiencies, and

numbers of laboratory animals used for research, evaluated for their statistical reliability. As a final

testing, and education. These were summarized, step, estimates were made of current levels of an-
50 “ Alternatives to Animal Use in Research, Testing, and Education

Table 3-1.—Research=Animai Use in the Federai Government, by Major Department and Division for

Fiscai Year 1983

Department of

Department of Defense Health and

Animals used USDA Commerce Misc. Air Force Army Navy Total Human Services

FDA NIDA

Facilities reporting . . . . . . . . 11 1 3 6 20 10 39 1 1

Dogs . . . . . . . . . . . . . . . . . . . . 25 0 994 635 827 344 2,800 113 51

‘/0 row. . . . . . . . . . . . . . . . . . . <1 0 11 7 9 4 31 1 <1

Cats . . . . . . . . . . . . . . . . . . . . 39 0 491 61 214 36 802 0 84

‘/0 row. . . . . . . . . . . . . . . . . . . 1 0 18 2 8 1 29 0 3

Guinea pigs . . . . . . . . . . . . . . 6,105 0 1,601 586 26,695 609 29,491 0 98

0/0 row. . . . . . . . . . . . . . . . . . . 9 0 2 1 41 1 46 0 <1

Hamsters. , . . . . . . . . . . . . . . 7,487 0 627 1,352 4,822 417 7,218 0

‘/0 row. . . . . . . . . . . . . . . . . . . 21 0 2 4 14 1 21 : o

Rabbits . . . . . . . . . . . . . . . . . 1,047 0 1,863 703 3,731 264 8,581 0 0

‘/0 row. . . . . . . . . . . . . . . . . . . 4 0 6 2 13 1 23 0 0

Primates ., . . . . . . . . . . . . . . 0 418 527 676 219 1,840 0 0

‘/0 row. . . . . . . . . . . . . . . . . . . : o 6 7 9 3 25 0 0

Rats . . . . . . . . . . . . . . . . . . . . 7,862 0 25,259 10,570 55,057 4,243 95,128 0 312

‘/0 row. , . . . . . . . . . . . . . . . . . 2 0 6 2 13 1 22 0 <1

Mice . . . . . . . . . . . . . . . . . . . . 30,625 0 72,085 6,140 143,503 42,094 263,822 0 600

‘/0 row. . . . . . . . . . . . . . . . . . . 3 0 7 1 14 4 26 0 <1

Wild animals . . . . . . . . . . . . . 24 43 1,377 34 2,762 479 4,652 0

‘/0 row. . . . . . . . . . . . . . . . . . . < 1 < 1 10 <1 19 3 32 : o

Total . . . . . . . . . . . . . . . . . . . . 53,214 43 104,715 20,806 238,287 48,705 412,315 113 1145

‘/0 row. . . . . . . . . . . . . . . . . . . 3 <1 6 1 15 3 25 <1 <1

KEY: USDA-United States Department of Agriculture; FDA-Food and Drug Admlnistration; NIDA-National Institute on Drug Abuse; NIH-National Institutes of Health;

CDC-Centers for Disease Control; NIOSH-National Institute for Occupational Safety and Health; DOT-Department of Transportation; EPA-Environmental Protection Agency; NASA-National Aeronautics and Space Administration; VA-Veterans’ Administration; CPSC-f.kmsumer Product Safety Commission.

Percentages may not add up to 100 due to rounding.

SOURCE: Office of Technology Assessment, from 1963 APHIS Annual Reports of Research Facilities (Form 18-23); CPSC data from K.C. Gupta, Deputy Director, Division of Health Sciences Laboratory, Directorate for Health Sciences, U.S. Consumer Product Safety Commission, Washington, DC, personal communication, Sept. 24, 19S5.

nual animal use in the United States. The purpose

of this exercise was to examine numbers on animal use and compare the reliability of estimates

from different data sources.

The figures published in this assessment

on the number of animals used are not absolute. They are only as accurate as the data

from which they were obtained. All publicly

available information on past and current animal

use was collected from a variety of sources, often

through personal contacts. Data from the two most

reliable sources, the Institute of Laboratory Animal Resources (ILAR) of the National Research

Council and the USDA’s Animal and Plant Health

Inspection Service, were corrected to take into account the actual years of reporting and the omission of certain data that were not received before

a deadline.

Laboratory-animal use was then estimated and

projected using statistical techniques where appropriate. For this purpose, the corrected ILAR and

APHIS data were used, as well as more indirect

means based on National Institutes of Health funding, National Cancer Institute (NCI) usage, and NIH

total usage as a function of NIH intramural use.

Although the number of animals bred should lead

to good estimates of animals used in the laboratory, the larger laboratory-animal breeders would

not confirm or deny sales figures that had appeared

in the news media and literature. Therefore, estimates based on such reports are of uncertain reliability.

Limitations of Animal-Use Study

Two types of limits on this study exist: intrinsic

and extrinsic. The major intrinsic limitations were

funding constraints and a limited time span during which the study could be performed. This prohibited the collection of raw data and required that

OTA rely on existing data sources. The extrinsic
Ch. 3—Patterns of Animal Use ● 5 1

Table 3-1 .—Research.Animal Use in the Federal Government, by Major Department and Division for

Fiscal Year 1983 (Continued)

Department of Health and Human Services

Animals used NIH CDC/NIOSH Total Interior DOT EPA NASA VA CPSC Total

Facilities reporting . . . 3

Dogs . . . . . . . . . . . . . . . 756

0/0 row. . . . . . . . . . . . . . 8

Cats . . . . . . . . . . . . . . . 503

0/0 row. . . . . . . . . . . . . . 18

Guinea pigs ... , . . . . . 23,973

0/0 row. . . . . . . . . . . . . . 37

Hamsters. . . . . . . . . . . 14,003

0/0 row. . . . . . . . . . . . . . 40

Rabbits . . . . . . . . . . . . 8,783

0/0 row. . . . . . . . . . . . . . 30

Primates . . . . . . . . . . . 4,452

0/0 row. . . . . . . . . . . . . . 61

Rats . . . . . . . . . . . . . . . 196,458

0/0 row. . . . . . . . . . . . . . 45

Mice . . . . . . . . . . . . . . . 533,094

0/0 row. . . . . . . . . . . . . . 52

Wild animals . . . . . . . . 2,787

0/0 row. . . . . . . . . . . . . . 19

Total . . . . . . . . . . . . . . . 784,809

% row. . . . . . . . . . . . . . 48

2

0

0

0

0

0

0

10

0

30

<1

287

4

3,750

<1

1,120

<1

0

0

5,197

<1

7

920

10

587

21

24,071

37

14,013

40

8,813

30

4,739

65

200,520

46

534,814

52

2,787

19

791 ,264

49

2

0

0

0

0

0

0

0

0

0

0

0

0

900

<1

923

<1

4,228

29

6,051

<1

1

30

<1

0

0

0

0

0

0

0

0

0

0

150

0

4,552

<1

0

0

4,732

<1

4

2

<1

0

0

978

2

1,723

5

842

3

33

<1

0

0

0

0

0

0

3,578

<1

2

14

<1

40

1

58

<1

0

0

74

<1

184

3

3,936

1

622

<1

232

2

5,160

<1

63

5,187

58

1,304

47

3,747

6

4,732

14

11,508

39

461

6

122,872 ‘

28

188,560

18

2,393

17

340,764

21

1

0

0

0

0

0

0

0

0

600

2

0

0

2,080

<1

0

0

0

0

2,680

<1

131

8,978

100

2,772

100

84,450

100

35,173

100

29,445

100

7,257

100

433,449

100

1,023,918

100

14,358

100

1,619,801

100

KEY: USDA-United States Department of Agriculture; FDA-Food and Drug Administration; NIDA-National Institute on Drug Abuse; NIH-National Institutes of Health;

CDC-Centers for Disease Control; NIOSH-National Institute for Occupational Safety and Health; DOT-Department of Transportation; EPA-Environmental Protection Agency; NASA-National Aeronautics and Space Administration; VA-Veterans’ Administration; CPSC-Consumer Product Safety Commission.

Percentages may not add up to 100 due to rounding.

SOURCE: Office of Technology Assessment, from 1983 APHIS Annual Reports of Research Facilities (Form 18-23); CPSC data from K.C. Gupta, Deputy Director, Division of Health Sciences Laboratory, Directorate for Health Sciences, U.S. Consumer Product Safety Commission, Washington, DC, personal communication, Sept. 24, 1985.

Table 3=2.—Total Numbers of Animals Used in Federal Government Facilities as

Reported to Congress in APHIS Animal Welfare Enforcement Reports, 1978-83

Fiscal year

1978 1979 1980 1981 1982 1983

Federal facilities

included in reports. . . . 188 150 118 131 131

Dogs . . . . . . . . . . . . . . . . . 20,128 15,605 13,153 13,930 6,369

Cats. . . . . . . . . . . . . . . . . . 5,354 4,709 3,388 3,183 1,940

Primates . . . . . . . . . . . . . . 7,286 5,031 3,459 3,081 6,907

Guinea pigs . . . . . . . . . . . 65,009 40,425 25,402 33,495 45,972

Hamsters . . . . . . . . . . . . . 45,291 25,213 17,830 32,367 35,220

Rabbits , . . . . . . . . . . . . . . 43,867 32,205 21,631 21,962 16,209

Wild animals . . . . . . . . . . 5,537 4,137 3,209 2,007 7,618

Total animalsa . . . . . . . 192,472 127,325 88,052 110,025 120,235

aT~tala fjo not lnCIU& rats or mice, two species that together account for the majority of animals used.

6,6 ;

1,825

1,837

36,033

18,992

16,355

8,037

89,747

SOURCE: Office Technology Assessment, from APHIS Animal Welfare Enforcement Reports, 1978-1983.
52 . Alternatives to Animal Use in Research, Testing, and Education

limitations include various information deficiencies, such as:

●

●

●

●

●

inadequacies of information on most of the

survey and data collection methodologies,

difficulties with definitions,

problems with categorizing

areas of use,

reporting requirements of

sources, and

animals under

different data

an inability to verify completeness of data

sources.

For example, there is often a discrepancy in the

definition of the term “use.” In some cases, the term

reflects the number of animals acquired; in other

cases, it corresponds only to those used in laboratory experiments. This distinction is frequently

obscured in the data sources, and only after careful reading of the documents (and, sometimes, personal inquiry) was the definition used in each case

clarified. This leads to large differences in numbers, since not all animals acquired are used in

experiments. It also makes any comparative analysis between surveys very unsound.

In addition to this problem of the difference between production and use, the extrinsic problem

of the number of animals not used in a procedure

because they do not fit the proper criteria comes

into any extrapolation of animal use from laboratory-animal market share data, A substantial proportion of the animals bred for research die or

must be discarded because they do not meet protocol specifications (age, sex, weight, general

health). The number has been estimated as between a few percent of those acquired to almost

50 percent. In general, the unused proportion of

a species is inversely related to the cost of the animals. In other words, the more expensive the animal, the less likely it will be unused, once bred

or purchased. Thus, nonhuman primates are much

less likely to go unused than are mice or rats; in

some cases 50 percent of a rodent species may go

unused. Using only one sex of a rodent species in

a given experiment, for example, would account

for 50 percent of the animals going unused. This

information must be borne in mind when comparing “production” with “use” and when estimating

animal use.

Overall, these limitations reflect on the accuracy

of the data and any projections based on them.

The limitations are such that the only reasonably

credible source for current use and projections

is APHIS, particularly its institutional data sheets

(the Annual Report of Research Facility discussed

earlier). Only the detailed APHIS institutional data

sheets for fiscal years 1982 and 1983 were used

in this assessment, though those for earlier years

were also available (although they would not have

had any data on mice or rats, which were not even

listed on the form until 1982). Consequently, the

APHIS data are less reliable for the years before

1982 inasmuch as these are based on reports to

Congress that did not contain late-reporting institutions. (The Animal Welfare Enforcement Reports

to Congress underestimate use of the mandated

species by 10 to 20 percent due to the cutoff date

and do not treat data from Federal institutions consistently (17).) For some species, such as fish and

birds, only rough estimates of use could be obtained, due to the diffuse nature of use and the

fact that they are not included in the APHIS data.

Critical Evaluation of

Animal-Use Estimates

In evaluating the reliability of various data

sources, the following parameters were considered:

●

●

●

●

ability to trace the methodology used in producing the numbers, including the survey

technique;

ability to extrapolate to nonreporting institutions, which implies that there is a clear statement as to which institutions did or did not

report data;

method of data collection, whether some formal manner or through a few interviews, resulting in broad estimates; and

ability to determine the fraction of animals .

reported as being actually used in lab experimentation, as contrasted to, for example, animal husbandry.

These parameters were chosen because meeting these criteria permits extrapolation of the

limited data to the entire population of institutions.
Ch. 3—Patterns of Animal Use ● 5 3

In general, if the numbers cannot be justified

through some rational process (such as the above),

too much significance should not be attached to

them.

These four criteria were used to assign a confidence rating to each data source. The confidence

categories are: ‘(excellent)” “good,” “fair,” ‘(poor, ”

and “indeterminate .“ (These ratings refer only to

the published numbers, not to their usefulness as

a predictive tool.) Such a confidence rating is necessarily subjective; the categories are comparative

and should not be viewed as absolute.

Upon reviewing all the data sources available for predicting the laboratory-animal use

in the United States, it is clear that no source

accurately portrays the number of animals

being used. Each has methodological problems that prevented it from accurately counting all users of animals. What follows is an analysis of the available data sources and how they

rank in comparison with the other surveys in terms

of confidence and reliability.

USDA Animal and Plant Health

Inspection Service (APHIS)

The 1982 and 1983 data were analyzed on a caseby-case basis. Copies of the original report forms

were obtained from USDA; they were sorted by

institution type, checked, coded, and entered into

a computer database. Comparing the 1982 and

1983 APHIS data (see table 3-5, in the ‘(Summary

and Analysis of Estimates” section) with the USDA

Animal Welfare Enforcement Report for 1980 (the

APHIS 1980 data in table 3-5) reveals a large discrepancy. The USDA reports invariably contain

lower numbers for all species, as the data sheets

received after the December 31 cutoff date are

not included in reports in either the current or

the next fiscal year. It is estimated that between

10 and 20 percent of the reports are not used to

compile the report to Congress in a given year (17).

This limitation does not apply to the results contained in the present compilation for 1982 and

1983, since all data for a given year were used no

matter when received. The assumption is made

that copies of virtually all of the data sheets received by USDA in the 1982 and 1983 are used

in this study. No verification was made of which

institutions did not report.

The number of institutions reporting to APHIS

has hovered around 1,000 since 1972. The numbers for 1982 and 1983 (shown in table 3-6, in the

“Summary and Analysis of Estimates” section) were

tabulated from the actual summary data sheets

provided to APHIS by the institutions and include

all possible reports. Even these figures—1, 127 for

1982 and 1,146 for 1983—are probably low, as not

all institutions submit reports. (The total number

of institutions registered by APHIS was 1,113 in

1982 and 1,166 in 1983; this excludes Federal agencies, which are not required to register.) Some of

the institutions may not report because they have

not used any animals that year, or because they

have only used exempt species.

For the six required species listed on the form

(dogs, cats, guinea pigs, hamsters, rabbits, and primates), the numbers reported provide a very close

approximation of the animals actually used. Thus

these data were assigned a confidence rating of

‘(excellent .“ (For a summary of all the data sources

discussed in this section and their confidence ratings, see table 3-3.) For exempt species (primarily

rats and mice), it is possible to estimate the number of unreported rats and mice by extrapolating

from the numbers reported (see the section on ‘(Estimate Using Corrected APHIS Data”). Some commentators (1)3)2 7) claim, however, that a certain

number of exempt animals go unreported—and

would be missed in an extrapolation-because they

are purchased directly by the user and not reported to the central facility. This contention could

not be confirmed. Therefore, the voluntarily reported data on rats and mice on the 1982 and 1983

APHIS annual reports received a confidence rating of “good. ”

ILAR Surveys

The Institute for Laboratory Animal Resources,

a component of the National Research Council,

periodically surveys users of laboratory animals

(18,19,20,21,22,23), although it is generally more

concerned with facilities and personnel than with

quantity of animals used. The ILAR data represent the number of animals “acquired by own
54 ● Alternatives to Animal Use in Research, Testing, and Education

Table 3-3.-ReIiabiiity of Various Data Sources

Years Confidence

Source covered rating Strength(s) Limitation(s)

USDA/APHIS:

Mandated species 1982-83 Excellent Required by law. Data available

by institution, thus extrapolation

to nonreporters is possible

Mandated species 1972-81 Fair Required by law. Data by 10 to 20 percent of institutions

institution available, but not not included in reports to Conused gress. Totals not consistent

(some years include Federal

agencies, others do not)

Data by institution available. Not required by law

Rats and mice were on the

form so anyone who reported

probably provided an accurate

number. Many did not realize

that these were voluntary since

they were listed on form. Extrapolation possible

Exempt species 1982-83 Good

ILAR Surveys of 1965-71 Poor Of some use in establishing

Laboratory Animal Use trends for that period

1968 Survey 1967 Fair Statistically sound survey.

Possibility of extrapolating to

other institutions

1980 Survey 1978 Fair Thorough and statistically

solid. Extrapolation to nonreporting institutions possible

Old data. Cannot extrapolate

to missing data

Limited to 683 Federal-granteligible institutions

Primary attention given to

nonprofit Federal-grant-eligible

institutions. Not required by

law to be filled out

W.B. Saunders & Co. 1965 Indeterminate Company defunct, survey

methodology unclear; no

evaluation possible

Foster D. Snell 1975 Indeterminate Data appear to be based on interviews with two breeders

Methodology unclear. Personnel no longer available

SOURCE: Office of Technology Assessment.

breeding and from commercial sources,” not necessarily the number actually used in experimentation.

The ILAR and APHIS surveys are so different

in their organization and methodology that it is

not meaningful to compare the two sources, even

in years for which data from both are available.

It is also difficult to point out significant changes

within this data source because the ILAR methodology varied over time and could not be verified

adequately, so changes in numbers are difficult

to substantiate.

ILAR Surveys of Laboratory Animal Use (20) consist of tables summarizing the results of questionnaires on the number of animals used for research.

As ILAR personnel cannot discern who was surveyed and who responded, extrapolation for missing data is impossible. The surveys could, however, be of some use in assessing trends between

1965 and 1971. A “poor” confidence rating was

given.

The 1968 Survey of Laboratory Animal Facilities

and Resources (21) appears to have been a very

thorough and statistically sound survey including

all known users of laboratory animals. The results

shown, however, are only for the 683 organizations eligible for Federal grants that responded because of the interest of the survey sponsor (NIH).

It is possible, however, to normalize for missing

data based on the reported biomedical research

expenditures for these 683 organizations of $920
Ch. 3—Patterns of Animal Use ● 5 5

Table 3-3.–Reliabiiity of Various Data Sources (Continued)

Years Confidence

Source covered rating Strength(s) Limitation(s)

Alex Brown & Sons 1981 Poor At the time, it was thought to Data based on a few interrepresent best estimate for lab views, and mostly broad

animals in U.S. market estimates

Andrew N. Rowan 1985 Poor Data distinguishes between Broad analysis with many

production, acquisition, and assumptions. Based mainly on

actual use one breeding facility

Amphibians:

Emmons 1989 indeterminate Giobal estimates

Culley 1981 Indeterminate Many assumptions

Nace 1974-81 Fair Fair detail for basis of Difficult to know actual

estimates numbers due to large number

of users

Various, on fish 1983 Fair Data consistent Global estimates only

usage

Various, on bird 1983 Poor Good detail by institutions Uncertainty about nonreporting

usage institutions, and fraction of

fowl used by lab experimentation

Data on animal trends:

Wadsworth Center, NY 1980-83 Poor Good detail of different Difficult to predict any trends

species used

Johns Hopkins, MD 1975-85 Poor Limited data that are

impossible to analyze

SOURCE: Office of Technology Assessment.

million in fiscal year 1967. (The results for all respondents, while not mentioned in the report, were

compiled and reported for comparison purposes

in the ILAR 1980 survey,) The confidence rating

was “fair. ”

The ILAR National Survey of Laboratory Animal Facilities and Resources (22) also appears to

be a thorough and statistically solid report, although the data (for fiscal year 1978) are now 8

years old. Since it also was funded by NIH, primary attention was given to nonprofit biomedical

research institutions eligible for Federal grants.

In addition, data were received from Federal organizations, commercial research labs, and the pharmaceutical industry. Seventy-two percent of the

2,637 questionnaires were returned; 47 percent

of those were acceptable, thus providing 1,252 respondents (including 992 nonprofit Federal-granteligibles, 137 commercial laboratories, 25 components of the DOD, 21 units of NIH, and 77 components of other Federal agencies). Although the

individual identities of the respondents are unknown, the biomedical research expenditures of

the nonprofit organizations are known. Since their

data are reported separately from all respondents,

an extrapolation to the unknown cases can be attempted based on the known national (meaning

“all use in the United States”) biomedical research

expenditures. This source was assigned a confidence rating of ‘(fair.”

W.B. Saunders & Company

W.B. Saunders&Company (41) surveyed the laboratory animal market in 1965 and projected figures for 1970. The survey and its estimates are

widely quoted as one of the first estimates of animal use. The survey methodology is unclear and

the company no longer exists, so these data fall

under the “indeterminate” category.

Foster D. Snell, Inc., for

Manufacturing Chemists Association

A study performed by Foster D. Snell, Inc., for

the Manufacturing Chemists Association (25) estimated that 35 million mice and 40 miIlion rats were
56 ● Alternatives to Animal Use in Research, Testing, and Education

produced domestically in the United States in 1975,

and that 20)000 monkeys were imported from

India. The report’s authors could not be located

and the methodology is unclear, thus making it

impossible to validate. It appears that the data are

based on interviews with personnel at two animal breeding facilities (Charles River Breeding

Labs, Inc., and White Eagle Farms) and perhaps

a few other people in industry, academia, and government. As it is difficult to give any credibility

to such data, the source was assigned a confidence

rating of “indeterminate. ”

Alex Brown & Sons

An Alex Brown&Sons (2) report on Charles River

Breeding Labs, Inc., stated that the company produces 22 million animals annually worldwide, specializing in mice, rats, guinea pigs, hamsters, and

primates. It did not give any breakdown by species, nor do any other analyses of Charles River.

The number was primarily a guess based on a few

interviews and so its value must be questioned.

The confidence rating of this source was “poor.”

Andrew N. Rowan

In a 1984 book, Of Mice, Models, & Men:A Critical Evaluation of Animal Research, Andrew N.

Rowan estimated that approximately 71 million

laboratory animals are used each year, including

45 million mice and 15 million rats (39), These

figures were obtained by looking at all the available data sources for animal use in the United States,

especially information on Charles River breeding

production. In 1985, Rowan revised these estimates

to distinguish between production, acquisition, and

actual use. The new estimates on animals used suggest that between 25 and 35 million animals are

used per year (40). As these are based on a very

broad analysis with many assumptions, they have

been given a confidence rating of “poor.”

Surveys and Estimates on Amphibians,

Fish, and Birds

There is little good survey information on laboratory use of amphibians, fish, or birds. Use of these

animals is not required to be reported on the USDA/

APHIS annual reports. Therefore, the only sources

of estimates are personal communications with

experts in these fields.

The most recent assessments of amphibian use

were the ILAR surveys of 1965-71, which indicated

the use of 3.37 million amphibians in 1971. As mentioned earlier, however, it is not known how to

normalize for institutions that did not report, so

the usefulness of these data are questionable and

the confidence rating is “indeterminate.”

Several individuals who use or produce amphibians were surveyed, yielding a wide range of estimates. A former general manager of a major supplier of amphibians estimated that approximately

9 million frogs were shipped by suppliers in 1969

for educational and teaching purposes (13). This

is a global estimate and so its confidence rating

was considered “indeterminate. ” An amphibian

researcher at Louisiana State University did a survey of the use of bullfrogs that estimated that

150,000 bullfrogs and 200,000 tadpoles” could have

been used in 1981 (a decrease since 1971, he found).

He then assumed that bullfrogs represent roughly

10 percent of amphibian use and estimated that

about 1 million frogs and 2 million tadpoles were

used in the United States for teaching and research

in 1981 (8). The assumptions in this method are

very general and so the value of this estimate is

questionable; an “indeterminate” rating was assigned. Finally, George Nace (34,35) estimated that

about 9 million frogs were shipped by suppliers

in 1971, but that this dropped to roughly 4.5 million in 1981 and stabilized at that level in 1984,

with 90 percent of the usage educational and 10

percent research. There is fairly good detail for

the basis of the estimates, but it is difficult to confirm the totals due to the large number of users.

This source was given a confidence rating of “fair.”

Reliable data on fish used in laboratories were

particularly difficult to obtain. Estimates were

received from commercial and institutional (including Government) users in the field. For fish over

half an inch long, the yearly use appears to range

between 500,000 and 1 million. For smaller fish,

the best estimate is that 2 million to 3 million are

used yearly. Most are used for toxicological studies.

Although the numbers are fairly consistent from

source to source, they are only global estimates

and so were given a confidence rating of “fair. ”

These numbers apply only to laboratory use. They

do not include fish that are used in the wild in

propagation, contamination, feeding, and other

ecological studies.
Ch. 3—Patterns of Animal Use ● 5 7

For birds, many of those completing the APHIS

data sheets voluntarily reported bird use under

the “wild animal” category. According to these data,

at least 33,910 birds were used in fiscal year 1982

and 29,781 in fiscal year 1983. Of these, the University of Maryland used 17)915 birds in 1982, and

12,305 in 1983 (46). Since this one institution used

such a large fraction of the reported total, inquiries

about other large possible users indicated that

many of the poultry research institutions (mostly

land-grant universities in the East and South) did

not report birds on their APHIS forms, The largest

of these, in terms of poultry research, is North

Carolina State University, from whom it was learned

that approximately 41,000 birds were used for

poultry science and 1,100 in veterinary schools

(7). Checking the APHIS data sheets for other landgrant institutions showed that most had reported

bird usage. In addition, discussions with researchers at several institutions established that only 80

to 85 percent of the poultry science usage is in

laboratories with the remainder mostly in feeding, management, and breeding studies. Therefore,

although there is good detail for many institutions

on bird use, there is uncertainty in the APHIS data

about nonreporting institutions and about the proportion of fowl used in actual experimentation.

Several individuals have estimated bird use in

the United States. James Will of the Animal Resource Center at the University of Wisconsin in

Madison, WI, estimated that 25,000 to 100,000

avian individuals are used for laboratory experimentation (54). Andrew N. Rowan of Tufts University School of Veterinary Medicine in Boston, MA,

estimated that at least 500,000 birds are used in

biomedical research (0o). Both of these figures are

based on very weak data and so are assigned a

confidence rating of “poor. ” Thus, using these estimates and the APHIS bird data, an annual use of

between 100,000and 500,000 birds is as accurate

an estimate as can be made.

Data on Trends in Animal Use

Several limited data sources exist that suggest

trends in animal use in the past several years. At

Wadsworth Center for Laboratories and Research,

New York State Department of Health (Albany, NY),

the use of mandated species decreased 40 percent

from 2,925 in 1980 to 1,754 in 1983. The use of

rats and mice also decreased substantially (22 percent), from 72,796 in 1980 to 56,681 in 1983, at

a time when total research dollars available continued to increase (11. At The John Hopkins School

of Hygiene and Public Health in Baltimore, MD,

the daily census of animals decreased from over

8,000 in 1975 to approximately 2,000 in 1985 while

animal care personnel dropped from 10 to 4 and

research expenditures more than doubled (14).

These data sources are limited in scope, use different counting mechanisms, and can be considered

anecdotal in nature. They were assigned a confidence rating of “poor. ”

Calculating Rat and Mouse Usage

Using these same data sources, estimates for annual laboratory use of rats and mice in the United

States were calculated. The criteria and scales described earlier were also applied to assign confidence ratings to the estimates. To gauge annual

laboratory-animal use, minimum average costs of

$4 per rat and $2 per mouse (6,15,24,30,36,55)

were assumed to represent conservative prices for

a typical research subject. This permitted extrapolations based on price to represent an expected

maximum of animals that could be purchased.

Three different methods were used to estimate

the use of rats and mice in the United States. The

first involved using indirect means for the calculations, while a second method used 1978 ILAR

data. The third, and most reliable, method relied

on corrected USDA/APHIS data and involved calculations using regression equations.

Indirect Estimates

Possible methods for estimating rat and mouse

usage under this category involve extrapolations

from data based on NIH funding, NCI usage, NIH

total use as a function of intramural use, and animal breeder information. For example, an estimate

based on NIH funding involves the following steps

and assumptions:

● NIH funds 37 percent of all national biomedical research expenditures (52).

● In 1983, NIH awarded $582,571)000 in direct

costs to 5,011 extramural projects utilizing rats

and other species (4). If it is assumed that all

38-75o 0 - 86 - 3
58 . Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

●

expenditures went to projects that used only

rats, an upper limit can be extrapolated for

rats purchasable using NIH funds.

Twelve percent of direct costs of NIHsponsored research funds go toward the purchase of supplies, glassware, chemicals, research animals, and items listed as expendable (55).

If it is assumed that half of the supply funds

went toward the purchase of animals, then

$34,954,260 would be available for the purchase of rats.

At $4 a rat, 8.7 million rats could be purchased.

In 1983, NIH awarded $531,519)000 in direct

costs to 4,080 projects using mice. At an average cost of $2 per mouse, 16 million mice could

be purchased with NIH funds.

Assuming that NIH supports 37 percent of animal use in the country, then the potential number of these two species purchasable in the

United States is estimated at 23.6 million rats

and 43.1 million mice. This indirect method

(whether it uses NIH data or NCI data or ani.

mal breeder information) involves many assumptions, limited data sources, and cannot

be considered very reliable. It was assigned

a “poor” confidence rating.

Estimate Using Corrected ILAR Data, 1978

The results of the 1978 National Survey (22) permit approximation of animal use for all users with

techniques that fill in the missing data of nonrespondents based on a method such as the following:

●

●

●

The NIH-grant-eligible nonprofit biomedical

research organizations responding to the survey reported biomedical research expenditures of $2,2 billion for 1978.

Total national biomedical research expenditures are estimated at $6.27 billion for 1978

(52).

If it is assumed that animal use (in numbers)

is proportional to the dollar amount spent on

research utilizing them and that the usage rate

of animals by all institutions is proportional

to that of nonprofit institutions, national usage

equals (nonprofit ILAR 1980) X 6.27/2.2. This

yields an estimate of 16 million mice and 5.6

million rats used in 1978. Such methods do involve some assumptions not easily justifiable

and so the confidence rating is somewhat

lower than for the ILAR data on which they

are based. In addition, they are based on information already 8 years old.

Estimate Using Corrected APHIS Data

About two-thirds of the institutions completing

APHIS annual reports for 1982 and 1983 volunteered information on the number of rats and mice

used. Regression equations based on those institutions reporting the specific species on the Annual Report of Research Facility forms were used

to estimate the numbers of rats and mice for those

institutions not reporting these species (17). The

estimates obtained using these regression equations and then simply applying the mean value for

reporting institutions to the nonreporters are

shown in table 3-4 (which summarizes all the estimates discussed). These regression equations yield

estimates of 8.5 million mice and between 3.4 million and 3.7 million rats used annually in 1982 and

1983; applying the mean value for reporting institutions to those that did not report yields higher

estimates. Given the fairly detailed database to

which the regression equations were applied, these

estimates received a confidence rating of “good. ”

The estimates generated from these corrected

APHIS data are likely the most accurate that can

be obtained with data currently available.

Summary and Analysis

of Estimates

Table 3-5 summarizes the various estimates on

animal use discussed in this chapter. Several factors reduce the usefulness of these data, however:

APHIS’s definition of animal (which excludes rats,

mice, and birds) and the exemption from regulation of research facilities that do in-house breeding and receive no Federal funds. These limitations

may cause the numbers generated from the APHIS

data to be underestimations of the total animal use

in the United States for research, testing, and education. For example, the Directory of Toxicology

Testing Laboratories published by the Chemical

Specialties Manufacturers Association, Inc., lists

110 facilities in the United States. In checking these

against the list of APHIS registered research facil-
Ch. 3—Patterns of Animal Use . 59

Table 3-4—Estimates of Rat and Mouse Usage in Laboratories, 1978, 1982, 1983

Mice Rats

(millions) (millions)

Confidence

Basis of estimation 1978 1982 1983 1978 1982 1983 rating

Indirect means—NIH funding . . . . — — 43.1 — — 23.6 Poor

Corrected ILAR data:

Nonprofit funding share. . . . . . 16.0 — — 5.6 — — Fair

Corrected APHIS data:

Regression . . . . . . . . . . . . . . . . . — 8.5 8.5 — 3.4 3.7 Good

Average . . . . . . . . . . . . . . . . . . . . — 10.2 11.2 — 4.1 4.6 Good

SOURCE: Off Ice of Technology Assessment.

ities, 40 percent were not registered and so would

not file a report. Any animals used in those facilities would not be reported in the APHIS data. The

1978 ILAR National Survey of Laboratory Animal

Facilities and Resources stated that 35 percent of

mice and 19 percent of rats acquired for research

were bred in-house by the researchers (22), so

these too might not appear on the the APHIS data

sheets. Thus, all these limitations mean the APHIS

data may be underestimations of total animal use,

but it is impossible to estimate if the difference

is significant. Ideally, the results based on APHIS

data could be compared with estimates based on

animal breeder numbers. However, since information on distribution of costs per animal is proprietary, such an analysis is impossible. Therefore, although the data contained in the APHIS reports

are the most reliable, they do not include all possible users of laboratory animals.

Inspection of some 150 institutional Annual Report of Research Facility forms raises several other

doubts as to the accuracy of the data collected by

APHIS. In general, the form seems to lack any instruction to the individual institutions on how it

should be filled out. As a result, there is no consistency in the ways in which forms are completed.

The reliability of the data on the forms today is

in question. Figures 3-2, 3-3, and 3-4, which exemplify the reporting problems, are actual forms returned to APHIS for 1983, although the institution

names have been deleted. For example:

● Some forms have an error that can lead to

miscalculations of the number of animals used:

Column F asks for the addition of columns

B +C +D +E. The actual number desired

is C +D +E. Thus, some reports have dou-

●

●

●

bled the number of animals used (since

B =C +D +E) (see fig. 3-2). These types of miscalculations, along with normal mathematical errors, were corrected in the OTA estimate of animal use in the Federal Government.

Thus, the numbers for Federal agencies in

these two sections are different for the same

APHIS institutional reports. (For Federal agencies, this difference is fairly small.)

In many cases, respondents did not seem to

understand how to classify the animals used

in the different experimental categories. If

the APHIS form is read literally, any animal

given drugs to avoid pain or distress is also

an animal that experiences no pain or distress and could be counted in both categories (See fig. 3-3).

The answers to the category “wild animals”

differed greatly. Some forms listed legitimate

wild animals, such as seals, while others included as wild such animals as gerbils, cattle,

sheep, and pigs (see fig. 3-4). In fact, the “wild

animals” line was often filled in with farm animals, which are exempt from being reported.

The forms are now improperly labeled in

that rats and mice are included under column A, “Animals Covered by the Act, ” yet

they are specifically exempted by USDA

regulation from coverage by the Animal

Welfare Act. Many institutions that filled out

APHIS forms may have been unaware that reporting rats and mice was voluntary.

These examples serve to characterize the present

system as lacking clarity and uniformity in definition and accurate reporting, Redesign and enhanced explanation of the APHIS form would lead

to collection of more accurate data on animal use.
Table 3-5.—Various Estimates of the Number of Animals Used in the United States

W. B. Saunders W. B. Saunders ILAR ILAR ILAR APHIS APHIS APHIS Health Designs

(estimate) (projection) (estimate)

Group Species 1965 1970 1967 1970 1978 198 0

a

1982 b1983 b1983

Number of reporting institutions . . . . . . . 1,371 1,523 1,252

Rodents Total

Mice

Rats

Hamsters

Guinea pigs

Other rodents

Rabbits Total

Carnivores Total

Cats Dogs

Other carnivores

Ungulates Total

Nonhuman primates Total

Birds Total

Amphibians Total

Frogs and toads

Other Total

ALL ANIMALS TOTAL

— 975 1,127 1,146 —

13,175,716

8,500,000

3,700,000

454,479

521,237—

509,052

237,771

55,346

182,425—

—

59,336

Ioo,oooc

500,000 C

—

4,000,000 c’

f

18,561,875

58,440,000

36,840,000

15,660,000

3,300,000

2,520,000

120,000

94,480,000

59,560,000

25,320,000

5,340,000

4,070,000

190,000

30,363,000

22,772,300

6,131,000

785,900

613,300

60,500

504,500

370,400

99,300

262,000

9,100

106,200

57,700

2,070,500

—

—

—

33,472,300

37,247,377 18,646,171

25,687,067 13,413,813

9,870,628 4,358,766

870,056 368,934

737,899 426,665

81,727 79,993

494,591 439,986

247,310 242,961

56,646 54,908

182,728 183,063

7,936 4,990

95,636 144,595

54,437 30,323

667,263 450,352

2,039,490 —

2,022,755 —

601,663d —

41.667.767 19,956,386

828,216 10,530,685 — 6,889,744 — 2,725,814

405,826 417,267

422,390 497,860 — —

12,156,377

7,913,167

3,269,494

454,479

521,237—

1,560,000 2,520,000 471,297 547,312 509,052

257,265 254,628

68,482 59,961

188,783 194,867 — —

237,771

55,346

182,425—

—

—

—

—

—

— — — —

— — 58,024 54,565 59,336

— — — —

—

—

— —

— —

—

—

49,10 2 — e —

60,000,000 97,000,000 . . 1,661,904 11,387,390 12,964,536

aDa

tq obtained from A“/ma/ we/fare Enforcement Ffepoti to Congress for 19S0. They do not include any numbers for rats and mice

bData ~ompild by H=

lth @signs, lnc, (RWhester, Ny) with all available Annual Reports of Re~arch Facilities The data for rats and mice are from volunta~ reporting of the use of these SpeCieS.

cEStimateS Stated are highest value Of a rough ran9e.

‘Marine mammals, fish, and reptiles.

‘Wild animals.

‘Fish.

SOURCE: Office of Technology Assessment.
Ch. 3—Patterns of Animal Use . 61

Figure 3-2.—Example A of APHIS “Annual Report of Research Facility”

UN ITEo ST A T ES OEPA RTM E N T o r AG RICU LTu R E I

1. OAT E O F REPOR T

AN IMAS- A NO PLANT HE ALTH INSPECTION SE RV ICE 1

.“”w! -..”” ”

vETERINARY SERVICE S ?larch 7, 1984 -. - - -—.

Th IS report Is rectutrect by law ( 7 USC 2 143). Fa!l

r

I report accoralng to the regulations cdn

result In an oraer to cease dna ales, st and to be sub 3 penalt Ies as provlaea for tn Section 2150. \

[

‘a’”” ‘

n-- -

” E D

i

UMtl NU. 0579-0036

I

2. HE AOQU A RTERS R ESEA RC M FACILITY f ,A’r2m@ .& A ddres.c, as WgSS.

I

tared wt(h L’SLl.\, include Z IP Cod? )

ANNUAL REPORT OF RESEARCH FACILITY

(’Required For Ldc/I Rcportl)tf Fucllif}, 11’/terc .4 ntmu/s ,ire ffeid

.4 d .-111 A trelldl~ig [ ‘ercn~]urla!; Has Respmlstbility)

INSTRUCTICsNS

Repssrtmg FacIIItv - complete Itcms 1 ckough 24 and submit to vour

Headquarters FacIII:>’ Attach additional sheets If ncccssary.

S. REGISTRATION N O.

4 R EPORTING F Acl LIT V f \“ome and Address, include Z IP Code /

I

Headquarters Facdity - complete ]tcms 25 though 27 and submit on or before

December 1 of’ each year for the precedin~ Fedcr~! fiscal }“ear (October 1, to

Septcmbcr 30’ to rhc Veterinarian In Ch.irgu fur the Sutc where t hc research

facd~t~ hcadqu~rtcrs IS rcgtstcrcd.

REPORT o F A N tM A LS uSEO IN ACTUAL RESE A RCfi, TESTING, O R EXPERIMENTATION - SSCtlOn 2.28 Of Animal welfare R09Ulatt0nS rS@UlreS aPPr@

Dr Ia te use of anesthetics, analgesics, ana tranau,1 Izlng arugs aur{ng re;eafch, test lng, or exDerlmentat Oon. Exsrertments !nvolvtng pain or atstress w!thout use of

tnese aruqs must De feoortea and a br !ef statement explatnnnq the researcn.

A. la. / c. ) D. }E. I F,

An&mals COvereC!

B Y A c t

Number of animals used Number of animals usea

in research, exper!mants,

New Num Ber of an!rnals usea

!a :ase.c:ci-l, :;:perfm, erots,

o. tests where agtwotsriate

or tests !nvolvtng pain or

An!mals !n research. exDerlmer, ts, distress without aamtn(s. TOTAL NO .

Aadeo th, $ or tests /rrvolv!rsg no pa~n

i anesthctlc, ● nalgestc, or tra!lon of apDr09rlate Of An#mals

tranau!ltzer drugs were

Year or rrlstress. anesthetic, analgeslc, or (Cok. B + C + D + k’)

aamlnfsterea to avofd

pain or alstress.

tranq ”ulozer drugs,

fA ttach brwf exp/anatlon} I

5. Dogs

~ 610 I

I

I o I 610 I o 1220 - —

7. Guinea Pigs 1 0 0 r!

~. iidmstcrs

o 0 1 (-)

I 9. Kabblts ?4 24 0 0 48

I

10. Primates

o 0 0 I f-l I n

I 11. Rats 4500 0 4500 0 9000

12. Mice 2000 1200 800 0 4000

Wii’&RKi?tT3i3 (specz~y)

~3.G~~bil

. -

~ 50 0 0 0 50

i<. sheep 8 1 7 16

~

5

’Cattl e 10 0 10 0 20

CERTIFICATION BY ATTENDING VETERINARIAN FOR REPORTING FACILITY OR INSTITUTIONAL COMMITTEE

I (we) hareby certify that the ;YIM wsa amount of ● sa19esIc. anestfsetlc, ● nd tranaulllzln9 drum used on an~mals durm9 ● ctual research, te3tln9 or •xoer~mem

tatlOn tnCJ;aln9 POSt-ODOratlva ● nd O,OSt-OrOCddUral CW8 was deefnea ● fsss?ooriate to relieve Daln Jnd dlstreas for tfso subject ● nimal.

16. SIG WATURE OF A fis?NDING U ETJ?Rl N4Rt AN s 7. ~STLE I a. OATC StGUEO

.3/s/P~ /

ATE SlGf4= D

22. w GN ATU Rhq COM MITTEE MEMBE R 23. fC4TLE “

CERTIFICATION BY HEADQ UARTERS RESEARCH PAcILITY OF F I CI A L

I CertlfY that the ● bove 15 true, COrreCt, and COm Olete ● nd that Professlorrally ● cceptable stana?rds governtng the care, tr~tment, ● nd uee of ● mmals Includlng

● rsgroertatc use of anesthetic, dfIa19eSW ana tranQu Nlzln9 arugs, durlnq actual raeezrch, testing. or axperlmwstat!on including post-operative and post-procedural

~re are bsdnq followea by the above research fac!llt tes Or Sites ( 7 U.S. c. Section 2 143).

2S SIGNATURE O F RESPONSIBLE O FFICl AL 26. TITLE 27, DATE SIGNSID

b

VS FORM 18-23 PreL,Ious edtl!on obsolete

{AUG 81)

SOURCE: Animal and Plant Health Inspection Service, U.S. Department of Agriculture.
62 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 3=3.-Example B of APHIS “Annual Report of Research Facility”

Thk reoort Is retaulrotl DY law ( 7 USC 2143). Failure to rWJrt acC0rd~n9 to tne ro91Jl~t10ns Can

-esult in ● n order to ceJse ● nd desist and to b. subject to penaltles as cwovidetl f In SectIon 2150.

UN 17=0 ST ATSSS OSS?ARTMCNT O F AG RICU LTU RC 1. DATE O F REPORT

ANIMAL ANO ● LANT HEALTH INSPECTION SSSRV I C C 10/17/8s I

FOR M APPROVED

VCTERINARV SERVICE S

OMB NO. 0579-0036 I

ANNUAL REPORT OF RESEARCH FACILITY

(Required For Each Reporting Facifity Where Animals Are Held

Artd An Attertdirtg Veterinarian MU Responsibility)

INSTRUCTIONS

Reporting Facility . complete items 1 through 24 and submit to your

Headquarters Facility. Attach additional sheets if necessary.

Headquarters Facility . complete items 25 through 27 and submit on or before

December 1 of each year for the preceding Federal fucal year (October 1, to

September 30) to the Veterinarian in Charge for the State where the research

facility headquarters is rcuistered.

REPORT OF ANIMALS USCO IN ACTUAL RSSSEARCH, TCST I NC. OR E X P

prlate use of anesthetics, ana19eslcs, ● nd tranqutlizlng drugs during research, tOSl

these drWS must be rePOrted ● nd a brief statement explaining thsj rsaearch.

4

Z . HE AOQU A RTE RS RESEA RCH FACI LITV (Name & Addre6& w rei?utered with USDA, melude Zip Code)

. -- ,

3. REGISTRATION N O

4. REPORTI NG FACI LITY (Name and Addrwa, include Zap Code)

II MC NT AT ION - Sect Ion 2.28 of Animal Welfare Regulations retruires aocwm

), or experimentation. Experiments involvlng pain or dlstreas without uee of

A . 8 . c . t D . E. F.

Number of animals Uie d Numbw of ● nimals used

In research, ● xperlmonts, In research, experlmcnts,

New Number of ● nimals used

Animals Covered or tests where ● ppropriate

or tests involving pain or

Animals in research, ● xperiments, distress without arYminls- TOTAL NO.

B Y A c t Added this or tests involvlng no pain anestlwtic, analgesic, or tratlon of ● ppropriate Of An!mals

Year transrullizer drugs were

or distress. anesthetic, analgesic, or (cola. + C + D + E)

● dmlnktered to ● void

Pain or distress. tran~ullizer drugs.

(Attach brwf explanation)

5. Dogs I 14 I 14

6. Cats 6 6 12

7. Guinea Pigs 18 18

8. Hamsters

I 36

I

9. Rabbits 130 130 260

10. Primates

il.. Rats 20 20 40

12. Mice 250 250 500

Wild Anisnda (specify) 13.

-14.

i5.-

CERTIFICATION BY ATTENDING VETERINARIAN FOR REPORTING FACILITY OR INSTITUTIONAL COMMITTEE

I (W.) hwcby csrtlfy that the typo ● nd ● mount of •nalgssl~ ● toathot.i~ ● fid trMIqulllZlra9 drugs used on ● tlmms during ● ctual rsaserch, t4Stln9 or ● Xparhrrem

tition Including peat-operathre and post-procedural c4re was desmed ● ssprowlate to r.lleV4 PSln ● nd dlatmaa fOr the subject ● fSl_l.

16. SS* A TUWC O r ~NOING VCTKRINARIA N s 7. TITLE 8 S. DA7C SIGNCD

19. s i ~ URE ~

/o/4/1~3

MCMBC R 20. TITL E 2t . DATE S#eNCO .

I I

22. SIG NATURC Of COMMITTC XMB.E R 23. TITLE 24. OATC SIGNCD

I I

CERTIFICATIC$N BY HEADQUARTERS RESEARCH FACILITY OFFICIAL

I certify that the ● bove Is true, COrrSCt, ● nd complete and that profosslonally ● cceptable standards 9overning the ~re, trsatmont, ● nd use of wslmals Irrcludlng

aPPrOPrlatO use of ● nOSttS6tlC, ● na194Sk, and tranquilizing strugs, durlrw ● ctual reasarch, testing, or sxparlmontatlon Inclsrdlng peat.opwatlw ● nd post-procedural

ure ~ rch facllltles or sltea (7 U.S. C. Sactlon 2143).

28. SI+NATUR* OF 27. DATE SIGNED

1- 1 1 VS FORM 18-23 Rsviorw ● ditfon obookte

(AUG 81)

SOURCE: Animal and Plant Health Inspactlon Service, U.S. Department of Agriculture.
Ch. 3—Patterns of Animal Use “ 63

Figure 3=4.—Example C of APHIS C’Annual Report of Research Facility”

&I&C& &w,r6 DI.w(7 USC21431. F.,lUreto,.,orta.co~d,.g tot.ereg.,.tiomcan

result in ● n order to cease ana desl$t ana to be sublect tO Penaltles as Drovlded fOr In section 2150.

T ATCS DEPARTMENT O F AG RICV LTU RE

DEG&wT&fh

1. OAT E O F RcPO RT

O ● LA NT H E A LTH INSPECTION SE RV ICf?

I

FORM APPROVED

VETERINARY sERVICE S 30 NOV 83 OMB NO. 0579-0036

2. HE AOQU ART E R S R ESE A RCU FACI LIT Y 1,\aMC A AOareSS, a W17Uw.ml&. B

tered with t)SD,l, Include XIP Code)

ANNUAL REPORT OF RESEARCH FACILITY

(Required For 12ZCII Reporflrrg Facility It’here Animak Are Held

Artd An .~ttendtng l’ctermurwt Ha-s Responsibility)

[

INSTRUCTIONS

I 3. REGISTRATION NO .

Roportmg Faclltty - complete Items 1 through 24 and subm]t to your

1

4 REPORT ING F AC! LIT + (A amc and Add?es$, !nc)ude Zw COde)

Headquarters Facihty. Atuch addmonal sheets If necessary.

Headquarters Facilny . complete Items 25 through 27 and submit on or before

December 1 of each year for the preceding Federal fual yczr (Octobe: 1, to

September 30) to the Vcceruuran m Charge for the State where the research

facilltv headquarters K reg~stered.

REPORT o F A NtM A LS USEO I N ACTU A L RESEARCH, TESTING, O R E X PE RI M IS NTAT ION - Sect ton 2.28 Of Animal We! fare Reguiat ,On S rCOU lreS aPOrG

prlate use of Jnesthetlcs, analgesics, and tranou[l Izlng drugs CIurlng research, teStln9, or 8x Perlmentatmn. Exper{ment$ tnvolvtng patn or dtstress wlrnout use of

these Orugs KIU51 be fCPOrterJ and a or !el statement exolaonlng the rS!sear Ch.

A . ifs. I c . I o. Ic. 1

F.

Number of ● n!mals used Numtser of ● nimals used

In reuarcn, ● xpeflments,

on fesearcn, exoer$ments,

N e w Number of animals used

An8mals Covered

or tests where aopromiate

or tests lnvolvtng Pain or

An!mals 1 In research, exver oments, d,strem without aamlnts. TOTAL NO .

B Y A c t I AcS~g?rthlS

anestnetlc. analgeslc, or Of An8mals

or rests Involvong no patn tfanaulllzer drugs were

tratlon of ● oprorwmte

or Olstress. anestnetlc. analgesic, or (Cols. X ● C ● D + L“)

● dm!nlsterest to ● vo!d

pain or cststress.

trancaualtzer dru9s.

(A ttoch bwrf ● xaslanation)

5. Dogs I

44 I 12 189 0 I

201

I

1

6. C&:s o { o 1

0 I o 0

7. Guinea Pigs I

383 I137 186 0 323

8. Hamsters ~ 207 0 207 [ o I 207

9. Rabbits I 638 ~ 40 598 0 638 1

10. Primates I o I 12 i 119 0 I 131

11. Rats 4357 1940 1444 I

o 3384

12. Mice 1373 363 739 0 1102

Wild Animals (spec:fy)

13. TURTLES 293 0 293 0 293

14. DOMESTIC PIGS 609 0 609 0 609

15

. GERBILS 100 0 100 0 100

CERTIFICATION By ATTENDING VETERINARIAN FOR REPORTING FACILITY OR INSTITUTIONAL COMMITTEE

I (We) hereby certlfY that th. tYPe ● nd ● mount of ● nalgeslc, anesthetic, ~nd trantsulllzlng drugs used on ● nimals dtsrln9 actual research, tssattng or ● xpertmen.

tation #nclurSlng POSt-OP*rative ● nd. oost-orocodural-r~ wasKteemeO ● ptxom!atc to relleve oaln ● nd distress for the subject ● nimal.

ts. sIC3NATu RE OF ATT fsNOING V =TEfelN4~~ —f 7. TITLE $8. OATE SIGNEO

30 NOV 83

t e. SIGNATURE OF C O SAM IT T C SS MS@fBER 20. TITLE 21. OATE SIGNE D

30 NOV 83

22. SIGNATURE O F COMMITTEE &

- .

EMBE R 23. TITLE 24 OATE SIGNE D

1 I

CERTIFICATION BY HEADQUARTERS RESEARCH FACILITY OFFICIAL

correct, and complete and tfsat rxofesslonally ● cceptable stanaards governing the care, treatment, and usc of animals Inclualng

● pwopriate use of anesthet analgeslc, and trancrutlazlng Orugs. Ourting ● ctual rosearcn, testtng, or ex$aertmentataon Including post-osserat!vo arm post- Proc@aural

above researcn facll It les or sites ( 7 U.S. C. section 214 3).

25. SIGN ATU RE O & 26. TITLE 27. OATE SIGNE D

I

30 NOV 83

b

,

VS FORM 18-23 Previous edat:on obsolete

[AUG 81)

SOURCE: Animal and Plant Health Inspection Service, U.S. Department of Agriculture.
64 . Alternatives to Animal Use in Research, Testing, and Education

Even with these limitations and qualifications,

the numbers generated by the APHIS data provide a range that can be used in discussions of animal use. The totals include: 1.8 million mandated

species, 100,000 to 500,000 birds, 100)000 to

500,000 amphibians, 2.5 million to 4.0 million fish,

and 12.2 million to 15.25 million mice and rats.

Therefore, it appears that between 17 million

and 22 million animals are used in united

States laboratories annually.

The largest group is represented by mice and

rats. For reporting institutions, mice represent 60.8

percent of all animals used, and rats 25.1 percent.

In addition, for the mandated species, certain institutions use specific species disproportionately

to their percentage of overall total use (see table

3-6). Fifty percent or more of all cats and dogs are

used by universities and medical schools. Guinea

pigs are used mostly by the pharmaceutical industry, whereas hamsters are used more often in biomedical research, and to a lesser extent in universities, medical schools, and the pharmaceutical

firms. Sixty-two percent of rabbits are used in

universities, medical schools, and the pharmaceutical industry, as are 75.6 percent of the primates.

For rats and mice, the trends indicated in table

3-6 are clouded by the fact that there was more

reporting of rat and mouse usage in 1983 than in

Table 3-6.–USDA/APHlS Data, Changes 1982-83

(reporting Institutions only)

Institution type

Universities Hospitals Bio- Toxicology Pharmaceu- State & Food, feed

& medical nonuni- medical testing Chemical tical, device local & miscel. Federal

schools versity research labs companies & diagnosis government Ianeous agencies Total

..— – rear

Rats:

1982

1983

0

/0 change

Mice:

1982

1983

0

/0 change

Dogs:

1982

1983

%O change

Cats:

1982

1983

0/0 change

Guinea

pigs:

1982

1983

0/0 change

Hamsters:

1982

1983

0/0 change

Rabbits:

1982

1983

‘/0 change

Primates:

1982

1983

0

/0 change

lnstitutions

reporting:

1982

1983

0/0 change

1,079,208

1,234,864

14

1,678,300

1,951,466

16

98,983

90,001

- 9

34,555

32,535

–5

82,198

64,554

–21

151,365

115,483

–23

173,716

158,058

- 9

23,353

22,201

- 4

410

402

- 2

86,472

108,430

23

203,768

222,080

8

13,622

12,605

- 7

2,716

2,265

–16

6,104

7,195

17

5,501

5,472

– 0.5

15,171

15,042

-0.8

557

1,059

90

129

140

8

343,915

408,938

18

1,579,664

1,512,424

–4

22,291

21,483

–3

7,697

6,788

-12

25,225

30,696

21

65,146

169,272

159

63,863

64,626

1

13,543

13,272

–2

167

159

–4

97,237

144,162

48

431,464

495,087

14

3,457

5,003

44

137

172

25

35,145

28,753

-18

12,954

11,922

–7

60,785

55,785

- 8

2,577

5,809

125

: :

8

176,874

114,215

-35

161,659

158,752

–1

2,194

1,591

–27

115

44

–61

18,182

14,722

– 19

3,180

612

–80

20,970

22,034

5

144

25

–82

27

31

14

558,630

778,425

39

1,669,629

2,021,157

21

37,604

38,311

1

9,073

8,624

–4

272,405

297,849

9

131,227

112,618

– 14

177,289

159,276

- 1 0

7,709

9,376

21

145

155

6

11,299

30,378

168

200,150

477,250

138

322

436

35

87

72

-17

9,044

10,090

11

8,401

3,193

–61

2,102

1,948

–7

329

243

–26

19

18

- 5

12,700

14,355

13

6,247

3,632

–41

3,698

3,400

- 8

2,040

2,092

2

1,504

930

–38

23

22

–4

1,862

2,504

34

66

82

24

26

32

23

359,479

439,729

22

958,863

1,071,339

11

12,696

9,595

–24

3,541

2,774

–21

48,053

66,448

38

39,490

35,885

- 9

31,554

29,779

–5

6,287

7,269

15

125

123

–2

2,725,814

3,269,494

19

6,889,744

7,913,167

14

194,867

182,425

–6

59.961

55,346

- 7

497,860

521,237

4

417,267

454,479

9

547,312

509,052

–6

54,565

59,338

8

1,127

1,146

2

SOURCE: Office of Technology Assessment.
Ch. 3—Patterns of Animal Use ● 6 5

1982. So, although it appears from table 3-6 that

the usage increased, this was in fact not so (as can

be seen from table 3-4). Data for all institutions

from the regression equations show no change in

mice and a small increase in the use of rats. However, since the same pattern of increase by institutional group reporting can be seen from table 3-6,

there has likely been no increase or decrease in

use of these two species between 1982 and 1983.

In table 3-6, the number of reporting institutions

includes those that reported any number for any

species, whether these included rats or mice or

not. Few significant changes occurred as a function of institution type for the 2 years surveyed.

No trend in animal use can be identified between 1982 and 1983, and the available data

provide no justification for predicting either

increases or decreases in future years. It

would have been possible to examine the 1981

APHIS data sheets and determine whether, on the

basis of 3 years’ data, a trend for the mandated

species existed, but the 1981 data sheets would

not indicate trends for rats and mice. The other

methods of estimating laboratory-animal use do

not match the reliability of the APHIS data, and

thus do not lend much credence to the numbers

reported in the past.

Future Animal Censuses

The major limitation with this estimate of annual laboratory-animal usage was the need to depend on available data sources, with all the limitations just described. Although the APHIS data

sheets were of considerable value, they still do not

substitute for an appropriately designed stratified

random sampling of all possible users. Only then

would all possible institutions be represented. The

APHIS scheme depends on institutions to request

certification. Some may be operating and not reporting to APHIS. Still, with considerable further

effort, a post-hoc stratification could be done based

on the APHIS data.

Estimates could be improved by two major approaches. The first, and least expensive, would involve the use of all annual APHIS reporting forms—

following an imperative redesign of the form—as

well as thoroughly determining which registered

institutions in each year did and did not report.

Then appropriate statistical estimation techniques

could be used on an institution-type and yearspecific basis to correct for missing data. The second, and more ambitious, approach would be to

conduct a stratified random sample study of all

possible users. The stratification would be by type

of institution, size of institution, and species of animals. From such a sample, appropriate statistical

techniques could be used to project to the entire

population of user institutions.

In 1985, the National Research Council’s Institute of Laboratory Animal Resources announced

plans for another in its series of surveys of experimental animal usage. The 1986 census will include

mammals and birds, but omit fish, amphibians, and

reptiles.

SUMMARY AND CONCLUSIONS

A rough analysis of the number of laboratory the individual annual reports furnished by each

animals used is important to provide some non- registered facility for 1982 and 1983 were evalutext in which to discuss alternatives to using ani- ated. Generally, it was found that great disparimals, evaluate progress toward the goal of using ties existed among the different sources. No sinfewer animals, and judge the effect that alterna- gle data source presents an accurate count of the

tives might have. OTA therefore evaluated exist- number of laboratory animals used in the United

ing data on the number of laboratory animals used States since not one includes all potential users.

each year in the United States. In addition, it is impossible to compare data among

The data sources considered included various sources due to the inadequacy of information on

reports and surveys published by the National Re- survey and data collection methodologies, definitions, areas of use, reporting requirements, and search Council’s Institute of Laboratory Animal

Resources, various market surveys, and the an- the inability to justify completeness of the data.

nual reports submitted to USDA’s Animal and Plant In a comparative analysis of data sources, it was

Health Inspection Service. For the latter source, found that the most useful data were the APHIS
.

66 ● Alternatives to Animal Use in Research, Testing, and Education

data sheets completed by every institution that uses

laboratory species regulated under the Animal

Welfare Act, APHIS requires that registered institutions report all use of dogs, cats, guinea pigs,

hamsters, rabbits, and nonhuman primates. Even

with this requirement, though, it seems that APHIS

does not receive animal-use information from all

possible users. The data from these forms were

found to be more accurate than the Animal Welfare Enforcement Report, a summary submitted

annually by APHIS to Congress. This report usually neglects 10 to 20 percent of the annual reports

(those submitted late, usually after December 31)

and so underestimates the actual number of dogs,

cats, guinea pigs, hamsters, rabbits, and nonhuman primates used.

For fiscal years 1982 and 1983, the numbers of

these kinds of animals used, according to the APHIS

data sheets, are shown in table 3-7. For other laboratory species—mice, rats, birds, amphibians, and

fish–the ability to obtain accurate estimates of the

number used is impaired by a lack of reliable data

sources. The best estimates are that 100,000 to

500,000 birds, 100,000 to 500,000 amphibians, 2.5

million to 4.0 million fish, and 12,2 million to 15.25

million rats and mice were used. (Animal use in

medical and veterinary education is estimated to

beat least 53,000 animals per year and is discussed

in ch. 9.) Total animal use in the United States,

therefore, is estimated as between 17 million and

22 million a year.

The great discrepancies in data sources meant

no trends could be observed overtime and among

different types of institution. Even within the

APHIS data for six kinds of animals, no clear trends

Table 3-7.–Animai Use Reported to the U.S.

Department of Agriculture, 1982 and 1983

Number used Number used

Animal in 1982 in 1983

Dogs . . . . . . . . . . . . . . . . . . 194,667 182,425

Cats . . . . . . . . . . . . . . . . . . 59,961 55,346

Hamsters . . . . . . . . . . . . . . 417,267 454,479

Rabbits. . . . . . . . . . . . . . . . 547,312 509,052

Guinea pigs . . . . . . . . . . . . 497,860 521,237

Nonhuman primates. . . . . 54,565 59,336

Total . . . . . . . . . . . . . . . . 1,771,832 1,781,875

aTOtalS d. not lncl~e ratg or mice, two species that together represent the

majority of animals used.

SOURCE: Office of Technology Assessment.

were found. Indeed, the most important finding

was that no accurate source exists on the numbers of animals used annually in the United States.

A stratified random sample of all possible user institutions done with a correct statistical analysis

would probably be the best way to estimate laboratory-animal use in the United States.

In the Federal Government, six departments and

four agencies use animals for intramural research

and testing. These investigative efforts range from

uncovering new knowledge that will lead to better health (within the National Institutes of Health),

to evaluating hazardous substances in consumer

products (within the Consumer Product Safety

Commission’s Directorate for Health Sciences), to

protecting the health of American astronauts

(within the National Aeronautic and Space Administration’s Life Sciences Division).

OTA used the APHIS Annual Report of Research

Facility forms to track animal use within the Federal Government itself by department (and by division within departments) and by species. In this

way, it was possible to identify what portion of

the estimated 17 million to 22 million animals used

yearly were used within Federal facilities. In 1983,

the Federal Government used at least 1.6 million

animals, largely rats and mice. Ninety-six percent

of the 1.6 million animals were used by DOD,

DHHS, and the VA. Of the total, about 9 percent

were dogs, cats, hamsters, rabbits, guinea pigs,

and nonhuman primates.

The APHIS forms require that all experiments

be categorized as: 1) involving no pain or distress;

2) involving appropriate anesthetic, analgesic, or

tranquilizer drugs to avoid pain or distress; or 3)

involving pain or distress without administration

of appropriate anesthetic, analgesic, or tranquilizer

drugs. Sixty-three percent of the animals used

within Federal departments and agencies were in

the experimental situation categorized as involving no pain or distress while 32 percent were given

drugs and only 5 percent experienced pain or

distress.

The APHIS reporting system lacks clear definitions and uniform reporting, If accurate data are

to be obtained, the forms must be revised and better explanations of how to complete them must

be provided.
Ch. 3—Patterns of Animal Use ● 6 7

CHAPTER 3 REFERENCES

1. Abood, L. G., Professor, Center for Brain Research,

University of Rochester, Rochester, NY, personal

communication, 1984.

2. Alex Brown & Sons, Inc., Charles River Breeding

Laboratories, inc., Market Smnrey (Baltimore, MD:

1981).

3. Bier, R., Bio-Research Laboratories, Ltd., Sennervil]e, Quebec, Canada, personal communication,

1984.

4. Bohrer, D., Division of Research Grants, National

Institutes of Health, Bethesda, MD, personal communication, 1984.

5. Borsetti, A., Staff Scientist, Office of Science Coordination, Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD,

persona] communication, 1984.

6. Charles River Breeding Laboratories, Inc., price list,

Wilmington, hlA, 1983.

7. Cook, R., North Carolina State Llniversity, Raleigh,

NC, personal communication, 1984.

8. Culley, D., Louisiana State University, Baton Rouge,

LA, persona] communication, 1984.

9. David, T., Staff Veterinarian, Aerospace Medical

Division, Air Force, U.S. Department of Defense,

Brooks Air Force Base, TX, personal communication, Jan. 18, 1985.

10. Digges, K., Deputy Associate Administrator for Research Development, National Highway Traffic

Safety Administration, U.S. Department of Transportation, Washington, DC, personal communication, March 1985.

11. Dodds, W.J., Division of Laboratories and Research,

New York State Department of Health, Albany, NY,

personal communication, April 1985.

12. Edington, C., Associate Director, Office of Health

and Environmental Research, Office of Energy Research, U.S. Department of Energy, Washington,

DC, personal communication, Nov. 16, 1984.

13. Emmons, M. B., ‘(Secondary and Elementary School

Use of Live and Preserved Animals, ’’Am”mals in Education, H. McGriffin and N. Browrdey (eds.) (Washington, DC: Institute for Study of Animal Problems,

1980).

14. Goldberg, A. M., Director, The Johns Hopkins Center for Alternatives to Animal Testing, Baltimore,

MD, personal communication, April 1985.

15. Guilloud, N., Ortho Pharmaceutical Corporation,

Raritan, NJ, personal communication, 1984.

16. Gupta, K. C., Deputy Director, Division of Health

Sciences Laboratory, Directorate for Health Sciences, U.S. Consumer Product Safety Commission,

Washington, DC, personal communication, Sept. 24,

1985.

17. Health Designs Inc., ‘(Survey and Estimates of Laboratory Animal Use in the United States, ” contract

report prepared for the Office of Technology Assessment, U.S. Congress, July 1984.

18. Institute of Laboratory Animal Resources, Animal

Facilities in Medical Research (Final Report), A Report of the Committee on the Animal Facilities Survey (2 parts) (Washington, DC: National Academy

of Sciences, 1964).

19. Institute of Laboratory Animal Resources, Animal

Facilities in Medical Research: A Preliminary Studv

(Washington, DC: National Academy of Sciences,

1962).

20. Institute of Laboratory Animal Resources, Annual

Surveys of Animals Used for Research Purposes

(Washington, DC: Nationa] AcademY of Sciences,

1965-71).

21. Institute of Laboratory Animal Resources, “Laboratory Animal Facilities and Resources Supporting Biomedical Research, 1967 -68,” Lab Anim. Care 20:

795-869, 1970.

22. Institute of Laboratory Animal Resources, National

Survey of Laboratory Animal Facilities and Resources (Washington, DC: National Academy of

Sciences, 1980).

23. Institute of Laboratory Animal Resources, NonHuman Primates: Usage and A~~ailabilituv for Biomedical Programs (Washington, DC: National Academy of Sciences, 1975).

24. Kellogg, C., Department of Psychology, University

of Rochester, Rochester, NY, personal communication, 1984.

25. Manufacturing Chemists Association, Studuy of PotentialEconomic Impacts of the Proposed Toxic Substances Control Act as Illustrated by Senate BillS 776

(Florham Park, NJ: Foster F. Snell, Inc., 1975).

26. Matchett, A., Animal Care Staff, U.S. Department

of Agriculture, Washington, DC, personal communication, 1984.

27. McArdle, J. E., Director, Laboratory Animal Welfare, Humane Society of the United States, Washington, DC, personal communication, 1984.

28. McCarthy, C., Director, Office for Protection from

Research Risks, National Institutes of Health, Public Health Service, U.S. Department of Health and

Human Services, Bethesda, MD, personal communication, October 1984.

29. Middleton, C., Chief Veterinary Medical Officer,

Veterans’ Administration, Washington, DC, personal communication, Oct. 3, 1984.

30. Miller, T., McNeil Laboratories, Ft. Washington, PA,

personal communication, 1984.

31. Moorehouse, K., Division of Wildlife Service, Fish
.

68 . Alternatives to Animal Use in Research, Testing, and Education

and Wildlife Service, U.S. Department of the Interior, Washington, DC, personal communication,

October 1984.

32. Moreland, A., “Animal Research Protocol Review

Within the Veterans’ Administration” (draft), Gaines.

vil]e, FL, 1984.

33. Mosed, R., Executive Director for Oceanic and Atmospheric Administration, National Oceanic and

Atmospheric Administration, U.S. Department of

Commerce, Rockville, MD, personal communication, September 1984.

34. Nace, G. W., Professor of Zoology, University of

Michigan, Ann Arbor, MI, personal communication,

1984.

35. Nace, G. W., Response to a questionnaire on the use

of frogs in the United States, questionnaire prepared

by Rolf Martin, Department of Chemistry, Brooklyn

College of the City University of New York, Brooklyn, NY, 1984.

36, New A., Director, Laboratory Animal Science, National Cancer Institute, Public Health Service, U.S.

Department of Health and Human Services, Bethesda, MD, personal communication, 1984.

37. Nicogossian, A., Director, Life Sciences Division, National Aeronautics and Space Administration, Washington, DC, personal communication, 1984.

38. Roberts, C., Director, Division of Veterinary Medicine, U.S. Department of Defense, Washington, DC,

personal communication, September 1984.

39. Rowan, A. N., Of Mice, Models, & Men: A Critical

Evaluation of Animal Research (Albany, NY: State

University of New York Press, 1984).

40. Rowan, A. N., Assistant Dean for New Programs,

Tufts University School of Veterinary Medicine, Boston, MA, personal communication, 1985.

41. W.B. Saunders and Company, “Market Survey)”

Inform. Lab. Anim. Res, 9(3):10, 1965.

42. Schultz, C., Chief, Sciences Branch, Technology Division, Office of Hazardous Materials Regulation,

Materials Transportation Bureau, Research and

Special Programs Administration, U.S. Department

of Transportation, Washington, DC, personal communication, September 1984.

43. Simmonds, R., Director of Instructional and Research Support, Uniformed Service University of

the Health Sciences, Bethesda, MD, personal communication, April 1985.

44. Stewart, W., Senior Veterinarian, Animal and Plant

Health Inspection Service, U.S. Department of Agriculture, Hyattsville, MD, personal communication,

November 1984.

45. Taylor, J., Staff Veterinary Officer, Naval Command,

U.S. Department of Defense, Washington, DC, personal communication, November 1984.

46. Thomas, O., Professor of Poultry Science, University of Maryland, College Park, MD, personal communication, 1984.

47. Thomas, R., U.S. Department of Energy, Washington, DC, personal communication, October 1984.

48. Ulvedal, F., Acting Director, Water and Toxic Substances Health Effects Research Division, U.S. Environmental Protection Agency, Washington, DC,

personal communication, September 1984.

49. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, Am”mal Welfare Enforcement: Report of the Secretary of Agriculture to the

President of the Senate and the Speaker of the House

of Representatives (annual) (Washington, DC: 1972

through 1983).

50. U.S. Department of Defense, Air Force Division,

Aerospace Medical Division Animal Use Review

Panel Meetings (Washington, DC: May 1984).

51. U.S. Department of Health and Human Services,

Public Health Service, National Institutes of Health,

1983 NIH Almanac (Bethesda, MD: 1983).

52. U.S. Department of Health and Human Services,

Public Health Service, National Institutes of Health,

NIH Data Book (Bethesda, MD: 1983).

53. U.S. Department of the Interior, U.S. Fish and Wildlife Service, Service Managment Plan (draft) (Washington, DC: October 1984).

54. Will, J. A., Director, Research Animal Resources

Center, University of Wisconsin, Madison, WI, personal communication, 1984.

55. Willett, J. D., Project Officer, Biological Models and

Materials Resource Section, Animal Resource Program, Division of Research Resources, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda,

MD, personal communication, 1983.
chapter 4

To use

interests

Ethical Considerations

either human or non-human animals for purposes that are not in their own

is both ethically unjustifiable and, in the long run, counter-productive.

Alex Pacheco

People for the Ethical Treatment of Animals

appropriately

March 15, 198.5

Fortunately there are many who, while deeply and concerned for the

compassionate treatment of animals, recognize that human welfare is and should be our

primary concern.

One cannot intelligently assess vivisection

areas of human life: for food, furs, leather,

Frederick A. King

Yerkes Regional Primate Research Center

Psychology Today, September 1984

in isolation f-rem animal exploitation in other

in so-called sports, in movies, in the wild.

Vivisection, properly seen, is simply one variation on the cultural theme of animal

sacrifice.

Michael A. Giannelli

The Fund for Animals, Inc.

March 10, 1985

The use of any particular animal-say, a sheep—in medical research is more important

than its use as lamb chops.

The

The Research

Carl Cohen

University of Michigan

News 35(1()- 1 2):9, 1984
CONTENTS

The Religious and Philosophical Traditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Ethical Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Moral Standing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Moral Constraints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Summary

Chapter4

and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page

72

75

76

79

82

84
Chapter 4

Ethical Considerations

The range of opinion on the rights and wrongs

of using animals to satisfy human needs is as broad

as the political spectrum itself. At one extreme,

animals are thought to be entitled to at least a portion of the respect, individual freedom, and dignity that are considered to be basic human rights.

Some say that animals should be recognized as belonging to a community that includes humans. At

the other extreme, humans are thought to have

broad and absolute authority over the lives and

interests of animals. From this perspective, expediency alone, not morality, dictates what we may

do with animals.

To illustrate the distance between these extremes,

a recent legal brief for animal rights can be contrasted with a televised interview with three scientists who perform animal experimentation. According to the brief (43):

If being alive is the basis for being a moral object, and if all other interests and needs are predicated upon life, then the most basic, morally relevant aspect of a creature is its life. We may

correlatively suggest that any animal, therefore,

has a right to life.

The scientists, in a televised exchange with Harvard

philosopher Robert Nozick, were asked whether

the fact that an experiment will kill hundreds of

animals is ever regarded by scientists as a reason

for not performing it. One answered: “Not that

I know of .“ When Nozick asked whether the animals count at all, one scientist replied, “Why should

they?” while another added that he did not think

that experimenting on animals raised a moral issue at all (45).

People at both extremes would probably agree

that, given a choice between experiments equivalent in cost and scientific value, one that does not

require the destruction of animals would be preferable to one that does. This consensus, however,

would probably evaporate if animal experimentation produced greater scientific validity or the

technique that used animals had significant cost

advantages.

In morals, as in politics, most people tend to shun

extremes. However, a middle view is at once the

most defensible and the most difficult to defend,

Pitted against extreme or esoteric positions, the

numbers on its side create a presumption in its

favor. Yet a presumption given only by the weight

of opinion will not amount to a moral justification.

A belief is not shown to be true simply by counting the votes of those who accept it. Some basis

for an opinion, independent of it being accepted,

must be found.

Adoption of a middle view is hazardous in two

respects. First, it runs the risk of inconsistency.

Propositions located at polar extremes will usually contradict one another, and a position that

seeks to incorporate both may find itself embracing a contradiction. In the case of toxicity testing,

for example, it may not seem possible to respect

the interests of experimental animals and yet use

them as tools for enhancing human health and

safety.

The second risk is that consistency will be secured at a price too high, by way of a theoretically

unattractive ad hoc device. In principle, two contradictory propositions can be reconciled simply

by making one an exception to the other. It could,

for example, be stipulated that the general rule

against harming animals does not hold when they

are used to test for toxicity. But it is one thing to

say this and another to give a reason for it. Complex rules, introduced for no reason other than

to remove a particular inconsistency, muddy a

point of view without shedding any light on the

hard moral cases it must address. More important,

they are arbitrary.

71
72 ● Alternatives to Animal Use in Research, Testing, and Education

THE RELIGIOUS AND PHILOSOPHICAL TRADITION S

Interest in the moral status of animals is by no

means modern. The ancient religions had much

to say about the place that animals were to occupy

in the cosmic scheme of things. Oriental creeds

were, as a rule, reluctant to draw a sharp distinction between humans and other species. All animal lives were judged worthy of protection and

some were thought to be sacred. The doctrine of

transmigration left still more room for caution—

any animal body might house a soul entitled to special care. The various forms of the doctrine of trans -

migration share the thesis that a single, continuous, immaterial individual may pass from one body

to another, which maybe of the same or a different species. If the latter, its conduct in the earlier

incarnation may determine the kind of body it inhabits next. For such reasons, the prescribed dietary regimen in the Orient was frequently vegetarian. Modern influences have relaxed, but not

wholly removed, the grip of these beliefs.

In the West, a different tradition took root, one

that seems to have assigned value to animals only

as they serve human purposes. Judeo-Christian

doctrine appears to have condoned an indifferent, if not openly exploitative, attitude toward nonhuman animals (38,45). (For an opposing view, see

refs. 6 and 49.) The Genesis account suggests that

humans are the last and most perfected of God’s

creatures. Humans alone, of all living things, bear

the likeness of God, and receive the divine commission to exercise “dominion over the fish of the

sea, and over the birds of the air, and over the

cattle, and over all the earth, and over every creeping thing that creeps upon the earth” (Genesis 1:26-

28; all Biblical references and quotations are to

the Revised Standard Version). After the flood, God

rewarded Noah and his sons with this blessing:

“Every moving thing that lives shall be food for

you; and as I gave you the green plants, I give you

everything” (Genesis 9:3). A brief Talmudic story

indicates that Judaic practice was to the same effect: “A calf was being taken to the slaughterer,

when it broke away, hid his head under the Rabbi’s

skirts, and lowed in terror. ‘Go,’ said he, ‘for this

wast thou created’ “ (12).

These passages do not warrant the inference that

humans are permitted to treat animals in any way

they please. Even when suffering is inflicted as

a means to some human end, humans are subject

to the condition of using the animal. Wanton cruelty would not be allowed. Nor is it clear just what

human dominion includes, until the terms of a

model ruler-subject relation are spelled out. Humans must presumably rule well, and the good

ruler does not take authorized but unjustified actions. Much depends, too, on whether human sovereignty over nature is to be thought absolute or

limited by a divine will that may have set some

value on animals in addition to their utility for

humans.

In a number of passages, the scriptures seem

to place a rein on the use of animals. Genesis confirms that God had already judged the world as

good–that is, possessed of some value–before humans were created (Genesis 1:3,10,13,18,21). And

on several occasions in the later books of the Old

Testament, humans are expressly directed to show

kindness to the animals under their control. Thus,

“you shall not muzzle an ox when it treads out

the grain” (Deuteronomy 25:4). And, “a righteous

man has regard for the life of his beast, but the

mercy of the wicked is cruel” (Proverbs 12:10).

The most persuasive evidence for restraint may

lie in the role-model of the good shepherd, often

cited in both testaments. At one point, by report

of the prophet Ezekiel, God becomes annoyed

(Ezekiel 34:2,4):

Ho, shepherds of Israel who have been feeding

yourselves! Should not shepherds feed the sheep?

. . . The weak you have not strengthened, the sick

you have not healed, the crippled you have not

bound up, the strayed you have not brought back,

the lost you have not sought, and with force and

harshness you have ruled them.

God’s own rule is often compared with the concern that shepherds should have for their flocks

(Ezekiel 34:11-13; John 10:11; Luke 15:4-7). De.

signed to show that God stands to humans as they

stand to animals—a kind provider even if there

are no duties to provide for them—that simile

would fail if the shepherds could wholly disregard

the welfare of their animals.
Ch. 4—Ethical Considerations . 73

Aside from this figurative guide, the New Testament is spare in its references to handling animals.

Saint Paul’s discussion of the proscription against

muzzling the ox suggests a human benefit: “Is it

for oxen that God is concerned? Does he not speak

entirely for our sake? It was written for our sake,

because the plowman should plow in hope and

the thresher thresh in hope of a share in the crop”

(I Corinthians 9:9-10). Thus, the thresher was to

let the ox feed from the corn being worked, not

so much for the good of the ox, but because a wellfed animal would yield a larger return.

This passage suggests a shift in sentiment from

the old to the New Testament. For Christians, the

paramount practical concern is the condition and

future of the immortal soul possessed by human

beings. Animals are not believed to have immortal souls, nor be repositories for human souls. In

the Christian world view, then, animals are left

without the one thing that has special value in

itself—a soul. An animal’s welfare is a good thing

only as it is good for the human being.

The letter containing Paul’s reading of the Old

Testament rule was written only a generation after Christ’s death, when Christianity was still anew

faith. The distinction between humans and other

animals hardened as the creed acquired the trappings of theory, but in such a way as to raise new

questions about its real source. The legacy of Greek

philosophy exercised such a pervasive influence

over Christian theology in its formative years that

the distinction could be traced to Athens as easily

as to Jerusalem.

It might be said that in theology all roads lead

back to Augustine or Aquinas. On the subject of

animals, the Augustinian position finds expression

in his critique of a competing doctrine, which, on

the premise that animals also had souls, would not

allow killing them. Augustine cited the conduct

of Christ as a lesson to the contrary (7):

Christ himself shows that to refrain from the

killing of animals and the destroying of plants is

the height of superstition, for judging that there

are no common rights between us and the beasts

and trees, he sent the devils into a herd of swine

and with a curse withered the tree on which he

found no fruit.

If Christ could use animals for his own purposes,

then so apparently could we. Augustine’s view,

however, was tempered in two respects. First, he

denied that animals were mere instruments of humans. As creatures made by God, they also possessed a good of their own (7)8). Second, animals’

utility was the use to which human intelligence

might put them, not the convenience or inconvenience that they might present. Augustine did

not hold that humans were to treat animals according to their own pleasure or displeasure (8).

Aquinas ’view of animals was more sophisticated

and less sympathetic. Every natural being that

underwent development had an end or perfected

state that God had created it to achieve. God made

humans, however, as free and rational agents, with

control over their actions. People’s lives took their

objectives from their designs. Being neither free

nor rational, an animal was merely a means to an

end existing outside it (in the form of some purpose that a rational individual might have for it).

Thus, the nonhuman animal was ordered, by nature and providence, to the use of humans (l).

From Aquinas’ perspective, the Old Testament

concern for animals had been appropriately characterized by Saint Paul. People should avoid mistreating animals not because this would be best

for the animals, but because cruelty could be harmful to humans. Strictly understood, disinterested

charity towards animals was impossible, since there

was no common fellowship between humans and

them (2).

In its essentials, this view prevails within the

Catholic Church today. Its implications for research

in the life sciences have not gone unnoticed. Writing at the turn of this century, Father Joseph Rickaby, the English Catholic moral theorist, denied

that the suffering of animals was an obstacle to

biological inquiry (42):

Brutes are as things in our regard: so far as they

are useful to us, they exist for us, not for themselves; and we do right in using them unsparingly

for our need and convenience, though not for our

wantonness. If then any special case of pain to

a brute creature be a fact of considerable value

for observation in biological science or the medical art, no reasoned considerations of morality
—

74 Ž Alternatives to Animal Use in Research, Testing, and Education

can stand in the way of man making the experiment, yet so that even in the quest of science he

be mindful of mercy.

Protestantism retains the thesis that humans enjoy a rightful hegemony over other animals, but

suggests a shift towards a “stewardship” interpretation of that role. John Calvin, the 16th-century

Reformation theologian, maintained that when

God placed animals “in subjection unto us, He did

it with the condition that we should treat them

gently” (13). They were brute beasts, to be sure,

but for Calvin as for Augustine they were also creatures of God. Calvin went a step further, however,

in making this fact about animals a limitation on

humans’ use of them. Here humans would seem

to be less the sovereigns of nature than deputies

appointed to manage God’s earthly estate. Every

creature would still be subject to God’s ownership

and control. A person was still worth more than

any number of sparrows, yet ‘(no one of them will

fall to the ground without your Father’s will” (Matthew 10:29). Thus, Karl Barth, a leading modern

Protestant theologian, urged that people possess

the right to use and sometimes to kill animals, but

only because God has so authorized it in order that

humans might live (9).

There have been a few distinguished Judeo-Christian defenders of a position much closer to the

oriental view. Saint Francis and Albert Schweitzer

both pressed for a principle of reverence toward

every living thing. But their ideal has been received

as just that: a norm perhaps for saints, and something all should desire, but not binding on imperfect individuals in less-than-ideal circumstances.

In the absence of mainstream philosophical support, the intellectual authority of the reverencefor-all-life rule is thought to be outweighed by the

personal prestige of its practitioners (21).

Until 1600, the philosophical mainstream was

Aristotelian. Using a much broader conception of

the soul than the current one, Aristotle distinguished living from nonliving beings by the presence or absence of some form of a soul, or lifegiving power. Its function might be nutrition,

sensation, desire, locomotion, or thought. The first

of these, but not the rest, was found in plants. All

animals had sensation and desire as well, and most

also had locomotion. Humans alone had the power

of thought (4). This advantage made humans naturally suited to rule over other living beings and

made animals natural slaves. Aristotle reached this

conclusion by generalizing from phenomena already at work within humans: Those with greater

rationality exhibited an internal mastery of reason over desire and an external mastery over those

who, because they lacked the mental equipment

to tend to more than their bodily needs, required

direction from others (5). This resulted in leadership by those most competent to rule.

Natural fitness implied that nature worked toward

certain ends that together formed a master plan.

The significance of the 17th-century scientific revolution lay not so much in its overthrow of church

authority in the empirical realm as in its discovery of a method and a subject matter (i.e., mechanics treated as a branch of physics) that dispensed

with the hypothesis that nature had purposes. Nature became simply the sum of matter in motion,

mathematically describable without reference to

goals that phenomena might serve.

The philosophical foundations for the new world

view were supplied by Rene Descartes, who recognized only two kinds of existence, material and

mental. Bodies were extended in space and time

and divisible into parts, with properties of size,

shape, and weight. Minds contained beliefs, emotions, and intentions, but no physical properties.

The human was a composite being-the only one—

with both a body and a mind (18).

Animals did not fit comfortably into the Cartesian scheme. They obviously had bodies, but did

they not also have sensations and desires? Descartes answered that in a sense they did, but that

their behavior could be duplicated by a machine,

while human behavior could not. In their use of

language and thought, humans revealed a capacity to respond to stimuli in a variety of ways,

whereas animals would respond in only one, “according to the arrangements of their organs” (19).

For all their differences, the Aristotelian and

Cartesian theories joined hands in making the activities that required reasoning the distinctive mark

of humanity. Both defined the human being as a

rational animal. That thesis was not questioned

until the following century, when British empiricists criticized it as inflated claims for the power

of reason. The Scottish skeptic David Hume con-
Ch. 4—Ethical Considerations ● 7 5

curred with Descartes that the human mind was

capable of creatively entertaining a variety of possible conclusions from a given body of experience.

But this, Hume argued (29), was nothing more than

a habit of inference formed from repeated obser -

vations, something that dogs could do as well (30):

'Tis necessary in the first place, that there be

some impression immediately present to their

memory or senses, in order to be the foundation

of their judgment. From the tone of voice the dog

infers his master’s anger, and foresees his own

punishment. From a certain sensation affecting

his smell, he judges his game not to be far distant

from him.

Secondly, the inference he draws from the present impression is built on experience, and on his

observation of the conjunction of objects in past

instances. As you vary the experience, he varies

his reasoning. Make a beating follow upon one

sign or motion for some time, and afterwards

upon another; and he will successively draw

different conclusions according to this most recent experience.

The issue dividing Descartes and Hume survives,

still unsettled, in current controversies over artificial intelligence and animal cognition. Recent decades

have witnessed an explosion of empirical investigations into the behavior of nonhuman animals

(26,35,50). Among these, various efforts to teach

higher primates how to use a nonverbal language

have captured the public’s imagination. Inferences

drawn from such studies, however, encounter two

obstacles. First, to argue that chimps consciously

use gestures in the same way that human deafmutes do is to assume a certain theory about the

relation between bodily behavior and mental operations. No consensus on mind-body relations exists

today. The same difficulty, it is worth noting, affects various efforts to use similarities in brain

structure and function as evidence for similarities in thought.

Even if such matters could be resolved, a greater

conceptual hurdle would remain: what is the connection between language and thought? Language

requires combining terms into well-formed sentences using rules of grammar and meaning. Linguistic mastery includes the capacity to create

novel sentences in situations not precisely like

those already encountered and the resources to

express thoughts indifferent modalities (as descriptions, questions, commands, and so on) (48). It also

seems to require recognition that something said

is true, false, or uncertain (17,24).

Although no one knows whether other primates

will ever approach human beings in linguistic performance, it would be a mistake to focus on that

issue. Evidence is mounting that animals can recognize visual patterns, remember where their food

is located, learn how to perform nonmechanical

tasks, and foresee where a moving prey will eventually be positioned, even if they cannot master

a language (26,50). In this sense, animals exhibit

intelligence as defined by ability to adapt to environmental conditions. From a Darwinian (evolutionary) perspective, humans do not hold a privileged status over animals. Humans are not more

highly evolved than other animals; all have evolved

to fill their respective niches.

Neither linguistic nor nonlinguistic findings hold

all the answers. The moral issue is not simply

whether animals have some and lack other abilities that human beings possess, but whether the

differences between them make for differences

in how humans and animals should be treated.

Sometimes the differences matter, common sense

might say, and sometimes they do not.

THE ETHICAL QUESTION S

HOW, if at all, should animals be used in research,

testing, and education? Before this can be answered,

a preliminary question must be asked (14,15,44,47):

What moral standing does an animal have? Is it

the kind of being to which humans could possibly

have moral duties and obligations? Taking one side

or another on the question need not include any

particular moral judgment. Whatever its resolution, the separable moral issue remains: what constraints, if any, regulate humans’ use of animals?

These constraints might be weaker if animals lack

moral standing, but not necessarily absent altogether.
76 . Alternatives to Animal Use in Research, Testing, and Education

Moral Standing

Modern moral theory operates under a “law conception” of ethics (3). It judges particular human

actions as right (lawful) or wrong (unlawful) as they

comply with or violate some universal principle

of conduct. In this, it departs from the classical

theory of the virtues, which makes individual character the unit of evaluation and does not attempt

to reduce ethics to a system of rules. Under the

law conception, moral standing also goes to persons, but it is not conferred by an individual, institution, or community. From this point of view, an

individual counts as a person because of some inherent characteristic. This is the chief reason why

it is within the moral domain to speak of the natural duties and the natural rights of a person. A legal system can, of course, recognize natural duties

and rights.

For obvious reasons, no one has ever argued that

animals can have moral duties (40). That would

require that they freely choose to act among alternatives they judge to be right or wrong—a skill

as demanding as full-blown linguistic competence

would be. Nevertheless, it is possible to take the

view that animals have moral standing but do not

have rights.

There are two broad theoretical approaches to

the subject of rights. The first, sometimes called

the will theory, would discourage efforts to attribute rights to animals. In its classical form, as given

by Emmanuel Kant, it would define a right as a

capacity to obligate others to a duty. Possession

of a right carries with it an authorization to use

coercion to enforce the correlative duty (3 I). This,

in turn, implies that the right-holder’s capacity is

a power of discretion, either to enforce or waive

the right. A right is therefore something that a

right-holder may choose to exercise or not. The

choice itself will be an act of will.

H.L.A. Hart, a leading contemporary defender

of the will theory, treats a right as a choice that

gives the right-holder authority to control the actions of someone else. The possessor of a moral

right has a moral justification for limiting the freedom of another, not because the action the rightholder is entitled to require has some moral quality, but simply because in the circumstances a

certain distribution of human freedom will be

maintained if the right-holder has the choice to

determine how that other shall act (28).

The will theory helps to avoid confusion between

claims of right, and other, separable requirements

to promote or secure some valued state of affairs

(e.g., to assist someone in need). Since animals could

not be said to have waived or exercised the rights

they had, all references to animal rights could simply be translated into talk of human duties.

Those who would assign rights to animals have

embraced the alternative interest theory of what

it means to have a right. A right, in their view, is

a claim to the performance of a duty by someone

else, but the right -holder need not be in a position

or possess the competence to make this claim by

an act of will. It is enough that the right-holder

has interests that can be represented (by others)

in a normative forum (20). These interests will include things that are intrinsically good and things

in which the right-holder “takes an interest, ” selfish or not (40). To have a right, then, will be simply to have interests that can be affected by someone else.

The interest theory surfaces in Peter Singer’s

Animal Liberation, among the first contemporary

theoretical statements of the case for animals. In

that work, Singer uses the term “right” to describe

any claim that individuals may make to have their

interests equally considered with those of others.

It implies, therefore, nothing more than a capacity for suffering, which both humans and animals

possess (45).

The modest measure of animal awareness that

such a test demands has been one source of its

appeal. It has not, however, been free of controversy. Some have objected that animals cannot

have interests because interests require beliefs and

animals cannot have beliefs in the strict sense (24,

36). This criticism suggests that pain-avoidance is

not an “interest” because it is not a “belief ,“ a distinction that seems more semantical than useful.

Nevertheless, a more serious charge remains. As

stated, the interest theory shows only that having

interests is a necessary condition for having rights,

not that it is sufficient. Singer himself has since

abandoned the attempt to show sufficiency and,
Ch. 4—Ethical Considerations 77

accordingly, recanted his earlier references to the

language of rights (46):

I could easily have dispensed with it altogether.

I think that the only right I ever attribute to animals is the “right” to equal consideration of interests, and anything that is expressed by talking of

such a right could equally be expressed by the

assertion that animals’ interests ought to be given

equal consideration with the interests of humans.

Singer effectively acknowledges Hart’s charge that

the notion of a right has lost its distinctive function in this context because it no longer refers to

the discretionary control that one individual has

over the conduct of another.

There is one very general consideration that appears to weigh against the will theory, if not entirely in favor of the interest theory. It underlies

a form of argument so ubiquitous in the animalrights literature that it deserves a name. The consistency argument is exemplified in the following

passage from an essay on vegetarianism by Tom

Regan. Rejecting rationality, freedom of choice,

and self-consciousness as conditions for having a

right to life, Regan adds (41):

It is reasonably clear that not all human beings

satisfy them. The severely mentally feeble, for

example, fail to satisfy them. Accordingly, if we

want to insist that they have a right to life, then

we cannot also maintain that they have it because

they satisfy one or another of these conditions.

Thus, if we want to insist that they have an equal

right to life, despite their failure to satisfy these

conditions, we cannot consistently maintain that

animals, because they fail to satisfy these conditions, therefore lack this right.

Another possible ground is that of sentience,

by which I understand the capacity to experience

pleasure and pain. But this view, too, must encounter a familiar difficulty—namely, that it could

not justify restricting the right only to human

beings.

In short, given that some human beings (infants,

mental defective, and senile adults) lack such capacity as well, Regan points to the inconsistency

of holding both that this capacity is a condition

of having a right and that all humans and only humans have moral rights. Any less burdensome test,

however, will presumably admit animals as possible right-holders (33)45). (For an opposing perspective, see refs. 22 and 24.)

This reasoning appears to overlook a significant

difference between an incompetent human being

and an animal. In most cases, human beings have

the capacity for rationality, freedom of choice, and

self-consciousness, whereas in all cases animals

do not. If most humans have these characteristics,

it might be appropriate (or at least convenient) to

treat humans as a homogeneous group, even though

some members lack these characteristics. If all

animals lack certain characteristics, it maybe similarly appropriate to treat them as a group, regardless of whether some humans also lack these

characteristics.

Furthermore, if rights do not imply present possession of the qualifying condition (as suggested

by the way that people treat those who are mentally incapacitated only for a time), then babies who

have yet to mature and people who have become

incapacitated after a period of competence will

still have rights. The animal, as far as can be ascertained, has never met and will never meet this qualification. The rare human being whose deficiency

is complete over a lifespan is nevertheless differently situated from the animal. The condition is

a disability—the loss of some skill the person would

normally be expected to have. The animal’s condition is not disabling, even though it lacks the same

skill. The very fact that the human has been deprived of an ability implies that the person has been

harmed; a human’s failure to acquire an ability

means that person is in need of help. The condition of the animal does not call for either inference. This difference, to be sure, makes no mention of rights. Yet it creates a special duty to meet

the human need that would not extend to animals.

Because the animal without a will has not lost what

it was biologically programmed to possess, it “needs”

a will only as a human might ‘(need” to fly. In neither case does the condition give rise to a moral

demand for assistance.

Ironically, the consistency argument contains

a basic inconsistency. On the one hand, the argument asserts that humans are not superior to animals; animals should therefore be treated like humans. On the other hand, the very nature of the

moral argument is promotion of morally superior

behavior: Humans should refuse to exploit other

species, even though the other species exploit each

other.
78 . Alternatives to Animal Use in Research, Testing, and Education

The consistency argument nevertheless succeeds

to the extent that it shows that the genera] reason

for moral concern in the cases discussed cannot

be limited to humans. Other things being equal,

the fact that a condition is harmful or threatens

harm to an individual—human or animal-creates

amoral reason to intervene. That reason need not

take the form of a duty owed to the victim, with

a correlative right that this would entail. It need

not always be a duty of any sort. The highest approval is often reserved for the good deed that,

like the good samaritan’s, goes beyond what duty

strictly requires.

There is a spectrum of possible positions, beginning atone end with a strict prohibition against

the cruel infliction of suffering, moving to a still

powerful requirement to lend help when the individual alone is in a position to provide it for someone

in great need, and then to the milder requirements

of charity and generosity when the individual can

provide them without great personal sacrifice

(even if others can do the same), and finally, at

the other extreme, to the highly praised but not

binding act of genuine self-sacrifice that distinguishes the moral saint. The moral vernacular covers this spectrum with a single term. The act in

question is called the ‘(humane” thing to do, and

sometimes failure to perform it is labeled inhumane.

The term itself refers to the actor, not the recipient. Humane treatment, following the Oxford English Dictionary, is “characterized by such behavior

or disposition toward others as befits a man.” This

meaning, which dates back to the 18th century,

applies to conduct marked by empathy with and

consideration for the needs and distresses of

others, which can include both human beings and

animals.

This does not mean that animals will generally

command the same degree of affection and attention as humans. The attitude of empathy, which

is the psychological spring for humane treatment,

consists in ‘(feeling like” the object of sympathy,

and the basis for this response must be a certain

understanding of what it is like to be in the other’s

position. Other human beings are much more accessible in this respect, not only because they are

structurally and functionally like each other, but

because they can communicate their feelings in

ways that animals can scarcely approach. In such

areas as the capacity for experiencing pain, however, the differences across species are by no

means so great as to make empathetic identification impossible. Here the mark of the humane individual will be the extent to which sympathy

jumps the barrier between species (11).

There are differences among animals, too, in the

capacities they have, the things they do, and the

relations they have with humans, all of which affect the moral weight that humane considerations

will have. A gorilla will gather more sympathy than

a trout, not so much because it is more intelligent

as because it exhibits a range of needs and emotional responses to those needs that is missing altogether in the trout, in which evidence of pain

can barely be detected. Predatory animals and wild

rodents rarely elicit affection because their characteristic activities do not mark them as helpless

and in need. Even within one species, the regard

an animal may receive will rise with the social ties

and responsibilities that human beings have developed with it. As a possible recipient of humane

treatment, the garden-pest rabbit will stand to the

pet rabbit much as the stranger does to an acquaintance.

Each of the morally significant differences

among animal recipients of humane treatment

builds on an analogy to the human case. Thus,

whatever the merits of the consistency argument

on the score of rights, it applies here because the

humane treatment principle crosses the species

border. Mary Midgeley has put the point eloquently

in another context (33):

[Animals] can be in terrible need, and they can

be brought into that need by human action. When

they are, it is not obvious why the absence of close

kinship, acquaintance or the admiration which

is due to human rationality should entirely cancel the claim. Nor do we behave as if they obviously did so. Someone who sees an injured dog

lying writhing in the road after being hit by a car

may well think, not just that he will do something

about it, but that he ought to. If he has hit it himself, the grounds for this will seem stronger. It

is not obvious that his reasons for thinking like

this are of a different kind from those that would

arise if (like the Samaritan) he saw an injured hu -
Ch. 4—Ethical Considerations • 79

man being. And he too may feel about equally justified in both cases in being late for his uncle’s

party.

Humane treatment is the most commonly cited

standard in Federal legislation concerning animals.

Its wide range of application due to its lack of precision, however, leads to a temptation to dismiss

it as a pious but essentially vacuous sentiment. A

theory of moral constraints is needed to determine

whether this or some other standard is sufficiently

precise to serve as a guide for legislation regulating the use of animals.

Moral Constraints

A rule that allows an individual to do whatever

that person wished would not be a moral rule.

Morality by its very nature operates as a check

on the tendency to go wherever desire leads. The

constraints it imposes can be applied prospectively,

contemporaneously, or retrospectively. Prospective analysis looks ahead to the possible consequences, while retrospective analysis may restrict

the results it is permissible to promote (37). Before the action is taken, it can be said that the action that morally ought to be performed is the one

with the best consequences. An individual succeeds

in this objective to the extent that an action produces as much benefit and as little harm as possible. During the course of the action, conditions

concerning the intention of the individual and the

consent of the recipient may have to be met before a moral license to pursue the best consequences is granted. The fact that a lie will produce

more benefit than the truth will not necessarily

make it the right thing to do.

Moral theories divide according to the weight

they give to one or the other kind of constraint.

In its purest form, the prospective approach holds

that an action or policy is right if it has better consequences, for everyone affected by it, than any

available alternative. The language here is carefully drawn. “Better” does not mean “morally better.” A good consequence is simply an outcome

that someone finds desirable. If an action gives

pleasure to someone, the enjoyment is a good thing;

if it causes pain, the person’s suffering would be

a bad thing. It is not necessary to ask whether the

pleasure or pain is morally fitting.

Intuition will ideally play no part in determining an outcome. One consequence will count as

better than another if, after assigning positive numerical values to its good elements and negative

values to its bad ones, the sum of positive values

exceeds that of negative values (10).

Better for whom? The utilitarian principle, still

the most influential formulation of the forwardlooking approach, holds that actions and policies

are to be evaluated by their effects, for good or

ill, on everyone, not just the individual alone or

some select group of individuals. Between an individual’s own good and the good of others, “utilitarianism requires him to be as strictly impartial

as a disinterested and benevolent spectator” (10,34).

The interests of each affected individual are to

count equally. Any two experiences that are alike

except that they occur indifferent individuals are

to be given the same value. Among utilitarians, enjoyment is a good and suffering an evil, and so every

animal with the capacity for such experiences will

also count as one individual. Sentience suffices for

possessing this value, even if it does not confer

rights. “The question, ” as Bentham once put it, “is

not, Can they reason? nor Can they talk?, but Can

they suffer?’’.

Because it extends the scope of moral concern

to animals without committing itself to a vulnerable theory of animal rights, utilitarianism has become the theory of choice among those who would

press for more constraints on humans’ treatment

of animals. Singer derives the credo that all animals are equal from the utilitarian conception of

equality (45). If the principle of utility requires that

suffering be minimized, and if some kinds of suffering are found in animals as well as humans, then

to count human suffering while ignoring animal

suffering would violate the canon of equality. It

would make a simple difference of location-in one

species rather than another—the basis for a distinction in value. Like racism, such "speciesism ”

enshrines an arbitrary preference for interests

simply because of their location in some set of individuals (45). (For arguments that speciesism is

not immoral, see refs. 16,23,51,52.)

As a general moral principle, utilitarianism is subject to several objections, the most serious being

that its standard of equality is much too weak to
80 ● Alternatives to Animal Use in Research, Testing, and Education

satisfy the demands of justice (25,37,39). Since it

only requires that individuals with interests be

given the same consideration, but in its summation of interests allows the claims of any one individual to be overridden by the sheer weight of

numbers on the other side, it seems to sanction

a tyranny of the majority that permits violations

of individual rights. This may not, however, undermine the utilitarian case for animals if animals have

doubtful standing as right-holders.

Some commentators have suggested that there

may be an acceptable double standard in morals,

consisting of a nonutilitarian principle for agents

with standing as persons and a utilitarian rule for

handling individuals with interests but not rights

(21,37). The use of different rules for different

kinds of individuals is already well established.

Rules that would be objectionably paternalistic if

applied to adults are admissible if restricted to children. The dangers are that inconsistent standards

might hold for the same individual or that differences between the two classes of individuals might

be arbitrary.

The suggestion that the adult-child and humananimal distinctions are comparably rational and

justifiable (21) is superficial for two reasons. First,

it does not seem to be arbitrary to distinguish between the adult and the child, because human society understands that children may be intellectually

and experientially unable to make wise choices.

Thus, society can choose for children that which

society believes is in their best interests. The problem with the human-animal distinction is that an

animal may in fact be able to make and communicate a decision that expresses the animal’s selfinterest: It wants no part of any scientific procedure that results in pain or distress. Even if the

animal could not make or communicate a decision,

it may be arbitrary to distinguish between such

animals and humans who are similar in their inability to make such decisions (the profoundly mentally handicapped), allowing society to use the

former but not the latter as research subjects.

The second difference between the adult-child

and human-animal distinctions relates to the purpose for distinguishing between two groups. The

first distinction is permissible because it allows society to protect the interests of the child, while

the purpose of the human-animal distinction is to

allow society to ignore, or at least diminish, the

interests of the animal.

The device of a double standard is often used

to explain the sharp differences in the constraints

governing the treatment of animals and humans

as experimental subjects. For animals the standard is humane treatment, which forbids unnecessary suffering but otherwise allows experiments

that harm and even kill the animal. That same rule,

proposed for human subjects, is generally considered unethical. There are many experiments in

which perfectly reliable results can only be obtained by doing to a human what is now done to

an animal. Nevertheless, without the subject’s informed consent—indeed, sometimes even with it—

such experiments are absolutely impermissible,

no matter how beneficial the consequence might

be. They would violate the rights of the human

subject.

The proscription against unnecessary suffering

is best understood as a corollary of the principle

of utility. Since suffering is a bad consequence,

there is an initial utilitarian onus against behavior

that would produce it. Such treatment calls for

justification. To meet this burden, a bare appeal

to some offsetting good consequence will not be

sufficient. The principle of utility, as formulated,

is comparative. It requires that an action or policy

have better consequences than any available alternative. Among the alternatives will be uses that

do not involve animal suffering. If one of them has

consequences at least as good as or better than

the one proposed, the suffering will be unnecessary. Other things being equal, then, it should prove

harder to establish necessity than the contrary,

since the former must rule out all the alternatives

while the latter need find only one.

Necessity is a relation between a means (an action or policy) and an end (its objective). Restricted

necessity takes the end as given—that is, not subject to evaluation—and asks only whether the

course of action suggested is an indispensable

means to that end, For example, in an LD50 test

for toxicity that uses 40 rats as subjects (see chs.

7 and 8), if no alternative procedure using fewer

or no rats could get the same results with the same

reliability, that test would be necessary in the re -
Ch. 4—Ethical Considerations ● 8 1

stricted sense. In unrestricted necessity, the end

is open to assessment on utilitarian grounds:

●

●

How likely is the objective to be met, in comparison with other possible goals? If the LD50 test

yields unreliable results, its necessity in the

unrestricted sense would be open to challenge.

Assuming that the objective will be met, how

beneficial will it be? Suppose, for instance, that

an LD50 test were to be run on a new cosmetic

not significantly different from those already

on the market. The test may be considered

unnecessary because the objective is unnecessary.

Unrestricted necessity is more difficult to prove,

because it always includes restricted necessity and

more. Thus, a stringent standard of necessity, one

that lets fewer procedures through, would require

that a procedure be necessary in the unrestricted

sense. In addition, since necessity is more difficult

to establish than the possibility of substitution, the

burden of proving both the existence of necessity

and the absence of alternatives could be placed

on those who would use the procedure. A more

lenient test could invert these priorities by presuming that the procedure is necessary and that

alternatives are lacking unless shown otherwise.

This approach would not expect the user to show

beforehand that no other alternative was available; it is generally followed when a research proposal is reviewed by a scientist’s peers or an institutional animal care and use committee (27).

Nonutilitarian positions on the use of animals

have one feature in common: Although virtually

none ignores consequences, they unite in denying that a course of action can be justified wholly

by appeal to the value of its consequences (39).

This leaves room for substantial variation, with

the differences traceable to the considerations they

would add in order to complete amoral assessment.

Ironically, both extremes in the animal treatment

debate are nonutilitarian. The hard line supporting unlimited exploitation of animals builds from

the premise that animals lack moral standing. Without rights, they cannot be recipients of a duty owed

to them. On some theories of value, moreover, enjoyment does not count as a good thing in itself,

nor is suffering per se an evil. Kant, for example,

thought that the only unconditional good was a

will whose choices are undetermined by desire

for enjoyment or fear of punishment (31). Not having a will, animals could not have this value.

Morally, they were indistinguishable from inanimate tools—mere means to be used for the purposes of beings who do have a will. Like Aquinas,

however, Kant did acknowledge an indirect duty

of kindness, given that “tender feelings toward

dumb animals develop humane feelings toward

mankind” (32).

The indirect duty theory stumbles in the attempt

to explain why there should be any empirical connection at all between people’s feelings for animals

and their feelings for other humans. Some similarity must be seen in the objects of the two sentiments if one is to influence the other; yet the theory says that there is no such likeness in reality.

Thus either a person’s motive is proof by itself that

humans have a direct moral interest in animals,

in which case the theory is mistaken; or the theory is correct and the individual has misunderstood it, in which case the person will be free, once

educated in the theory, to abuse animals without

fear that this will tempt abuse of human beings.

Kant cannot have it both ways: He cannot require

individuals to act on a belief that his own theory

alleges to be false (33).

The Kantian position could be turned on its head

if animals had moral standing after all. In The Case

for Anhnal Rights, Regan gives the most cogent

defense to date for that view. He concedes that

animals are not moral agents: Since they are unable to choose freely among impartially determined

moral alternatives, they cannot have any moral

duties. At least some animals, however, have beliefs, desires, memory, a sense of the future, preferences, an identity overtime, and an individual welfare of their own (41). In these respects, they are

indistinguishable from human infants and mental defective, who also fail to qualify as moral

agents. Nevertheless, these animals possess an inherent value, independent of the value that their

experiences may have, that gives them standing

as “moral patients” — that is, as individuals on the

receiving end of the right and wrong actions of

moral agents. They have this value equally, and

equally with moral agents (40). Inherent value in

turn gives them a claim, or right, to certain

treatment.
82 . Alternatives to Animal Use in Research, Testing, and Education

Regan’s major thesis is that, as moral patients,

animals enjoy a presumptive right not to be harmed.

He considers this principle a radical alternative

to utilitarianism. But once the reference to rights

is filtered out, the utilitarian might find Regan’s

theory quite congenial. Both Regan and utilitarians

would hold that harm to animals is a bad consequence and so it would be wrong, in the absence

of an overriding consideration, to harm them. The

conflict between the two theories, therefore, lies

in the kind of justification that each theory would

permit to overturn this presumption.

Regan offers two guiding principles (40). By the

first, when the choice is between harm to a few

and harm to many and when each affected individual would be harmed in a comparable way, then

the rights of the few ought to be overridden. As

Regan acknowledges, the utilitarian commitment

to minimize suffering would have the same result.

By the second principle, when the choice is between harm to a few and harm to many, if a member of the affected few would be worse off than

any member of the affected many, the rights of

the many ought to be overridden. This “worseoff” rule parts company with utilitarianism in setting aggregate consequences aside and protecting

minority interests.

In view of this possibility, it is surprising to find

that Regan calls for a blanket prohibition against

the use of animals in research and toxicity testing. That conclusion would follow only if his two

rules for defeating the right not to be harmed could

never be successfully invoked in these areas. Regan is apparently drawn to this result by a constraint he attaches to the rules: They hold only

for harms suffered by innocent victims. Animals

are always innocent, in the sense that Regan gives

to that term (41). But human patients will be, too,

and at least sometimes human agents will also be.

Regan would have to show that these occasions

can never arise in research, testing, or education,

or that, if they do, the human agent/patient never

faces the greater harm. His analysis does not show

this.

This difficulty aside, Regan’s theory can be read

as holding, first, that the necessity standard cannot be applied until the innocence of all parties

has been established and, second, that when it does

apply, the worse-off rule should replace the utility principle in cases where they diverge.

It is unclear whether the worse-off rule is preferable to the utilitarian principle for the purposes

of animal use. But the notion of innocence, with

its judicial implications, appears to have no place

in the issue of experimental-subject rights for three

reasons. First, the notion that animals are always

innocent because they cannot be otherwise is problematic. Innocence makes sense only when guilt

does, because innocence means that one has done

no wrong though doing wrong was an option. If

animals are not rational decisionmakers, if they

cannot choose between right and wrong, then the

concept of innocence has little meaning. Second,

most human subjects are probably innocent in the

sense that Regan uses the term, so that the concept does little to advance the theory that experimenting on humans is preferable to experimenting on animals. Finally, even a guilty person

may have certain rights. While a person guilty of

a crime against society maybe imprisoned or otherwise punished, society holds that the guilty have

a right to avoid cruel and inhumane punishments.

Bioethics similarly rejects the involuntary use of

guilty prisoners in medical experiments.

SUMMARY AND CONCLUSIONS

The present debate over animal use in research,

testing, and education is marked by a cacophony

of voices. A critical survey of the religious and philosophical backgrounds to the debate yields some

hope that, if the competing voices were muted by

reflection, they would begin to coalesce as variations around a single theme. That theme would

be the standard of humane treatment, extended

to animals as well as to humans.

Much has been made of the historical contrast

between Western and Oriental religious views on

animals. The biblical and theological texts in the

Judeo-Christian tradition do not give us a principle of unconditional respect for animals. Humans

alone are accorded inherent value as being created in the image of God, and this gives them a

license to use animals for their own purposes. Not,

however, to abuse them. Cruelty and callous in-
Ch. 4—Ethical Considerations . 83

difference to the needs of animals find no scriptural support, and virtually all religious thinkers

condemn them. If God is a good shepherd, treating humans kindly without being bound to, humans can be as much to the animals in their care.

The Christian position thus amounts to a synthesis of two elements in tension. On the one hand,

animals are inferior in worth to humans, as the

body of a person is inferior to the soul. On the

other hand, they are not so inferior that their own

welfare cannot stand in the way of unbridled use

of them.

Modern religious and philosophical patterns of

thought are branches of the same ancestral trunk.

It should not be surprising, then, that the philosophical tradition exhibits the same tension on the

subject of animals. Humans have standing as persons—that is, as individuals who can assume duties

and enjoy rights. To join them, animals must at

least be capable of possessing rights. But they cannot assume duties and do not have the power of

discretion that gives rights a distinctive role in

morals. Consistency suggests rights should be

ascribed to animals once rights are given to infants

and mentally handicapped humans who also lack

discretion. Yet it would be inconsistent to assert

that humans are not superior to animals while suggesting that humans should refuse to exploit other

species, even though other species exploit each

other.

Even if animals are not moral persons, however,

it does not follow that they are mere things, morally

indistinguishable from machines. They are sufficiently like humans in one morally relevant respect—their capacity for suffering in basic forms—

to generate a moral claim on humans. It would

be inconsistent to hold that, other things being

equal, human suffering ought to be relieved, but

animal suffering ought not.

Because it extends the scope of moral concern

to animals without committing itself to a vulnerable theory of animal rights, utilitarianism has become the theory of choice among those who would

press for more constraints on humans’ treatment

of animals. If the principle of utility requires that

suffering be minimized, and if some kinds of suffering are found in animals as well as humans, then

to count human suffering while ignoring animal

suffering would violate the canon of equality. It

would make a simple difference of location-in one

species rather than another—the basis for a distinction in value. Like racism, such “speciesism”

enshrines an arbitrary preference for interests

simply because of their location in some set of individuals.

The rule that suffering ought to be relieved, in

humans or animals, is the principle of humane

treatment. It covers a large and heterogeneous

range of situations; the most germane, for the debate over animal use, are those in which someone

inflicts suffering on someone else. The humane

treatment principle establishes a presumption

against doing this, but that presumption can be

overcome—always in the case of animals, and

sometimes even in the case of a human—by showing that the harm done is necessary. Necessity here

is not bare utility, but necessity overall. The harm

must not only be a means to a good end, it must

be the only means. A broader definition of necessity might also require that the harm be a means

to an end whose value is considered in light of the

degree of harm necessary to achieve that end. In

addition, necessity always implies a comparison

with available alternatives.

Animal use in research, testing, and education

creates a conflict of interests between the liberty

that humans have to use animals for human ends

(knowledge, health, safety) and the need that animals have to be free of suffering. There is no reason why either one of these broad interests should

always prevail over the other. The fulcrum on

which they are balanced is the necessity standard

itself. That is, when the suffering inflicted on animals is not necessary to satisfy a desirable human

objective, the animal interest will prevail. And

when the suffering is unavoidable, the human interest will be controlling. Animals are morally entitled to be treated humanely; whether they are

entitled to more than that is unclear.
84 ● Alternatives to Animal Use in Research, Testing, and Education

Reprinted with permission from CHEMTECH 15(1):63, Copyrlgnt 1965, American

Chemical Society.

CHAPTER 4 REFERENCES

1. Aquinas, T., Summa Contra Gentiles, tr. English Dominican Fathers (New York: Benzinger Brothers,

1928).

2. Aquinas, T., Summa Theological, tr. English Dominican Fathers (New York: Benzinger Brothers, 1918).

3. Ancombe, G. E. M., “Modern Moral Philosophy )’’Philosophy 33:1-19, 1958.

4. Aristotle, De Anjma/, tr. K. Foster and S. Humphries

(New Haven, CT: Yale University Press, 1954).

5. Aristotle, PoJitics, tr. E. Barker (Oxford, England:

The Clarendon Press, 1952).

6. Attfield, R., The Ethics of Environmental Concern

(New York: Columbia University Press, 1983).

7. Augustine, The Catholic and Manichean Ways of

Life, tr. D.A. Gallagher and I.J. Gallagher (Boston,

MA: The Catholic University Press, 1966).

8. Augustine, The City of God, tr. H. Bettenson (New

York: Penguin, 1972).

9. Barth, K., Church Dogmatics, tr. G.T. Thompson

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169, 1983.

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(Animal Husbandry and Moral Duty, ”

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Ch. 4—Ethica/ Considerations ● 8 5

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Morality of Animal Research,” Hastings Center Report 15(5):32-43, 1985.

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Sign Language (New York: Random House, 1979).

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—

chapter 5

The Use of Animals

in Research

I know that half of what I teach as fact, ” said a wise medical pedagogue, “will be proved

false in 10 years. The hard part is that I don’t know which half. ” His statistics may not be

exact, but the notion is right enough. No one knows which half, and it is impossible to

know except in retrospect.

That is what research is—the reason for the prefix. The half that is wrong is at least as

important as the half that is right, because the new questions come in ferreting out the

errors-and new answers too.

Kenneth L. Brigham

Vanderbilt University School of Medicine

N. Engl. J. Med, 312:794, 1985
CONTENTS

Page

The Role of Animals in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Nonhuman Primates in Biomedical Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Experimental Animals’ Contribution to Coronary Artery

Bypass Graft Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Use of Multiple Species in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Choice of Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

The Role of Animals in Behavioral Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

What is Behavioral Research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Why Are Animals Used in Behavioral Research? . . . . . . . . . . . . . . . . . . . . . ....101

Methods of Behavioral Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........102

Use of Multiple Species in Behavioral Research . . . . . . . . . . . . . . . . . . . . .. ....103

Pain and Distress in Research Animals . . . . . . . . . . . . . . . . . . . . . ..............103

Animal and Nonanimal Protocols in Biomedical and

Behavioral Research Reports . . . . . . . . . . . . . . . . . . . . . ...................105

Survey Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......106

Survey Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........106

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...108

Chapter 5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..109

List of Tables

Table No. Page

5-1.Some Uses of Nonhuman Primates in Research on Human

Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

5-2. Some Anatomical, Physiological, and Metabolic Similarities and

Differences Between Humans and Various Laboratory Animals . . . . . . . . . . . 97

5-3. Classification of Research Experiments and Procedures According

to the Degree of Pain or Distress for the Animal . . . . . . . . . . . . . . . . . . . . . . .105

5-4. Classification of Published Research Protocols in

OTA Survey of 15 Journals . . . . . . . . . . . . . . . . . . . . . . ...................106

5-5. Percentage of Papers (Average, 1980-83) Using Animal, Nonanimal,

and Human Subjects in 15 Biomedical and Behavioral Research Journals

Surveyed by OTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................107

Figure

Figure No. Page

5-1. Steps in Biomedical Research That Preceded Successful

Coronary Artery Bypass Graft Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Chapter 5

The Use of Animals in Research

Research, as the word denotes, is an ongoing

search—a search for new information and for

novel ways to apply existing information. Research assumes a multitude of directions in a wide

variety of disciplines. It is not surprising, then,

that the use of animals in research—and the potential for alternatives to using them—mirrors the

multifaceted nature of research itself.

Viewed broadly, almost any research investigation involving members of the animal kingdom,

including humans, and sometimes even members

of the plant kingdom, can be categorized as biomedical research. In this sense, biomedical research covers a long list of disciplines: anatomy,

anesthesiology, behavioral biology, biochemistry,

biomedical engineering, biophysics, cardiology,

cell biology, dentistry, developmental biology, endocrinology, entomology, epidemiology, genetics,

gerontology, histology, immunology, metabolism,

microbiology, molecular biology, neurology, nutrition, oncology, parasitology, pathology, pharmacology, physiology, psychology, radiology, reproductive biology, surgery, teratology, toxicology, veterinary science, virology, and zoology.

When considering animal use—and alternatives

to animal use—in research, it is useful to isolate

behavioral research from the broader category

of biomedical research. Behavioral research is a

part of biomedical research, yet is distinguished

from the larger topic by the nature of the experiments, the identity of the researchers, and the

kinds of alternatives available (see ch. 6).

This chapter defines and describes animal use

in biomedical and behavioral research. Also included are the results of a brief survey done by

OTA of the use of animal and nonanimal methods in published research reports in selected disciplines of biomedical and behavioral research.

THE ROLE OF ANIMALS IN BIOMEDICAL RESEARC H

To discuss alternatives to using animals in biomedical research, it is important to review the

context in which animals are presently included.

A comprehensive review of this subject (see ref.

41) is beyond the scope of the present assessment.

However, animals’ broad role in contemporary

biomedical research can be at least partly delineated by considering:

● the manifold contributions to biomedical research of a single group of animals—nonhuman primates;

● the role of experimental animals in the development of a single medical procedure,

namely coronary artery bypass surgery; and

● the reasons multiple species are used in biomedical research.

These perspectives illustrate two fundamental

principles of animal use in biomedical research.

First, a single species or group of animals often

serves a multitude of purposes in widely varying

research enterprises. Second, a single advance in

applied research often represents results generated from many species.

Nonhuman Primates in

Biomedical Research

Primates—humans, monkeys, and apes—share

a common genetic basis and anatomical, physiological, biochemical, and behavioral traits that

provide unique research opportunities. As a consequence, humans and other primates are susceptible to many of the same diseases and have

many of the same disease-fighting capabilities. Reviewing the use of nonhuman primates is also

appropriate because they are relatively expensive”

research animals (e.g., a rhesus monkey costs

from $600 to $2,000) and the object of much public interest. Two recent reports describe the role

of primates in biomedical research (29,45). Those

89

38-750 0 - 86 - 4
✙✐● Alternatives to Animal Use in Research, Testing, and Education

reports are summarized in table 5-1; highlights mans had been made by the early 1900s, but the

of the studies follow. cause of the disease was still unknown. A breakthrough occurred in 1908, when scientists experPolio imentally transmitted the poliovirus to monkeys

for the first time. Studies in rhesus and cynomolgus

The development of the polio vaccine exempli- monkeys and in chimpanzees followed isolation

fies the key role of primates in the research lab- of the virus, but a vaccine remained elusive. Af -

oratory. Many thorough studies of polio in hu- ter nearly a half-century, researchers were able

Table 5-1.—Some Uses of Nonhuman Primates in Research on

Human Health and Disease

Human health concern Primate experimental model

Acquired immune deficiency syndrome

(AIDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chimpanzee, African green monkey

Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . Cynomolgus monkey

Balding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Stumptail monkey

Cancer from solid tumors . . . . . . . . . . . . . . . . . Chimpanzee

Cholesterol gallstones . . . . . . . . . . . . . . . . . . . .Squirrel monkey

Circadian rhythms . . . . . . . . . . . . . . . . . . . . . . . .Squirrel monkey

Cornea transplant . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, African green monkey,

Stumptail monkey, Patas monkey,

Cynomolgus monkey

Dental implants . . . . . . . . . . . . . . . . . . . . . . . . . . Pig-tailed monkey

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Celebes black macaque

Dietary fats and heart disease . . . . . . . . . . . . .Cynomolgus monkey

Embryo transfer . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Cynomolgus monkey

Eye damage from ultraviolet radiation . . . . . . . Rhesus monkey

Eye disorders in children . . . . . . . . . . . . . . . . . . Rhesus monkey

Fetal alcohol syndrome . . . . . . . . . . . . . . . . . . . Pig-tailed monkey

Fetal surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Genital herpes . . . . . . . . . . . . . . . . . . . . . . . . . . .African green monkey

Gilbert’s syndrome . . . . . . . . . . . . . . . . . . . . . . . Bolivian squirrel monkey

Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Hearing impairment. . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Hepatitis B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Chimpanzee, African green

monkey

Herpes-virus-induced cancer . . . . . . . . . . . . . . . Owl monkey, Marmoset

High blood pressure . . . . . . . . . . . . . . . . . . . . . . Cynomolgus monkey

Hyaline membrane disease in newborns. . . . . Rhesus monkey, Pig-tailed monkey

In vitro fertilization . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Chimpanzee, Baboon,

Cynomolgus monkey

Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Inflammatory bowel disease . . . . . . . . . . . . . . .Marmoset

Laser surgery on damaged nerves . . . . . . . . . . Baboon

Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Sooty mangabey

Liver disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chimpanzee, Owl monkey, Rhesus monkey

Male and female behavior patterns . . . . . . . . .Rhesus monkey

Male birth control . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Cynomolgus monkey

Menopausal problems. ., . . . . . . . . . . . . . . . . . . Rhesus monkey, Stumptail monkey

Mother-infant behavior . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Motion sickness . . . . . . . . . . . . . . . . . . . . . . . . . Squirrel monkey

Nonhormonal fertility regulation . . . . . . . . . . . . Bonnet monkey, Chimpanzee

Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Baboon

Parkinson’s disease , ... , . . . . . . . . . . . . . . . . . Rhesus monkey

Polio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Cynomolgus monkey,

Chimpanzee

Premature labor . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey, Baboon

Rh factor disease . . . . . . . . . . . . . . . . . . . . . . . . Rhesus monkey

Slow viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Owl monkey, Squirrel monkey, Stumptail

monkey

Systemic lupus erythematosus . . . . . . . . . . . . . Cynomolgus monkey

SOURCES: Adapted from “Toward Better Health: The Role of Primates in Medical Reaearch,” Primate News 21(1):1-24, 1984;

and F. A. King and C. J. Yarbrough, “Medical and Behavioral Benefits From Primate Research,” Physlo/ogkt 28:75-87,

1985,
Ch. 5—The Use of Animals in Research . 91

to grow the poliovirus in human tissue culture

(15), and an effective vaccine became available to

the public in 1955. When the vaccine was developed, monkey kidney tissue was essential for production of pure virus in great quantities, and live

monkeys were essential for safety and effectiveness testing. Today, noninfectious polio vaccine

can be produced in continuously propagating cells

without the need for monkeys, although monkeys

are required to test for safety. The impact of the

polio vaccine has been dramatic: In 1952, at the

height of one epidemic, 58,000 cases of polio

occurred in the United States; in 1984, just 4 cases

were reported (39).

Hepatitis B

Hepatitis B is the most dangerous form of hepatitis, a debilitating liver disease characterized by

fever, weakness, loss of appetite, headache, and

muscle pain. There are nearly 1 million hepatitis

B virus carriers in the United States today, and

the infection is estimated to cost $1 million per

day in this country. Worldwide, there are some

200 million carriers, primarily in Asia and Africa.

Up to 1 percent of those infected with hepatitis

B die of the disease, and 5 to 10 percent become

chronic carriers of the virus who can remain infectious indefinitely (21). Since there is no known

treatment for hepatitis B infection, prevention is

essential.

Research with rhesus monkeys and chimpanzees led to the development just a few years ago

of a vaccine, derived from human plasma, against

hepatitis B infection. In 1981, the Food and Drug

Administration (FDA) licensed this vaccine for human use. In 1984, recombinant DNA technology

was used to prepare a hepatitis B vaccine from

yeast cells (the first vaccine for human use so

produced). Prior to its trial in 37 human volunteers, this yeast recombinant hepatitis B vaccine

was administered to African green monkeys in

order to gauge its effectiveness (52). These new

vaccines are expected to have a worldwide impact on the disease, and they may also reduce the

incidence of hepatocellular carcinoma, a form of

liver cancer associated with chronic hepatitis B

infection (40).

Herpes

Estimates of the number of persons afflicted

with recurrent genital herpes virus infections

range from 5 million to 20 million worldwide (61).

A new antiviral drug, acyclovir, was recently licensed for use against human genital herpes infections and appears to yield antiviral and clinical benefits when taken orally (48). Acyclovir was

extensively tested in African green monkeys. The

opportunity to run such tests arose because of

a natural outbreak of a virus closely related to

that causing both chickenpox and shingles (i.e.,

herpes zoster) in humans. The infected monkey

colony at the Delta Regional Primate Research

Center in Louisiana enabled scientists to study the

herpes disease process and test antiviral drugs.

In 1984, researchers reported an in vitro model

system for studying the herpes simplex virus,

using human fetal nerve cells as the host. This

in vitro model is expected to enable analysis of

the state of the herpes virus as it establishes and

remains latent in human nerve cells (62).

High Blood Pressure

High blood pressure, when untreated, increases

the risk of stroke, heart disease, and kidney failure. In most cases, the cause or causes of high

blood pressure remain unknown, and the condition is a public health problem of immense proportions. Data from the early 1980s indicate that

fully one-third of Americans use medication to

control blood pressure. From 1971 to 1981, visits

to physicians for diagnosis and therapy of high

blood pressure increased by 55 percent, while

visits for all other causes decreased by approximately 5 percent (32).

Monkeys are used to examine mechanisms of

high blood pressure because the natural hormone

molecules controlling blood pressure (e.g., the kidney hormone renin) are identical in humans and

other primates. In contrast, the renin molecules

of humans and nonprimate species are dissimilar. In addition to using monkeys to study the ef -

fects of diet and drugs on high blood pressure,

researchers are examining the genetic transmission of high blood pressure. One breeding colony

of cynomolgus monkeys exhibiting high blood
92 “ Alfernatives to Animal Use in Research, Testing, and Education

pressure has been monitored for 5 years; this permits the study of high blood pressure in parents,

offspring, and future generations to analyze the

tendency to inherit the condition.

Parkinson's Disease

Parkinson’s disease is a neurological disorder

of older adults characterized by palsy and rigid

muscles. Progress in understanding the cause and

development of the disease and in refining methods of long-term drug therapy has been hampered by lack of an adequate animal model. Attempts to induce the disease in rats, guinea pigs,

and cats either have failed to produce all the

symptoms or have yielded symptoms that do not

last long and so cannot be effectively researched.

In 1983, the first animal model of Parkinson’s

disease was developed. Scientists at the National

Institute of Mental Health (NIMH) induced a form

of parkinsonism in eight rhesus monkeys by giving them a drug, l-methyl-4-phenyl-1,2,3)6-tetrahydropyridine (MPTP), that selectively destroys

specific cells in the substantial nigra, a region of

the brain destroyed in humans by Parkinson’s disease. The monkeys exhibited all the major clinical features of Parkinson’s disease in humans.

They also responded dramatically to L-dopa, the

standard medication for people with this disease

(8). NIMH researchers have speculated that the

availability of this new animal model may lead to

understanding the reason Parkinson’s disease occurs in older adults, the course of the disease, and

drug therapy and its side effects (30).

In 1984, squirrel monkeys were used to shed

further light on the mechanism of MPTP-induced

parkinsonism. Pargyline, a drug currently prescribed for high blood pressure in humans (Eutonyl, Abbott Laboratories, North Chicago, IL),

was used to prevent the neurotoxic effects of

MPTP (31). These results in squirrel monkeys suggested that MPTP itself may not be the actual neurotoxic agent. Instead, attention is now focused

on an MPTP metabolize and on the mechanism

of MPTP metabolism in the brain (33).

Baldness

Like many men, stumptail monkeys become

bald as they age. This trait has made the stumptail monkey the animal of choice in baldness

research. Although it is not life-threatening, baldness is a matter of concern for many people: Haircombing patterns suggest that many men desire

to have hair where there is none, and advertisements for hair restoration abound in the popular

media. The public spends large sums on hairrestoration nostrums, and in 1985 the FDA proposed banning the sale of all nonprescription drug

products sold to prevent or reverse baldness, having concluded there is no scientific evidence that

such lotions and creams are effective (50 FR 2191).

A drug originally developed to manage high

blood pressure, minoxidil, has the unexpected

side effect of causing thick hair growth from follicles that normally produce only fine, downy

hair. To test the potential of minoxidil for hair

growth, researchers applied it externally to the

bald front scalp of stumptail monkeys. The results

with monkeys showed promise, and clinical trials

are now in progress with bald men across the

United States. Monkey studies are continuing to

assess the effects and safety of minoxidil as a

means of counteracting hair loss.

Menopausal Hot Flashes

Of the 30 million postmenopausal women in the

United States, as many as 75 percent have experienced or will experience hot flashes brought

on by increased blood flow to the skin. Hot flashes

produce a feeling of warmth for several minutes,

and they are often followed by sweating. These

physical symptoms may be accompanied by nervousness, irritability, and depression. At present,

physicians can treat the symptoms of menopause,

but the causes of the symptoms remain unknown.

Research into the mechanisms of menopause and

the development of therapy for menopausal

problems has been hampered by the difficulty of

studying this condition in animals. This difficulty

stems from three facts: only primates, and no

other nonhuman species, have menstrual cycles;

monkeys do not exhibit symptoms of menopause

until at least age 25; and monkeys brought into

the laboratory from the wild are rarely of menopausal age.

Throughout the last decade, researchers have

studied the menstrual cycle and its cessation in
Ch. 5—The Use of Animals in Research ● 9 3

~ .

Left: Bent, flexed posture and absence of movement

exhibited by a rhesus monkey treated with the drug

MPTP to induce Parkinson’s disease. Other symptoms

in both monkeys and humans include tremor, eyelid

closure, difficulty swallowing (drooling), and difficulty

with vocalization and speech.

Right: Reversal of abnormal posture and return of normal movement following treatment with L-dopa. The

right photograph was taken 2 hours after the left one.

Photo credit: f?. Stanley Bums, National Institute of Mental Hea/th

First animal model of Parkinson’s disease, developed in 1983

a limited number of rhesus monkeys reaching 25 and of hormones in the control of this problem.

to 30 years of age (11). In 1984, hot flashes were Once the underlying mechanisms that produce

described in another primate, the stumptail mon- hot flashes are better understood, more effective

key (25). The aim of developing an animal model treatments may be developed for women who

for hot flashes is to determine the role of the brain suffer from menopausal problems.
94 Ž Alternatives to Animal Use in Research, Testing, and Education

Experimental Animals’ Contribution

to Coronary Artery Bypass

Graft Surgery

A second way to describe the role of animals

in biomedical research is to review the ways in

which a single advance in applied biomedical research came about. As an illustration of this process, the development of the coronary artery bypass graft operation, recently recounted (9,46),

is summarized here.

Coronary or arteriosclerotic heart disease, often

caused by a narrowing or blocking of the arteries

supplying blood to the heart, is the number one

cause of death in the United States. In 1982, it

was responsible for approximately 500,000 deaths

(59). Coronary artery bypass graft surgery was

introduced in the early 1970s. In this procedure,

which has become the primary surgical approach

to treatment of coronary artery disease, a grafted

vessel is attached to the coronary artery to circumvent the constricted portion. The graft improves the blood and oxygen supply to the heart

muscle. The growth of the procedure has been

quite rapid: Approximately 70,000 operations

were performed in 1977; 160,000 in 1981 (7); and

191)000 in 1983 (38).

Coronary artery bypass graft surgery is now

the most commonly performed major operation

in the United States (7). It is accepted as far more

effective than medication in relieving the severe

chest pain, or angina pectoris, associated with

coronary heart disease (47). The long-term benefit of this procedure, in terms of mortality, varies

among patient groups (60).

The experimental steps leading to the successful coronary artery bypass graft operation are

depicted in figure 5-1, in which the cardiac surgeon stands at the summit of Mt. Coronary Artery Bypass. In the early stages of research—that

is, in the foothills of the mountain—there was a

great deal of variability in the kinds of animals

required. Studies in frogs, reptiles, horses, cats,

dogs, sheep, and deer contributed to scientists’

understanding of the fundamental principles of

circulation, blood pressure, and temperature regulation. As problems became more specialized,

the choices of animal species became more restricted. Dogs, chimpanzees, and, ultimately, humans contributed to the later stages of research

leading to the coronary artery bypass. Virtually

every step up Mt. Coronary Artery Bypass required initial stages of study on living animal

models of various species.

Today, in retrospect, the experimental steps

leading to this surgical procedure appear as a simple and logical progression. In this sense, figure

5-1 is deceptive. It is important to note that the

first step was not predictive of the second step,

the second not predictive of the third, and so on.

The advance from each step involved uncertainty,

missteps, and serendipity. All are inherent in the

process of basic biomedical research. Moreover,

only a poor understanding exists of the path leading from basic to applied biomedical research. Although Mt. Coronary Artery Bypass stands as a

bona fide illustration of the integration of data

drawn from several species, it was formed without a blueprint.

Use of Multiple Species in

Biomedical Research

The contributions of animals are an important

part of the history of human health, disease, and

medicine. It is noteworthy that animals have not

only contributed to human welfare, but deterred

from it as well. The benefits and detriments derived from animals involve numerous species.

The number of animal diseases labeled zoonoses-diseases transmissible from animals to

humans–now stands at about 200. These exact

a heavy toll of human morbidity and mortality

on a worldwide scale. Research to combat zoonoses logically focuses on the species that are the

principal sources of the diseases. And the more

species that are infected by a particular agent,

the greater are the biological resources available

for research to overcome it. Numerous animal

vectors of an infectious agent provide increased

opportunities for the study of variation among

species in the incubation of, transmission of, and

susceptibility to the infectious agent. Most of the

threats to humans from animals—including rabies, tuberculosis, brucellosis, toxoplasmosis, anthrax, and dengue fever—infect a sufficient va-
Ch. 5—The Use of Animals in Research ● 9 5

Figure 5-1.—Steps in Biomedical Research That Preceded Successful Coronary Artery Bypass Graft Surgery

dog, human

L:’QJ~:““ ~

Direct autograft - dog, human

:.,

-M -

$ 1 1

SOURCE: Redrawn from W, C Randall, ‘iCrises in Physiological Research,” Physiologist 26:351 -356, 1963, after J. H. Comroe, Jr., and R. D. Dnpps, “Ben Franklln and

Open Heart Surgery,” Circ Res. 35:661-669, 1974
 . Alternatives to Animal Use in Research, Testing, and Education

riety of species that effective research on their

control has been possible (19). Perhaps ironically,

the same diverse mix of species that transmits disease to humans forms the substrate for research

to ameliorate human disease.

Infection of multiple animal species has led to

virtual control in industrial countries of the

plagues just mentioned. Yet a paucity of animal

vectors or models hampers control of certain

other human infectious diseases. Leprosy, herpes,

and gonorrhea (which are not zoonoses) have yet

to be brought under control, owing partly to the

lack of effective animal models. Recent discoveries

of leprosy and herpes infections in primates, the

culture of the leprosy bacillus in armadillos, and

adaptation of the gonorrhea organisms to some

species of laboratory animals offer promise that

effective animal models will soon become available for research (19). Yet research on other conditions of still-unknown etiology, such as Alzheimer’s disease, remains impeded by the inability

to identify an appropriate animal model.

Additional impetus for employing a variety of

species in the course of research comes from a

consideration of the immune response, which recognizes material that is foreign to the body. The

immune system thus serves as an animal’s defense

against infections due to viruses, fungi, or bacteria. When foreign proteins, or antigens, are introduced into an animal, the immune system responds by manufacturing a protein of its own,

an antibody, to counter the invader. This is the

principle on which the development of vaccines

is based: An antigen is injected, and it stimulates

production of an antibody that combats the foreign antigen.

The strength of an immune response varies

from species to species, and even within a species, according to the genetic constitution of the

animal used. Researchers often cannot gain a full

understanding of how to develop useful vaccines

unless they test several species to examine subtle differences in immune responses. In this way,

species differences in response to foreign antigens

are found and can be exploited in the production

of effective vaccines for humans and animals. It

is this use of the immune system that has controlled most of the major infectious viral diseases,

including smallpox, which was controlled through

the use of the cowpox, or vaccinia, virus.

No one animal species is the complete research

model for the human. In general, nonhuman primate species have the greatest anatomical, physiological, and metabolic similarities to humans. Yet,

as table 5-2 indicates, much important biological

information can be provided by using dissimilar

organisms. (This table oversimplifies the use of

various animals in studying human health and disease because it does not rate the closeness of the

similarity of the conditions between humans and

animals (19).)

It is important to establish any new biological

principle or a new phase of understanding a disease condition in as many species as possible in

order to improve safely the extrapolation from

one animal to another and to humans (19). Research results derived from multiple systems in

varied species, such as those listed in table 5-2,

complement each other to approximate human

anatomy, physiology, and metabolism.

Some biomedical research, collectively known

as veterinary research, seeks to understand the

life processes of animals and applies this knowledge to serve animals themselves, as well as humans. Veterinary research addresses the normal

structure and function of animals and the causes,

diagnosis, prevention, and treatment of disease

in experimental animals and clinical (i.e., patient)

animals. Research on food- and fiber-producing

domestic animals supports the utilization of plant

and animal resources for human sustenance.

Veterinary research plays a prominent role in

controlling diseases of importance in food-producing animals and, hence, of importance to humans.

Veterinary research supports, and is closely allied with, veterinary medicine. Practitioners of

veterinary medicine maintain and improve the

health and well-being of animals. The profession

concentrates on the health of animals important

for food and fiber and on companion animals.

other species receiving veterinary attention include laboratory animals, fish and aquatic animals, and zoo and wild animals, Thus, the majority of veterinary medicine addresses 30 to 40

different species of economic, ecologic, and environmental importance. These include:

● domestic animals (e.g., cats, cattle, chickens,

dogs, donkeys, goats, horses, sheep, and

turkeys);
Ch. 5—The Use of Animals in Research ● 9 7

Table 5-2.—Some Anatomical, Physiological, and Metabolic Similarities and

Differences Between Humans and Various Laboratoy Animals

Conditions, systems, or structures

Animal Similarities to humans Differences from humans

Cat . . . . . . . . . . . . . . . . . Splenic vasculature

Sphenoid sinus in skull

Liver

Middle ear and ear drum

Epidermis

Cattle. . . . . . . . . . . . . . . Ascending colon

Electrolyte excretion

Chicken . . . . . . . . . . . . . Palate

Chinchilla . . . . . . . . . . . Inner ear structures

Dog . . . . . . . . . . . . . . . . Pituitary gland vasculature

Renal arteries

Splenic vasculature

Sphenoid sinus in skull

Superficial kidney vasculature

Liver

Epidermis

Adrenal gland innervation

Goat. . . . . . . . . . . . . . . . Embryonic blood circulation

Guinea pig . . . . . . . . . .Spleen

Immune system

Horse. . . . . . . . . . . . . . . Pulmonary vasculature

Bile duct

Pancreatic duct

Lung

Mouse . . . . . . . . . . . . . . Senile hepatic changes

Pig . . . . . . . . . . . . . . . . . Maturation of red blood cells

Cardiovascular tree

Teeth

Adrenal gland

Skin

Penile urethra

Retinal vessels

Spleen

Reaction to foreign protein

Laryngeal structures

Sweat glands

Mediastinum (interior chest tissue)

Development of embryonic gonads

Sleep

Heat regulation

Digestion

Plasma gamma globulins in

newborn

Sleep

Heat regulation

Vomiting

Sweat glands

Retinal vessels

Lymphoid tissue in liver

Pituitary gland

Respiratory system

Oviduct

Reproductive system

Acetate metabolism

Intestinal circulation

Anal sacs

Sweat glands

Pancreatic ducts

Heat regulation

Sleep

Laryngeal nerves

Mediastinum

Stomach and digestion

Heat regulation

Sweat glands

Vomiting

Sleep

Plasma gamma globulins in

newborn

Sweat glands

Carotid body

Spleen

Cecum and colon

Gall bladder

Plasma gamma globulins in

newborn

Spleen

Spleen

Liver

Plasma gamma globulins in

newborn

Sweat glands
98 ● Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

●

●

●

●

Table 5-2.—Some Anatomical, Physiological, and Metabolic Similarities and

Differences Between Humans and Various Laboratory Animals (Continued)

Conditions, systems, or structures

Animal Similarities to humans Differences from humans

Nonhuman primates . . Brain vasculature lnguinal canal

Rabbit . . . . . . . . . . . . .

Rat . . . . . . . . . . . . . . . .

Sheep . . . . . . . . . . . . .

Intestinal circulation

Placenta

Pancreatic duct

Adrenal gland

Innervation

Nucleic acid metabolism

Teeth and mandible

Brain

Larynx

Kidney

Reproductive performance

Menstrual cycle

Spermatozoa

.Splenic vasculature Liver

Spleen Sweat glands

Immunity Lung elasticity

Innervation

Middle ear and ear drum

. Spleen Cardiac circulation

Senile splenic changes Abdominal circulation

Senile pancreatic changes No gall bladder

. Splenic vasculature Stomach and digestion

Sweat glands Heat regulation

Breeding

Vomiting

Sleep

Plasma gamma globulins in

newborn

SOURCES: Adapted from B.M. Mitruka, H.M. Rawnsley, and D.V. Vadehra, Animals for Researclr, Mode/s for the Study of Human

Disease (New York: John Wiley & Sons, 1976); and W.1. Gay and J.D. Wlllett, “The Spectrum of Biological Systems

and the Selection of Models, ” in National Symposium on Imperatives in Research Animal Use: Scientific Needs

and Anima/ Welfare, NIH Pub. No. 652746 (Bethesda, MD: National Institutes of Health, 1965).

laboratory animals (e.g., mice, rats, guinea

pigs, rabbits, hamsters, and ferrets);

nonhuman primates (e.g., baboons, newworld monkeys, and old-world monkeys);

exotic birds (e.g., parakeets, parrots, cockatiels, and cockatoos);

birds of prey (e.g., falcons, hawks, and

eagles);

freshwater and marine fish;

marine mammals (e.g., porpoises and whales);

large terrestrial mammals (e.g., deer, antelope, elk, lion, tigers, elephants, and llamas);

and

assorted reptiles and amphibians.

Choice of Species

The variety of animal species used in research

spans the animal kingdom, and some species are

used more often than others (see ch. 3). Various

reasons exist for

search:

●

●

●

●

Some species

using particular species in reare more available than others.

For example, certain primate species are in

chronic short supply. Conversely, in the case

of rats and mice, large numbers of commercial breeding businesses can supply particular strains, ages, and sex on the purchaser’s

demand.

Existing databases and literature have been

built on a particular species. Additional work,

in order to contribute to the field in a direct

way, needs to be based on the same species.

For most research purposes, nonendangered,

commercially available animals are preferred

over endangered ones.

Some species exhibit the physiology or behavior of interest in a more vivid and robust

form than do other species. For example, the

desert-adapted kangaroo rat is the species of
Ch. 5—The Use of Animals in Research Ž 99

●

●

●

choice for studies of the kidney’s role in

water conservation,

Certain aspects of physiology or behavior are

exhibited by only a limited number of species. For example, studies of echolocation are

best done with bats, which emit sounds in

radar-type fashion.

The costs of acquisition vary widely among

species. For example, a mouse costs approximately $2, a hamster approximately $5, and

a guinea pig approximately $19. (The actual

cost for a particular species varies with the

sex, strain, weight, age, quantity ordered,

method of shipping, and distance shipped.)

Maintenance costs vary widely among species. Depending on the laboratory lifetime of

the animal, maintenance expenses can quickly exceed acquisition costs. For example,

THE ROLE OF ANIMALS I N

Like all of biomedical research, behavioral research relies on animals to identify models for and

aid in the understanding of human phenomena.

Behavioral research has the further goal of understanding the behavior of animal species of economic or intrinsic interest to people.

Behavior encompasses all the movements and

sensations by which organisms interact with both

the living and nonliving components of their environment (2). The environment includes not only

objects and events external to the organism, but

internal events as well (e.g., visceral cues, motivations, and emotions). Behavior is not an object

or a thing. It is a process that continues in most

organisms until they die. Even sleep is a form of

behavior. Unlike coloration or size, behavior is

a dynamic property that functions primarily to

enable an organism to adapt to changing environmental conditions.

What is Behavioral Research?

Classes of Behavioral Research

There are several classes of behavioral research, each with a distinct focus:

● Abnormal Behavior. In the broadest sense,

abnormal behavior is any that deviates from

●

maintaining a mouse in a research laboratory

costs approximately 5 cents per day, a hamster approximately 11 cents per day, and a

guinea pig approximately 40 cents per day.

(The actual per diem cost varies among different animal facilities, depending, for example,

on accounting practices and local labor costs.)

Results obtained from different species varv

in their ability to be generalized, both among

animals and between animals and humans.

Generalizations are more readily made among

species that are more closely related than

among species that are less closely related.

Attempts to identify alternatives to using animals

in research are likely to be influenced by these

considerations.

BEHAVIORAL RESEARCH

●

●

●

●

●

normal patterns. Instances among animals include seemingly suicidal, self-induced beachings by whales, phobic and neurotic problems in pets, and various laboratory-induced

animal models of human psychopathology

(e.g., depression, drug addiction, or obesity).

Aggression Aggression can be defined as an

organism’s threatening to inflict, attempting

to inflict, or actually doing physical harm to

another organism.

Animal Movements Animal movements represent major changes in location over time

and space, such as patterns of migration,

herding, homing, navigation, orientation, and

dispersal.

Body Maintenance. Behaviors that function

to provide body maintenance and homeostasis include hunger, thirst, respiration, thermoregulation, excretion, grooming, preening,

and parasite removal.

Cognition Although this label has been used

indiscriminately to encompass practically all

aspects of learned behavior (36), the term is

more strictly applied to instances of apparentmentalistic activity in animals (e.g., consciousness, thinking, imagery, self-awareness,

intention, or attribution).

Communication. Communication consists

of an exchange of information between two
92 ● Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

●

or more organisms that results in a change

in behavior. Instances of this range from

those that are stereotyped and instinctive,

such as the dance “language” of honey bees,

to those that might appear to have a symbolic

basis, as in the case of the recent attempts

to teach chimpanzees various forms of sign

language. Depending on species, communication can involve visual, auditory, olfactory,

or tactile cues.

Exploration and Activity. In addition to instances of curiosity and exploratory behavior,

patterns of activity included in this discipline

are circadian rhythms, sleep, hibernation,

roost-time restlessness, and different patterns

of locomotion (e.g., swimming, swinging, or

flying).

Habitat and Food Selection. Habitat and

food selection refer to the areas where animals live under natural conditions (e.g., freshwater streams, forests, or deserts) and the

ways they exploit resources. Areas of inquiry

by behavioral researchers include competition between species and optimal foraging

strategies.

Learning Memory, and Problem Solving.

These behaviors are represented by the acquisition and retention of new information

that allows organisms to anticipate recurring

environmental events, as well as changes in

behavior that maximize or minimize certain

outcomes. Included in this discipline is the

cultural transmission of information from

one generation to the next and imitation.

Motivation and Emotion The study of motivation looks at mechanisms and manipulations

that activate and sustain behavior. Emotion

typically includes reactions that accompany

different motivational states and is often associated, for example, with fear, anxiety, apprehension, pleasure, and rage.

Predator-prey Relations As a consequence

of selective pressure associated with predation, many prey species have developed an

extensive and elaborate array of predator

defenses couched in terms of sensory and/or

behavioral adaptations, such as burrowing or

voluntary immobility. Likewise, predators

use a variety of behavioral strategies in prey

identification and capture.

●

●

●

●

Reproduction and Parental Care. Patterns

of courtship, mate selection, copulatory behavior, nest building, nurturing, and care of

offspring all fall within this discipline.

Sensation and Perception. Sensation and

perception refers to the ways in which organisms detect and interpret their environment. Topics included in this discipline include studies of sensory mechanisms, the

development of search images, and highly

specialized sensory mechanisms, such as

echolocation.

Social Behavior. Social behavior is defined

by a situation in which the behavior of one

organism serves as a stimulus for the behavior of another, and vice versa. Instances

of social behavior range from simple forms

of aggregation to complex exchanges among

individuals (e.g., dominance, cooperation, and

reciprocal altruism).

Spacing Mechanisms Spacing mechanisms

are intimately tied to social behavior, and

range from such topics as individual distance

to the maintenance of territories.

Behavioral v. Biomedical Research

Distinctions between behavioral and biomedical research, although they are commonly made

(and are followed in this assessment), frequently

break down. Behavior, in the final analysis, is a

biological phenomenon, Behavior presupposes a

living organism, and the way that organism behaves is influenced in complex ways by its genetic

makeup, hormonal status, physiology, and neurochemistry. Intervening between the input of environmental events and the output of behavioral

events are complex neuroanatomical networks involving receptors, electrochemical reactions,

nerve impulses, and effecter organs. Behavior

does not occur in a vacuum. The biology of the

organism provides the foundation that makes behavioral events possible.

It is increasingly apparent that many aspects

of behavioral research must be viewed in conjunction with biomedical research. Strong components of both behavioral and biomedical research

are evident, for example, in the study of obesity,

hypertension, drug addiction, headaches, aggression, alcoholism, sexual dysfunction, brain dam-
Ch. 5—The Use of Animals in Research ● 101

age, epilepsy, schizophrenia, depression, learning disorders, smoking, anorexia nervosa, stomach

ulcers, mental retardation, and a variety of other

psychological disorders.

Why Are Animals Used in

Behavioral Research?

Control

The use of animals under laboratory conditions

enables the manipulation and control of a variety of factors that in different settings would confuse, contaminate, and confound any attempt to

interpret a behavioral outcome. Animal models

also allow the control of genetic background,

prior experience, temperature, humidity, diet,

and previous social encounters. When these variables are uncontrolled, observed behavioral responses can be virtually impossible to interpret.

objectivity

Two prerequisites to any research are objectivity and impartiality. When humans study humans, as can be the case in behavioral research,

unique problems may arise. Not only can it be difficult for the investigator to remain objective in

interpreting behavioral phenomena, but a variety of other complications can arise from the social relationship among those conducting the research and those participating as subjects (50).

The use of nonhuman species partially ameliorates this problem.

Developmental Effects

Among many species behavior changes as a

function of age. The problem this poses for human research is one of time. Human development

continues for many decades. To chart behavioral

changes within the same persons would take

many years, involving exhaustive followup studies

and the ever-present danger of losing research

subjects, for example, because of death or relocation. The alternative to such longitudinal work

is to conduct cross-sectional studies, where simultaneous samples are drawn from different age

groups. A problem in this case is that sociological and cultural changes over time (e.g., 50 years

ago, an eighth-grade education was the norm)

confound apparent differences between people

of different ages. Because a range of lifespans is

available among laboratory species, the use of animal models can minimize or circumvent altogether some problems associated with the study

of behavior over time.

Genetic Effects

There is growing evidence of a variety of genetic effects on behavior (23). With animal models,

selective breeding studies can establish, pinpoint,

and quantify genetic effects on behavior. The opportunity for human research in this area, apart

from studies of identical twins, is limited.

Methodology

The fact that animals cannot talk seems at first

to constitute a serious disadvantage to conducting behavioral research with animals. Yet, the

stark limits of trans-species communication help

to keep human investigators unbiased in their

work. The use of animal models forces the behavioral scientist to develop objective, operational

definitions and research techniques that may later

be applied to humans.

Lower Complexity

Behavior, notably human behavior, can be extremely complex. The use of animals that appear

to be structurally and functionally less complex

presents a way to identify some of the basic elements and principles of behavior that might otherwise remain inextricably embedded in a mosaic

of other factors.

Species-Specific Behaviors

Certain behavioral phenomena fall outside the

realm of human sensory or motor abilities. For

example, flight, echolocation, infrared detection,

and homing require the use of nonhuman species as subjects for research purposes.

Heuristic Value

Research on the behavior of animals has been

an important source of hypotheses about human

behavior and an impetus to research on humans

(35). Much of what is now known about the prin-
102 ● Alternatives to Animal Use in Research, Testing, and Education

ciples of learning, for example, was initially derived from research on animals. Likewise, a variety of therapeutic techniques (e.g., desensitization)

were derived from work with animals, Human

studies were done to verify what was learned

from animal research and to gauge the limits of

extrapolation from animals to humans.

Practical Application to Animal Species

In addition to providing models of a variety of

biomedical and psychological problems in humans, research on animal behavior is in many instances focused on benefits to the animals themselves. For example, an understanding of behavior

has proved crucial for designing optimal captive

environments for the protection and breeding of

endangered species (55). Increased attention has

also been paid to the behavior of farm animals.

The study of mother-infant attachments, social

behavior in groups, stress resulting from overcrowding and confinement, and habitat preferences has led to important insights into farmanimal welfare and husbandry (13,27,54).

It is also noteworthy in this context that knowledge gained about behavioral problems in humans

through animal research is now being applied to

animals. Effective treatments have been developed for aggressive problems in cats (5) and fears

and phobias in dogs (24)58).

A knowledge of animal behavior has helped

identify and solve ecologic problems. The discovery and subsequent synthesis of insect sex attractants, or pheromones, has important implications

for the control of agricultural pests. Rather than

having to use toxic pesticides applied over vast

areas, there is already some application and much

future potential in baiting traps with specific

pheromones, which precludes environmental

contamination.

One unique application of laboratory findings

to the solution of ecologic problems involved studies of taste-aversion conditioning in rats (18). Researchers paired unpleasant, chemical- or radiation-induced illness with different flavors. After

just one or two trials, rats developed highly durable aversions to the flavors paired with unpleasant

stimuli. outside the laboratory, by pairing lithium-chloride-induced illness with the flesh of various prey species, it is now possible to control coyote attacks on sheep and turkeys (14). Indeed, one

or two trials is sufficient to eliminate attacks on

specific domestic farm animals but leave the coyote free to feed on alternative prey (22).

This procedure has recently been extended to

reducing crop damage by crows and even appears

to have promise for dealing with cancer patients

undergoing radiation therapy (l). (A frequent

complication of radiation therapy has been unpleasant gastrointestinal illness that the patient

generalizes to all food; the patient may be unable to eat. Using the principles of conditioned taste

aversion developed in rats, it is now possible to

circumvent the problem by restricting patients

to one particular kind of food during radiation

treatment, so that the aversion that develops is

specific to that food alone.)

Individual Animals in the

Service of Humans

Behavioral research occasionally centers on a

trait of a particular species that maybe especially

well suited to assist humans. For example, using

animals to help handicapped persons has required

a knowledge of animal behavior. Seeing eye guide

dogs, usually German shepherds or golden retrievers, assist the blind (20), and trained capuchin monkeys perform as aides for quadriplegics

(63). Pet dogs and cats have been shown to have

therapeutic value for psychiatric patients (10), the

handicapped (12), and the elderly (49), and they

may even hold promise for alleviating depression

resulting from loss of a child (57).

Methods of Behavioral Research

The methods of behavioral research are as varied as the disciplines, but most fall into one of

three general categories: field studies and naturalistic observation; developmental studies; and laboratory studies.

Field studies represent an attempt to examine

the behavior in question as it occurs under natural circumstances, Such studies do not typically

involve attempts to manipulate or control the conditions of observation. watching animals in natural conditions has frequently been suggested as
Ch. 5—The Use of Animals in Research • 103

an alternative to using them in laboratory research (6,44). The following benefits and limitations of naturalistic observation have been recognized:

●

●

●

●

Naturalistic observation is frequently a starting point. Observation of animals in the field

provides a base of descriptive information

and serves as a source of hypotheses to be

subsequently tested under laboratory conditions,

Naturalistic observation can be used to compare behavior observed in the field with that

occurring in the laboratory to assess the extent to which an artificial environment may

alter behavior, and whether the results can

be generalized.

Field studies can increase the efficiency with

which animals are used by providing important information on natural species variables

and biological constraints on behavior.

The principal drawback to naturalistic observation is the absence of control. Under natural conditions, events frequently change in

both important and spurious ways, often

making it impossible to establish cause-andeffect relations (37).

Behavioral research often requires study of one

animal or a group through time, as development

proceeds. Among many species the emergence of

different patterns of behavior is a reflection of

both maturational and experiential factors. Developmental variables have been identified as being important in the expression of such diverse

behaviors as aggression, communication, activity,

learning, and social behavior.

Laboratory studies undertake to manipulate

and control the condition of observation so as to

specify more precisely the variables and conditions that influence the behavior in question. Most

laboratory studies of behavior can be subdivided

into those that attempt to identify the environmental determinants of behavior and those concerned with the organic basis for behavior.

Within the latter category are a number of approaches involving attempts to identify the neu -

roanatomical, neurochemical, endocrinological,

and genetic underpinnings for behavior.

Use of Multiple Species in

Behavioral Research

Many behavioral phenomena appear common

to different species. Patterns of migration, for example, are common to such diverse groups as insects, fish, birds, and even some species of mammals. Much the same appears true for learning,

motivation, and bodily maintenance. Yet, generalizations about categories of behavior (e.g.,

parental care or hoarding) in unrelated species

may be misleading, because the species evolved

independently (34). Moreover, comparing the performance of different species on a simple task

may have no bearing on larger issues such as intelligence (26). What used to be seen as general

principles and “laws” of learning, for example,

now turn out to be specific to certain species under certain situations (3,4,53).

There are some behaviors that are of limited

scope across species but of profound importance

in terms of their bearing on the question of human behavior. For example, the capacity to recognize one’s own reflection in a mirror has only

been found in humans, chimpanzees, and orangutans, and much the same may apply to instances

of intentional deception, gratitude, grudging, sympathy, empathy, attribution, reconciliation, and

sorrow (17).

PAIN AND DISTRESS IN RESEARCH ANIMAL S

There are two general kinds of animal ex- tion of pain and the monitoring of the responses

perimentation in which pain may occur. First, to pain are usually integral parts of the experithere are studies that investigate the nature of mental procedure. The goal is the prevention,

pain itself and the anatomical, behavioral, chem- treatment, and amelioration of human and aniical, pharmacological, and physiological mecha- mal pain. The second, and much larger, class of

nisms responsible for it. In such studies, the inflic- animal experimentation in which pain may occur
104 Ž Alternatives to Animal Use in Research, Testing, and Education

consists of those studies in which pain is but a

byproduct of the procedures used (28).

When indices of pain are observed or anticipated in living research animals as byproducts of

an experimental protocol, the investigator is both

informally and formally obliged to supply pain relief. (For a further discussion of the investigator’s

responsibilities in this area, see chs. 4, 13, 14, 15,

and 16.)

Pain relief for a laboratory animal is usually accomplished by one of three means. An analgesic is an agent that relieves pain without causing loss of consciousness. The most frequent use

of analgesic drugs in laboratory animals is likely

to be in the postoperative period. An anesthetic

is an agent that causes loss of the sensation of

pain, usually without loss of consciousness. An

anesthetic may be classified as topical, local, or

general, according to the breadth of its effect.

Topical anesthetics find only limited use in animal research, usually as components of ointments

applied to minor injuries, whereas local anesthetics are used for many minor surgical procedures. The use of local anesthetics requires postsurgical care, because anesthetized surfaces are

particularly liable to accidental and self-inflicted

damage (43). General anesthetic, either injected

or inhaled, is widely used in research. A tranquilizer is an agent that quiets, calms, and reduces anxiety and tension with some alteration

of the level of consciousness and without effecting analgesia. Tranquilizers are particularly useful in reducing distress and resistance to confinement.

The perception of pain is largely subjective. It

is best described as an awareness of discomfort

resulting from injury, disease, or emotional distress and evidenced by biological or behavioral

changes. A frequent companion to pain is distress—the undesirable stress resulting from pain,

anxiety, or fear (51). Distress can also occur in

the absence of pain. An animal struggling in a restraint device may be free from any pain, but it

may be in distress.

Despite the difficulty associated with objectively

defining pain, it can usually be recognized. The

most obvious sign is an animal’s behavior (16)42,

56),

●

●

●

●

●

●

●

Signs of pain include the following:

Impaired activity. Animals may be relatively inactive or may remain completely immobile within their pen or cage. If they do

move, it is often with an abnormal gait, such

as limping or not using a leg.

Change in personality. Pain may result in

guarding behavior (attempting to protect or

move away). Animals may also be uncharacteristically aggressive.

Restlessness. Animals may move about

continually or may rise up and lie down

repeatedly.

Decreased intake. Food and water consumption are usually severely retarded, often

to the extent that moderate or severe dehydration can occur.

Abnormal vocalization. Dogs may whine or

whimper, rats and hamsters may squeak at

a high pitch, and primates may scream or

grunt.

Abnormal posture. Dogs, cats, and rodents

may tense the muscles of the back and abdomen to effect a “tucked-up” appearance.

Self-mutilation. Dogs and rodents may

gnaw at the site of a lesion on their own flesh

or, for example, remove their own tumor.

In identifying pain, all these criteria must be

considered in conjunction with the nature of the

experimental procedure and the previous normal

behavioral characteristics of the animal. Also, it

should be noted that no one criterion is a wholly

reliable indicator of pain.

An experimental procedure probably involves

pain if it includes, for example, induction of any

pathological state, administration of toxic substances, long-term physical restraint, aversive

training, or major operative procedures such as

surgery and induction of physical trauma. Various procedures employed in the research laboratory can be compared, ranking each for the estimated degree of pain for the animal subject (see

table 5-3). Educated estimates of pain perception

in animals can be made by understanding animal

behavior; by drawing analogies based on compar-
Ch. 5—The Use of Animals in Research ● 105

Table 5-3.—Classification of Research Experiments and Procedures

According to the Degree of Pain or Distress for the Animal

Level of

pain/distress Examples of types of experiments Examples of procedures

Absent or

negligible .

●

●

Low ●

●

●

Moderate ●

●

High

Noninvasive behavioral testing

Studies of migration or homing

Dietary preference studies

Determination of pain threshold

Manipulation of blood chemistry

Experiments carried out on anesthetized

animals that do not wake up again

Behavioral study of flight or avoidance

reactions

Operations carried out under anesthesia or

analgesia, with the animal waking up or

experiencing the cessation of the action of

the painkiller (postoperative pain)

Chronic stress studies

Drug withdrawal studies

Studies of certain infectious agents

Experiments on mechanisms of pain in

conscious animals

Experiments on mechanisms of healing

Studies of radiation toxicity

●

●

●

●

●

b

●

●

●

●

●

●

b

●

●

●

●

●

●

●

●

●

●

●

●

●

Banding for identification or tracking

Field observation

Fecal examination

Conditioned learning with food reward

Flinch or jump response

Injections

Tube feeding

Tattooing

Administration of anesthetic

Surgery under deep anesthesia and subsequent

sacrifice

—Removal of organs for histological or biochemical

investigation

—Culture of surviving organs

Blood sampling

Stimulation of unanesthetized animal

Biopsies

Implantation of chronic catheters

Castration

Mild electric shock

Implantation of electrodes

Central nervous system lesions

Exposure of internal organs

Food or water restriction for more than 24 hours

Prolonged physical restraint

Chronic sleep deprivation

Intense electric shock

Production of pain clearly beyond threshold tolerance

Induction of burns or wounds

Surgery on conscious animal

SOURCE: Office of Technology Assessment.

ative anatomy, physiology, and pathology; and by enced by laboratory animals—ranging from abbasing inferences on subjective responses to pain sent or negligible to high-can provide a basis for

experiences by humans. Careful attempts to esti- efforts to minimize the pain or distress caused

mate and categorize the degree of pain experi- by research procedures.

ANIMAL AND NONANIMAL PROTOCOLS IN BIOMEDICAL AND

BEHAVIORAL RESEARCH REPORTS

One way to measure the balance of animal and mal and nonanimal protocols in contemporary renonanimal methods in research is to survey the search.

end-product of experimentation—the published

literature. OTA examined approximately 6,000 re- Fifteen leading scientific journals were selected

search reports published from 1980 through 1983 to represent disciplines within biomedical and bein an effort to document the prevalence of ani- havioral research, These journals were chosen be-
.

106 ● Alternaives to Animal use in Research, Testing, and Education

cause of their primary emphasis on research done

in the United States by American scientists and

because of the respect accorded them by scientists in each discipline. The editors of all 15 subject manuscripts to independent peer review

prior to publication.

For each year from 1980 through 1983, OTA

examined the first 100 research papers published

in each journal; in a few cases, fewer than 100

papers were published in a given year. Short communications and review articles were not included. In each report, OTA checked whether animals were used. Thus, the materials and methods

employed in each article were categorized as either use of animals, no use of animals, or use of

humans. ‘(Animal” is defined as described earlier

(see ch. 2), any nonhuman vertebrate. “Use” of

animals is defined conservatively as any use of

an animal in an experiment. Table 5-4 lists some

examples of the ways specific protocols were

categorized by OTA.

Survey Findings

The results of this survey indicate that the research journals—and perhaps the disciplines they

represent—fall into two categories:

Table 5-4.—Classification of Pubiished Research

Protocois in OTA Survey of 15 Journais

Examples of protocols classified as use of animals:

Whole animals used as experimental subjects

Animals used to obtain cell, tissue, or organ of interest

Animals used in the establishment of new cell, tissue, or

organ cultures

Extraction of protein or other biological molecule from

animals

Production of antibodies by whole animals or animal

components

Use of egg, sperm, or embryo from animal source

Use of animal epidemiologic data

Examples of protocols classified as no use of animals:

Use of invertebrate organisms

Use of computer systems

Use of previously established cell lines

Acquisition of biological molecules from a commercial

manufacturer

Use of physical or chemical systems

Examples of protocols classified as use of humans:

Use of living human subjects

Use of cadavers

Use of human placenta

Use of human blood cells or components

Use of human epidemiologic data

SOURCE: Office of Technology Assessment.

● journals representing disciplines that have already largely incorporated nonanimal methods into the research process; and

. journals representing disciplines that either

have not incorporated, or may not have available, nonanimal methods.

For most of the 15 journals (see table 5-5), published protocols fall predominantly into just one

of the three categories of methods; in many cases,

over 80 percent of the protocols are in one category. Only Cell, representing cell biology, had a

majority of articles using nonanimal methods. The

American Journal of Cardiology contained a majority of articles using humans or human materials as research subjects. All the remaining journals except Developmental Biology and the Journal of Biological Chemistry included a majority

of articles using animals. Developmental Biology

and the Journal of Biological Chemistry contained

approximately equal percentages of articles employing animal and nonanimal methods.

The 12 biomedical research journals included

in this survey cover a diverse array of disciplines

under this one rubric. The differing patterns of

animal, nonanimal, and human use make generalizations misleading at best and perhaps impossible. In the same way that biomedical research

itself is not monolithic, the patterns of animal use

among disciplines of biomedical research are not

uniform. Perhaps not surprisingly, veterinary research, insofar as it is represented by two journals, relies primarily on animals, a minimal percentage of nonanimal methods, and no protocols

with humans.

The three behavioral research journals included

in this survey registered a predominance of animal methods—more than 90 percent of the protocols in each case. The research reported in these

journals involved minimal use of humans or

nonanimal methods. Other behavioral research

journals, for example those reporting on clinical

psychology, largely publish reports of research

with human subjects.

Survey Limitations

This attempt to gauge the implementation of

nonanimal methods in selected areas of biomedical and behavioral research had certain limita-
Ch. 5—The Use of Animals in Research ● 107

Table 5-5.–Percentage of Papers (Average, 1980-83)

Using Animal, Nonanimal, and Human Subjects in

15 Biomedical and Behavioral Research Journals

Surveyed by OTA

Percentage of papers using:

Journal Animals Nonanimals Humans

to distinguish between different vertebrate species. Any alternative protocol, therefore, that

tended to reduce or refine an existing animal procedure was still categorized as “use of animals. ”

An example of the problem of overestimation

of animal use by a survey such as this exists in

immunology. Today, antibodies, needed in most

immunology research, can be obtained by injecting rabbits with foreign proteins, or antigens, and

extracting the antibodies that the rabbit produced

or by using mouse spleens and the monoclinal

antibody technique to produce antibodies to an

antigen. Each process requires animals. Once the

monoclinal cells are in culture, however, there

is a virtually unlimited supply of the needed antibody, and there is essentially no further need for

animals. Thus the monoclinal technique can decrease animal use, as was the case in many of the

most recent articles surveyed in the Journal of

Immunology. These articles, though, were still

coded under the “use of animals” category because the primary methods and materials involved animals. But the total number of animals

in a given experiment decreased, for they were

used in just one aspect of the experiment instead

of two. The monoclinal antibody technique is being used as an alternative to the repeated use of

rabbits, yet its impact is underestimated in a survey such as this. The OTA scoring of protocols

published in the Journal of Immunology did not

reflect certain reductions that are currently being implemented.

Along with underestimating the implementation

of nonanimal methods, the boundaries within

which the OTA survey was carried out also

tended to overestimate the use of animals as experimental subjects. This was due principally to

two factors included in the scoring procedure

under animal use-epidemiologic studies and the

study of biological molecules obtained from

animals.

Epidemiologic data are the primary sources in

some articles in the American Journal of Cardiology, the Journal of the National Cancer Institute, and in many veterinary studies. These protocols were included under “use of animals,” yet

they did not manipulate animals in any way as

experimental subjects.

Biomadical research:

American Journal of

Veterinary Research . . . .

Journal of Animal

Science . . . . . . . . . . . . . . .

Endocrinology . . . . . . . . . . .

American Journal of

Physiology . . . . . . . . . . . .

Anatomical Record . . . . . . .

Proceedings of the Society

of Experimental Biology

and Medicine . . . . . . . . . .

Journal of Immunology . . .

Journal of the National

Cancer Institute . . . . . . . .

Developmental Biology . . .

Journal of Biological

Chemistry . . . . . . . . . . . . .

Cell . . . . . . . . . . . . . . . . . . . .

American Journal of

Cardiology. . . . . . . . . . . . .

Behavioral research:

Behavioral and Neural

Biology . . . . . . . . . . . . . . .

Journal of Comparative

and Physiological

Psychology . . . . . . . . . . . .

Phvsioloav and Behavior . .

96 4a o

4

b

8

96

91

0

1

90

88

6

3

4

9

10

10

7

19

83

71

60

54

9

46

31

0

9

2

39

31

52

67

12 0 88

96 4 0

96

93

3

1

1

6

aprimarily virus research.

bprimarily computer rn~d~lin~ or grain fermentation applicable to ruminant

nutrition.

SOURCE: Office of Technology Assessment.

tions. The conservative scoring procedure tended

to underestimate the use of alternatives to animals as defined in this assessment (see ch. 2). For

instance, if an experimental protocol used both

animal and nonanimal methods, it was categorized under use of animals. If a study involved

both nonanimal methods and humans, it was

counted as use of humans. Further, if a study involved both animal methods and humans, it was

counted as use of animals. The approach used to

categorize protocols took into consideration only

the replacement, not the reduction or refinement,

of animal methods. Whether a protocol involved

1 or 100 animals, it still fell under the category

of “use of animals, ” and all reports bore equal

weight in determining percentage of protocols

using humans or animal or nonanimal methods.

In addition, there was no attempt to quantify the

pain or stress of an animal in an experiment or
108 ● Alternatives to Animal Use in Research, Testing, and Education

Obtaining many biological molecules that are

studied experimentally requires that they be extracted from animals who produce them. Subsequent experiments on these molecules themselves

(reported, for example, in the Journal of Biological Chemistry) do not involve animals at all. In

such cases, animals may be used in preparation

for an experiment but are not actually involved

in the experiment being performed. Therefore,

protocols that involved animals as donors of biological molecules (e.g., bodily fluids) for an experiment prior to its initiation were also included

under use of animals, and this tended to overestimate the use of animals as research subjects.

It is important to distinguish between the number of published articles involving animal methods and the actual number of animals used in research. The OTA survey provides no information

on the latter. Some protocols may involve only

a few animals, while others may employ tens or

hundreds. Moreover, depending on the species

and type of research, some subjects might be used

in multiple experiments. In primate research, for

example, it is not uncommon for animals to be

used in a succession of either related or unrelated

studies over a period of years; this would not be

the case for rodents.

SUMMARY AND CONCLUSIONS

Biomedical and behavioral research center on

the understanding of human health and disease

and rely on animals to achieve this goal. They use

animal subjects to understand not only human

phenomena, but animal phenomena as well. The

broad spectrum of enterprises involved in these

fields of research includes disciplines ranging

from anatomy to zoology. Although the varied disciplines that make up biomedical and behavioral

research have distinct foci, they often overlap.

Animals are used throughout these disciplines

to address an array of questions. Nonhuman primates, for example, have contributed to an understanding of polio, hepatitis B, high blood pressure,

Parkinson’s disease, baldness, menopausal hot

flashes, and other human conditions. Beyond the

nonhuman primates, diverse species are used in

biomedical research because of their anatomical,

physiological, and metabolic similarities to or

differences from humans. Principles and techniques developed in varied animal species (e.g.,

dog, horse, and sheep) may combine to support

a single application to humans, as in the case of

coronary artery bypass graft surgery. In behavioral research, different animal species may

also be used to learn about characteristics unique

to the species under study, usually one of economic importance or intrinsic interest to humans.

Animals may suffer pain or distress in the

course of research on the mechanism of pain, or,

more generally, as a byproduct of experimental

procedures. In such cases, the investigator is

obliged to supply pain relief to the animal or to

justify withholding pain-relieving drugs as necessary to the experiment. Institutional animal care

and use committees play an important role in

overseeing this process (see ch. 15). Pain relief is

usually effected by the administration of analgesic, anesthetic, or tranquilizing agents. Indices of

pain can usually be recognized in experimental

animals, and experimental procedures can be

ranked according to estimates of the degree of

pain produced. Such a ranking provides a basis

for efforts to minimize the pain caused by research procedures.

An OTA survey of published research reports

in 15 scientific journals documented the prevalence of animal v. nonanimal protocols in contemporary research. Each research journal, and perhaps the discipline it represents, can be identified

by a characteristic balance of protocols using animals, nonanimals, and humans. The data permit

research journals to be classified as representing

disciplines that either rely on nonanimal methods or that do not incorporate such methods (or

do not have them available). In the same way that

research itself is not monolithic, patterns of animal use and the use of nonanimal methods among

research disciplines are not uniform.
Ch. 5—The Use of Animals in Research s 709

CHAPTER 5

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Chapter 6

Alternatives to Animal Use

in Research

Unless we get a handle 011 what is happening in the mammalian brain, there’s no way of

knowing whether any of these [invertebrate] models is right or not.

Richard F. Thompson

Stanford University

Science 85 6(4):33, 1985

Investigators often ask statisticians how many observations they should make (fortunately,

usually before the study begins). To be answerable, this question needs fuller formulation.

There is a resemblance to the question, How much money should I take when I go on

vacation? Fuller information is needed there too. How long a vacation? Where? With whom?

Three questions need to be answered before the sample size is determined. How variable

are the data that will be collected? How precise an answer is needed? How much

confidence should there be in the answer obtained? These questions can be well worth

probing even if the question of sample size will foreseeably be answered by the size of the

budget or the time available for the study. Sometimes a planned study is dropped because

sample-size analysis shows that it has almost no chance of providing a useful answer under

the constraints of time or budget that apply.

Lincoln E. Moses

Stanford University

N. Engl. J. Med. 312:890-897, 1985
CONTENTS

Page

Continued, But Modified, Use of Animals in Biomedical Research . ............114

Reduction in the Number of Animals used . ...................,....,.,..114

Substituting One Species for Another . . . . . . . . . . . . . . . . . . . . . . . . . . ........116

Reduction of Pain or Experimental Insult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117

Use of Living Systems in Biomedical Research . ............................118

In Vitro Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..118

Invertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....122

Micro-organisms ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........123

Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....................123

Use of Nonliving Systems in Biomedical Research . ................,........124

Chemical and Physical Systems . . . . . . . . . . . . . . . . . . . . . . ......,..........,124

Epidemiology: Using Existing Databases . . . . . . . . . . . . . . . . . . . . . ............124

Computer Simulation in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . ........124

Continued, But Modified, Use of Animals in Behavioral Research . ............126

Reduction in the Number of Animals Used . ............................,126

Substitution of Cold-Blooded for Warm-Blooded Vertebrates . ..............128

Reduction of Pain or Experimental Insult . . . . . . . . . . . . . . . . . . . . . . .........130

Use of Living Systems in Behavioral Research . . . . . . . . . . . . . . . .. .. ... ... ,...133

Invertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....,.133

Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . ....135

Use of Nonliving Systems in Behavioral Research . . . . . . . . . . . . . . . . . . . . . . . ,..136

Computer Simulation in Behavioral Research . . . . . . . . . . . . . . . . . . . . . . . . .. ....136

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....138

Chapter preferences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........139

List of Tables

Table No. Page

6-1. Research Methods Involving Living Components. . . . . . . . . . . . . . . . . . . ., ., .113

6-2.Properties of In Vitro Culture Systems. . . . . . . . . . . . . . . . . . . . . . . . . . .. ....119

6-3. Some Examples of Computer Simulation of phenomena in

Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...125

6-4. Some Examples of Computer Simulation of Behavioral phenomena . .......137

List of Figures

Figure No. Page

6-1. Apparatus for Remote Blood-Sampling via Chronic, Intravascular Catheter

From Unrestrained Ferret . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......,118

6-2, Schematic of Experimental Organ Perfusion . . . . . . . . . . . . . . . . . . . . . ......120
Chapter 6

Alternatives to Animal Use in Research

Alternatives to animal use in biomedical and behavioral research fall into four broad categories:

●

●

●

●

continued, but modified, animal use, including a reduction in the number of animals

used, improved experimental design and statistical analyses of results, substitution of coldblooded for warm-blooded vertebrates, substitution of laboratory mammals for domestic

or companion mammals, and reduction of pain

or experimental insult;

use of living systems, including in vitro cultures (of cells, tissues, and organs; see table

6-l), embryos, invertebrates, micro-organisms, and plants;

use of nonliving systems, such as chemical

or physical systems; and

computer simulation.

In this chapter, various disciplines within biomedical and behavioral research are surveyed in

order to focus attention on the most promising

areas for development of alternatives to animal

methods. Areas not amenable to the implementation of such alternatives are also identified.

As noted in chapter 5, distinctions within and

among the varied disciplines of biomedical and behavioral research are artificial in one sense: Boundaries among disciplines are often blurred, and

broad areas of overlap exist. Yet the examination

of discrete areas of research highlights the great

variability among disciplines in the potential for

using alternatives to animals.

Using alternative methods in research holds several advantages from scientific, economic, and humane perspectives, including:

●

●

●

●

●

●

●

●

reduction in the number of animals used;

reduction in animal pain, suffering, and experimental insult;

reduction in investigator-induced, artifactual

physiological phenomena;

savings in time, with the benefit of obtaining

results more quickly;

the ability to perform replicative protocols on

a routine basis;

reduction in the cost of research;

a greater flexibility to alter conditions and variables of the experimental protocol;

reduction of error stemming from interindividual variability; and

the intrinsic potential of in vitro techniques

to study cellular and molecular mechanisms.

At the same time, these methods are fraught with

inherent disadvantages, including:

●

●

●

reduced ability to study organismal growth

processes;

reduced ability to study cells, tissues, and organ systems acting in concert;

reduced ability to study integrated biochem -

ical and metabolic pathways;

Table 6-1 .—Research Methods Involving Living Components

Isolated perfused Isolated tissue or Isolated single Subcellular

organs using: tissue sample using: cell using: constituents using:

liver striated muscle fat cells nuclei

muscle iris liver cells mitochondria

heart trachea neurons microsomes

lung bronchi glial cells Iysosomes

adrenal gland lung striated muscle cells synaptosomes

pituitary gland uterus smooth muscle cells cell membranes

intestine intestine red blood cells muscle actin/myosin

testis seminal vesicle leukocytes

skin vas deferens platelets

spleen bladder mast cells

kidney spleen

salivary gland

fat pads

liver slice

SOURCE” Adapted from W. Paton, Man and Mouse: Anima/s in Medical Research (New York: Oxford University Press, 19S.4),

1 1 3
114 ● Alternatives to Animal Use in Research, Testing, and Education

reduced ability to study behavior;

reduced ability to study the recovery of

damaged tissue;

reduced ability to study interaction between

the organism and its environment;

reduced ability to study idiosyncratic or

species-specific responses;

reduced ability to distinguish between maleand female-specific phenomena; and

. a handicap to probing the unknown and phenomena not yet identified.

This general listing of advantages and disadvantages provides a framework for examining the use

of alternatives in specific disciplines of biomedical and behavioral research. Many of these pros

and cons are cited in this chapter’s detailed description of alternatives.

CONTINUED, BUT MODIFIED, USE OF ANIMALS

IN BIOMEDICAL RESEARCH

Animal use in biomedical research can be modified in a number of ways, including strengthening experimental design to use fewer animals, reducing the degree of experimental insult, and

substituting one organism for another. In the

case of substitution, cold-blooded vertebrates may

supplant warm-blooded ones.

Reduction in the Number

of Animals Used

Up to half the animals used in research protocols

may be untreated, or control, animals. The importance of using parallel, internally controlled designs for experimentation may be one of the first

lessons learned by science students whose results

are rejected for not providing comparable data

from treatment groups of animals matched for size,

age, sex, and dosage. Studies with investigatorinitiated, internal controls support substantially

stronger inferences than those without them.

Common and Historical Controls

Fewer animals may be used in an experiment

by sharing a control group with other investigators or by not using a concurrent control group.

In both cases, all the physical and genetic characteristics of the treatment group(s) must be matched

to those of the control group, and the conditions

under which the data are collected must be as precisely duplicated as possible. There are difficulties unique to each method. Investigators may encounter constraints on their particular study when

sharing controls. For example, sharing may be impossible if one group needs to extend its studies

beyond the time agreed for termination and autopsy of the shared animals, or if the actions of

one group adversely affect the other, as might happen by the inadvertent spreading of a parasite or

pathogen. In the case of historical controls, the

difficulty rests in exactly duplicating earlier conditions. Use of such controls must be carefully documented and justified (82).

Animal Sharing

Another way to use fewer animals is to share

individual experimental animals or their tissues

between research groups. Although this method

may encounter the same types of difficulties described for the sharing of controls, it appears to

be gaining in popularity among compatible groups,

At the University of Virginia, investigators in endocrinology (Department of Internal Medicine) and

in the molecular genetics of heme synthesis (Department of Biology) use the pituitaries and livers

of the same rats even though the two departments

are on opposite sides of the campus (54).

Research animals may also be shared among different sites. This is especially practicable in the

case of long-lived primates. As long as sequential

protocols are not deemed inhumane or scientifically conflicting, primates may be shipped from

one research site to another. The Primate Research

Institute (PRI) of New Mexico State University, for

example, will loan chimpanzees and rhesus and

cynomolgus monkeys to qualified U.S. scientists.

PRI currently has 240 chimpanzees on campus,

with another 150 animals on loan.
Cjq. 6—Alernatives to Antirnal Use in Research Ž 115

Using animals maximally in a confined area is

a mandatory part of experimental design in the

research program of the National Aeronautics and

Space Administration (NASA). Protocols typically

call for investigators to combine projects and make

efficient use of one small group of animals (125).

Improved Experimental or

Statistical Design

“Every time a particle of statistical method “is

properly used, fewer animals are employed than

would otherwise have been necessary,” wrote Russell and Burch some 27 years ago (174). Since then,

progress has been made both in the number of

statistical tools available and in the training of investigators in the use of these tools. Yet training

still lags behind the availability of tools. Insufficient information for critical evaluation and inappropriate statistical analyses appear frequently in

the literature, particularly with investigators using

the t-test in cases for which analysis of variance

is the appropriate measure (82).

An analysis of variance simultaneously tests two

or more parameters of treatment groups for indication of significant difference. When the test statistic falls in the rejection region, the researcher

can be reasonably sure that a real difference exists between treatments. The t-test estimates the

difference between the mean values of one parameter of two treatments. It is a powerful measure

of significance when the number of comparisons

is small, but it is subject to an increasingly large

potential for error as the number of parameters

grows. Using multiple t-tests increases the risk of

finding a significant difference between treatments

where there is none. Such observations are not

esoteric, since poor summarization and statistical

usage may reflect poor experimental design, calling into question the results of an investigation

and leading to otherwise unnecessary repetition.

At least one group, the Harvard Study Group on

Statistics in the Biomedical Sciences, is pursuing

ways to improve statistical practice and reporting (64).

Serial sacrifice, crossover, and group sequential testing are three experimental designs that can

reduce animal use in laboratory research (82). In

serial sacrifice, animals with induced effects are

randomly selected for sacrifice and examination

for the occurrence and progress of effects over

time. Such studies, as in radiation oncology (22),

have the dual advantage of cutting short the time

some animals must spend in an affected state and

providing information about changes within the

animal other than those observed when it is allowed to die without further interference. The primary disadvantage is that survival information is

compromised; therefore, the resulting data cannot be compared with other studies in which survival serves as an end point.

A crossover design maybe appropriate for studies in which short-term effects are expected. Each

animal serves as its own control by first receiving

either a drug or a placebo, and then receiving the

reverse. Such a design can be highly useful in laboratory and clinical testing, but crossovers must

be used judiciously. Should there be any unexpected long-term effects, the entire test is invalidated and would need to be repeated as two separate tests.

In the group sequential design, treatment groups

are compared with each other in stages. For example, if two groups are given the same dosage

of two different drugs, experimentation at higher

dosages is undertaken only if there is no statistically significant difference between the responses

of the two groups. The sooner a difference between groups is observed, the fewer the number

of trials run. Both crossover and group sequential

designs have potential applications in anesthesiology, endocrinology, nutrition, pharmacology, radiology, teratology, and toxicology.

A commonly mentioned method of reducing the

number of animals used is smaller treatment

groups. Yet within the biomedical research community a frequently heard complaint is that too

few animals to yield useful estimates are likely to

be included in each treatment group, particularly

in fields such as radiology (95). Problems of this

nature generally grow out of the extreme economic

pressures being applied to investigators to control animal costs. Well-established techniques such

as saturation analyses, particularly radioimmunoassays, have radically reduced the number of animals used for any one procedure, but they may

have resulted in little or no reduction in overall
116 ● Alternatives to Animal Use in Research, Testing, and Education

use, since they have made previously difficult analyses more accessible to many more investigators.

Substituting one Species

for Another

In some instances, laboratory mammals (e.g., rodents) or nonmammalian vertebrates can be used

in place of companion mammals (e.g., dogs), domestic species (e.g., sheep), or primates (e.g., monkeys).

As more information on the physiology, biochemistry, and endocrinology of laboratory mammals

and nonmammalian species accumulates and is

demonstrated to be like or unlike that of humans,

greater use can be made of laboratory species,

which in turn can generate more information and

reduce future needs for research. Comparative

neuroscience is perhaps the most rapidly expanding field and is related to physiology, biochemistry, pharmacology, developmental biology, and

zoology (33). Some brain components have been

found to be remarkably similar between vertebrate

species (69).

Economics plays a large part in the selection of

how many and what kind of animals will be used

in some research (see ch. 11). An investigator following upon previous work will generally begin

with the species already in use, changing only if

money becomes scarcer or if a better model is

clearly demonstrated. Investigators starting anew

are likely to seek the advice of a facility veterinarian or of colleagues as to which species best fits

their needs and to begin with the smallest acceptable animal. Still other researchers deliberately

begin work with a novel animal model in order

to create a new research niche.

One of the principal reasons for the increased

use of rodents in all areas of biomedical research

has been the availability of genetically homogeneous or pathogen-free strains. For some studies,

however, a further degree of genetic definition

is needed. These studies require that the research

animal carry some specific genetic traits that are

suited to the objectives of the research, Because

of their high reproductive potential, rodents are

ideal for this type of “custom designing” and extensive use is being made of these animals in a variety of disciplines (109). Oncology and immunology are two of the more familiar areas of use (92).

Pharmacological research using an ethanol-preferring strain of rats has prepared the way for exploration of the genetics of alcoholism (212). Further,

the male Lewis rat, an animal that rapidly acquires

testicular lesions and antibodies to sperm after

vasectomy, is a candidate for study of the reversal of vasectomy. This research could answer questions of human concern in anatomy, physiology,

immunology, endocrinology, and reconstructive

surgery (100).

Chickens and their embryos play an important

role in developmental biology, endocrinology,

histology, and zoology. Other current uses are in

molecular biology, in which embryonic chicken

brain tissue is being cultured to study the neuralcell adhesion molecule (193), and biochemistry, in

which the embryonic chicken liver is being used

to study the acquisition of hormone responsiveness during embryogenesis (62). In cardiology, turkeys with inherited Turkey Round Heart disease

serve as models of cardiomyopathy (107), and turkey erythrocytes are fused with amphibian erythrocytes to study receptors that mediate physiological functions in heart, smooth muscle, and

other tissues (199).

Frogs have long been used in anatomy, biochemistry, developmental biology, physiology, and zoology. They continue to be widely used in those disciplines and, additionally, are currently being used

by NASA in radiology studies (125). In dental research, frogs are used to assess digital transplants

to augment tooth and jaw regeneration (101). The

newt Triturus-able to regenerate its limbs, eye

lens, tail, and spinal cord—is used in developmental biology to explore mechanisms of organ regeneration (90). Turtles are used in physiology to study,

for example, retinal mechanisms subserving color

vision. The cone cells of the turtle retina are especially conducive to such research (161).

Fish are used in research to a lesser degree than

other vertebrates, considering that there are over

30,000 species and their care is relatively uncomplicated. It has been suggested that fish would make

excellent subjects for nutritional research, since

many are known to show specific vitamin deficiency symptoms (210). Physiologists have used goldfish to study the implications of myelin-sheath

resistances in demyelinating diseases (73). Rainbow trout embryos are being used in oncology re-
Ch. 6—Alternatives to Animal Use in Research Ž 117

search (93). Further, there has been recent interest in a specialized feature of some piscine species:

the electric organ. This tissue is exceptionally rich

in a single class of cholinergic synapses. Biochemists, geneticists, and molecular biologists working

with this material have determined that the structure of the acetylcholine receptor protein is remarkably like a human’s (39).

Reduction of Pain or

Experimental Insult

Until recently, the probability of a research animal receiving the correct amount or type of anesthetic depended largely on the inclination of individual investigators. They could accept information

about anesthesia available from previous research

or attempt to improve on it. In some cases where

little information was available, guesswork was

required. Now, the enhanced presence of facility

veterinarians and animal care and use committees

with oversight authority (see ch. 15) has resulted

in experimental animals being recognized as veterinary patients entitled to protection from as much

pain and distress as possible, while maintaining

the integrity of research.

Analgesics, anesthetics, and tranquilizers are the

principle tools for the reduction of experimental

pain and distress (see ch. 5). Terminal anesthesia

and death has become the method of choice following major organ surgery on animals, even though

it might be argued that observation of the healing

process logically constitutes a part of surgical research (224). Where postsurgical study is considered necessary, as in cardiology, intensive postoperative control of pain can be used in lieu of

maintaining the animal under general anesthesia

until death (24).

Advances in Instrumentation

New types of instruments are critical to a reduction in experimental insult, as they can lead directly

to the more refined or reduced use of live animals

or living material. In the past decade, practically

every piece of instrumentation in biomedical laboratories has been adapted to handle “micro” samples or has been replaced by new microtechnology. Some examples of microinstrumentation

include:

● In reproductive physiology, a 1.0 microliter

sample of rat epididymal fluid collected by

micropuncture can be used to examine sperm

motility, determine total protein, and determine androgen-binding protein activity (207).

● In biochemistry and molecular genetics, electrophy biological techniques are being used to

explore the possibility of recording the opening and closing of single membrane channels,

tiny pores controlling cellular function (105).

● To study leukemias, blood diseases, and inborn errors in metabolism, a method for measuring the enzyme kinetics within a single white

blood cell has been developed (134).

● A device is available that will dispense a 1.0

microliter sample as 1)000 aliquots (1 nanoliter

each) for use in biochemical enzyme research

or for clinical samples such as cerebrospinal

fluid from infants (97),

The use of small samples for analysis by mass

spectrometry (146) and by gas or liquid chromatography (86,208) exemplifies minimally invasive

technology. Each year, an entire issue of Science

magazine is devoted to trends in analytical instrumentation (2,3). Continued developments in analytical instrumentation, including noninvasive

imaging techniques such as magnetic resonance

imaging (MRI), will likely reduce the experimental

insults faces by research animals.

In vivo measurements using fiber optics now provide miniaturized spectrophotometric analysis

from within the ducts and blood vessels, determine blood velocity, measure temperature changes,

monitor intracranial and intracardiac pressure,

measure fluorescent marker molecules in tumors,

measure pH, and even determine glucose concentration (166). Fiber optics offer great promise: They

can be inserted into vessels and ducts via small

catheters with little discomfort and into the abdominal cavity using local anesthetics (a laparoscopy), and they can be used repeatedly within the

same animal to obtain measurements without permanent damage. Chronic intravascular catheters

are used in a similar way to obtain repeated blood

samples for hormone measurement from freely

moving, undisturbed animals (see fig. 6-1) (189).

Other minimally invasive techniques in animal

research include immunoscintigraphy, amniocentesis, and use of the laser. In immunoscintigraphy,
-. —

118 . Alternatives to Animal Use in Research, Testing, and Education

Figure 6=1.–Apparatus for Remote Blood-Sampling

via Chronic, Intravascular Catheter

From Unrestrained Ferret

-

SOURCE: C.L. SIsk, Michigan State University.

the production of target-specific monoclinal antibodies has improved the ability of external radioimaging techniques to locate tumors and to identify certain noncancerous diseases; radiolabeled

antibodies attach to the target tissue and are then

visualized (59). Amniocentesis is used for the early

detection of genetic diseases, teratological events,

and fetal distress, particularly in domestic species

(67). A new application of the laser in oncology

involves its ability to initiate a lethal photochemical reaction in cancerous tissue during photoradi -

ation therapy (41).

Some apparently new noninvasive techniques

are actually adapted, miniaturized, or computerized versions of older methods. One such example is a small, inflatable tail cuff used to measure

blood pressure in a rat’s tail during hypertension

studies (225). In another example, urine is used

in some specialized methods: In physiological research, electrical impedance measures canine urinary output (1).

Tandem mass spectrometry is being used for

breath analysis to screen for diabetes, cirrhosis,

renal disease, and ovulation. Many diseases remain

to be examined, but there is potential for use of

this technique in toxicology, nutrition, metabolic

diseases, endocrinology, anesthesia, physiology,

and pathology (133).

A technique developed for the determination of

the quality of agricultural crops (162) and the percent of fat in beef (135) uses amplified, digitized,

computer-corrected diffuse reflectance spectrophotometry in the near-infrared region. It involves

simply placing an appropriate sensor on the surface of the skin and it can be adapted for oncological, physiological, and nutritional research (102).

Other increasingly popular noninvasive techniques include ultrasonography -which is used

in cardiology to locate vessels (145), to determine

blood-flow velocity (176), and to detect early atherosclerosis (108)-and magnetic resonance imaging, used to examine the energetic of skeletal muscle in gerontological research (201), to diagnose

metabolic disorders (32), and to provide details of

molecular structure and dynamics in liquids and

solids (130).

USE OF LIVING SYSTEMS IN BIOMEDICAL RESEARCH

In Vitro Research

In vitro biomedical research entails the maintenance of organs, tissues (or fragments of organs

and tissues), and cells outside of the body. Depending on the conditions of harvesting and preparing

the living material for in vitro maintenance, the

cells may be grown as a population of independent cells (cell culture) or with the normal tissue

or organ architecture preserved. In the former,

the cells may be encouraged to proliferate, resulting innumerous descendant cell populations suitable for studies on growth, nutrition, cell division,

and gene expression and regulation.

Table 6-2, which summarizes the characteristics of in vitro systems, makes it clear that as organization is disrupted or lost, the in vitro system

has less and less of the kind of intercellular and

intracellular interactions that characterize organs,
Ch. 6—Alternatives to Animal Use in Research ● 119

Table 6-2.-Properties of In Vitro Culture Systems

Expression Genetic alteration

Preparation and Level of tissue similar to by mutation Environmental

consequences organization Reproducibility in vivo and/or selection control

Intact system (no consequence). . . . +++ + +++ + +++ + + +

Organ culture (remove influences of

whole organism). . . . . . . . . . . . . . . . +++ + +++ + + to + + + + + +

Tissue culture (remove influences of

whole organisms). . . . . . . . . . . . . . . + + + + + + + to + + + + + + +

Primary cell cultures (disrupt

intercellular relationships) . . . . . . . 0 ++ + to + + + + +++ +

Cell lines (intercellular relationships

are reduced; cell proliferation is

enhanced, at times with little

control) . . . . . . . . . . . . . . . . . . . . . . . 0 ++++ + to + + + + to + + + + +++ +

KEY: + + + + = High degree; + + + = Moderate degree; + + = Modest degree; + = Some degree; O = None.

SOURCE: Adaoted from R.M. Nardone and L.A. Ouellette, “Scoge of ‘Alternatives’: Overview of the State of the Art, ” contract re~orl cweoared for the Office of Technoloav-.

Ass&sment, US, Congress, July 1984.

tissues, ’and cells in the body. Nevertheless, improved accessibility of added chemicals and the

opportunity to achieve genetic homogeneity by

cloning and genetic manipulation by selection and

fusion are important trade-offs. Indeed, at times

cell-to-cell interaction may interfere with an experimental objective (156).

The explosive growth of in vitro research during the 1960s and 1970s is illustrated by the fact

that the index of Tissue Culture had 84 pages of

entries in 1965, 207 pages in 1970, 566 pages in

1975, and 636 pages in 1980, when the publication was discontinued because computerized information retrieval was warranted. There is virtually no field of biomedical research that has not

been affected by in vitro technology. In vitro models for the study of cell senescence, atherosclerosis, development, growth, and immune reactions

are illustrative of the diversity of applications in

biomedical research (156).

The specific conditions that best support the

maintenance, growth, or differentiation of each

type of culture must be determined before any

useful information can be garnered. Some of the

general requirements of culture systems are combinations of the proper gas atmosphere, humidity, temperature, pH, and nutrients. other culture

systems may also have specific light, motion, pressure, and physical or chemical support requirements, Under the proper conditions, many can be

subculture for months or frozen in liquid nitrogen for years without loss of their unique, differentiated properties.

The ability to maintain many continuous cell lines

has opened the floodgates of experimentation and

made the new technologies accessible to all the

disciplines of biomedical research. Other advantages include ease of transport from one laboratory or country to another, the ability to culture

both normal and abnormal tissue for comparison

and research, the use of human cells to eliminate

species variation, and the ability to expose cultures

directly to exogenous molecules at specific concentrations for precise time periods. Disadvantages

include the changes in structure or function observed in some cultures, and the fact that isolated

systems give isolated results that may bear little

relation to results obtained from the integrated

systems of whole animals.

Organ Culture

At some point in the history of research, investigators have attempted with varying success to

isolate and maintain every major and minor mammalian organ, for a variety of purposes. In recent

years, improved techniques, such as the availability of artificial blood media, have increased the

probability of successful organ culture. Blood, or

artificial blood media, can be pumped through the

organ to sustain it (“perfusion”) (see fig. 6-2). Current applications of organ perfusion include the

study of protein synthesis in lactating guinea pig

mammary tissue (136) and the use of human placentas in toxicology studies, with additional potential for use in oncology and gerontology research (99).
_

120 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 6=2—Schematic of Experimental

Organ Perfusion

PRESSURE - . ,A - OXYGENATOR

SOURCE: C. Chubb, The University of Texas Health Science Center at Dallas.

Organ Perfusion: Mouse Testis With

Pipette Introduced Into Artery

Photo credit: C. Chubb, The University of Texas Health Science Center at Dalias

whole organs are not generally amenable to longterm in vitro culture or growth. The size and complexity of whole organs make it impossible for them

to receive sufficient nourishment for normal function without external support. Nevertheless, whole

organs are fundamental to many types of anatomy,

histology, and pathology because of their suitability for the examination of relationships between

cells and tissues, and they can be sustained in culture for hours or days.

Cryostat sections (thin slices of frozen tissue cut

with a microtome) through organs are maintained

in vitro for oncology studies into organ-specific

adhesion of metastatic tumor cells. This method

closely reflects the in vivo event and therefore

could eventually reduce the use of whole animals

in a very active research area (159).

Whole mammalian embryos, in addition to their

obligatory use in the investigation of basic developmental biology, have been cultured in vitro for

other purposes. Protocols have included examinations of the effects of hormones and teratogens

(42).

Tissue Culture

Many normal and pathological tissues from humans and a variety of animal species can be successfully maintained and studied in culture. Indeed,

the progress that has been achieved since 1907,

when R.G. Harrison first maintained frog neural

tissue outside of the body for weeks, has changed

the field of tissue culture from an art into a science.

Keeping cultures of anything other than bacteria

or viruses alive for more than a few hours was

problematic until the 1950s) when investigators

began to gain a better understanding of the requirements of cells and the addition of antibiotics

to culture systems. The viability of cultures was

extended substantially by controlling bacterial contamination.

In tissue culture, isolated pieces of a living organism are maintained with their various cell types

arranged as they were in the original organism

and with their differentiated functions intact. Such

cultures are both “better” and “worse” than cultures of a single cell type. They are better in that

the effects of manipulation can be observed in a

more natural environment and different cell types

can interact as they would in vivo. They are worse

in that they are much more difficult to maintain.

Although tissue-culture experiments require the

sacrifice of an animal, they can be viewed as alternatives to animal use since numerous sections of

adjoining tissue can be removed and compared.

In this way, two or more treatments are administered to tissues, rather than to a number of individual animals.
Ch. 6—Alternatives to Animal Use in Research ● 121

Tissue culture is being successfully employed

in many disciplines of biomedical research. In neurology, the use of embryonic rat mesencephalon

tissues to examine the destruction of dopamine

neurons has replaced the use of primates (154).

Prior to this development, the monkey had served

as the best model for the study of degenerative

effects observed in humans. Adult rats, cats, and

guinea pigs have been shown to be resistant to

the destruction of dopamine neurons. Metabolic

studies of an experimental antiarthritis agent have

made use of the inside of hamster and rat intestinal walls (202). Physiological experiments examined the dynamics of secretion with mouse

epididymis (70).

Cell Culture

Although cell culture is not a new technique,

developments and applications during the past decade have come so rapidly as to create whole new

research institutions and industries. Cell culture

today touches every discipline of biomedical research, as well as clinical practice. The following

illustrates the pervasiveness of this approach in

biomedical research:

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Eggs and sperm from many species have been

used by endocrinologists, physiologists, and

biochemists to study the mechanisms involved

in fertilization and early development (58,157).

A hamster ovary cell line and its mutants are

being used to explore the biochemistry of a

membrane-associated protein essential to all

animal cell function (175).

In oncology, human interferon derived from

bacterial recombinant DNA induces a transformation of human white blood cells similar

to that observed during infection, cancer, and

rheumatoid arthritis. This change in white

blood cells provides clues to the pathology of

cancer (216).

Steroid metabolism is being studied using cultured rat epididymal cells (29).

A monkey kidney cell line was employed to

demonstrate the metabolic effects of several

general anesthetics (26).

Geneticists are developing an in vitro method

of studying heme gene expression (54).

Surgical research into the use of cultured human epitheliums for permanent coverage of

large burn wounds has moved from the laboratory into clinical trials (76).

In immunology, studies on antibody synthesis

and response have been bolstered by the Nobelprize-winning elucidation of monoclinal antibodies. In its initial steps, this technique consumes large

numbers of animals, as the varying immune responses of many mice are probed. Then, cloned

cells from the spleen of one mouse can be exploited

to produce valuable, highly specific antibodies. Antibodies so produced can obviate the need for many

rabbits, sheep, and even humans in the large-scale

production of antibodies. Perhaps of even greater

importance for research is the high quality of the

antibody produced by monoclinal cells. A comprehensive listing of current research being conducted

with monoclinal antibodies from cloned cells is

beyond the scope of this assessment. Some of the

diagnostic potentials of monoclinal antibodies being ‘ “ “ “ “ “ ‘

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explored in biomedical research are:

the characterization of malignant and benign

tumors;

the identification of autoimmune antibodies

in rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, and other autoimmune diseases;

the identification and quantification of serum

proteins, hormones, and their cell-surface

receptors;

the monitoring of therapeutic drugs and identification of novel therapeutic drugs;

the rapid diagnosis of bacterial, viral, fungal,

and parasitic diseases;

the monitoring and identification of lymphoid

and hematopoietic cells in disease states; and

pregnancy testing.

Biologists have developed techniques for the controlled disruption of cells that can leave many organelles intact or allow the harvesting of selected

intracellular membranes. These fractions have

proved to be invaluable in the search for information at the molecular level. For example, microsomal membrane fractions from rat and human

liver have been used in comparative anesthesia

research (27). In endocrinology, human placental

and ovarian microsomes were used to demonstrate

inhibition of steroid hormone synthesis by plant

chemicals (112). In dentistry, proteins purified

from unerupted fetal buds were shown to be in38-750 0 - 86 - 5
—.

122 ● Alternatives to Animal Use in Research, Testing, and Education

hibitory toward seeded enamel growth in culture

(56). In virology, infected cell nuclei isolated from

a hamster cell line were used to study influenza

virion RNA replication (16). In metabolic studies,

the inhibition of chick-embryo-derived collagen

fibril formation by glucose suggests a direct relationship between excess glucose and poor wound

healing observed in people with diabetes mellitus

(126). One of the most unique uses of subcellular

fractions involves the bringing together of mixed

species systems in biochemical studies of protein

transport across intercellular membranes. For example, researchers studying intracellular protein

translocation used dog pancreatic microsomes, bovine pituitary and rabbit reticulocyte messenger

RNA, bacterial nuclease, and a wheat germ cellfree system to elucidate the structure of the signal recognition particle (213).

Human Tissues and Cells

Cultured human fetal lung cells have been found

to be excellent hosts to support the developmental

cycle of a protozoan parasite that causes severe,

persistent, life-threatening diarrhea in immunodeficient patients. There has been no effective therapy for this illness, so the in vitro system offers

an opportunity to study the parasite’s behavior,

development, and metabolism and provides a potential method for screening therapeutic agents

(50).

Virologist and oncologists have been very quick

to take advantage of new human in vitro culture

systems. For example, an embryonal carcinoma

cell line from the stem cells of a teratocarcinoma

is being used to study cytomegalovirus replication

(83). Lysis of herpes simplex virus (HSV) type 2 is

being investigated using human monocytes (117),

and HSV latency is studied by using isolated neurons obtained from human fetuses (220).

The use of postmortem material from humans

has significance in many areas of biomedical research, but particularly in neurology. Investigators

studying the unconventional slow-virus diseases

use brain tissue from humans with CreutzfeldtJakob disease and from animals with scrapie (144).

Postmortem material from schizophrenics has provided evidence for two distinct categories of that

disease (181), and temporal lobe structures from

Alzheimer patients have revealed specific pathological cellular patterns in the brain hippocampal

formation (104).

Examples of the use of human tissue for investigations aimed at human treatment can today be

drawn from every discipline of biomedical research. Advances in in-vitro culture methods are

likely to increase this use further. Postmortem tissue use is likely to continue.

Invertebrates

Invertebrates represent over 90 percent of nonplant species on the earth. Although their body

structure is much less similar to humans than is

vertebrate body structure, invertebrate anatomy,

physiology, and biochemistry offer avenues for

new approaches that have been only partially

explored.

Caenorhabditis elegans, a 1 millimeter roundworm,

is of intense interest to developmental biologists.

As they have traced this nematode’s complete cell

lineage, it offers an unprecedented opportunity

for the study of individual living cells (38).

Other terrestrial invertebrates are used in many

disciplines of biomedical research. For example,

flies, bees, earthworms, and leeches are involved

in various aspects of anatomy, physiology, and biochemistry (5,33). Ants and bees are used in vision

research (4). Fruit flies are well known for their

participation in genetic studies. Age-related metabolic changes in other insects are being investigated for possible use in aging research (184).

Marine invertebrates represent an important,

largely untapped research resource. one commentator (190) has suggested that the lack of opportunity by medical scientists to learn marine biology

and the failure of marine biologists to learn pathology have combined to leave marine species overlooked. A notable exception to the underuse of

marine invertebrates is neurobiology. The coelenterates, including hydra, corals, anemones, and

jellyfish, have helped scientists understand primitive nervous system biochemistry. Lobsters and

squid have contributed to knowledge of brain anatomy and physiology, and the grazing snail and crayfish have broadened understanding of cell biology (33).
Ch. 6—Alternatives to Animal Use in Research ● 123

Four advantages of using invertebrates in biomedical research are:

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different phylogenetic levels of structural and

functional specialization can be exploited (e.g.,

different types of circulatory systems, novel

chemical compounds);

invertebrates reproduce rapidly and produce

numerous offspring; experiments can be executed in days and weeks instead of months

and years;

storage, upkeep, and maintenance are inexpensive; and

invertebrates are not prone to spreading dis -

ease throughout a colony;

The overwhelming disadvantage is the considerable phylogenetic distance between invertebrates and humans.

Micro-organisms

From its origins within the medical disciplines

of bacteriology, pathology, and virology, the study

and use of microorganisms has branched out to

influence practically every area of biomedical research, as these examples indicate:

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Salmonella typhimurium—bacteria used in

mechanistic studies in genetics (124) as well

as the Ames mutagenicity/carcinogenicity test

(see ch. 8);

Escherichia coli—bacteria used by developmental biologists to derive theories of gene

control (90) and by molecular biologists in recombinant DNA research (75);

Streptococcus mutans—bacteria used in dental research on the metabolic activity of plaque

(91);

Bacillus subtilis (bacteria) spores, Artemina sa -

lina (brine shrimp) eggs, and Sordaria fimilcula (fungi) ascospores-all incorporated into

NASA’s biostack (monolayer of biological test

organisms sandwiched between thin foils of

different types of nuclear track detectors) radiology experiments inside Spacelab I (31);

Tetrahymena pyriformis—a ciliate protozoan

being used to study the effects of anesthetics

on metabolism (44); and

a host of microscopic protozoans, metazoans,

and rotifers used to investigate the physiology and biochemistry of photoreception and

vision (4).

The advantages of using micro-organisms in biomedical research are fourfold: They reproduce

rapidly at body temperature; rapid division (every

20 to 30 minutes) makes them useful for shortterm studies; multigenerational studies can be performed in a short period of time; and they are inexpensive in terms of storage, upkeep, and maintenance. The major disadvantage stems from the

fact that these are unicellular organisms: As a consequence, the interaction of cells cannot be studied (156).

Plants

One advantage of using organisms from the plant

kingdom is that they lack anything resembling a

nervous system. Presumably, plants do not feel

pain; they appear to be good potential alternatives

to animals. Plants, like micro-organisms, are relatively easy and inexpensive to propagate (156).

Although there is some interest in the potential

use of plant cells in toxicology and oncology research (191), the use of whole cells from plants

is obstructed by their very rigid cell-wall structure compared with the relatively fluid animal cell

membrane. This prevents their use in many disciplines where intimate cell surface contact or

transmembrane communication is essential.

Once removed from the cell, comparable organelles from plants and animals (including microorganisms) are essentially indistinguishable in both

appearance and function. For example, in studies

having potentially broad applications in endocrinology and immunology, yeasts have been found

to contain active steroid hormone systems (118).

Yeast is used in cell biology in studies of the import of proteins into mitochondria, organelles that

are essentially the same whatever their source

(129). An extensive literature in cell biology, genetics, molecular biology, and virology supports the

use of subcellular fractions from plants and animals, separately or together, for research into basic

molecular mechanisms (213).
124 ● Alternatives to Animal Use in Research, Testing, and Education

USE OF NONLIVING SYSTEMS

Chemical and Physical Systems

Long before the advent of modern technology,

researchers were constructing chemical models

of certain phenomena that occur in living systems.

There is a long and rich history in biochemistry,

for example, of the application of nonliving systems to experimentation (128,147).

Enzyme biochemistry continues to be a principal

area of application of nonliving methodology in

biomedical research. Enzyme mechanisms maybe

studied in a totally chemical system. Magnetic resonance imaging is used to obtain from enzymes

in solution detailed structural data and information about the mechanism of enzyme action. By

combining MRI with cryoenzymology-the use

of enzyme solutions held at subzero temperatures—

enzymatic reactions can be slowed enough to study

intermediate products that would ordinarily exist for too short a time to be detected. Investigations that had been restricted to in vivo manipulations can now be expanded into a far wider range

in vitro (131).

In dental research, a chemical system mimics

the mechanics of the formation of dental caries.

A two-chambered diffusion cell pairs an excess

amount of specific protein crystals with a chemical solution of artificial “plaque-saliva .“ Dissolution

of the crystals can be studied under varying chemical conditions relevant to a better understanding

of the caries process (40).

In the field of membrane biophysics, the advent

of synthetic membranes has proved a boon to research and stands as one of the premier examples

of nonliving alternatives to animal use. Liposomes

are synthetic vesicles made of protein and fatty

molecules. Their structure can be dictated by the

investigator, who can combine proteins and lipids

of different types and in different ratios to yield

COMPUTER SIMULATION

Modern approaches to biomedical research describe the functions of living systems at all organizational levels by the language of science—mathematics. Knowledge is acquired by investigating

IN BIOMEDICAL RESEARCH

an artificial membrane. As with true biological

membranes, the barriers formed by liposomes are

selectively permeable. These artificial membranes

are particularly useful in basic studies of the transport of molecules across membranes and of membrane damage (12).

Except for the use of mannequins to simulate

accident victims in the transportation industry and

in trauma centers, the principal use of physical

and mechanical systems today is in education (see

ch. 9) rather than in biomedical research. However, it is not inconceivable that future combinations of mechanical and electronic technology

could provide biomedical researchers with artificial research subjects capable of independent, unanticipated responses.

Epidemiology:

Using Existing Databases

The use of existing databases to gain new information and insights in biomedical research may

be a major underused resource, if the paucity of

published results is any criteria. One study that

relied on such information concentrated on the

relationship between 17 nutrients and the potential for development of hypertension cardiovascular disease in more than 10,000 people from the

database of the National Center for Health Statistics’ Health and Nutrition Examination Survey

(HANES I) (137). The results proved to be highly

controversial, with some of the criticism aimed

at the use of the database (119).

Too little information is currently available to

evaluate fully the potential dimensions of the salutary use of epidemiologic databases in basic biomedical research. The possibility exists that their

enhanced use may constitute an important nonanimal method.

relationships among cells, tissues, fluids, organs,

and organ systems. By the processes of trial and

error and of hypothesis and testing, relationships

begin to be understood and can be described by
Ch. 6—Alternatives to Animal Use in Research ● 125

mathematical expressions. These can range from

simple, linear functions to various types of curved

functions to multidimensional surface functions

and may involve kinetic data expressed by differential equations. Variables in these equations include

physical terms, such as time, temperature, weight,

energy, force, volume, and motion. Complex mathematical relationships may be developed to express

these cause-and-effect relationships more clearly.

In some instances, a relatively simple relationship

may be shown to exist, but this is unusual, since

living systems are highly interactive and multidimensional in nature (48).

A relationship that can be reasonably expressed

in a mathematical equation maybe considered to

be a candidate biological model. The limits within

which the expression will hold determine the utility and validity of the model. If it is possible to

change one or more parameters in the equation,

and thereby obtain the same response or responses

as found in live animal research, the model may

be used to “simulate”a biological preparation. Simulation implies that an investigator can manipulate

the parameters at will and observe the resultant

effects on the model. Used in this way, computer

simulation is a useful tool for research and especially for suggesting new mechanisms or hypotheses for further study (48).

At the subcellular level, information is usually

gained by electron microscopic examination or by

analytical methods for the sequencing of amino

acids and nucleic acids. Such information tends

to be of a descriptive or topological nature rather

than numerical. Recent strides in genetic engineering based on increased knowledge of DNA, RNA,

and protein amino acid sequencing have required

computers to store and match nucleic acid and

amino acid sequences numbering in the millions

(163). These capabilities are not equivalent to simulation, but they share with simulation a reliance

on computers for storage and processing.

At the level of one or a few cells, models are being sought for computer simulation of sliding filament systems—believed to be the basic movement

of muscle fibers, cilia, and flagella (28). Modeling

of the function of individual cone cells in the eye

is under study at the National Institutes of Health

(NIH) (167).

Most efforts toward computer simulation of biological systems are directed at higher levels of organization, such as organs and organ systems. This

bias is a consequence of the need to understand

numerous feedback systems within living systems.

Feedback systems are the basis for an organism’s

ability to maintain a homeostatic, or steady, state,

Feedback mechanisms involve several organs as

well as communication via the bloodstream and

nervous system. For a simulation to succeed, the

system must be considered as a whole. In modeling the cardiovascular system, for example, a simulation must take into account the heart, brain,

lungs, and kidneys.

In the 1980s, computer modeling of organ systems is progressing on many fronts. The brief sampling of simulations listed in table 6-3 illustrates

the variety of organ systems under study.

One development in this field deserving particular attention was the establishment by NIH’s Division of Research Resources in 1984 of the National

Biomedical Simulation Resource, a computer facility at Duke University that may be used onsite

or over a telephone data network. Any project in

which the results are free to be published in open

scientific journals and where no profit is involved

can apply to use the facility. Training sessions introduce biological scientists to the concepts of modeling, and special aid is provided in the development of simulation software (120). Projects under

Table 6-3.-Some Examples of Computer Simulation

of Phenomena in Biomedical Research

Kidney function:

• Transport of electrolytes, nonelectrolytes, and water

into and out of the kidney (142)

Cardiac function:

● Enzyme metabolism in cardiac muscle (214)

● Cardiac pressure-flow-volume relationships (1 52)

● Malfunctions of instrumented cardiovascular control

systems (9)

Lung function:

● Respiratory mechanics (150)

Sensory physiology:

● Peripheral auditory system, and single auditory nerve

fiber transmission of vibrations (180)

Neurophysiology:

● Impulse propagation along myelinated axons (73)

Developmental biology:

● Shape changes i n embryonic celIs that develop into

mature organs (98)

SOURCE: Office of Technology Assessment,
126 . Alternatives to Animal Use in Research, Testing, and Education

way in 1985 involved research in cardiology, phys- Limitations on the utility of computer simulaiology, endocrinology, toxicology, and neurology. tions stem from the lack of knowledge of all possiSpecific simulations included: ble parameters that may play a role, however slight,

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regulation of sodium, potassium, and calcium

in heart muscle;

electrolyte diffusion in heart muscle;

propagation of activity in heart muscle;

heart volume potentials;

mathematical modeling of blood coagulation;

regional dose responses in the human and animal lung;

ciliary motility;

cochlear function in the inner ear; and

a molecular model of ion transport in nerves

in the melange of feedback-mechanisms that constitute living systems. Basic biomedical research

at all levels, some of it involving live animals, will

continue to provide the new knowledge required

to improve existing simulations and develop models

where no satisfactory one exists. The development

of increasingly powerful computer programs depends on the use of animals in biomedical research.

and muscles.

CONTINUED, BUT MODIFIED, USE OF ANIMALS

IN BEHAVIORAL RESEARCH

As in biomedical research, the continued, but

modified, use of animals in behavioral research

encompasses reducing the number of animals used

through changes in experimental design and statistical analyses, substituting cold- for warmblooded vertebrates, and lessening the degree of

pain or experimental insult in general, and in pain

research in particular. Compared with biomedical research, behavioral research offers markedly

fewer opportunities to substitute cold-for warmblooded vertebrates and to use in vitro cultures,

and it holds little chance of using nonliving systems.

Reduction in the Number of

Animals Used

Improved Experimental Design and

Statistical Analyses

Individual animals vary in their behavior both

between subjects and, in the case of one subject,

over time. The goal of a behavioral experiment

is to identify patterns that remain when these two

sources of variability have been eliminated or taken

into account. An investigator attempts to conclude

that observed effects are due to the conditions being manipulated in the experiment and not to extraneous factors. This decision usually rests on the

outcome of statistical tests. Ensuring the validity

of such tests or improving their design can mean

that fewer experiments are needed. Enhanced statistical rigor, however, may lead to increases or

decreases in the number of animals required in

a particular protocol.

Statistical Power.—A statistical test’s sensitivity in detecting experimental effects is termed its

“power.” The most widely recognized method of

increasing power and, hence, the sensitivity of an

experiment is to use a large sample of subjects.

Typically, the more variable the results, the more

power is needed to detect an effect and, therefore,

the greater the need for large samples. Although

the magnitude of variability cannot be determined

prior to an experiment, the amount of variability

likely to be encountered can be estimated by conducting small, pilot studies or by examining previous research in the same or related areas. Given

an estimate of variability, statistical tables can be

used to determine the sample size needed to attain certain levels of power (221).

In certain instances, the methods of increasing

power may reduce, not increase, the number of

animals needed:

● Choosing a lower level of statistical significance (i.e., the likelihood that the results were

due to chance) increases power and reduces
Ch. 6—Alternatives to Animal Use in Research “ 127

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the number of subjects needed. However, this

also increases the chances of concluding that

the experimental procedure produced an effect when in fact the effect was due to chance

alone. By convention, researchers generally

accept the probability of a chance effect of

5 percent or less as a statistically significant

result.

Greater precision in the conduct of an experiment may reduce variability and increase

power. For example, highly precise behavioral

measurements coupled with the elimination

or control of extraneous variables would reduce the need for large numbers of subjects

(198).

The use of different statistical analyses can

increase the sensitivity and power of a protocol (e.g., analysis of the data by parametric

rather than nonparametric statistical tests)

(198).

Alterations in experimental designs can increase power. Factorial designs (where two

or more treatments are manipulated concurrently), for example, are more powerful and

can be used instead of testing the effects of

different treatments in separate experiments.

Not only does the use of factorial designs increase power, it requires fewer untreated,

control subjects than multiple concurrent

studies do. It is important to note, however,

that in areas that have not been heavily researched there are inherent dangers to the

use of factorial designs. For example, there

may be no observed effect of treatments given

in combination, as one treatment cancels the

effect of another. Without sufficient background information on the effects of the treatments administered individually, this finding

would be erroneously interpreted.

Power is increased as the magnitude of the

treatment effect is increased. ‘Treatment effects can be maximized by choosing widely

spaced levels of the treatment variables or by

including conditions that are thought to maximize the appearance of the phenomenon

under study (113).

Within-Subjects Design.–Many experiments

on animal behavior are conducted using a betweensubjects design, That is, different groups of animals are given different treatments, and the performances of the different groups are compared.

However, individuals also vary in their behavior.

Depending on the degree of variability, large numbers of subjects maybe needed in each group to

obtain statistically significant results. Under certain conditions, however, a within-subjects (or

repeated measures) design can be used that requires only one group of animals instead of many.

Under these conditions all members of the group

serve in all treatment conditions. The advantage

of this technique is that it minimizes variability

by taking into account individual differences. The

major drawback, however, is the possibility of contaminating the data and nullifying the results:

Treatments already received by a subject may influence, and thereby confound, performance under subsequent treatments. Carry-over effects can

be partially offset by counter-balancing, wherein

the experimenter ensures an equal occurrence of

each experimental treatment at each stage of the

experiment; this balances any effect of prior testing equally overall treatment conditions (1 13). Although within-subjects designs are effective in reducing both variability and the number of subjects

needed, the inherent danger of carry-over effects

in many instances may invalidate the use of such

designs.

Random Block Design. -Randomized block design consists of assigning subjects to groups based

on evidence of their being similar to one another

in one or more characteristics known to be related

to the behavior under investigation. Two or more

such blocks are formed and then each block is assigned randomly to the treatment conditions. This

design reduces variability by restricting the degree of individual differences within blocks, and

thereby increases power (113). Although randomized block designs are effective in lowering the

number of animals needed in an experiment, they

are not applicable to all areas of behavioral research. The technique requires substantial prior

knowledge of the behavior being investigated and

is therefore limited to intensively researched areas.

Analysis of Covariance.—An analysis of covariance uses the same information as randomized

block designs except that an estimate of variability is not needed beforehand. The covariance pro-
128 ● Alternatives to Animal Use in Research, Testing, and Education

cedure is applied to data after they are collected

to adjust for chance differences among groups.

The analysis increases power, and fewer animals

may be needed to obtain statistically significant

results (113).

Single-Subject Design.—In some instances inferences can be made about populations from very

small samples. This is common in psychophysical

experiments in which there is a substantial prior

body of evidence indicating that the behaviors under investigation do not vary appreciably within

the population at large (e.g., visual sensitivity to

light). Although such experiments can be conducted using just one subject, two or three are

typically used to guard against the possibility of

misleading results from an atypical subject (198).

In other than psychophysical experiments, the

general procedure in single-subject research consists of choosing a baseline (which involves measuring the frequency of occurrence of the behavior

of interest), changing one treatment variable at

a time, temporarily withdrawing the experimental

treatment to assess its causal effects, and repeatedly measuring the baseline behavior before and

after each treatment. (More sophisticated experimental designs available for single-subject research

are reviewed in ref. 96.) Single-subject designs are

increasingly used in animal operant conditioning

and human clinical research (187). Statistical analyses of these are reported infrequently due to the

lack of many statistical techniques for handling

such data, although using time-series analyses to

test for changes over time is one acceptable method

available (111),

A limitation to studying a single subject is the

uncertainty of the generality of the findings, a problem commonly dealt with by replicating the experiment with different subjects (96). Thus the reduction in animals used may be illusory.

Inbred Strains.-One way of reducing variability (and hence increasing power) is to use highly

homogeneous populations of subjects. Inbred

strains of animals, produced as a result of 20 or

more generations of brother-sister matings, represent one approach, though it is usually much

more expensive than using randomly bred animals.

Inmost inbred strains all subjects are highly identical genetically and genetically stable; they change

only as a result of the slow accumulation of mutations. In contrast, outbred stocks of animals are

genetically variable. They contain an unknown and

uncontrollable degree of genetic variation that may

obscure or mask experimental treatment effects.

Inbred strains not only increase statistical power,

they also reduce variability between experiments

conducted indifferent laboratories or in the same

laboratory at different times (68).

It can be argued that experiments should rely

on animals drawn from heterogeneous, outbred

populations in order to get a broad genetic basis

for results that can be extrapolated, for example,

to heterogeneous human populations. Yet the

differences between different inbred strains are

usually greater than the differences between individuals of an outbred stock. Greater generality,

then, may be obtained by conducting experiments

with two or more inbred strains (68).

Sharing Animal&—A team approach to research questions across biomedical and behavioral

research disciplines could reduce the number of

animals needed for behavioral research (173). For

example, researchers studying a behavioral phenomenon by noninvasive means could, at the experiment’s conclusion, give their animals to biologists investigating the anatomy or physiology of

that species. Likewise, scientists from different disciplines could collaborate on research proposals:

A psychologist maybe interested in studying predator-prey relations, while a biologist wants to study

endocrinological changes in response to stress; ef -

fective collaboration could yield two different data

sets from the same animals.

Substitution of Cold-Blooded for

Warm-Blooded Vertebrates

The modified use of animals in biomedical research includes the replacement of mammals and

birds with fish, amphibians, and reptiles. In behavioral research, however, the often vast differences between species are likely to make such substitutions difficult. At the moment, researchers

know more about why warm-blooded vertebrates

cannot be replaced with cold-blooded ones, as this

description of seven behavioral research disciplines illustrates.
Ch. 6—Alternatives to Anirnal Use in Research ● 129

Aggression

Aggressive interactions between members of the

same species have been studied in a variety of fish

and reptile species under both laboratory and field

conditions. Considerable work has been done on

intermale rivalry among sticklebacks (183) and cichlid fish (11). Aggressive interactions among coldblooded vertebrates are frequently stereotyped

and species-specific. Among sticklebacks fish, for

example, full-fledged attacks can be elicited by a

model that is the same color but a different shape

(30). In contrast, aggression in primates can embody a variety of highly sophisticated introspective social strategies such as deception, grudging,

delayed retaliation, and reconciliation (77). Thus

extrapolation among all vertebrates of the results

of research into aggression is difficult.

Animal Movements

Migration and homing abilities have been intensively studied in several species of fish, particularly eels and Pacific salmon. Among American and

European eels, for example, the eggs hatch in the

Sargasso Sea, near Bermuda. The juvenile fish

make a year-long migration toward the coasts of

North America and Europe. On reaching sexual

maturity in 7 to 15 years, the adult eels migrate

back to the Sargasso Sea to breed (217), a movement primarily dependent on the use of chemical

cues in the water (60). In contrast, birds use solar,

stellar, and magnetic cues to navigate, and whales

use the topography of the ocean floor and coastline to remain on course for migratory purposes.

Such dramatic differences in the way different species respond to and perceive the environment limit

the use of cold-blooded vertebrates in modeling

animal movements of warm-blooded ones.

Communication

Visual cues, such as changes in coloration, posture, or body appearance, have been shown to

be important determinants of social interaction

among fish (3o), which, unlike most mammals, generally have color vision. Fish also exhibit dramatic

changes in appearance, such as flaring of the gill

apertures, which are relatively rare among mammals. Auditory communication is marked by species differences, too. Communication among amphibians and reptiles, primarily to attract a mate,

consists of simple one- or two-note utterances.

Vocalization in birds and mammals consists of a

wide range and variety of sounds. Moreover, unlike cold-blooded species, many birds have to learn

species-specific songs. Many rodents communicate

by ultrasonic vocalizations (123) that have no apparent counterpart among cold-blooded species.

Learning, Memory, and

Problem Solving

Learning has been studied in a variety of diverse

species (179, 183), and many differences are manifested. Comparing learning in goldfish and turtles

with that in rats yields both similar and distinguishing features. For example, rats show a decrement

in performance when an accustomed reward is

changed, while goldfish and turtles do not (23).

The existence of so-called biological boundaries

of learning (182), apparently shaped by unique ecological pressures, precludes most substitutions of

one species for another in learning paradigms.

Predator-Prey Relations

Prey-catching behavior and predator avoidance

have been studied in fish, frogs, and turtles (60,

103,203). The similarity across species in behaviors

used by prey to avoid being caught suggests that

when a general question about reactions to predation (rather than the behavior of a given species) is of interest, cold-blooded vertebrates can

substitute for warm-blooded ones (103). But there

is growing evidence of neurochemical differences

underlying predator avoidance behaviors even

among birds and mammals (78).

Predators exhibit marked differences across species. Frogs, for example, sit passively and wait for

an insect to come within striking distance, while

some carnivores have developed sophisticated

hunting strategies that often embody elements of

cooperation and may even culminate in sharing

foods (30).

Reproduction and Parental Care

With some notable exceptions (e.g., the African

Mouthbreeder fish), parental care of offspring is

absent inmost cold-blooded vertebrates, since the

eggs are typically abandoned shortly after fertili -
130 . Alternatives to Animal Use in Research, Testing, and Education

zation. In contrast, all birds are subject to some

type of parental care, and mammalian parent-offspring relations become even more complicated.

Species differences in external versus internal fertilization, seasonal breeding, courtship, pairbonding, and nest-building preclude substitutions

of one species for another in this research.

Sensation and Perception

The sensory and perceptual differences among

species are vast. For example, many snakes’ primary mode of prey identification is chemical cues

transferred from the tongue to a structure at the

roof of the mouth, called Jacobsen’s organ. Ingestively naive baby snakes appear to have an innate

preference for prey extracts that represent speciestypical foods across a variety of different snakes.

Each species shows unique attack profiles that appear to be independent of maternal diet and not

subject to modification by experience (e.g., baby

snakes of a minnow eating species that are forcefed liver still show attack responses to minnow

extracts but not to liver) (34,35).

In contrast, baby rats seem predisposed to eat

the same diet as their mother, and the flavor of

the maternal milk serves as a medium for the transmission of cues that rat pups use to make their

initial food choices. Manipulating maternal diet

during lactation has produced corresponding

changes in subsequent pup food preferences.

Moreover, rat pups poisoned in association with

a mother’s milk later avoid the types of food she

had been eating (74).

Reduction of Pain or

Experimental Insult

As noted earlier, a general anesthetic is preferable to a local one for surgical manipulations because it suppresses both pain and fear (114). Painrelieving drugs should be administered to animals

after surgery whenever this would not interfere

with the behavior under study, and animals should

be carefully monitored so that any complications

that develop may be treated (197).

Transection of the spine or brain stem is recommended for surgical experiments when possible,

because it renders the animal incapable of feeling

pain (114). This technique has limited applicability in behavioral research, however, as postsurgi -

cal behavioral assessment requires a relatively

intact animal. Similarly, the nonrecovery experiments on completely anesthetized animals that

were described earlier, in the biomedical research

section, are rarely used in behavioral research,

since most behaviors of interest do not occur when

the animal is unconscious and behavioral testing

is typically conducted postsurgically. Multiple surgeries on the same animal are to be avoided whenever possible, because painful consequences may

be cumulative (197).

The analysis of pain in behavioral research is

complicated by recent theoretical and empirical

developments suggesting that fear and pain activate quite different kinds of behavior (25). Rather

than being on a continuum, as might seem to be

the case intuitively, data suggest that fear and pain

are associated with fundamentally different motivational systems. Fear activates species-specific

defensive behaviors, such as freezing, flight, or

fighting, that serve to minimize encounters with

pain-producing stimuli (e.g., predators). Pain, on

the other hand, appears conducive to the kinds

of behaviors that provide for healing and recuperation (e .g., rest, grooming, licking the affected area,

and sleep). A growing body of evidence shows that

fear takes priority over pain, and that fear can actually inhibit pain under some circumstances (possibly through the release of endogenous opiates).

For example, soldiers who are wounded in battle

frequently continue fighting and feel no pain from

their injuries until after they are removed from

the front lines (211). Likewise, a deer wounded

by hunters may flee the scene with defensive behavior indistinguishable from that of uninjured

animals, But once the deer is out of danger, painrelated recuperative behaviors predominate (25).

Brain Manipulation

In studies of the physiological bases of behavior,

the recording of brain-wave patterns maybe substituted for electrical stimulation whenever possible, and brain areas may be stimulated instead

of lesioning or ablating sections of the brain (121).

These techniques, however, are not completely

interchangeable. Recording neuronal firing as an
Ch. 6—Alternatives to Animal Use in Research . 131

animal behaves allows correlational inferences to

be made, but not causal ones. If the experimental

goal is to determine a particular brain area that

is responsible for a certain behavior, that area must

be manipulated directly. Electrical stimulation of

brain areas is useful in establishing causal relationships, and the most definitive and reliable results are obtained when stimulation is used in conjunction with lesioning or ablation (20).

Drug Administration

In research on the behavioral effects of experimental or currently available drugs, animals are

injected either intraperitoneally (within the body

cavity), intravenously, intramuscularly, or intracranially (within the skull, via an implanted cannula). Depending on whether the drug must be

given repeatedly, the injection procedure can be

stressful and may cause discomfort. Within the

last decade alternative administration methods

have been developed that may replace the need for

multiple injections in some chronic drug treatment

studies. Capsules of porous rubber (Silastic@,

produced by Dow-Corning) implanted beneath the

skin release a drug slowly into the animal’s body,

and stress produced by repeated injections is

avoided. The method produces minimal discomfort and is well tolerated by animals (63). Small,

implantable minipumps are also available to deliver drugs for days or weeks.

The use of aerosols has also been suggested (174);

although this would seem to hold promise for alleviating the stress of injections, it has drawbacks.

For example, animals may differ greatly in their

inhalation rates, and dispersal of the drug into the

air prevents adequate control of drug dosage.

Food Deprivation

It is important to distinguish between the different methods of depriving animals of food and the

reasons for using any method. In most cases, animals are deprived of food to motivate them to perform various tasks or behaviors for food reward.

The nature of the subject’s performance of such

tasks—and not the food deprivation—is the object

of study.

Food deprivation is typically applied one of two

ways: Animals are deprived of food for a standard period of time (e.g., 24 hours) prior to testing

or they are maintained at some percentage of their

normal body weight (e.g., 80 percent) (43). Each

procedure has advantages and disadvantages. Food

deprivation for specified intervals of time is easy

to implement, but it fails to take into account species differences in metabolic rates, For example,

24 hours of food deprivation for a mammal is less

severe than it would be for a bird, while for a snake

it would be inconsequential. Maintaining animals

at a percentage of normal body weight avoids this

problem, but it requires daily handling and the

delay of the trial for long periods of time to stabilize body weights.

When food deprivation is applied according to

a standard time period in behavioral protocols, the

most common interval is 24 hours (43). It is noteworthy that the feeding of domestic pets once a

day parallels this laboratory protocol. When maintaining animals at some percentage of their normal

body weight, behavioral protocols usually involve

up to 20 percent weight loss (43). Experimental

animals’ reduced food intake is associated in some

instances with enhanced longevity (172).

Several suggestions have been made to reduce,

ameliorate, or eliminate food deprivation in behavioral research:

●

●

●

●

Water deprivation, sometimes used concurrently with food deprivation, should be used

to motivate behavior only if thirst or drinking is the object of study. Water deprivation

affects an animal’s physical condition more

severely than food deprivation does, because

death by dehydration occurs much more rapidly than death by starvation (121).

The normal eating pattern of a species should

be taken into account when deciding on the

duration of food deprivation. For example,

sparrows eat only during the light hours of

the day; hamsters feed largely at night.

In some cases, food deprivation might be

avoided by using a highly preferred food as

a reward (121).

Food deprivation may also be avoided by taking the experiment into the animal’s living

quarters, so that it is required to perform for
132 • Altematives to Animal Use in Research, Testing, and Education

food as and when it wants to eat. In this way,

any deprivation would be self-imposed as

under natural conditions (121,151). This technique has been used successfully in work on

sensory-motor functioning in monkeys (168).

Pain Research and the Use of

Electric Shock

The experience of pain is a highly adaptive capacity. It prevents organisms from engaging in behaviors that would otherwise prove maladaptive.

For example, humans who are congenitally insensitive to pain become terribly scarred and mutilated, often develop a sense of being invincible,

and have short life expectancies (141)143,196). Perhaps because pain plays such an essential role in

regulating the behavior of organisms, pain thresholds are surprisingly consistent across a great

diversity of species (115). The discovery of endogenous opiates in earthworms (5) and recent

findings with spiders (61) suggest that invertebrates may also feel pain.

Pain can be induced through mechanical, thermal, electrical, or chemical stimuli (127). Of the

various stimuli used for research purposes, electric shock at the levels normally used in experimentation is the only one that does not damage tissue.

Most studies of pain in animals use what are called

flinch-and-jump thresholds—an index of the minimal amount of electric shock or heat needed to

produce a reaction. Electric shock is used as a

stimulus for research into the mechanism of pain

for

●

●

●

several reasons:

Electric shock is easily quantifiable. The parameters of shock can be manipulated and

specified with a high degree of precision over

a wide range.

Electric shock can be administered so as to

have a discrete or gradual onset and offset.

Electric shock of the type most often used (i.e.,

a brief current of 0.001 amperes, the equivalent of a tingling sensation in the finger) does

not yield physical damage, bleeding, or tissue

destruction.

However, electric shock is a highly atypical stimulus (79). No contemporary terrestrial species appears to have evolved under conditions of electric shock. The question of whether data obtained

this way are widely generalizable in mechanisms

of pain remains unanswered.

A survey of the 608 articles appearing from 1979

through 1983 in the American Psychological Association journals that typically publish animal research (e.g., Journal of Comparative and Physiological Psychology and its successors Behavioral

Neuroscience and Journal of Comparative Psychology) identified 10 percent of the studies as using

electric shock. Four percent of the studies administered inescapable shocks stronger than 0.001 amperes. Most of the experiments with electric shock

involved rodents; those with monkeys, dogs, and

cats accounted for 0.5 percent of the total 608 articles (43).

Recommendations that have been made to reduce pain or discomfort in animal experiments involving aversive stimulation include:

●

●

●

●

●

●

The lowest possible level of electric shock

should be used that will at the same time maintain the behavior under study (52). However,

this may reduce the statistical power and require a large sample size.

Animals should be given predictable rather

than unpredictable shock and an opportunity

to control its termination (52). Rats, for example, will choose to receive more shocks at

greater intensity in order to receive a warning cue prior to each shock delivery (10).

If aversive stimulation must be used, alternatives to electric shock such as loud noise or

bright lights should be considered (121).

In developing models of chronic pain, the

model should closely simulate a particular

chronic pain syndrome in humans (e.g., arthritis or cancer). Otherwise, there is no justification for the procedure (114).

Animals should have an opportunity to control the intensity of the stimulus in chronic

pain studies. While the objection to this might

be that, given this option, the animal would

“turn off” the pain stimulus, this might be circumvented by giving a preferred food reward

for keeping the stimulus “on” at a given level,

as in experiments with electric shock titration

techniques (114).

A reward, such as a preferred food, should

be used for the correct responses instead of

a punisher, such as electric shock, for incorrect response (121).
Ch. 6—Alternatives to Animal Use in Research ● 133

USE OF LIVING SYSTEMS

In behavioral research, using living components

derived from whole animals or living nonanimal

systems as alternatives to animals could conceivably involve embryos; cell, tissue, and organ cultures; invertebrates; and plants. The greatest potential in this area, however, appears to rest with

the use of invertebrates.

Several factors limit the use of embryos (used

here to refer to the conceptus, embryo, and fetus

prior to birth) as an alternative or complement to

young or adult animals:

●

●

●

●

●

Some studies involving embryos may be conducted when the subject is very close to birth

or hatching. The advanced developmental status of the organism at this point raises the same

kinds of ethical considerations that would apply to the use of postnatal animals (see ch. 4).

In behavioral studies involving mammalian

embryos, the mother is necessarily involved

in most experimental manipulations performed

on the embryo. As a consequence, embryological manipulations on mammals cannot logically avoid the use of adult mammals.

Behavioral studies using embryos may involve

testing for effects later in adult life (e.g., behavioral teratological studies). In these instances, embryos are not being used as alternatives, since the procedures also require

postnatal assessment.

Only a limited number of behaviors can be

studied in embryos, partly because of practical problems associated with access to the

embryo.

Embryos live in a dramatically different environment than fully developed adult animals.

This difference constrains the generalizabil -

ity of behavioral data obtained from them.

Cell, tissue, and organ cultures do not figure

prominently in the equation of alternatives to animal use in behavioral research. In isolation and

in culture, cells, tissues, and organs exhibit few

activities that fall among the disciplines of behavioral research.

A rare example of the use of cell culture in behavioral research comes from studies of the biochemical basis of depression and manic mood

BEHAVIORAL RESEARCH

changes. Skin fibroblast cells obtained from humans and maintained in culture for several months

were assessed for their ability to bind a variety

of pharmacologic agents. The cultured cells of patients and relatives of patients with manic-depressive illness exhibited markedly different biochemical properties than the cultured cells of persons

without a history of manic depression (155). One

commentator characterized this as ‘(a step forward,

applying to psychiatry the techniques of tissue sampling and cell culture that have been of great value

in characterizing molecular abnormalities in numerous medical diseases” (192). Continued development of this line of research could reduce the

use of animals in such investigations.

Invertebrates

Few behavioral studies use invertebrates as subjects (139). As a consequence, relatively little is

known about invertebrate behavior. In behavioral

research, invertebrates offer a fertile testing

ground for any theory that claims to be broadly

based across the phyla of the animal kingdom (138).

Certain groups of invertebrates are promising subjects for behavioral research.

The brains of octopuses and squid approach

those of vertebrates in relative size and complexity (178). Visual discrimination learning has been

studied extensively in the octopus. Octopuses can

discriminate between pairs of geometric shapes

that differ with respect to vertical, horizontal, and

oblique orientations. The octopus and squid show

learning performance on a par with mammals on

such tasks as detour problems, reversal learning,

delayed response, and delayed reinforcement

(178,218).

Among all the invertebrates, the only species

with a neuroanatomy and learning ability comparable to vertebrates are the octopus and squid.

Practical problems in obtaining, transporting, and

housing these marine species have always precluded their widespread use as alternatives in behavioral research (178), However, recent advances

in the laboratory culture of octopuses make them

promising research candidates, although providing live food (e.g., shrimp) on a consistent basis
—

134 . Alternatives to Animal Use in Research, Testing, and Education

remains a major logistical obstacle. The development of a dead or artificial food ration is currently

a high priority in octopus culture (88). The same

highly developed nervous system that makes the

octopus and squid desirable replacements for vertebrates may cause some ethical objections to use

of these invertebrates. In addition, their adaptation to a completely aquatic existence would also

make tenuous any extrapolations to the behavior

of terrestrial mammals.

Starfish and sea urchins exhibit habituation—

the waning of a response to stimuli, as a result of

repeated elicitation of that response—and they can

learn escape behaviors in response to a cue paired

with aversive stimulation (46).

Earthworms exhibit habituation (45), can learn

to associate light with a food reward (66), and can

learn to travel a maze to receive darkness and moisture as reinforcing stimuli (85). Flatworms are also

of considerable interest, since they represent a

bilateral body form, as do mammals. Flatworms

exhibit a concentration of nervous tissue and sensory organs in the anterior, or head, portion of

their bodies, and they have refined internal organ systems (47). Flatworms exhibit habituation,

can be conditioned to avoid alight after it has been

paired with shock, and can learn to approach an

area for food reward. There are also claims that

such learned events are remembered after these

worms undergo regeneration, and that learning

can be transferred from one animal to another

by cannibalism (reviewed in ref. 47).

Insects are valuable behavioral models in communication, navigation, learning and memory, and

behavioral genetics.
Ch. 6—Alternatives to Animal Use in Research ● 135

●

●

●

●

Communication. Honeybees recruit others

to a new food source through a dance performed at the hive that conveys distance and

directional information (209). Many species

of insects (e.g., moths and ants) communicate

chemically by pheromones, which serve sex

attractant, repellant, and/or trail-marking

functions (reviewed in ref. 30). Other species,

such as the cricket, communicate by songs

produced by rubbing body parts together (19).

Navigation. Honeybees have demonstrated

extraordinary abilities to locate and return to

a food source “mapped out” for them by other

bees. They can also return to an artificial feeding source designed for experimental purposes to test their navigation abilities (37,

209)215).

Learning and Memory. Habituation has been

demonstrated in a variety of insect species (46).

Honeybees also appear capable of more advanced forms of learning, such as learning to

associate a specific color with a food reward,

and they can remember this association after

a 2-week interval (219). Cockroaches can learn

to leave their preferred dark retreats and stay

in the light to avoid being shocked; ants have

been trained to travel a maze to receive food

rewards (85).

Behavioral Genetics. Because of the relative

ease with which their chromosomes and individual genes can be identified, fruit flies have

been used extensively to elucidate the genetic

basis for a variety of behaviors (132).

Habituation has been demonstrated in a variety

of spiders (45), and spiders are capable of learning and remembering the location of prey in their

webs (85). They can also be trained to associate

food dipped in quinine or sugar with different

tones (46).

Even though protozoa possess both plant- and

animal-like characteristics and lack nervous tissue, some forms of learning have been demonstrated in these single celled organisms. Habituation has been demonstrated in paramecia (45).

Although the results generated much controversy

(reviewed in ref. 45), one investigator claimed to

have trained paramecia to enter a specific area

of their water container in order to receive food

reinforcement (81). It has also been reported that

paramecia show spontaneous alternation in a T-maze,

a phenomenon also observed in rodents (139).

A recent study of learning ability in paramecia

has demonstrated classical conditioning of an escape movement (94). This study also found that

paramecia develop memory for the training event,

since significantly fewer trials were needed 24

hours later to relearn the response. Data such as

these challenge the widely held assumption that

learning is a property of synaptic interactions between nerve cells—absent in protozoa—and not

of individual cells themselves.

Plants

From a behavioral perspective, plants differ from

animals in two principal ways. First, plants lack

the means of achieving rapid intra- and interorganismal communication and coordination due

to the absence of a nervous system. However,

plants do regulate intra-organismal activities occurring at different sites through the use of hormones.

Plants and animals thus share the basic principles

of endocrine function. Second, plants differ from

animals in that they are stationary. They must wait

for energy to come to them, while most animals

move about to obtain different sources of energy.

Despite these differences, plants do show rudimentary forms of behavior (188). Plants can grow

and move in response to light, and some plants

have achieved the capacity for relatively rapid

movement to exploit certain animals as prey (e.g.,

the venus fly trap). The mimosa plant, which can

fold its leaves when touched, has been a subject

of particular interest. Certain of its cells appear

to generate primitive action potentials-electrical

activity that may be analogous to neuronal functioning in animals (186). There have also been

reports that the folding response of the mimosa

plant shows habituation (6) and even some of the

rudiments of classical conditioning (8). Although

some claim evidence of feelings, emotions, and

even thinking in plants based on polygraph recordings (206), others contend these are artifactual (80).

A number of plants defend themselves from

predators via thorns, stickers, or toxic chemicals

that produce sickness, irritation, or even death if

touched or consumed. It has been demonstrated
136 Alternatives to Animal Use in Research, Testing, and Education

that some plants, under attack by insects and These impressive features of the botanical world

micro-organisms, develop highly sophisticated notwithstanding, it is unlikely that plants will make

defenses involving the emission of antibiotic-like an important contribution to behavioral research.

substances and chemicals that inhibit insect diges- The lack of a central nervous system, and in partive enzymes. Indeed, some plants can apparently ticular a brain, renders the plant an inappropricommunicate chemically with as-yet-unaffected ate model for use among the disciplines of beneighboring plants to induce leaf-chemistry havioral research.

changes in advance of infestation (reviewed in

ref. 164).

USE OF NONLIVING SYSTEMS IN BEHAVIORAL RESEARCH

Inanimate chemical or physical systems are unlikely to prove useful in behavioral research, for

reasons intrinsic to the nature of behavior. A dynamic, emergent process, behavior functions to

allow organisms to adapt to moment-to-moment

changes in the environment. In a sense, all behavior

ultimately functions to aid and abet survival and

reproduction (50. Adaptation, survival, and reproduction are not properties of nonliving systems.

And behavior involves information processing and

a continuous series of choices among an array of

alternatives (140). Although chemical or physical

systems may change in response to certain environmental stimuli, the nature of such changes does

not involve decisionmaking or information-processing.

Behavior is a byproduct of interactions between

sensory, neural, hormonal, genetic, and experiential factors. As such, it is influenced by the situation at hand, the developmental history of the

organism, and prior experience with similar and

related situations. It appears inappropriate to imbue inanimate chemical or physical systems with

the capacity for experience. Devoid of such a capacity for experience, nonliving systems are unlikely alternatives to using animals in behavioral

research.

Examples of the application of chemical or physical systems to behavioral research are sparse. One

involves the use of chemical reagents to mimic the

properties of rhythmic behavioral phenomena in

animals. Certain chemical reagents exhibit changes

in state that oscillate periodically in a fashion similar to some biologically based rhythms. However,

the chemical reactions themselves remain poorly

understood (222).

COMPUTER SIMULATION IN BEHAVIORAL RESEARCH

A computer simulation is an operating model that

depicts not only the state of a behavioral system

at a particular point in time but also changes that

occur in that system over time. Because dynamic

processes are of quintessential importance in behavioral research, computer simulation stands as

a potentially useful tool for the behavioral scientist.

In order to simulate a living system, a computer

programmer must have information about that

system. The more information at hand, the better

the simulation (53). In the strictest sense, a completely accurate simulation presupposes that everything that there is to know about the system in

question is known. To construct a computer simulation that would fully replace the use of a live

organism in behavioral research would require

knowing everything about the behavior in question, which in turn would preclude the need for

a computer simulation for research purposes.

Yet, if computer simulation cannot fully replace

living organisms, it can and does contribute to behavioral research. Although the fundamental behavioral qualities of adaptation, survival, and reproduction do not pertain to computer programs,

computer soft ware does, for example, embody information processing and decisionmaking. Exam-
Ch. 6—Alternatives to Animal Use in Research ● 137

pies of recent attempts toward computer simulation in behavioral research are listed in table 6-4.

Computer simulations are used in behavioral research in a number of ways. Statistical simulations,

in particular, are increasingly frequent. For example, one computer program simulates randomchoice behavior in mazes (194), and two programs

simulate random movements of animals under

various conditions (17,49). The output generated

by these kinds of simulations is compared with

animal-generated data to see if factors other than

pure chance are influencing the animals’ behavior.

Statistical simulations are also used to test hypotheses that may not be subject to empirical confirmation. One investigator used a computer simulation to test the proposition that “if enough

monkeys were allowed to pound away at typewriters for enough time, all the great works of

literature would result” (21). The larger objective

Table 6-4.—Some Examples of Computer Simulation

of Behavioral Phenomena

Spacing mechanisms and animal movements:

● Space use and movement patterns (17,49)

● Movements of juvenile Atlantic herring (110)

● Animal spacing (153)

● Mosquito flight patterns (165)

● Foraging of the honey eater bird (169)

● Random choice in radial arm mazes (194)

Learning, memory, and problem solving:

Ž Classical conditioning (15,18)

● Learning in neural systems (177)

● Habituation (195)

● Behavior in a psychoecological space (84)

● Mechanisms for reducing inhibition (223)

Sensation and perception:

● Visual pattern analysis (13)

● Landmark learning by bees (37)

● Chemical recruitment in ants (106)

Communication:

● Bird song (55,185)

● Animal vocalizations (57)

Sensation and perception:

• Neuron models (122)

● Neural basis for pain and touch (148)

Body maintenance:

● Food intake (14)

Ž Control of drinking behavior (204)

Reproduction and parental care:

● Sexual behavior of the male rat (72,205)

Ž Infanticide in Iangurs (89)

● Evolution of reproductive synchrony (116)

● Mating behavior of Spodoptera littoralis (200)

SOURCE: Office of Technology Assessment.

in this study was to determine if the extreme cases

of human genius could be accounted for through

chance processes.

The simulation was based on an initial assumption that monkeys typing at random— or a computer simulation using random numbers–would

generate huge volumes of nonsense. Statistical

properties of the English language (e.g., the relative frequencies of individual characters or sequences of characters) were added to the simulation. As higher-order properties of English (i.e.,

the relative frequencies of three- and four-letter

sequences) were incorporated into the algorithm,

the rate of generation of intelligible words, phrases,

and sentences increased. These results led to a hypothesis that genius could be simulated by a process of random choice with a weighting procedure,

subject to a prior preparatory process in which

an individual absorbs the necessary operational

patterns that characterize the discipline. In studies

such as this, it is not merely the output generated

by the computer model that is of interest, but the

simulation process as well.

Computer simulations have considerable heuristic value (65): They may yield insight about the system or phenomenon being modeled (71) and, as

a consequence, stimulate additional research. The

value of computer simulation as a heuristic device

has been summarized as follows (158):

Simulation gives a means of exploring the plausibility of models in which theoretical sophistication exceeds the state of the art in empirical testing. Simulations provide tools for empirically

analyzing theories in order to better understand

their implications and predictions. Simulations

are a means of exploring interactions between

components of complex models. They pose a practical challenge to operationalize theoretical constructs, which can lead to incidental discoveries

about related processes. Finally, they engender

a concern with issues of process control that contributes to the development of general principles

with broad applications.

Computer simulation holds promise for understanding complex cognitive processes. For example, the computer is often considered analogous,

at least in some ways, to the human brain (7)—

both process large amounts of information, and

their respective outcomes are a consequence of
138 Alternatives to Animal Use in Research, Testing, and Education

multiple, relatively simple operations. On the other

hand, there are major differences:

●

●

●

●

computers have larger and many fewer components than the brain;

computer operations occur with much greater

speed than neural operations;

computers operate through sequential processing; and

computers attend to all input, while the brain

is selectively attentive.

Such differences do not, however, preclude the

use of computers as functional models (170). Moreover, one advantage of computers is that they demand rigorous and exact description. And an investigator need not invoke a variety of hypothetical

or mentalistic variables (e g., hope, fear, desire,

and intention) to describe their functioning (170.

It is important to note that any predictions generated by a computer simulation must be tested

and verified using the system the computer was

designed to replace (149). In this sense, the use

of animals in behavioral research is likely to continue in lockstep with the development of computer simulation software.

One commentator summarized the use of computers as an alternative to animals in behavioral

research in this way (114):

At the present time and for the foreseeable future it seems clear that the computer will not be

a feasible substitute for experiments on animals.

The fundamental reason is that a computer cannot acquire data other than those that are generated by carefully designed experimental studies

in animals. What the computer does provide is

a superb technique for processing vast amounts

of data with great speed and accuracy and for

presenting them in almost any manner the investigator desires. To suggest that enough data are

already available from previous work, so that

from them programs can be generated and subjected to a variety of permutations that would lead

to new insights, overlooks an important fact. In

any animal experiment there are numerous variables over which we have little control, and there

are virtually always as many more about which

we as yet know nothing but which may have very

significant influences on the phenomenon under

investigation. In real life, which after all is what

matters in biologic research, these variables may

be crucial and may give important clues to entirely unsuspected phenomena that are sometimes far more important than the original subject of the study. In a word, computers do not

generate new concepts or acquire new data. They

process data and permit the investigator to view

it in more manageable or novel ways, and this

may facilitate new hypotheses or insights.

In summary, computer simulation can serve to

facilitate behavioral research. The need for certain protocols may be precluded, or protocols may

be refocused by computer simulation before they

commence. Modeling techniques using computer

simulation lead to the refinement of experimental

protocols to be conducted on animals (36). Yet as

the preceding quote implies, in facilitating behavioral research computer simulation may actually increase, rather than decrease, the use of animals because data can be analyzed more quickly

and in much greater detail, leading to proportionately more hypotheses to investigate (87,160).

SUMMARY AND CONCLUSIONS

Animal use in research can be modified in a number of ways, including strengthening experimental

design to minimize the number of animals used,

reducing the degree of experimental insult, and

substituting one species for another. The outright

replacement of animals with nonanimal methods

in research is not at hand, and, because of the nature of biomedical and behavioral research, in

many instances it is not likely to become feasible.

Advances in instrumentation are critical to the

more refined or reduced use of live animals or living material. In the past decade, practically every

piece of instrumentation in biomedical laboratories

has been adapted to handle ‘(micro” samples or

has been replaced by new microtechnology. The

use of small samples for analysis by mass spectrometry and by gas or liquid chromatography

leads to less invasive technology. Fiber optics, for
Ch. 6—Alternatives to Animal Use in Research ● 139

example, can be used to perform analyses inside

ducts and blood vessels with little discomfort and

no permanent damage to the animal. Continued

developments in analytical instrumentation, including noninvasive imaging techniques such as

magnetic resonance imaging, will likely ameliorate

the degree of experimental insult faced by research

animals.

In vitro technology has affected virtually every

field of biomedical research. This technology entails the maintenance of organs, tissues, and cells

outside of the body and may affect research animal use in two important ways. First, when organs, tissues, or cells are removed from animals

and cultured, experiments may be conducted with

fewer animals than would be necessary in wholeanimal experiments and, of course, without pain.

Cells from one animal, for example, may be divided

among a dozen experimental cultures and a dozen

control cultures, replacing 24 animals that might

be used in a comparable whole-animal experiment.

Second, when cells proliferate in culture, commercially available cell lines can completely eliminate animal use in some experiments. Such cell

cultures are derived directly from preexisting cell

cultures—not animals, Researchers have used, for

example, a monkey kidney cell line to study the

metabolic effects of general anesthetics.

In vitro experiments are not equivalent to wholeanimal experiments. In in-vitro systems, as organization is disrupted or lost, the in vitro system

has less and less of the kind of interactions that

characterize cells in the body. This can be an advantage and a disadvantage. Interactions may cause

extraneous phenomena that obscure the process

under study. Conversely, the absence of interactions may produce results that are at variance with

what actually occurs in the live animal. Conclusions drawn from in vitro studies must eventually

1.

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Cell biologists, for example, use yeast cells as a

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Hard and fast distinctions between biomedical

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Invertebrates are used extensively in behavioral

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organisms has challenged the widely held assumption that these phenomena are properties of the

interactions of nerve cells rather than of individual cells, and has opened new avenues of research

with nonanimal methods.

Computer simulation is a valuable tool in biomedical and behavioral research, but it does not

stand as a replacement for animal use. The development of new and more sophisticated computer

simulations in biomedical and behavioral research

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The Use of Animals in Testing

Distress caused by the Draize eye test is sometimes so acute that rabbits do scream out in

pain.

Close-Up Report

Humane Society of the United States

1985

Laws should neither push the science where it is not yet ready to go nor hold the science

to procedures that have been modified or replaced.

Geraldine V. Cox

Chemical Manufacturers Association

March .20, 1985
CONTENTS

Page

Testing Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .l50

Designing a Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150

Use of Standardized Test Methods and Guidelines . . . . . . . . . . . . . . . . . . . . ....152

Pharmacokinetics ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . .153

Acute Toxicity Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . . .153

Skin and Eye Irritation/Corrosion Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .154

Repeated-Dose Toxicity Tests.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1s4

Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................155

Developmental and Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . ...........156

Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..............156

Mutagenicity . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..157

Current Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .157

The Role of Government in fasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... ...157

Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158

Environmental Protection Agency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161

Consumer Product Safety Commission. . . . . . . . . . . . . . . . . . . . . . . ...........164

Department of Labor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .164

Department of Transportation . . . . . . . . . . . . . . . . . . . . . ...................164

Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..165

Centers for Disease Control ..+... . . . . . . . . . . . . . . . . . . . . . . ...............165

Federal Trade Commission. . ., . . . . . . . . . . . . . . . . . . . . . ...................165

State Uses of Animal Testing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...165

Pesticide Registrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...165

Identification and Classification of Toxic Substances . . . . . . . . . . . . . . . . . . . . . .166

Product Liability Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........167

The Manufacturer’s Duty to Produce a Safe Product. . . . . . . . . . . . . . . . . . . . . .167

Methods of Testing Required, ,..., . . . . . . . . . . . . . . . . . . . . . ...............168

Summary and Conclusions , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....168

Chapter preferences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . . . . . .. ...169

Table

Table No. Page

7-1. Number of Animals Needed to Detect Carcinogenicity in 90 Percent of

All Tests for a Statistical Significance of 0.05 . .........................156
Chapter 7

The Use of Animals in Testing

Testing for the safety or efficacy of a substance

or product accounts for a major use of animals

as defined in this assessment, most of which are

rats and mice (see ch. 3). Of these, probably the

largest portion are used in developing drugs. A

significant portion are also used to test other substances—pesticides, industrial chemicals, and consumer products—to assess possible toxicity and

to establish conditions under which they can be

used safely.

Research and testing have been differentiated

for purposes of this assessment, but the boundary between them is not sharp. From the standpoint of developing alternatives, a key difference

is that a particular test maybe performed for hundreds, perhaps thousands of substances and use

hundreds or thousands of animals, whereas a given

research method will be used on far fewer. As a

corollary there are far more research procedures

than testing procedures from which to choose, Furthermore, individual researchers are much more

likely to develop their own methods than are those

conducting testing. These differences make the

task of developing alternatives more manageable

for testing than for research.

Testing for efficacy has some attributes of research and some of toxicity testing. A particular

protocol may be used on a small number of substances and is likely to be tailored either to the

application or to the family of substances being

tested. Experimenters testing for efficacy need to

have a better understanding of the mechanisms

by which a particular effect occurs than those testing for toxicity, primarily because efficacy testing is closely related to the physiological mechanisms that the new drug may affect, whereas toxic

effects may be quite independent. Finally, an important distinction of efficacy testing is that the

animals used would ordinarily be diseased.

Other kinds of tests include those for safety

other than for toxicity, as in testing of diagnostic

techniques or quality control tests in the manufacture of medical devices. These have endpoints

even more specific than those for toxicity, and are

thus good candidates for the development of alternatives (see ch. 8).

Toxicity testing is the focus of this and the following chapter for three reasons. First, this is an

area of animal use in testing in which the government has great influence on nongovernmental activities. Second, these tests are used in a more routine fashion than are tests for efficacy or general

safety and therefore have a greater tendency to

lag in the application of state-of-the-art technology. Third, toxicity tests include methods that have

attracted the largest political attack.

All substances can be toxic at some exposure

level, even water. Conversely, even substances

known to be highly toxic maybe harmless at low

doses or under certain circumstances. Determining the hazard to humans requires information

about the potential hazard and the expected level

of exposure, resulting in an estimate of the probability that a substance will produce harm under

certain conditions (8). This assessment of risk is

a scientific endeavor, whereas the management

of risk is a sociopolitical one (31,36).

Although toxicity data on humans are invaluable

in conducting risk assessments, they are usually

unavailable. Some information comes from epidemiologic studies or episodes of accidental human exposure. Most often, however, testing on

animals is used. An appropriate weight is given

to the following factors on a case-by-case basis,

considering the seriousness of the hazard and the

kind of assumptions needed to estimate risks to

humans:

●

●

●

●

●

•

the relationship between dose and response;

the effects at the molecular, cellular, organ,

organ system, and whole-organism levels;

conflicting results between studies and possible explanations for the conflicts;

the effects of structurally similar substances

on humans or animals;

any known metabolic differences between humans and the test species that could affect the

toxic response; and

statistical uncertainties and difficulties in extrapolating to a low dose (55).

149
150 ● Alternatives to Anima/ use in Research, Testing, and Education

TESTING

Toxicology as a science began in the 16th century and has advanced with the growth of the

chemical, pesticide, drug, and cosmetic industries.

The concept of protecting the public from harmful effects of chemicals dates back to laws of ancient civilizations that made it illegal to adulterate

the food supply (25). The importance of toxicology to public health has received considerable attention in the United States since the 1930s. Public awareness of the value of toxicological testing

has also been furthered by disasters such as Minamata disease (methyl mercury poisoning in Japan),

the thalidomide tragedy, and, more recently, the

development of cancer in those exposed to diethylstilbestrol (DES) in utero.

Designing a Test

There are two approaches to toxicology-mechanistic and descriptive—and these affect the design of experiments and the choice of biological

end points to be measured. Mechanistic toxicology focuses on the chemical processes by which

a toxic effect occurs and relies heavily on the techniques of physiology, biochemistry, and analytical chemistry to monitor these processes. A simple example of this approach would be a series

of experiments showing that a certain substance

is metabolized in the liver, that one of the byproducts of metabolism happens to be a potent

liver carcinogen, and that liver cancer typically

follows administration of that substance. Mechanistic tests are custom designed and are closely

related to research. They can contribute greatly

to the design and interpretation of descriptive tests,

Mechanistic toxicology plays a major role in the

development of methodologies that could replace

whole-animal testing.

Descriptive toxicology deals with phenomena

above the molecular level and may rely heavily

on the techniques of pathology, statistics, physiology, and pharmacology, e.g., the evaluation of

changes in the appearance of an organ or its constituent cells, the presence of tumors, or signs of

irritation. This approach does not necessarily require an understanding of the mechanisms by

which toxic effects occur, although if mechanistic information were available, it would be used.

METHODS

In terms of the test substance and species in the

preceding hypothetical case, descriptive toxicology would show that a certain substance causes

liver cancer in a particular species within a certain time. It might also show the approximate relationship between the substance dose and the incidence of the liver cancer. Regulatory schemes

requiring testing most often rely on descriptive

toxicology.

Mechanistic toxicology provides an approach to

extrapolation from one species to another based

on known similarities and differences in physiology. The closer the test animal is biologically to

humans or the greater the number of species in

which the effect is detected, the more likely it will

occur in humans as well. The reliability of extrapolations from descriptive experiments is greatly

enhanced when mechanistic information is also

used. Similarly, the use of mechanistic information in the design of descriptive tests contributes

greatly to the reasonableness of any later extrapolation to humans if human toxicity data are lacking.

Most state-of-the-art toxicological tests require

whole animals. Although in vitro alternatives are

being developed (see ch. 8), different end points

would be measured. For example, whole animals

will probably continue to be needed to look for

effects in previously unknown target organs, to

evaluate effects that represent an interaction of

multiple organ systems, to monitor metabolism and

pharmacokinetics, or to evaluate healing or diminished responsiveness to the toxic substance. Thus,

whole-animal use is unlikely to stop entirely in the

foreseeable future.

Choice of Species and Strain

In 1$104) the Food and Drug Administration (FDA)

was still using human employees to test food preservatives (e.g., boric acid, salicylic acid, their derivatives, and formaldehyde) for toxicity (25). Use

of animals remained limited until a few decades

ago, when breeding technology provided large

numbers of animals with carefully controlled

genetic characteristics, thus allowing toxic effects

to be more easily detected than had previously

been the case. Animal use has grown with increas-
Ch. 7—The Use of Anima/s in Testing Ž 151

ing demands by the public for safe and effective

products.

The most appropriate animals are ideally those

that, for the substance being tested, predict the

human response most accurately. There is no other

animal wholly identical to humans in terms of toxic

effects. The choice of animal is influenced by

known similarity to humans for the organ system

or mechanism of interest, as well as convenience

of breeding or purchasing, familiarity with the species, existing data, lifespan, ease of handling under

experimental conditions, cost of obtaining and

maintaining, litter size, and gestation period. Rodents have been used extensively, as have rabbits,

primates, and dogs.

Rodents have been used in almost all carcinogenicity testing despite the fact that such tests are

the most difficult to extrapolate to humans. Mice

and rats have been used because their lifespan is

short, they are small and easily handled, and they

have a number of metabolic pathways and pathological responses similar to those of humans. Some

specially developed strains are sufficiently susceptible to cancer that test groups can be small. These

factors contribute greatly to the economic feasibility of conducting carcinogenicity testing with

rodents. Extensive experience in using them, and

in using particular strains, is often an important

reason for continuing their use (55). A large amount

of data are already available on spontaneous tumors

at specific organ sites (l).

Although rodents are routinely used for many

kinds of tests, other animals maybe used for specific reasons. For example, the rabbit is used for

eye irritation tests because it has large, easily

manipulated eyes and because its eyes have many

characteristics found in human eyes (19). Hens

have been shown to be a good model for delayed

neurotoxic effects of organophosphorous compounds (12).

Dose Levels and Route and

Duration of Exposure

The way in which exposure to a substance occurs can affect the kind and severity of toxic effects. For example, if a chemical does not present

a hazard when applied to skin because it is not

absorbed, it may nonetheless be very toxic if taken

orally. When the route of exposure does not affect

the portion of the dose taken up or its distribution

in the body, testing might be done in the manner

most easily controlled. For other than the most

preliminary tests to characterize toxicity, most

would administer the substance by the same route

as would occur in the course of accidental exposure

or use by humans. Sometimes the palatability, volubility, stability, or volatility of a substance will determine which routes are feasible.

Certain tests, such as the acute toxicity for a single exposure, are used as inexpensive screening

tools for estimating the relative hazard presented

by a substance. As discussed later in this chapter,

the acute toxicity test known as the LD50 is used

in classification schemes for the transportation or

disposal of chemicals. Acute toxicity testing might

also be used to determine the risks of one-time

exposure, as might occur in an accident. Ordinarily, the duration of exposure in an animal study

is greater (at least in proportion to the lifespan)

than the exposure period for which data will be

used in extrapolating the risks to humans.

The dose levels administered depend on a variety of factors. On the one hand, it is not possible

to detect long-term effects if the dose is so large

that many animals die before the end of the test.

On the other hand, administered doses representative of human exposure levels may not produce

detectable effects with what may be considered

a reasonable number of test animals. Generally,

three dose levels are used; they are chosen so as

to span the range of responses from a “no-observedeffect level” to fully observable toxic effects,

For carcinogenicity and other long-term testing,

the highest dose should be one that will produce

measurable toxicity without significantly altering

lifespan. Other levels may depend on whether the

carcinogenicity is being looked for in combination

with chronic toxicity (55). The lowest dose could

be one for which there are no observed effects

or it might be related to the level of estimated human exposure (38).

Another approach is to choose doses that will

yield levels in the blood similar to those expected

for humans. Although this is perhaps a more realistic test, effects may be more difficult to detect.

In addition, the criterion of similarity may require
152 “ Alternatives to Animal Use in Research, Testing, and Education

more than one administration per day because

metabolic rates and excretion rates tend to be

faster in small animals than in humans (24).

Statistical Considerations

To obtain valid results, an experiment must be

designed so that what is measured provides useful

and sufficiently accurate information. Statistical

methods allow a scientist to estimate the minimum

number of test animals from which conclusions

can be drawn to estimate the reliability of any conclusions. Statistical analysis can help reduce the

number of animals needed for a particular test

procedure.

To allow for the unexpected (including death,

illness, or error), the number of animals used always exceeds the minimum number needed to detect expected effects reliably. Determining that

minimum number of animals is more difficult for

longer tests, both because the passage of time

makes the probability of something going wrong

during the experiment increase, and because certain problems are more likely to occur as the animals age.

Another factor affecting the number of animals

needed is the variability in the sensitivity of individual animals to the substance involved. Thus,

as few as 6 animals might be used for an eye irritation test or 10 per dose level for an acute toxicity

test. In carcinogenicity or teratogenicity testing,

many of the animals maybe unaffected by the test

substance, and 100 animals may be needed for each

dose level.

Most species experience some cancer and other

diseases during their life. Any measurement of incidence as it relates to the dose given must be taken

against this background incidence, which is gauged

in an (untreated) control group. Control groups

may also be important if a test substance is being

carried in a particular vehicle needed to administer

the test substance, such as in solution with another

chemical, that is not itself being tested (vehicle control group). The sensitivity of the test animals to

a substance known to be toxic may also be measured for comparison (a positive control group). Because there are so many variables that can influence a test, toxicologists consider it vital that the

control and test groups be drawn from the same

pool of animals and be tested concurrently.

Any experiment suffers from experimental error, of which there are three sources: the natural

variation due to differences among test animals,

the variation in experimental conditions, and error

arising in measurement. Determining the amount

of error is crucial to drawing reliable conclusions

from experimental results, but it is also important

to keep the error as low as possible by controlling

conditions carefully. Differences among test animals are controlled by using genetically similar

and sufficiently large groups for each condition.

Even minor environmental factors can influence

toxic response (15,23). Sources of measurement

error depend on the measurement technique and

the equipment.

Use of Standardized Test Methods

and Guidelines

Testing methodologies are standardized to control experimental variables, thus allowing results

to be easily compared. Methodologies may become standardized through round-robin testing

in many labs, through publication and imitation,

and through development by recognized organizations or agencies. Methodologies or guidelines

are published by the Food and Drug Administration, the Environmental Protection Agency (EPA),

the Organization for Economic Cooperation and

Development (OECD), the National Cancer Institute, the American Society for Testing and Materials, the American National Standards Institute,

the British Standards Institute, the International

Agency for Research on Cancer, and others (see

app. A for information on FDA, EPA, and OECD

guidelines).

The most important reason to strive for compatibility among guidelines is to avoid the need to

repeat identical tests to satisfy particular requirements of various governments and agencies. Compatibility can also avoid nontariff trade barriers,

Any government that would like to change its testing requirements to further the cause of animal

welfare needs to consider the effects of its policies on testing in other countries.
Ch. 7—The Use of Animals in Testing ● 153

Pharmacokinetics

Pharmacokinetic studies provide information

about the mechanisms of absorption, about a substance’s distribution among the various body compartments, and about metabolism and elimination.

They facilitate the interpretation of results from

other tests and their extrapolation to humans because the distribution and elimination of a foreign

substance will often explain its toxicity or lack

thereof.

Absorption of a substance into the body can occur by a variety of routes. If exposure is by inhalation, absorption can occur in the lungs, in the pathways leading to the lungs, and sometimes in the

gastrointestinal tract. If exposure is by mouth, absorption would occur as the substance passes

through the gastrointestinal tract. What is not absorbed is excreted in the feces, With dermal exposure, the substance must be absorbed through

the skin. If exposure is via injection into a body

cavity, the substance cannot be removed without

the involvement of other parts of the body.

Once a substance is absorbed, it maybe excreted

unchanged. Excretion could be through the skin,

in the urine, feces, semen, or breast milk, or, if

it is volatile, in exhaled air. It might also be stored

in tissues, organs, or body fluids, perhaps for the

life of the organism. A substance might also be

chemically modified until it can be excreted or until

the body is unable to metabolize it any further.

This metabolism normally takes place in the liver,

the site where detoxification of substances takes

place. A test substance or its metabolic products

can react with the chemicals that make up the

body, perhaps resulting in toxic effects.

Pharmacokinetic studies are usually conducted

through the sampling of body fluids, both those

that are excreted (urine, saliva) and those that are

not (blood, cerebrospinal fluid). Tissue samples are

often taken, although normally not until the end

of a study (4).

Acute Toxicity Tests

Acute toxicity testing is used to detect the toxic

effects of single or multiple exposures occurring

within 24 hours. These are frequently the first tests

performed in determining the toxic characteristics of a substance and may serve as a basis for

classification or labeling or for concerns about accidental exposure. The results are used to establish

toxicity relative to other substances, to determine

specific toxic effects, and to provide information

on the mode of toxic action and the relationship

between dose and adverse effects. Results may also

help in designing long-term tests.

One of the most common acute toxicity tests is

the LD50 (from Lethal Dose for 50 percent), developed in 1927 for comparing batches of dangerous

drugs (52). The LD50 is calculated to be the dose,

within statistically established confidence intervals, at which half the test animals can be expected

to die upon exposure to a test substance. A substance is administered once by the oral, dermal,

or parenteral (injection into a vein or the body

cavity) route or it is inhaled. The animals, usually

rodents, are observed for 14 days and then sacrificed so that their organs and tissues can be evaluated for gross changes. Other measurements and

observations can be added to increase the amount

of information this test provides.

A related procedure is the limit test. A high dose

is given, often 5 g/kg body weight (54); if no animals die, the test ends. This is based on the assumption that if an organism is not killed by an

extremely large dose, it does not matter what dose

it takes to actually cause death. Other tests using

fewer animals have been devised and are receiving growing acceptance (see ch. 8).

Acute toxicity testing has its limitations, particularly because the end point is death. Death can

come about in many ways and the mechanism is

not conveyed in the numerical value of an LD50.

In addition, the results may vary greatly both

among and within species, with the animals’ sex,

age, and diet, and with other test conditions. Acute

toxicity testing, although not necessarily the classic LD50 procedures, will continue to be of interest because there are many substances for which

the toxic effects of acute exposure are quite different from those produced by chronic exposure (8).

It may also continue to be used in selecting doses

for long-term studies. Nonetheless, circumstances

may be identified in which acute toxicity testing

is not needed because other tests more relevant

to the use should be performed. The Toxicity Committee of the Fund for the Replacement of Ani38-750 0 - 86 - 6
154 . Alternatives to Animal Use in Research, Testing, and Education

reals in Medical Experiments recommended that

study of the consequences of not acquiring knowledge of acute toxicity of products be undertaken

and that in the case of products such as drugs,

LD~Otests should be replaced by acute toxicity tests

that emphasize the nature of the effects observed

(18).

Skin and Eye Irritation/Corrosion Tests

Irritation is the production of reversible tissue

damage such as swelling, while corrosion is the

production of irreversible tissue damage. Skin and

eye irritation tests normally involve acute exposure. Repeated exposure can be used to test for

allergic reactions, which involve the organism’s

immune system, and cumulative effects. Skin irritation studies are used to initially characterize a

substance’s toxicity and to develop precautionary

information for situations in which human skin

or eye exposure is possible.

Although it is not yet possible to reliably predict

the degree of irritation or corrosion a substance

will cause, a considerable body of knowledge exists. The factors that determine damaging effects

to eyes or skin are:

● intimacy and duration of contact,

● physical properties that determine the amount

of penetration, and

● the reactivity of the substance with tissues (10).

Intimacy is affected by both the ability of the substance to spread over the surface (such as soaps

or detergents) and its concentration. Penetration

of the skin or other membranes is greatest in substances with small molecular size and with abilities to mix with both water and oil. A substance

that can react with proteins and enzymes in tissues is especially damaging if it can penetrate to

the delicate structures of the eye (50).

Skin irritation tests are usually conducted on rabbits, guinea pigs, rats, and mice, although other

mammals may also be used. The test substance

is applied to a small area of skin from which the

fur has been clipped or shaved and maybe held

in place with a dressing. Using untreated skin of

the same animal for comparison, the degree of redness or blistering is scored at intervals (e.g., 38,54).

There are many similarities between the skin

cells of humans and other mammals, but there are

important differences as well. For example, there

are structural differences that affect permeability (32). Animal models have been shown to be particularly poor in the evaluation of mild irritants

(27). The extrapolation of animal models is further

complicated by large differences in the race, age,

and skin condition of humans (21,26,58).

The method most commonly used to evaluate

eye irritation is the Draize test, which has remained

largely unaltered since it was introduced more than

40 years ago (9). A single dose of a substance is

applied to one eye of at least three adult rabbits.

The other eye remains untreated. The degree of

irritation or corrosion to the cornea, iris, and conjunctival is scored by comparison with standard

pictures over a period of 3 days. The rabbits may

be observed for 3 weeks to determine whether

the effects are reversible.

A substance shown to be highly corrosive to skin

will be highly irritating to the eye and thus might

not be tested. Similarly, a substance with a pH of

2 or less (strongly acid) or 11.5 or more (strongly

alkaline) is assumed to be highly irritating or corrosive to skin or eye and need not be tested (38,54).

The cornea tolerates substances with a pH ranging from 3 to 11 variably, with the severity of a

reaction depending in large part on a substance’s

ability to affect protein structure or function

(17,35).

Repeated-Dose Toxicity Tests

Humans are often exposed repeatedly to a substance and this does not necessarily cause the same

effects as an acute, one-time exposure. Chronic

toxicity effects differ from acute toxicity ones when

the test substance or its metabolizes accumulate

in the organism to a toxic level or when it causes

irreversible toxic effects that accumulate with each

administration (8). Rats are most frequently used,

and testing in a second, nonrodent species, usually a dog, is also common.

Repeated or prolonged exposure to the test substance is used in chronic, subchronic, and shortterm toxicity tests. The term chronic generally
Ch. 7—The Use of Animals in Testing ● 155

refers to tests with exposure for at least 1 year

or most of the lifetime of the test species. Subchronic usually refers to tests of intermediate duration-3 to 6 months. Short-term repeated dose toxicity tests last from 2 to 4 weeks.

Some have suggested that there is little to be

gained by exposures of more than 6 months duration for chronic toxicity testing (18)34). One commentator has argued that studies of 3 to 6 months

are easier to interpret because the complicating

effects of aging are avoided (44)45). Another finds

longer tests necessary for detecting effects that

occur only late in life or for which cumulative toxicity is an important consequence (42).

Throughout repeated-dose testing, animals

would be observed for general appearance, respiratory problems, central and peripheral nervous system function, coordination, and behavioral

changes. During and following the course of exposure, observations are made of hematology

(hematocrit, white cell count, platelet count, clotting factors), ophthalmology, electrolyte balance,

carbohydrate metabolism, liver and kidney function (as determined from concentrations of certain substances in the blood), body weight, and

the appearance of lesions. After the animals have

been sacrificed, observations are made of body

surfaces, orifices, cavities, and organs. Microscopic

examinations are made of selected tissues and organs, of gross lesions, and of organs that changed

in size. one technique used in repeated dose toxicity testing to determine whether the toxic effects

are reversible is to give a satellite group the highest dose of the test substance and then give the

animals time to recover before sacrificing them.

Carcinogenicity

Cancer is a major human health concern, striking one out of four and killing one out of five Americans (53). Consequently, carcinogenicity is an important animal test. Detecting human carcinogens

presents special problems because a latency period

of 20 years or more can occur. Animal testing, particularly in rodents, is useful because the latency

period for tumor formation is much shorter (1 to

2 years for rodents), thus allowing potential human carcinogens to be detected during testing and

before use, at which point they could become major public health problems. It is also much easier

to control the animal environment than the human environment, and therefore to investigate

causal relationships.

Although many human carcinogens were discovered without animal testing, several have been

identified by first using such tests, e.g., DES, vinyl

chloride, and bis(chloro-methyl) ether (55). Animal use has its limitations; many substances cause

cancer only in certain species. The known human

carcinogens benzene and arsenic have never

proved to be animal carcinogens. Hundreds of substances have been identified as carcinogens in tests

with one or more animal species but not in humans, in part because of insufficient human epidemiologic data and in part because some of them

undoubtedly do not cause cancer in humans (41).

Nonetheless, the use of animals in testing for carcinogenicity is widely endorsed (55).

Carcinogenicity testing is more costly and requires far more animals than other tests. Chronic

toxicity testing may use about 160 rats and 32 dogs,

whereas carcinogenicity testing would use about

400 rats and 400 mice. (In order to economize, carcinogenicity testing and chronic toxicity testing

are often combined. ) Cancer is easy to detect if

tumors are visible, but it can only be detected in

its early stages by microscopic examination of multiple samples of 30 or more tissues and organs that

may appear normal. Typically, 500,000 data points

must be analyzed (41).

These large numbers of animals and multiple

data points are needed for statistical reasons. Cancer has a high background incidence and large variations from animal to animal, making it difficult

to establish that cancer was caused by the test substance. The higher the incidence of spontaneous

cancers, the more difficult it is to establish a link

between cancer and the test substance. For example, if the background rate of cancer is 10 percent and the common criterion for statistical significance of 0.05 is used, the number of animals

required to detect carcinogenicity in 90 percent

of the tests is as shown in table 7-1. As can be seen,

if a test substance causes cancer in 80 percent of

the animals, 48 animals are needed to demonstrate

carcinogenicity. If the incidence is only 15 percent,

over 3,000 animals are needed. It has been suggested that the background incidence could be re-
156 “ Alternatives to Animal Use in Research, Testing, and Education

Table 7.1 .—Number of Animals Needed to Detect

Carcinogenicity in 90 Percent of All Tests

for a Statistical Significance of 0.05

Number of animals

Rate of incidence caused by (3 dose levels

test substance (percent) plus control group)

80. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

60. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

40. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

20. . . . . . . . . . . . . . . . . . , . . . . . . . . . . 1,020

15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,304

SOURCE: Adapted from l.F.H. Purchase, “Carcinogenicity/’A nh-naLs artdA/ter.

natives in Toxicity Testktg, M. Balls, R.J. Ridden, and A.N. Worden (eds,)

(New York: Academic Press, 1983).

duced, and the sensitivity of the method thereby

improved, if animals were not kept under conditions that aggravate cancer (excessively nutritious

diet, little exercise, and isolation) (42).

Developmental and Reproductive

Toxicity

The effects of chemicals on human reproduction are difficult to assess because of the complexity of the reproductive process and the many kinds

of insults that can be inflicted before reproductive maturity as well as during fetal development

(8). Reproductive functions that can be harmed

by foreign substances include the storage and

maturation of the germ cells, fertility (including

factors that affect sperm maturation and implantation of the fertilized egg), and the development

of the fetus. Possible toxic effects to the fetus include birth defects (teratogenicity), low birth

weight, abnormal gestation time, and prenatal or

postnatal death (7).

There are a variety of experimental protocols

by which these effects can be determined in animals. Some involve more than one generation;

others involve evaluation of a fetus before birth.

Exposure to a substance can start before the female ovulates or as late as some specific stage of

fetal development. Exposure can be chronic or

acute. The great variety of procedures available

can lead to a certain amount of overlapping testing (2).

Rats and rabbits are the most commonly used

species. Mice and hamsters and other mammals

are used as well. Three dose levels are normally

used, the highest of which causes minimal toxicity

in the adult female. Groups of about 20 pregnant

females are typically used. In the OECD Testing

Guidelines, if no teratogenic effects are observed

at a dose of 1,000 mg/kg body weight, other dose

levels are not necessary (38).

Neurotoxicity

Neurotoxicity (damage to the nervous system)

is observed in acute and chronic testing, but the

range of neurotoxic effects is so great and the signs

so varied that special tests for damage to the nervous system are sometimes warranted, Neurotoxic

effects that tend to be associated with acute exposure are functional, sometimes reversible changes

in the nervous system that might not involve structural damage or degeneration. Most chronic neurotoxic effects do involve structural changes or degeneration and are not readily reversible (6). The

type of neurotoxic effect tends to depend on the

size of the dose and the duration of exposure (46).

There are many types of nerve cells, each performing special functions. Damage can occur to

the functioning of the cell itself, to its connections

to other nerve cells or to muscle cells, or to the

supporting cells. Neurotoxicity can be manifested

in the following ways: motor disorders such as

weakness, lack of coordination, paralysis, tremor,

convulsions, or slurred speech; sensory disorders

such as numbness, pain, or auditory, olfactory,

or visual deficits; disturbances of autonomic function such as sweating, incontinence, vomiting, impotence, or tear formation; increased state of

excitability such as hyperactivity, irritability, or

euphoria; impairment of short-or long-term memory, disorientation, or confusion; sleep disorders;

psychiatric disturbances; impaired temperature

regulation; or alterations in appetite, or weight gain

or loss (6).

More than any other kind of toxicity test, neuro -

toxicity does not lend itself to standard procedures

or in vitro tests because the range of effects is so

broad. There are considerable differences among

species, and little standardization of tests across

species has occurred. Neurotoxicity tests would

typically follow acute or chronic toxicity ones in

which neurotoxic effects had been observed or

were suspected (6).
Ch. 7—The Use of Animals in Testing ● 157

Mutagenicity

A mutation is a permanent change in a gene that

is passed along to any descendants of the cell. Thus,

mutations in germ cells will be passed along to offspring. If recessive, the mutation will not be observed in the offspring but will become part of

the gene pool from which future generations will

draw. If the mutations dominant, it may be lethal

to the developing fetus or it might affect the offspring in a variety of ways, including impairing

its fertility. If the damage is to a somatic cell, the

mutation could lead to cancer or, in a developing

fetus, birth defects.

There are several nonanimal and in vitro tests

based on mammalian or human cells that would

be considered alternative mutagenicity tests (see

ch. 8). There are several whole-animal tests as well.

One is the dominant lethal assay, in which a male

is exposed to the test substance and then mated

with an untreated female. Part way through the

pregnancy, the female is killed and the number

and condition of the fetuses observed. Another

is the heritable translocation assay, in which the

male progeny of treated males are mated with untreated females and the effect on fetuses determined. The mutations transmissible to the next

generation are of special interest because of their

implications for the human gene pool (5).

The in vivo sister chromatid exchange and mouse

micronucleus tests rely on microscopic examination of the chromosomes themselves after the test

substance has been administered to the whole animal. In vitro versions of these techniques also exist

(see ch. 8). Changes can be observed using a microscope. Host-mediated assays are a hybrid of nonanimal and whole-animal techniques in which the

test substance and a micro-organism are administered to an animal and the effects on the microorganism determined (5).

Current Trends

Many factors are likely to influence testing practices in the near future. Public pressure to use alternatives to whole animals, increasing costs of using

animals, and improvements in toxicological methods are likely to reduce the use of some tests, such

as the LD50 and the Draize eye irritation tests. This

pressure is also likely to result in changes in some

existing tests in order to reduce animal suffering.

These developments could bring about a review

of current legal requirements for testing, perhaps

reducing the amount of testing per chemical and

the number of animals per test. Such a review,

as well as advances in the state of the art, might

better tailor testing to the substance being examined and to the circumstances of human exposure.

On the other hand, the number of substances being tested could increase with greater regulatory

or product liability requirements, with greater

funding available for testing, or with less expensive tests available.

Interpretation and extrapolation of test results

to humans can be expected to improve as the mechanisms of toxic responses are better understood.

Increasing use of pharmacokinetics and mechanistic studies is likely to result in improved designs

and better selection of tests.

THE ROLE OF GOVERNMENT IN TESTING

The Federal Government and each of the States

are involved in testing in a variety of ways. Perhaps the most important are various explicit and

implicit requirements for testing under existing

statutes. Another area is the funding of research

and development leading to new methods (see ch.

12). Yet another is the funding of toxicological testing, conducted primarily by the National Toxicology Program (NTP), supported largely by the National Institute of Environmental Health Sciences.

This program, chartered in 1978, is a cooperative

effort among agencies within the Department of

Health and Human Services (see chs. 11 and 12).

Four principal Federal agencies have a significant role in animal testing for regulatory purposes:

FDA, EPA, the Consumer Product Safety Commission (CPSC), and the Occupational Safety and Health

Administration (OSHA). Other agencies whose regulatory activities affect animal use include the
158 . Alternatives to Animal Use in Research, Testing, and Education

Centers for Disease Control (CDC), the Department

of Transportation (DOT), the Federal Trade Commission (FTC), and the US. Department of Agriculture (USDA). Animal testing is also funded by

the Department of Defense.

Testing is covered by several types of statutes

and regulations. Most common are laws that require a product to be safe and effective. Given the

state of currently accepted technology and practice, such a statute implicitly (although not explicitly) calls for animal testing. Such tests are routinely expected as an indication of meeting the

standard of product safety and effectiveness. A

second stimulus for animal testing involves premarket approval. Under this authority, testing with

animals is explicitly required by regulations of the

agency involved. Or, animal testing may be explicitly required by statute, as in the case of the Federal Hazardous Substances Act administered by

CPSC. As a practical matter, it makes little difference whether the tests involving animals occur

under implicit or explicit statutory or regulatory

authority: The procedures used are quite similar.

The specific tests performed and the methodologies used may be dictated by informal or formal

requirements of the agency. These may take the

form of promulgated regulations, published guidelines, unpublished guidelines, or customary practices. Some guidelines and the use of specific tests

are accepted internationally (see app. A.)

With these general principles in mind, this discussion summarizes current Federal regulatory

requirements relating to testing with animals (see

also app. B). This review is not intended to evaluate the justification of such testing, only to describe

its scope and magnitude. It is meant to provide

sufficient background to permit an evaluation of

the reasons testing is conducted and of the regulatory needs that any alternatives to such testing

must satisfy.

Food and Drug Administration

FDA is responsible for administering several statutes that regulate animal and human food, animal

and human drugs, medical devices, cosmetics,

color additives, and radiological products. This

regulation takes place primarily under the 1938

Federal Food, Drug, and Cosmetic Act as amended

(21 U.S.C. 301 et seq.) and the Public Health Service Act of 1944 (42 U.S.C. 200 et seq.).

FDA evaluates each product on a case-by-case

basis. The exact testing regime is determined by

considering the type of product, the method of

exposure, the amount and duration of intended

use, and the potential hazards associated with the

specific product. In support of its regulatory responsibilities and to assure quality testing, FDA

has issued standards for good laboratory practice

(see ch. 13) and has developed guidelines and testing protocols. Although some special guidelines

or testing protocols are established for specific

products, most tests are the same as or similar to

the toxicological tests used by other agencies. Appendix A lists the types of tests used.

The National Center for Toxicological Research

(NCTR) in Jefferson, AR, and the National Toxicology Program are the research and testing arms

of FDA. Although NCTR and NTP have no direct

regulatory responsibilities, they provide information needed to evaluate the safety of chemicals.

Research that involves the use of animals or alternative methods includes studies of effects of lowdose, long-term exposure to chemicals; development of new methodology to investigate toxic effects; study of biological mechanisms of toxicity;

and investigation of methods for estimating human

health risks using experimental laboratory data.

The misbranding or adulteration of virtually any

product regulated by FDA is prohibited. In addition, testing is required both to substantiate labeling claims and to demonstrate safety. These requirements should be assumed to apply to the

substances and products discussed in this section

unless otherwise stated.

Food for Humans

Under the law, a food additive is defined as a

food substance that is not “generally recognized

as safe” (as defined in the Federal Food, Drug, and

Cosmetic Act) and that has not previously been

approved as safe by FDA or USDA between 1938

and 1958. No such additive may be used until it

has been subjected to extensive toxicity testing,

a food additive petition has been submitted to FDA,

and FDA has approved the additive as safe and

promulgated a food additive regulation governing its use.
Ch. 7—The Use of Animals in Testing ● 159

The safety of an additive is established by evaluating data from combinations of tests. The amount

of testing that must be performed is determined

by the amount of information already available

and the degree of toxicological concern. Guidelines

have been developed (Toxicological Principles for

the Safety Assessment of Direct Food Additives

and Color Additives Used in Food (56), known as

the Red Book) that contain detailed procedures adequate to meet minimum requirements. However,

manufacturers are permitted to modify the testing as they deem necessary as long as the data are

equal to or better than what would be derived by

using the guidelines.

Food safety has been important to FDA since the

early 1900s. However, the use of animals to test

food additives was not begun until the passage of

the 1954 Pesticide Chemical Amendments and the

1958 Food Additive Amendments. The most famous amendment, sponsored by Delaney, required

that any additive that induces cancer in animals

or in humans be banned.

Drugs for Humans

FDA regulates all human drugs, including biological ones. The 1938 amendments of the Federal

Food, Drug, and Cosmetic Act require drug manufacturers to submit evidence to FDA that a new

drug is safe prior to commercialization. Safety

evaluations are primarily based on preclinical animal testing and subsequent clinical testing in humans. In 1962, amendments to the act required

that the effectiveness of a new drug also be demonstrated, and this is accomplished through clinical testing.

The requirements to use animals to test new human drugs depend on the proposed scope of clinical investigation and on the drug’s anticipated use,

Determining the best procedures for testing is complex because of the variation that exists in the use

and activity of drugs. Testing must be tailored to

each drug and specific requirements are determined by considering the route of administration,

the target population, the length of treatment, and

the relationship of the drug to others already in

use. In addition to the formal procedures required

under the Good Laboratory Practices regulations

(see ch. 13), guidelines are available to aid manufacturers in designing test protocols. Manufacturers commonly discuss their programs with FDA

before and during testing, as well as afterward.

Guidelines are available for tests required for

drugs intended for oral, parenteral, dermal, inhalation, ophthalmic, vaginal, and rectal uses, and those

used in combination. Duration of proposed human

administration is a major factor for determining

the particular animal test species, the number of

animals, and the duration of the test.

Biological products—any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, or allergenic product used

to prevent, treat, or cure human diseases or injuries—are regulated under the Public Health Service Act and the Federal Food, Drug, and Cosmetic

Act. As with drugs, before a new vaccine or allergenic can be marketed, the manufacturer must

provide test data to show that the product is safe

and effective. FDA Center for Drugs and Biologics

licenses the product and the manufacturing facility. For some products, tests are performed on each

batch to assure that standards of potency and

safety are met prior to release. For most of these,

requirements are specified in the Code of Federal

Regulations.

Food and Drugs for Animals

Food for pets, food-producing animals, and any

other animal is subject to the same basic regulatory requirements as food for humans, with the

addition of testing in the target species.

The Federal regulation of animal drugs, medicated feeds, and feed additives began under the

1938 act. The 1968 Animal Drug Amendments consolidated animal food and drug laws, keeping the

1962 standard for safety and effectiveness. The

basic intent of these statutes and their resultant

regulations is to avoid using substances that may

leave harmful residues in animal products intended

for human consumption, and to avoid harm to

food-producing and other animals.

FDA regulates all animal drugs except those

derived from living matter (biologic), which are

regulated by USDA. Animal drugs may not be misbranded or adulterated. Testing is done to substantiate labeling claims and to prove safety. A “new
160 ● Alternatives to Animal Use in Research, Testing, and Education

animal drug” is defined as one not “generally recognized as safe” and effective. It must be tested

to demonstrate both safety and effectiveness before marketing is permitted.

Medical Devices

Extensive regulatory provisions relating to the

safety and effectiveness of medical devices for humans were enacted in 1976 (21 U.S.C. 321). For

devices available before then, FDA may at anytime

require that proof of safety and effectiveness be

submitted. For post -1976 medical devices that are

substantially equivalent to those for humans before 1976, the same rule applies. But for those not

substantially equivalent, testing must be undertaken to prove both safety and effectiveness, a premarket approval application must be submitted

to FDA, and FDA must approve the device as safe

and effective before it maybe marketed. Because

of the diversity of medical devices, the testing required is tailored specifically to the product involved and there are relatively few guidelines.

As the materials involved and methods of application are often unique, determining the safety

of medical devices from the standpoint of toxicity

presents special problems. Consequently, recommendations for specific tests are based on an evaluation of the following factors:

●

●

●

●

●

the population for which the device is intended, with special reference to the target

group’s age and sex, and the benefit to be

derived;

the intended use of the device and its potential to contact the body or, for leachable or

absorbable materials, to be distributed in the

body;

the location of the device in the immediate

vicinity of various organs that might be adversely affected by its presence;

the size of the device and the amount of

leachate potentially available to the body; and

chemical or toxicological information suggesting the potential for adverse toxic effects, such

as when a leachable substance belongs to a

chemical family that contains compounds with

known potential for these effects.

Requirements for testing ophthalmic devices and

products, color additives used in devices, and female contraceptive devices are more standardized.

For color additives used in devices, the same types

of tests are recommended as for color additives

used in foods. For female contraceptive devices,

the requirements are the same as those used for

contraceptive drugs.

Medical devices for animals may not be misbranded or adulterated either. Testing can involve

animals and is undertaken to substantiate labeling claims and safety. The law does not require

premarket approval of such devices, however.

Cosmetics

Although the law prohibits misbranding or adulteration of cosmetics, FDA has no statutory authority to require testing of cosmetics for safety

(other than their color additives) before they are

marketed. However, animal testing is commonly

undertaken to substantiate labeling claims and, by

regulation, FDA has stated that any cosmetic with

an ingredient that has not been substantiated for

safety or that itself has not been substantiated for

safety in its final product form must bear a prominent label declaration that the safety of the product has not been determined.

Color Additives

The law requires that any color additive used

in food or drugs for animals or humans, in medical devices for humans, or in a cosmetic must be

proved safe; must be the subject of a color additive petition filed with FDA; and must be determined by FDA to be safe before it is used (2 1 U.S.C.

321 et seq.). Color additives in use at the time of

the enactment of this provision in 1960 have been

placed on a provisional list and are subject to the

same requirements for testing and approval as

post-1960 color additives.

Radiological Products

The law authorizes FDA to regulate the emission of radiation from electronic products through

the establishment of performance standards and

a program of research and other activities to minimize human exposure. Testing on electronic product radiation is undertaken both in relation to proposed and promulgated performance standards

and to determine other aspects of potential hazard for humans from such emissions.
Ch. 7—The Use of Animals in Testing ● 161

Environmental Protection Agency

In fulfilling its statutory responsibilities, EPA

uses toxicity data derived from animal testing in

a variety of ways. EPA has the authority to require

such data be submitted under laws it administers,

but data are obtained through other means as well.

They are submitted voluntarily by those who conduct or sponsor testing and are obtained from the

open literature, from other government agencies,

through contracts and grants, and from EPA laboratories.

This section describes the regulatory programs

for which animal testing data are needed and the

authorities under which existing data or testing

can be required. (EPA’s testing guidelines are described in app. A.)

Pesticides

The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (Public Law 92-516, 7 U.S.C. 136

et seq.) is designed to protect human health and

the environment from adverse effects of pesticides

while allowing the benefits of their use. This is

done by granting or denying registrations; approving labeling; setting maximum residue levels on

or in raw agricultural commodities; and establishing procedures for safe application, storage, and

disposal. In registering the approximately 50,000

formulations of “pesticide products,” EPA uses

comprehensive registration standards that include

animal testing data, as well as physical properties,

analytical methods, and descriptions of manufacturing and use conditions.

EPA also relies on animal toxicity data when it

issues emergency exemptions, experimental-use

permits, and temporary tolerances for experimental purposes in response to unexpected and

temporary food or health emergencies. Emergency

exemptions may be granted to State or Federal

agencies for uses not included in the registration.

Experimental-use permits allow large-scale testing of new pesticides or new uses of a registered

pesticide.

The Agency’s Data Requirements for pesticide

Registration specify the kinds of material that must

be submitted to EPA to support registration of each

pesticide under Section 3 of FIFRA. EPA uses the

information to determine the identity and composition of pesticides and to evaluate their potential adverse effects and environmental fate. Tests

are either ‘(required” or “conditionally required”

depending on such factors as the results of preliminary tests, whether the pesticide use is for a

food crop, whether the use is experimental, where

and how the pesticide is to be applied, and the fate

of the pesticide residue. Certain tests are required

for new products, and guidelines for conducting

these tests have also been developed (40 CFR 158,

49 FR 42856). Many are conditionally required

through “tiered testing,” whereby the results of

the first tier of tests determine the need for additional ones. Three tiers have been described.

There is some flexibility in the application of

these testing requirements, but EPA is to be consulted if test protocols other than those described

are to be used. Additional flexibility in the testing

requirements is available through EPA’s procedures for waivers and for minor uses (40 CFR 158).

Virtually all data are submitted in the context

of obtaining, maintaining, or renewing a registration. Another requirement is that the registrant

must submit any health or safety information that

would be of interest to EPA regarding a registered

pesticide. This includes the submission of ongoing

or completed studies for pesticides subject to registration standards, cancellation, or review; incidents

involving adverse effects to human or nontarget

organisms resulting from exposure; or incidents

regarding lack of efficacy that could indirectly pose

a hazard to human life.

Industrial Chemicals

The Toxic Substances Control Act (TSCA) (15

U.S.C. 2601) authorizes EPA to regulate chemical

substances that present an “unreasonable risk” of

injury to health or the environment and to require

the reporting or development of data necessary

for EPA to assess risks posed by a given substance.

Toxicological testing data derived from animals

form the basis for risk assessment and subsequent

regulatory actions taken by EPA in implementing

TSCA.

If a chemical substance presents an unreasonable risk, EPA can regulate its manufacturing, processing, distribution in commerce, use, or disposal.
162 ● Alternatives to Animal Use in Research, Testing, and Education

Such regulatory actions would be based on toxicity data and exposure data, as well as on data regarding the beneficial uses of the substance. Regulation can be in the form of prohibiting or limiting

certain actions, requiring warnings or instructions

for use, or requiring the submission or retention

of certain records.

If EPA has reason to believe that a substance

presents an unreasonable risk but the agency lacks

sufficient information to make such a finding, it

can require reporting of existing toxicity or exposure data. EPA can also require that a substance

be tested in animals for specific toxic effects.

Under TSCA, EPA has authority to require testing of industrial chemicals if testing is needed to

perform a risk assessment. To aid in identifying

relevant chemical substances, TSCA authorized

an interagency testing committee to make suggestions. EPA must consider these suggestions and

either initiate rulemaking or publish reasons for

not doing so.

TSCA requires that 90 days before the manufacture or import of a “new” chemical (a chemical

not on the TSCA Inventory of Chemical Substances)

can begin, a Premanufacture Notification must be

submitted to EPA. The submitters must provide

all information in their possession or control related to health or environmental effects or to exposure. EPA can also require hazard or exposure

information for substances already in commerce.

Air

The Clean Air Act (42 U.S.C. 7401 et seq.) requires

the Federal and State Governments to take certain actions to improve or maintain the quality of

ambient air. Animal testing data support various

activities under the act. EPA designates certain substances as “criteria pollutants” and establishes national standards for ambient air based on toxicity

and other concerns. Under Section 112, EPA also

designates certain very toxic pollutants as “hazardous” and establishes standards for their emission or other control.

For registrations of any fuel or fuel additive, the

EPA Administrator may require the manufacturer

to conduct tests to determine whether there are

potential short- or long-term health effects. Tests

may be for acute effects, chronic effects, immunotoxicity, carcinogenicity, teratogenicity, or mutagenicity.

Radiation

EPA’s authority over radiation was delegated in

the President’s Reorganization Plan of 1970 (35 FR

15623), under which EPA makes recommendations

to other Federal agencies (the Nuclear Regulatory

Commission, the Department of Energy, and OSHA)

regarding acceptable levels of emissions for the

byproducts of producing fuel-grade uranium and

from other low-level wastes. Most of the data used

to develop regulatory standards were gathered

from humans inadvertently exposed to radiation,

but data from animals are used for genetic and

other effects, dose-response relationships, and metabolism.

Water

The Clean Water Act (33 U.S.C. 466) requires

Federal and State efforts to restore and maintain

the integrity of U.S. waters. Data needed to fulfill

these requirements are obtained primarily from

testing fish and other aquatic organisms.

The 1977 amendments to the act listed toxic substances that are commonly referred to as the 126

priority pollutants, primarily because of their toxic

effects on humans and animals. These are controlled through nationally uniform limitations on

the effluents containing them. Water Quality Criteria have also been promulgated for permissible

ambient concentrations of these substances and

are used to establish State water quality standards.

Other toxic chemicals will also be regulated under

the Clean Water Act.

The Clean Water Act calls for National Water

Quality Criteria to be derived. The complete data

set is developed by conducting a series of acute

and long-term bioassays using organisms from at

least eight different families. Acute tests are required on a salmonid, another family belonging

to the class Osteichthyes (bony fish), and another

representative of the phylum Chordata. The longterm tests required are chronic tests with one species of fish and a bioconcentration test with one

aquatic species,
Ch. 7—The Use of Animals in Testing . 163

In 1982, EPA published a Water Quality Standards Handbook that provides guidance for developing site-specific water quality criteria that reflect

local environmental conditions based on toxicity

testing in fish.

The Safe Drinking Water Act (42 U.S.C. 300) is

designed to protect public drinking water supplies

through minimum national standards that are implemented by the States. Under this act, EPA also

regulates the underground injection of fluids and

other imminent or substantial hazards to drinking water. In addition, health advisories are prepared on specific problems.

Primary drinking water regulations are developed for certain contaminants that may have adverse effects on human health, Maximum contaminant levels are established or health advisories

published using mammalian testing data.

EPA’s authority over groundwater is based on

a number of the laws that the agency administers.

The management of groundwater is a joint Federal and State responsibility, but EPA provides technical assistance to State agencies and prepares

advisories dealing with common problems that endanger groundwater. To some extent, these support activities rely on toxicity data.

Because groundwater is the source of drinking

water for about half the U.S. population, the identification and characterization of groundwater

problems is an important part of the drinking water

program. Over 700 synthetic organic chemicals

have been identified in various drinking water supplies. Some epidemiologic evidence is available, and

more is being collected to help characterize the

toxicity of these contaminants, but animal testing

data are mainly used.

Solid Waste

The Resource Conservation and Recovery Act

(RCRA) (Public Law 94-580, 48 U.S.C. 6901) protects public health and the environment by controlling the disposal of solid waste and by regulating the management and handling of hazardous

waste materials. EPA is authorized to develop regulations governing the generation, transportation,

treatment, storage, and disposal of hazardous

wastes. These regulations, in addition to State laws

on waste, are enforced by the States.

Animal testing is used to identify hazardous

wastes. Toxicity is one of the criteria. RCRA regulations list chemicals that have been determined

to be hazardous and processes that are presumed

to generate hazardous waste. Analytical procedures for determining the contents of waste are

also described, as are criteria for determining

whether the contents are toxic or otherwise hazardous. When information does not exist for certain wastes, EPA must develop it. RCRA does not

require those who generate hazardous waste to

test the toxicity of the waste.

Because RCRA deals with solid waste, the predominant health problems arise from the leaching of waste from disposal sites. EPA is in the

process of selecting and validating tests for characterizing waste. These will look for acute and

chronic effects on aquatic animals, primarily fathead minnows. Partial or full life-cycle bioassays

and fish bioaccumulation tests will also be required.

The potential hazards to humans are characterized with several mutagenicity tests.

Data from tests with humans and animals are

used under RCRA to develop “acceptable daily intake” levels that are regulated under the act. Because of the nature of exposure to these wastes,

data from short-term and dermal tests are not used.

Superfund

The Comprehensive Environmental Response,

Compensation, and Liability Act (CERCLA) (42

U.S.C. 9601), known as Superfund, authorizes the

Federal Government to clean up or otherwise respond to the release of hazardous substances or

other pollutants that may endanger public welfare. The most significant activity under CERCLA,

from the standpoint of animal testing, is the designation of hazardous substances. Substances designated as hazardous under certain sections of

other laws (TSCA, the Clean Air Act, the Clean

Water Act, and RCRA) are also considered hazardous under CERCLA, and the EPA Administrator is to designate specific amounts of hazardous

substances to be “reportable quantities, ” based in

part on toxicity data.

One activity under CERCLA that diminishes the

need for animal testing (because it assembles data

on humans) is the compilation of a Toxic Substances
—

164 ● Alternatives to Animal Use in Research, Testing, and Education

and Disease Registry under the Department of

Health and Human Services. This registry will track

persons exposed to hazardous substances, along

with the medical testing and evaluation that follows the exposure.

Consumer Product Safety

Commission

The CPSC administers the Consumer Product

Safety Act (I5 U.S.C. 401 et seq.), the Federal Hazardous Substances Act (15 U.S.C. 1261 et seq.), the

Poison Prevention packaging Act (15 U.S.C. 1471

et seq.), and the Flammable Fabrics Act (15 U.S.C.

1191 et seq.).

The Consumer product Safety Act empowers

CPSC to prevent unreasonable risks of injury from

consumer products. Included are both the risk of

acute and chronic toxicity and the risk of physical

injury. Under this statute, industry regularly conducts animal toxicity testing to determine the safety

of consumer products.

The Federal Hazardous Substances Act provides

for the regulation of hazardous substances used

in or around the household. These are defined as

any substance or mixture that is toxic, corrosive,

flammable, or combustible, that is an irritant or

a strong sensitizer, or that generates pressure

through decomposition, heat, or other means, if

such substance may cause substantial personal injury or illness during customary or reasonably

foreseeable handling or use. Unlike its usual method of letting a regulatory agency or the manufacturer determine what kind of testing is needed to

determine safety, in this act Congress defines a

“highly toxic” substance in terms of the results of

the LD50 test and requires certain labeling when

the LD50 is less than 50 mg/kg body weight, 2 mg/l

of air inhaled for an hour or less, or 200 mg/lcg

of dermal exposure for 24 hours or less. Although

the act does not literally require that these tests

be done, a manufacturer cannot know whether

they are in compliance with the act unless they

perform the tests. CPSC has issued regulations regarding testing requirements needed to determine

whether a substance is a skin or an eye irritant

(16 CFR 1500).

The Flammable Fabrics Act authorized regulation of wearing apparel and fabrics that are flammable. Industry regularly conducts animal testing to determine the toxicity of substances applied

to fabric in order to reduce or eliminate flammability.

Department of Labor

The Occupational Safety and Health Act of 1970

(29 U.S.C. 651 et seq.) requires the National Institute for Occupational Safety and Health (NIOSH)

to conduct health hazard evaluations of the workplace (see section on Centers for Disease Control).

A goal of the act is that no employee suffer

diminished health as a result of conditions in the

workplace. To this end, employers have a duty to

communicate safety information about substances

present in the workplace through labels, material

safety data sheets, and training. Most safety testing is done with animals.

Under the Federal Mine Safety and Health Act

of 1977 (30 U.S.C. 801 et seq.), employers must

determine whether substances found or used in

mines are potentially toxic at the concentrations

at which they occur.

Department of Transportation

The Hazardous Materials Transportation Act (49

U.S.C. 1801 et seq.) requires that any materials

shipped in interstate commerce be properly labeled and contained in a manner reflecting the

degree of hazard present. DOT requires that acute

toxicity studies be carried out on substances not

already classified or for which toxic effects to humans or test animals are not already known. A

substance would be treated as a class B poison (and

thus as presenting a health hazard during transportation) if its administration to 10 or more rats

at a single dose of a specified amount (orally, dermally, or by inhalation) killed at least half the animals within 48 hours. Analogous authority exists

for the U.S. Coast Guard under the Dangerous

Cargo Act (46 U.S.C. 179) and the Ports and Waterways Safety Act (33 U.S.C. 1221 et seq.).
Ch. 7—The Use of Animals in Testing ● 165

Department of Agriculture

USDA administers the Virus-Serum-Toxin Act

of 1913 (21 U.S,C. 151 et seq.), under which it

licenses animal biologics. The regulatory requirements are similar to those administered by FDA

for other animal drugs. Animal testing is undertaken to substantiate labeling claims for animal

drugs and to prove their safety. The testing required by USDA for proof of safety and effectiveness of these animal biological drugs is extensive.

Under a series of statutes, USDA exercises close

inspection authority over the processing of meat,

poultry, and eggs for human consumption. These

statutes prohibit any misbranding or adulteration,

Testing is required to substantiate labeling claims.

Although most safety issues are handled by FDA,

testing may also on occasion be required by USDA

to demonstrate safety under particular conditions.

USDA administers a number of statutes designed

to control and eradicate disease in plants and animals. This authority extends from research through

to control of interstate and foreign transportation.

Substantial testing is undertaken by USDA in pursuing these statutory mandates.

Centers for Disease Control

The Public Health Service Act (42 U.S.C. 201 et

seq.) authorizes CDC to take appropriate action

to prevent the spread of communicable disease.

Pursuant to this authority, CDC regulates any agent

that could cause such illnesses. CDC uses animal

data to determine the agents that should be regulated.

Under the authority of the Occupational Safety

and Health Act of 1970, the National Institute for

Occupational Safety and Health, a component of

CDC, develops and periodically revises recommendations for limits of exposure to potentially hazardous substances or conditions in the workplace.

When morbidity cannot be explained on the basis

of current toxicological knowledge, NIOSH must

design toxicological investigations to discover the

cause. Such occupational hazard assessments are

based on data on humans and animals collected

by NIOSH.

Federal Trade Commission

The Federal Trade Commission Act (15 U.S.C.

41 et seq.) prohibits any advertisement that is misleading in a material respect. FTC has adopted the

position that an advertiser must have adequate substantiation for any claims relating to safety or effectiveness. Thus, manufacturers and distributors

regularly test their products, using data on humans

and animals to substantiate their claims.

STATE USES OF ANIMAL TESTING DATA

States engage in a variety of regulatory activi- Pesticide Registrations

ties that rely directly or indirectly on animal testing data. One of the most important longstanding All States are required to register pesticides un -

uses is the registration of pesticides. Air, water, der Section 24 of FIFRA. Most States have 5,000

and waste have also been the subject of State leg- to 10)000 pesticides registered and grant 5 to 10

islation in recent years. State laws often use ani- emergency exemptions per year. As part of the

mal testing data for the identification and classifi- registration process, States receive animal testing

cation of substances for control. Several States have data for evaluation. Much of the time, the inforalso enacted right -to-know laws that may give peo- mation is required only in summary form, unless

ple greater access to testing data, although such the State specifically requests the raw data. The

legislation does not necessarily affect the amount data are usually obtained directly from the regisof testing done. trant to avoid possible delays or confidentiality
166 ● Alternatives to Animal Use in Research, Testing, and Education

problems. Although States generally rely on EPA’s

assessment of data for registration purposes, they

regularly review it for emergency exemptions and

special local needs (22).

California and Florida have the largest pesticide

programs. These States also have the authority to

require additional testing (e.g., field testing locally).

In addition, California also recently passed a law

giving its Director of Food and Agriculture the authority to require data for which EPA has granted

a waiver or exemption (e.g., experimental-use permits). California law also requires that data gaps

for 200 pesticides be filled and that the first report of an injury to a worker exposed to a pesticide be reported to the Health Department (California Food and Agriculture Code, Div. 7, ch. 2).

Identification and Classification of

Toxic Substances

Identification and classification of substances is

an important function in most environmental laws.

Such activities take place under each Federal environmental statute. Coordination among offices in

EPA or with other agencies is common. State agencies also coordinate these activities with their Federal counterparts.

Sometimes, Federal law or regulations are simply adopted by a State and remodified. For example, certain provisions of the New York and Florida

regulations governing hazardous wastes incorporate, by reference, EPA regulations appearing

at 40 CFR 261 and its Appendices (New York Compilation of Rules and Regulations, Title 6, ch. 366).

These regulations list hazardous waste and their

constituents, provide analytical procedures to determine the composition of a waste so that it can

be classified, and provide for variances from these

regulations that may be granted by EPA’s Administrator. Much more common are statutes that incorporate Federal laws and regulations and that

add other requirements or combine Federal requirements in new ways.

The Wisconsin Pollution Discharge Elimination

Law (Wisconsin Statutes Annotated, ch. 147)

adopts EPA effluent limitations, effluent standards,

and prohibitions. In addition to substances already

regulated by EPA, Wisconsin effluent limitations

apply to all toxic pollutants “referred to in table

1 of committee print number 95-30 of the Committee on Public Works and Transportation of the U.S.

House of Representatives.” Additional pollutants

are to be identified under Section 147.07 of the

Wisconsin law.

The Colorado Hazardous Waste Management

Regulations (Code of Colorado Regulations, Title

5, ch. 1007) adopt EPA toxicity provisions of 40

CFR 261 but include “any other substance which

has been found to be fatal to humans at low doses,

or in the absence of human data, has an oral LD50

in the rat of 50 mg/kg or less, an inhalation LC50

(lethal concentration) in the rat of 2 mg/l or less,

or a dermal LD50 in the rabbit of 200 mg/kg or less .“

The Texas Water Quality Acts (Texas Water

Code, Title 2, chs. 5, 26, 30, 313) use several Federal laws to classify a substance as hazardous:

CERCLA; the Water Pollution Control Act; the Solid

Waste Disposal Act; the Clean Air Act; and TSCA.

If it is hazardous under any one of these laws, it

is hazardous for purposes of Texas law.

Under Oregon Hazardous Waste Management

Regulations (Oregon Administrative Rules, ch. 340,

div. 62, 63), a substance is considered toxic if it

is a pesticide or pesticide manufacturing residue

and has one of the following properties:

● oral toxicity in a 14-day test with an LD50 less

than 500 mg/kg,

. inhalation toxicity over 1 hour with an LC50

less than 2 mg/l gas or 200 mg/m3 dust or mist,

● dermal toxicity over 14 days with an LD50 less

than 200 mg/kg, or

● aquatic toxicity over 96 hours at an LC5o less

than 250 mg/l.

It would also be considered toxic if it contains a carcinogen identified by OSHA at 29 CFR 1910.93(C).

Washington Dangerous Waste Regulations (Washington Administrative Code, Title 173, ch. 303) require the polluter to use EPA toxicity information,

EPA’s Spill Table, NIOSH’s Registry of Toxic Effects

of Chemicals (see ch. 10), and any other reasonably available sources to determine if a pollutant

is toxic. Carcinogens are identified by an International Agency for Research on Cancer finding that

a substance is a positive or suspected human or

animal carcinogen. Additional criteria are provided
Ch. 7—The Use of Animals in Testing ● 167

in the Toxic Category Table, which contains five

categories of hazards based on an LC50 test for fish,

an oral LD50 for rats, an inhalation LC50 for rats,

and a dermal LD50 for rabbits.

Some State laws do not explicitly provide for harmonization with Federal requirements regarding

the identification and classification of toxic substances. Under the California Air Pollution Laws

(California Air Pollution Control Laws, 1979 Edition), the California Air Resources Board and the

State Department of Health Service are to prepare

recommendations for substances to be regulated

and to consider all relevant data. State officials may

PRODUCT LIABILITY

Toxicological testing and research play an important role in the law of product liability. Manufacturers are responsible for knowing what dangers their products may present and must pay for

any damages these products cause. Animals are

used to discover possible dangers, and courts may

award damages to a party whose injuries could

have been prevented with additional testing or research (see ch. 11).

This discussion of product liability law focuses

primarily on drugs because animal use plays such

an important role in determining safety. Drugs are

also an interesting case study because they are reviewed for safety and effectiveness by the Food

and Drug Administration before they are marketed, and yet satisfying FDA’s testing requirements does not necessarily fulfill the manufacturer’s duty to test.

The Manufacturer’s Duty to Produce

a Safe Product

In general, a manufacturer has a duty to produce a safe product with appropriate warnings

and instructions. This is based on an individual’s

responsibility to exercise care to avoid unreasonable risks of harm to others. The duty extends to

all persons who might foreseeably be injured by

the product manufactured. Under the Uniform

Commercial Code—a law governing commercial

transactions involving goods, which varies only

request information on any substance under evaluation, although they do not have the authority to

require testing. However, any person who wishes

the board to review one of its determinations must

specify additional evidence that is to be considered. Similarly, the California Hazardous Waste

Control Act (California Health and Safety Code,

Div. 20, chs. 6.5, 1039; California Administrative

Code, Title 22, div. 4, ch. 30) directs the California

Department of Health Services to prepare lists of

hazardous waste and extremely hazardous waste

and to develop regulations for their management.

CONSIDERATIONS

slightly from State to State—failure to produce a

safe product results in liability for the manufacturer for the damages thereby caused.

Generally, an injured plaintiff must prove that

the drug in question was unreasonably dangerous, that the defect existed at the time the drug

left the manufacturer’s control, that the consumer

was injured or suffered damages from the use of

the drug, and that the defect in the drug was the

proximate cause of the injury (13,37).

product liability law inmost jurisdictions follows

the “strict liability” standard—that is, no matter

how careful a manufacturer is, it is liable for injuries caused by its products. Some jurisdictions only

hold the manufacturer to a high standard of care,

and many that do have strict liability standards

also have exceptions.

One exception is for drugs that are necessary

but that cannot be made safe. Some have a high

risk of harmful side effects but treat conditions

that are even more harmful if left untreated, such

as rabies (57). (Conversely, when the advantages

a product offers are small, such as where vaccines

were combined instead of using multiple injections,

the manufacturer is more likely to be held liable

(51).) Another exception is for products for which

no developed skill or foresight could have avoided

the harm (14). Even though a toxic effect might

not have been tested for using existing methods

with animals, a manufacturer must not ignore in-
168 ● Alternatives to Animal Use in Research, Testing, and Education

juries its product may cause after marketing (13).

Similarly, if a new test becomes available, the manufacturer may be required to use it (14,29,47).

Methods of Testing Required

A manufacturer must normally use the safest

and most effective testing method available. Thus,

when monkeys provided the only reliable means

for testing polio vaccine, they had to be used to

test individual batches of drugs, despite the difficulty and expense of obtaining them (20). Although

no cases could be found pertaining to drugs, this

standard might not apply when testing is impractical in relation to the risk of harm (30,48).

Testing must reflect conditions of actual use as

closely as possible. Thus, where the drug DES was

to be used on pregnant women, the manufacturer

should have tested pregnant animals and was held

SUMMARY AND

The most widespread kind of testing with animals is conducted for the elucidation of toxicity

from drugs, chemicals, and so forth. Toxicology

has advanced with the growth of the synthetic

chemical industries and the use of chemicals in

consumer products. Toxicological testing is used

in the assessment of hazards and the management

of health risks to humans. The use of animals for

such testing did not become common until a few

decades ago; it now accounts for several million

animals per year.

Many toxicological tests are standardized to aid

in the comparison of results and because they have

been shown to be acceptable tools for measuring

certain phenomena. Most of the standard tests are

descriptive in that they indicate an end result but

do not necessarily elucidate the processes leading

to it. Knowledge of the mechanisms by which a

toxic effect occurs allows much greater reliability in extrapolation to humans.

The design of a test involves many trade-offs.

The choice of species is affected by its physiological similarity to humans, its cost and availability,

and the amount of data for other substances availliable for cancer in offspring (3). Several smokers

have tried to recover from cigarette manufacturers. They have been denied recovery to date because when they started smoking, the risk of cancer had not been demonstrated (28,40)43).

A judge or jury would normally decide whether

testing was adequate, but if there was a failure

to comply with regulatory requirements, this would

normally prove insufficient testing (16)33,39). However, compliance with such requirements would

not prove that testing was adequate (14).

In addition to examining what tests were done,

the judge or jury might look at the adequacy of

the test protocols themselves. For example, the injured plaintiff might argue that the number of test

animals was not large enough to determine if a

risk was presented (11) or that the conditions under which the drug was tested did not represent

actual use conditions (49,51).

CONCLUSIONS

able for comparison. The route of exposure, duration of exposure, and size of doses are affected

by the possible nature and extent of exposure in

humans, by the dose needed to produce a measurable toxic effect, and by convenience. Expected

variability in the toxic response governs the numbers of animals used.

Commonly used tests include the following:

●

●

●

●

●

acute toxicity—a single dose at high enough

concentrations to produce toxic effects or

death, often used to screen substances for relative toxicity;

eye and skin irritation—usually a single exposure, generally used to develop warnings

for handling and predict accidental exposure

toxicity;

repeated-dose chronic toxicity—repeated

exposure for periods ranging from 2 weeks

to more than a year, used to determine the

possible effects of long-term human exposure;

carcinogenicity—repeated exposure for

most of lifespan, used to detect possible human carcinogens;

developmental and reproductive toxicity–
Ch. 7—The Use of Animals in Testing ● 169

a variety of exposures to determine the pOS -

sible production of infertility, miscarriages,

and birth defects;

. Ž neurotoxicity--a variety of doses and routes

to determine toxic effects to nerves, with toxic

end points such as behavioral changes, lack

of coordination, or learning disabilities; and

. mutagenicity—a variety of methods for determining if genetic material of germ or somatic cells has been changed.

To aid in the design of tests and in the extrapolation of results to humans, studies are sometimes

done to determine the mechanisms by which toxicity occurs or to characterize the processes by

which the test substance enters, is handled, and

leaves the body.

The Federal Government has considerable impact on testing practices through a variety of laws

and regulations. Sometimes testing is required for

premarket approval; more often, it is implied by

requirements for safe and effective products. In

only a handful of instances, such as the Federal

Hazardous Substances Act administered by the

Consumer Product Safety Commission and the

Hazardous Materials Transportation Act administered by the Department of Transportation, do

Federal statutes explicitly require animal testing.

The four agencies with the largest roles are the

Food and Drug Administration, the Environmental

Protection Agency, the Consumer Product Safety

Commission, and the occupational Safety and

Health Administration. FDA uses animal testing

data in the approval of food additives, drugs, biologics, medical devices, and color additives for humans and animals. EPA and State Governments

use such test results in the registration of pesticides and the regulation of industrial chemicals,

as well as in the protection of water and air and

in the regulation of waste disposal. CPSC relies on

animal data in identifying and regulating risks to

consumers, while OSHA indirectly uses them in

requiring employers to maintain a safe workplace.

Testing also plays an important role in the liability of a manufacturer for unsafe products. In most

States, a manufacturer is responsible for any injuries arising from use of its products, regardless

of how much testing was done. Exceptions may

be made where suitable tests do not exist or the

product is known to present risks but those risks

are preferable to the harm that would occur without the product, as in the case of rabies vaccine.

Despite the problems of extrapolating to humans

and other shortcomings of animal testing techniques, the use of animals in testing is an integral

part of the Nation’s attempt to protect human

health. Ideally, as the practice of toxicology advances, there will be less emphasis on numerical

values in certain tests and more consideration of

the mechanisms by which toxic effects occur.

CHAPTER 7 REFERENCES

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3. Bichler v. Eli Lilly and Company, 436 N. Y.S.2d 625

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Substances Applied Topically to the Skin and Mu-
170 . Alternatives to Animal Use in Research, Testing, and Education

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10. Duke-Elder, S., Textbook of ~phthahno]ogy Therapeutics (St, Louis, MO: C,V. Mosby, 1954).

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15.

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18.

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Frankel v. Styer, 386 F.2d 151 (3rd Cir. 1967).

Freidenwald, J. S., Hughes, W .F., and Hermann, H.,

“Acid Burns of the Eye,’ ’Arch. Ophthalmo]. 35:98-

108, 1946.

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Experiments, “Report of the FRAME Toxicity Committee, ” Animals and Alternatives in Toxicity Testing, M. Balls, R.J. Riddell, and A.N. Worden (eds.)

(New York: Academic Press, 1983).

19. Goldberg, A. M., Director, The Johns Hopkins Center for Ahernatives to Animal Testing, Baltimore,

MD, personal communication, April 1985.

20. Griffi”n v. U. S., 351 F. Supp. 10 (E. D. Pa. 1972).

21. Grove, G. L., Duncan, S., and Kingman, A. M., “Effect of Aging on the Blistering of Human Skin With

Ammonium Hydroxide, ’’l?r. J, Dermato]. 107:393-

400, 1982.

22. Hart, A., National Agricultural Chemicals Association, Washington, DC, personal communication,

September 1984.

23. Heine, W., “Importance of Quality Standard and

24

25

26

Quality Controi in Small Laboratory Animals for

Toxicological Research)” Animals in Toxicologl”cal

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Heywood, R., “Long-Term Toxicity,” Animals and

Alternatives in Toxicity Testing, M. Balls, R.J. Ridden, and A.N. Worden (eds.) (New York: Academic

Press, 1983).

Hutt, P. B., and Hutt, P. B., II, “A History of Government Regulation of Adulteration and Misbranding

of Food, ’’Food Drug Cosmetic La wJ. 39:2-73, 1984.

Kingston, T., and Marks, R., “Irritant Reactions to

Dithranol in Normal Subjects and Psoriatic Patients, ”

Br. J. Dermatol. 108:307-313, 1983.

27. Kligman, A. M., “Assessment of Mild Irritants, ’’Prin -

ciples of Cosmetics for the Dermatologist, P. Frost

and S.N. Horwitz (eds. ) (St. Louis, MO: C.V. Mosby,

1982).

28. Lartique v. R.J. Reynolds Tobacco Company, 317

F.2d 19 (1963).

29. Leibowitz v. ortho Pharmaceutical Co., 224 Pa. Su -

per, 418, 307 A.2d 449 (1973).

30. Livesley v. Continental A40tors Corporation, 331

Mich. 434, 49 N.W.2d 365 (1951).

31. Lowrance, W .W., Of Acceptable Risk—Science and

32,

33,

34.

35.

36.

37.

38.

39.

404

41.

42.

43.

Determination of Safety (Los Altos, CA: William

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R.J, Ridden, and A.N. Worden (eds.) (New York: Academic Press, 1983).

McComish v. DeSoi, 42 N.J. 274,200 A.2d 116 (1964).

McNamara, B. P., “Concepts in Health Evaluation of

Commercial and Industrial Chemicals, ” New Concepts in Safety Evaluation, M .A. Mehlman, R .E. Shapiro, and H. Blumenthal (eds.) (New York: John

Wiley & Sons, 1976).

Morton Grant, W., and Kern, H. L., “Cations and the

Cornea,” Am. J. Ophthalmo]. 42:167-181, 1956.

National Academy of Sciences, Toxicity Testing

Strategies to Determine Needs and Priorities (Washington, DC: National Academy Press, 1984).

Nicklaus v. Hughes Tbo] Company, 417 F.2d 983 (8th

Cir. 1969).

Organization for Economic Cooperation and Development, Guidelines for Testing of Chemicals, and

addenda (Paris: 1981).

Orthopedic Equipment Company v. Eutsler, 276

F.2d 455 (4th Cir. 1960).

Pritchard v. Liggett and Meyers Tobacco Company,

295 F.2d 292 (3rd Cir. 1961).

Purchase, I. F. H., ‘

( Carcinogenicity,” Animals and

Alternatives in Toxicity Testing, M. Balls, R.J. Ridden, and A.N. Worden (eds.) (New York: Academic

Press, 1983).

Roe, F.J .C., “Carcinogenicity Testing, ’’Animals and

Alternatives in Toxicity Testing, M. Balls, R.J. Ridden, and A.N. Worden (eds.) (New York: Academic

Press, 1983).

Ross v. Phi]lip Morris and Company, 328 F.2d 3 (8th

Cir. 1964).

44. Salsburg, D. S,, “The Effects of Lifetime Feeding

Studies on Patterns of Senile Lesions in Mice and

Rats,” Drugs Chem, Tox. 3:1-33, 1980.

45, Salsburg, D. S., “Statistics and Toxicology: An Overview ,“ Scientific Considerations in Monitoring and

Evaluating Toxicological Research, E.J. Gralla (cd.)

(Washington, DC: Hemisphere, 1981).
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46. Schaumburg, H. H., and Spencer, P., “Central and

Peripheral Nervous System Degeneration Produced

by Pure n-Hexane: An Experimental Study, ” Brain

99:183.192, 1976.

47. Schenebeck L’. Sterling Drug, Inc., 423 F.2d 919 (8th

Cir. 1970).

48. Sieracki v. Seas Shipping Compan&v, 57 F. Supp. 724

(E. D. Pa. 1944).

49. S[romsodt v. Parke-Davis and Companvv, 257 F. Supp.

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48 (2nd Cir. 1969).

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53. U.S. Congress, Office of Technology Assessment,

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1981).

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Health and Environmental Effects Test Guidelines

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Science and Technology Policy, “Chemical Carcinogens: A Review of the Science and Its Associated

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56. U.S. Food and Drug Administration, Toxicological

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784, 792 (1968).

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Corneum, ” .J. invest. Derznato). 62:563-568, 1974.
Chapter 8

Alternatives to

Animal Use in Testing

Queen: I will try the forces

Of these compounds on such creatures as

We count not worth the hanging, but none human . . .

Cornelius: Your Highness

Shall from this practice but make hard your heart.

Shakespeare, Cymbeline

Act I, Scene VI

The experimental means to be used for safety evaluations is left open to suggestion. As

unorthodox as this might sound, leaving such means open for consideration is the best

solution. Safety evaluations should not be based on standard, specified series of tests. They

are best approached by first raising all pertinent safety questions and then searching for

the experimental means to provide the best answers. Under such circumstances, even the

standard LD test might on occasion be the best experimental means to resolve outstanding

satfety questions.

Constantine Zervos

Food and Drug Administration

Safety Evacuation and Regulation of Chemicals 2,

D. Homburger (cd.) (Base]: Karger, 1985)
—.—

CONTENTS

Page‘

Continued, But Modified, Use of Animals in Testing . . . . . . . . . . . . . . . . . . . . . ..175

Avoiding Duplicative Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

Reducing Pain and Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Use of Living Systems in Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

In Vitro Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Nonanimal Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .179

Use of Nonliving Systems in Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Chemical Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Mathematical and Computer Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Epidemiologic Data on Humans . . . . . . . . . . . . . . . . . . . . . . . . . . ..:...... .181

The LD50Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...181

Using Fewer Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .182

The Limit Test and Other Refinements . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..182

In Vitro and Nonanimal Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .182

Skin and Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ]83

In Vitro Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .183

Chick Embryo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Repeated-Dose Toxicity Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......185

Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Microorganism Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....186

In Vitro Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Tests Using Insects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Carcinogenicity ...,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..187

The Ames Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .187

Use of the Ames Test in a Battery of tests . . . . . . . . . . . . . . . . . . . . . . . . . .188

Current Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...188

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Chapter preferences.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Table

Table No. Page

8-1. The Response of Known Human Carcinogens to Rodent Carcinogenicity

and Bacterial Mutagenicity Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..188

Figure

Figure No. Page

8-1. Chronological Sequence of Chick Embryo Chorioallantoic

Membrane Assay.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..184
Chapter 8

Alternatives to Animal Use in Testing

Alternatives to using animals in testing serve the

same purposes that using whole animals does—

protecting and improving human health and comfort. The technologies on which alternatives are

based result primarily from biomedical and biochemical research. Several of them are reviewed

in this chapter, though they are discussed in

greater detail in chapter 6. Some alternatives that

might eventually replace the tests covered in chapter 7 are also described here.

Notable progress in the move to alternatives has

been achieved in certain areas (78). For example,

biochemical tests to diagnose pregnancy have replaced those using rabbits, and the Limulus amebocyte lysate test, which relies on the coagulation

of a small amount of blood from a horseshoe crab,

has replaced rabbits in testing for the presence

of bacterial endotoxins that would cause fever

(25,117). Many companies have modified the widely

used LD5O test to use fewer animals (22) and have

otherwise refined the methods used to test for toxicity (100). Mammalian cell culture assays are used

extensively in industrial laboratories for safety testing of medical devices (52,53) and pharmaceutical

CONTINUED, BUT MODIFIED,

It has been suggested that many more animals

are used for testing than are needed (90) and that

changes in experimental design or improved methods of data analysis could substantially reduce the

number of animals used. Each experiment has

unique requirements (see ch. 7), and the ways in

which the number of animals might be reduced

will vary accordingly.

Many of the methods discussed in chapter 6 for

the modified use of animals in research are also

applicable to testing, such as gathering more data

from each animal or improving the analysis of results by using random block design or covariance

analysis. In random block design, animals with a

particular characteristic, such as litter mates or

animals of a certain size, are randomly assigned

to different groups to balance whatever effect

substances (1,84) and as immune response assays

(97,98).

The development of alternatives to animals in

testing has accelerated in recent years with the

establishment of programs having development

and implementation of alternatives as their goal

(see ch. 12). However, the barriers to adoption of

these tests are more than the technical barrier of

developing and validating anew technology. Testing is an integral part of many regulatory schemes

and product liability law, and validation ultimately

rests on acceptance by the scientific, regulatory,

and legal communities.

Public concern over animal

to be increasing in tandem

for product and drug safety

use in testing appears

with public concern

. Ironically, the public’s-increasing concern for safety could lead to

more testing. Yet it also provides an incentive to

develop new techniques, particularly those that

promise to be cheaper and faster than current

whole-animal methods. A further irony is that developing alternatives, as well as validating them,

sometimes requires animal use.

USE OF ANIMALS IN TESTING

these variables might have. If the groups being distributed are sufficiently large, the results can also

be analyzed to determine the effect of the masking variable (47). Covariance can be used to analyze results when some of the experimental variables are uncontrolled but known, thus estimating

their effect on the results.

As in research, the number of animals needed

as controls can be reduced by using the same group

as a control for several simultaneous experiments.

A laboratory’s ability to do this will be limited by

its size and the amount of lead time available to

allow testing to be coordinated. Another difficulty

is that environmental conditions must be exactly

the same and the tests must start and finish at exactly the same times. The reduction in animal use

that simultaneous experiments brings about is

175
176 ● Alternatives to Animal Use in Research, Testing, and Education

modest because the control group should be larger

if it is being used in several simultaneous experiments (34),

The use of historical data for control groups is

constrained by the difficulty of exactly duplicating the conditions of a study. However, the size

of the groups and other controlled variables can

be better planned if historical data are used to discover the background incidence of specific tumors

or other diseases before testing begins. This use

of historic controls has been recognized by the

National Cancer Institute, the world Health Organization, the Canadian Government, and the nowdefunct Interagency Regulatory Liaison Group

(104). The Federation of American Societies for

Experimental Biology has developed a data book

containing such information based on the Laboratory Animal Data Bank (see ch. 10) (2).

Avoiding Duplicative Testing

Animal use in testing can and has been reduced

by industry and others through improved communication and cooperation in the planning and execution of testing, thereby avoiding unintentional

duplication. Trade groups such as the Chemical

Manufacturers Association, the Pharmaceutical

Manufacturers Association, and the Soap and Detergent Association play important roles in this coordination.

The sharing of data after testing has occurred

is often done for pesticides (see chs. 10 and 11).

And in 1978, the Food and Drug Administration

implemented a policy of permitting approval of

new drug applications solely on the basis of published scientific papers (113). The possibility of an

unintentional repetition of an experiment is also

avoided through the work of organizations such

as the Chemical Industry Institute of Toxicology

(CIIT) (Research Triangle Park, NC). Using contributions from member companies, CIIT conducts

toxicological tests and distributes the results

widely.

Governments contribute greatly to information

sharing, which allows duplicative testing to be

avoided, by providing both access to test results

and information about their own planned and ongoing tests. The International Agency for Research

on Cancer makes it easy for duplicative carcinogenicity testing to be avoided by informing testing

facilities and governments about planned and ongoing testing, Federal and international databases

and publications also contain information about

planned tests and those under way (see ch. 10).

Reducing Pain and Distress

As with research, testing can be modified to reduce animal pain or distress in two ways: by providing relief with drugs or by changing the procedures so that less pain or distress is produced (see

ch. 6). A third alternative might be to use a less

sensitive species, but there is no method by which

relative distress among species can be discerned.

Relief from pain and distress is accomplished through

analgesics, anesthetics, tranquilizers, or sedatives

and modification of the test itself.

Few pain-relieving drugs have been developed

and marketed for animals. Little information is

available on recommended doses (122) or on the

likely effect on test results. Thus, before pain relief could be incorporated into a test, it would be

necessary to determine the needed dose and the

effect on the toxic response, thus using additional

animals as well as subjecting them to pain.

Several small changes that do not interfere with

the experimental design can be made by an investigator. Small needles can be substituted for large.

Animals can be comforted by petting. Social animals can be caged in groups, although there are

often reasons that multiple housing cannot be used.

Smaller doses can be used and tests can be ended

at the earliest feasible time. Sometimes, smaller

doses will actually result in increased sensitivity

of the test (38). Making such changes sometimes

depends on the attitude and expertise of individual researchers rather than the contents of testing guidelines, which may not be sufficiently

detailed.
Ch. 8—Alternative to Animal Use in Testing . 177

USE OF LIVING SYSTEMS IN TESTING

As detailed in chapter 6, two kinds of living systems can reduce whole-animal use—in vitro systems based on animal or human components (cell,

tissue, and organ cultures) and systems based on

organisms not considered animals for purposes

of this report (micro-organisms and invertebrates).

(Some people consider both of these in vitro

system s.)

In Vitro Systems

Cells, tissues, and organs can be kept alive outside a living organism and used for testing. Although animals are still required as a source for

these in vitro systems, the animal would experience distress for a much shorter time, and perhaps less distress overall, than occurs with wholeanimal testing because it would be killed before

any experimental manipulations were carried out.

Occasionally, different cells, tissues, or organs from

the same animals can be used for different investigations. In addition, many fewer animals would

be required for a given test, in part because variability in the toxic response is smaller than it is with

whole-animal tests and in part because one animal can be used for multiple data points, further

reducing variability. The fact that human tissues

sometimes can be used confers an additional advantage because the need for extrapolation from

animal data is obviated.

These isolated components also have disadvantages. They are usually unable to produce the complete physiologic responses of a whole organism.

The components often become undifferentiated

and lose their ability to perform their special functions when isolated from the organism, particularly when the sample is broken up into its constituent cells, and even more so when the cells

replicate. Another disadvantage is that the effect

of the route of exposure, a variable that can have

profound effects on test results, is often impossible to determine.

There are many measures of damage to differentiated or undifferentiated cells—the rate of reproduction, the rate of synthesis of certain substances,

Microscopic View of Cell Culture From Rabbit Corneal Epitheliums

Photo credit: Kwan Y. Chan, University of Washington
178 ● Alternatives to Animal Use in Research, Testing, and Education

changes in membrane permeability, and damage

to some part of the cell structure. Those functions

having to do with viability and growth are most

frequently measured because they require an integration of many physiologic events within the

cell, are sensitive, and lend themselves to automation (73).

Quantifiable tests are preferred over subjective

ones, and a wide variety of quantitative approaches

are available to measure irritation, including the

release of prostaglandins (35); the production of

enzymes (46), proteins (57), antigens, antibodies,

or hormones (73); and the migration of certain

white blood cells (macrophages) to the area of irritation (12,101). Irritation can also be measured

by the extent to which cells exfoliate from the surface of the tissue. The extent of damage can be

determined by counting cells and by examining

the nuclei (1O2). Another indicator of irritation,

the integrity of cell membranes, can be monitored

through the uptake of nutrients through the cell

wall. Where the nutrient uptake is active (that is,

when the cell is required to expend energy for

transport), uptake can also be used to indicate

changes in metabolism (86,102).

Liver cells have been the subject of considerable

research, in part because they play such an important role in an organism’s removal of toxic substances and in part because they retain most of

their special functions when cultured. The response of liver ceils to toxic substances may be

measured in many ways: the use of sugar as an

indication of metabolic activity; the production of

proteins or other substances that have been correlated with toxicity; uptake of amino acids as an

indication of protein synthesis; changes in appearance that parallel those observed in livers of whole

animals (106); and morphological changes and reductions in viability (75). Other promising techniques in this rapidly expanding field include culturing:

●

●

●

●

beating heart cells to detect the effect of certain vapors on irregularities in heartbeat (68);

rabbit kidney tubules to detect substances that

can cause acute renal failure, and rat vaginal

tissue to test vaginal irritancy of contraceptives (27);

various kinds of cells to test for biocompatibility of implants (15,52,53); and

nerve cells to test for the synthesis of neuroDispensing Apparatus for Deiivery of Cuiture Medium to Ceiis Within a Piastic Cuiture Piate

Photo credit: The Johns Hopkins University
Ch. 8—Alternative to Animal Use in Testing ● 179

transmitter chemicals, the formation of synapses, and the conduction of impulses (7).

Although tissue and organ cultures may approximate more closely the physiology of the human

or whole-animal model, they are more difficult to

manipulate than cell cultures (see ch. 6). Sophisticated equipment must be used to monitor and control the environment and to perfuse the sample

with nutrients. Where the sample is more than

a few cell layers thick, uniform delivery of the test

substance, nutrients, and oxygen is difficult, as is

the removal of waste products. Cell differentiation can usually be maintained in tissue and organ cultures, albeit with some difficulty (50).

Human placentas have proved quite useful in

testing the ability of a drug to cross the placenta

from mother to fetus. There are certain logistical

problems with this method, however. The placenta

must be transferred to the perfusion apparatus

within 5 minutes after it is eliminated from the

uterus, and it is only useful for about 3 hours afterward (77).

Nonanimal Organisms

There are a variety of nonanimal organisms that

can replace some animals in testing, ranging from

plants to single-celled organisms to invertebrates.

All of these can respond to certain noxious stimuli,

and some may experience pain. However, many

commentators believe that they do not experience

pain or suffering in the same way that animals do,

particularly in those cases where there is no brain

or neural tissue (90). The use of such organisms,

which has never been controlled under any Federal or State law, is regarded as a replacement for

animals in this report.

Micro-organisms

In recent years, increased emphasis has been

placed on the use of bacteria and fungi to measure certain genotoxic effects. A major advantage

of these organisms is that they can be cultivated

much more easily and quickly than most animal

or human cells. Their genetic makeup is simple

compared with that of animals and humans and

the fact that a great deal is known about it facilitates their use, particularly in toxicological research leading to new methods (74). A change in

genetic material is relatively easy to detect and

characterize. Fungal systems have been shown to

be especially useful in mutagenicity testing and

seem to be more sensitive than bacteria (126), perhaps at the expense of falsely indicating a hazard.

Other species that have proved useful include slime

molds, algae, and protozoa (74).

Protozoa, although rather primitive overall, frequently have specialized functions that mimic those

of humans. For example, the cilia of protozoa respond to smoke or phenols as do the cilia in the

human bronchial tube (5). Various protozoans have

been used in toxicity testing of cigarette smoke.

protozoans are currently being evaluated for use

in screening tests for carcinogenesis, mutagenesis, and reproductive toxicity (93).

Invertebrates

Invertebrates have made major contributions in

biomedical research because certain aspects of

their physiology are sufficiently similar to that of

mammals (74). Although models for toxicity testing require greater similarity to animals or more

thorough characterization of differences than

models for research, invertebrates offer exciting

possibilities.

Of the invertebrates, insects offer the greatest

selection of models, there being over 2 million species from which to choose (74). Among them, the

fruit fly, Drosophila rnelanogaster, is the best understood. procedures have been developed for detecting mutagenicity (18), as well as teratogenicity (11) and reproductive toxicity (93).

The sea urchin has long been a favored test

organism for basic reproductive research (74). Consequently, the mechanisms and procedures of

testing this invertebrate can easily be developed

and performed. The sea urchin model for fertilization and development can be used in screening

for reproductive toxicity, teratogenicity, and mutagenicity. Nematodes, annelids, and mollusks are

also used for alternative mutagenesis testing regimes and, additionally, mollusks are used in the

area of reproductive toxicology. Sponges, mollusks,

crustaceans, and echinoderms are being used in

metabolism studies, as understanding metabolize

formation in nonmammalian species can lend insight to interspecies variation (93).
180 ● Alternatives to Animal Use in Research, Testing, and Education

USE OF NONLIVING SYSTEMS IN TESTING

Animal use can sometimes be avoided altogether

with nonliving biochemical or physiochemical systems, although most such systems currently require animal derived components. Computer simulation can also be used when there are sufficient

data available for substances related to the one

of interest and when the mechanisms of toxicity

are at least partially understood.

Chemical Systems

Whole animals have been replaced with analytical chemistry for tests involving detection of a substance or measurement of potency or concentration, such as for vaccines, anticancer drugs, and

vitamins (10). However, toxicity testing in nonliving systems is quite limited at this time.

Recently developed methods of detection or

measurement are based on the selective binding

that occurs between a particular substance and

the antibodies to it. In an assay for botulism toxin

(which traditionally required up to 200 mice), antibodies obtained from rabbits are modified so that

the binding of the toxin can be detected easily. The

rabbits are initially injected with a small, harmless dose of the botulism toxin. Small amounts of

blood are then removed from the rabbits at regular intervals. In 4 weeks, a rabbit can produce

enough antibody, with little discomfort, to perform

tests that would otherwise require thousands of

mice (32).

Chemical systems that test for toxicity are based

on determining whether a substance undergoes

a specific reaction. For example, it is well known

that carbon monoxide binds to hemoglobin in the

blood, thus greatly reducing the blood’s ability to

carry oxygen. The extent to which a substance

would displace oxygen in hemoglobin can be a

measure of its ability to produce asphyxiation. Substances can also be tested in isolation for their effects on enzymes crucial to certain bodily functions.

An important limit of chemical systems is that

they do not indicate the extent to which an organism can recover from or prevent these reactions.

For example, a substance that binds strongly to

hemoglobin may not be a problem because it is

not absorbed. A substance will not have a significant effect on an enzyme of interest if it is excreted

before it has an effect.

Physiochemical systems have some ability to

determine whether a substance will be absorbed

and what will happen to it. The tendency of a substance to accumulate in a biological system can

be roughly estimated by the relative proportions

that dissolve in equal volumes of water and the

organic solvent octanol (34,55). Artificial skin made

with filter paper and fats is being tried as a means

of mimicking absorption of cosmetics and drugs

(45). Reactivity and other toxicity-related properties can be deduced from chemical structure alone

(109).

Mathematical and Computer Models

Advances in computer technology during the

past 20 years have contributed to the development

of sophisticated mathematical models of quantitative structure activity relationships (QSAR). These

models are used to predict biological responses

on the basis of physical and chemical properties,

structure, and available toxicological data. The limitations of such models are due in part to a lack

of understanding of the mechanisms by which

toxic effects occur.

In applying QSAR, the biological effects of chemicals are expressed in quantitative terms. These

effects can be correlated with physiochemical

properties, composition, and/or structure. Frequently used properties include an affinity for fats

versus water (octanol/water partition coefficient),

the presence of certain reactive groups, the size

and shape of molecules, and the way reactive fragments are linked together.

The simplest extrapolation is for a series of

closely related chemicals. The several characteristics they have in common need not be incorporated into the model as variables. This type of

analysis has been performed for several hundred

families of chemicals and has established that relationships within a series are fairly predictable (64).

Another approach, more broadly applicable, is

to examine the contributions of various portions

of a molecule. In more elaborate computer pro-
Ch. 8—Alternative to Animal Use in Testing . 181

grams, it is possible to identify likely reactions and

cascading physiological events in various species,

techniques first developed for pharmacology (54).

A similar approach is the use of multitiered classification schemes that use large databases to draw

semiempirical conclusions (36).

Epidemiologic Data on Humans

Perhaps the most useful alternative to animal

testing is epidemiologic studies on humans. Such

studies were used to detect carcinogenicity in humans as early as the 18th century (49,85,87). The

most well known study detected scrotal cancer

in chimney sweeps (85). A more recent example

in which epidemiologic evidence was used to detect a human carcinogen was the finding that vinyl chloride causes a rare liver cancer in humans

(26). A major disadvantage of epidemiologic studies

is that considerable human exposure can take place

before a toxic effect is detectable, particularly in

the case of diseases that take many years to develop. Another disadvantage is that they can be

quite expensive to conduct. Privacy must also be

considered (112), preventing many data that would

be useful from being collected or analyzed.

Epidemiologic studies may be divided into three

general types: experimental, descriptive, and observational. Experimental epidemiology is the human equivalent of animal testing—providing or

withholding a substance to determine its toxic or

beneficial effects. Such studies are greatly limited

by ethical and legal considerations, as well as the

difficulties involved in securing the cooperation

of a large number of people.

Descriptive epidemiology analyzes data on the

distribution and extent of health problems or other

conditions in various populations, trying to find

correlations among characteristics such as diet,

air quality, and occupation. Such comparisons are

frequently done between countries or smaller geographic regions, as is the case for cancer statistics

collected and analyzed by the National Cancer Institute (9).

observational epidemiology uses data derived

from individuals or small groups. Data would be

evaluated statistically to determine the strength

of the association between the variable of interest

and the disease. In cohort studies, a well-characterized and homogeneous group is studied over

time. In case-control studies, a control group is

selected retrospectively based on variables thought

to be relevant to the effect, Both methods rely on

an accurate prediction of the variables that are

important and are subject to various selection

biases (62)112).

THE LD50 TES T

The LD5O testis one of the most widely used toxicity tests, and the development of alternatives to

it is regarded by many as a high priority. As described in chapter 7, this acute toxicity test measures the amount of a substance needed to kill half

the population of the test species. The LD5O is

used as a rough indicator of the acute toxicity of

a chemical,

The LD5O is useful for testing biological therapeutics, although there remain few such substances for which the LD5O is the only available

means of standardization (13)90). Other applications, perhaps not so well justified (90), are determining doses for other toxicological tests and set -

ting regulatory priorities.

There has been political pressure to abolish the

LD5O and it has been criticized by many toxicologists on scientific grounds. It has poor reproducibility and the results are difficult to extrapolate

to humans because there are so many mechanisms

by which death could occur (70,90,125).

Despite the many criticisms of the LD5O, most

toxicologists agree that acute toxicity information

has valid uses, and that measurements of lethality

also are important. Nevertheless, the precision with

which the LD5O is measured is often unjustified

for several reasons. First, most applications of the

information do not require precision. Second, even

if the information were precise for a given species, the LD5O varies so much from species to spe-
182 Ž Alternatives to Animal Use in Research, Testing, and Education

cies that extrapolation to humans is only rough.

Third, the LD50 of a given substance varies significantly from laboratory to laboratory, and even in

the same laboratory.

Various regulatory classification schemes make

distinctions between levels of toxicity (“highly toxic”

versus “toxic, ” versus “moderately toxic, ” versus

“nontoxic”). The LD50 for two neighboring levels

typically differs by a factor of 4 to 10. Yet, the

reproducibility of test results does not justify even

these distinctions. A recent study, though not necessarily typical, indicates the magnitude of the

problem. A series of LD5O tests were performed

in 60 European laboratories for five substances

on one species. The LD5O for one substance ranged

from 46 mg/kg body weight to 522 mg/kg, possibly ranging over three toxicity levels in some classification schemes. Although the variations were

not this large for the four other chemicals tested,

the smallest variation was 350 to 1,280 mg/kg. Each

test was done with 50 or more animals so that the

results would be precise (61).

Using Fewer Animals

The standard LD5O requires at least three groups

of 10 animals or more each. An alternative procedure for determining the Approximate Lethal Dose

(ALD) was developed as early as the 1940s (29),

in which individual animals are administered doses

that increase by 50 percent over the previous dose.

Depending on the initial dose level, the total number of animals needed is usually 4 to 10. Because

the test substance might not be cleared between

doses or because there maybe cumulative effects,

the ALD can be lower than the LD50, perhaps by

70 percent, though more typically by less than 20

percent (29).

Many other acute toxicity tests that require fewer

animals than the LD50 have been developed (14,

17,33,61,69,71,94,105,107). Most require that the

doses increase sequentially, thereby allowing the

experiment to stop when a certain limit is reached.

Thus, fewer animals die in the conduct of a test,

but its duration could increase from 2 weeks to

a month or more. Although many investigators

are moving to less precise LD5O tests, no generally

accepted alternative seems to have emerged.

The Limit Test and

Other Refinements

If a substance is not lethal at high doses, its precise LD5O is not very important. In the limit test

(80), a small number of animals is given a single

oral dose, e.g., 5 g/kg body weight. If no animals

die and no major ill effects occur, no further testing is needed. However, this limit is so high that

this approach may have little practical value in reducing animal use (24).

Rather than determining the dose that is lethal,

studies can also be done to detect toxic effects at

doses that are not lethal. As with the LD5O, increasing doses can be administered to a small number

of animals, perhaps stopping when some limit is

reached. This approach can be further refined so

that animals that are in distress could be sacrificed

without affecting the outcome of the test (14).

In Vitro and Nonanimal Methods

Cell toxicity—changes in cell function or death

of cells-can sometimes be used to detect acute

toxicity. However, cell toxicity cannot be expected

to function as a replacement for the LD5O because

lethality can occur by so many mechanisms that

are supercellular. Cell toxicity is particularly useful in comparing members of chemical families,

such as alcohols and alkaloids (79).

At present, mathematical modeling has limitations, although it may have some utility in rangefinding and in screening substances for testing

(109). Modeling of acute toxicity fails to meet one

of the criteria suggested by a working party on

quantitative structure activity relationships, namely

that the mechanism by which the response occurs

should involve a common rate determining step

(88). Nonetheless, in a large study involving thousands of substances, a computer program was developed that predicted LD5O values within a factor of 2.5 for 50 percent of the substances and

within a factor of 6 for 80 percent. Considering
Ch. 8—Alternative to Animal Use in Testing Ž 183

the reproducibility of the test itself, this might be

satisfactory for some purposes, and it certainly

warrants further investigation. Furthermore, many

of the larger deviations in this study, upon further examination, were found to involve reporting errors. This program relied on a multi-tiered

classification scheme based on chemical structure

(36).

SKIN AND EYE IRRITATION

The widely used Draize eye irritation test and,

to a somewhat lesser extent, the skin irritation test

have been criticized because of the amount of pain

inflicted and because they are unsatisfactory models for human irritation (91,95). First, the rabbit

eye has structural differences, such as a thinner

cornea and differing tearing apparatus (103), and

animal skin is much less sensitive and discriminating than human skin (56,63). Second, both of these

tests are sensitive to too many variables, making

reproducibility poor (83,118).

As with most tests, the number of animals used

can sometimes be reduced. Several refinements

have also been proposed. For example, screening

tests based on pH or skin irritancy might also serve

as alternatives to eye irritancy tests in limited circumstances, although preliminary studies indicate

that this approach is frequently misleading (119).

Other refinements involve local anesthetics (51,65,

110), applying smaller (43) or more dilute (120)

doses, and testing whole eyes in vitro (20). The latter method has particular appeal when cow eyes

are used because they are so readily available from

slaughterhouses. In the case of smaller doses, a

recent comparison with over 500 accidental human

exposures showed that doses smaller than those

now in use yielded results more predictive of the

human response while causing less severe irritation (38).

Skin and eye irritation are similar in many respects. Thus, even though little work has been done

to develop alternatives to skin irritation tests, the

many approaches just summarized for eye irritation may eventually be applied to skin testing as

well (91).

In Vitro Tests

Several in vitro alternatives have been examined,

and it appears to some commentators that no single alternative will be adequate, but that a battery

of in vitro tests might be a useful replacement (67).

Several types of cell cultures have been used in

developing an in vitro test for eye irritation. The

cells used are rabbit and human corneal cells (72),

mouse and hamster fibroblasts, human hepatoma

cells, and mouse macrophages (96).

A variety of effects have been used as surrogates

for eye irritation, such as the rate of uptake of uridine as an indication of cell functioning and recovery, visible changes in cell structure, decreases

in the concentration of cell protein (96), and release of plasminogen activator from the injured

cells (21). Some techniques appear promising, particularly in their ability to rank substances based

on irritancy, Rapid progress is being made in the

development of techniques, but none can be considered validated at this time (91).

To date, little work has been done on in vitro

replacements for skin irritancy testing. However,

the growth of skin in tissue culture is of interest

for treating burn victims, and it is expected that

culture techniques currently being developed for

that purpose can be used in testing methods. In

addition, it has also been suggested that suitable

specimens can be obtained from cadavers and

surgery and from judicious use of human volunteers (63).

Chick Embryo

One test system receiving considerable attention

is the fertilized chicken egg. A part of the eggshell

is removed and the test substance applied to the

chorioallantoic membrane surrounding the developing embryo (see fig. 8-l). This test has the potential for assessing both eye and skin irritancy.

The chorioallantoic membrane of the chick embryo is a complete tissue, including arteries, capil-
184 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 8-1.—Chronological Sequence of Chick laries, and veins, and is technically easy to study.

Embryo Chorioallantoic Membrane Assay An embryonic membrane tested after 14 days of

incubation responds to injury with a complete inflammatory reaction, a process similar to that inDay O duced in the conjunctival tissue of the rabbit eye.

The embryonic membrane can show a variety of

signs of irritation and has capabilities for recovery (59,60).

/ Assessment of toxicity is made and the embryo

●

●

●

Day 14

size,

contours and surface,

color,

retraction of surrounding chorioallantoic

membrane,

spokewheel pattern of vessels,

● overall grade of severity, and

● necrosis (confirmed microscopically).

Although this is, strictly speaking, an in vivo test,

the chorioallantoic membrane does not have nerve

cells, and thus it is unlikely that the organism experiences any discomfort. In addition, fertile eggs

are inexpensive and do not require elaborate animal room facilities.

Day O. Fertile eggs are incubated at 37” C. Day 3. The shell is

penetrated in two places: A window is cut at the top, and 1.5 to 2

milliliters of albumin is removed with a needle and discarded. The

chorioallantoic membrane forms on the floor of the air space, on

top of the embryo. The window is taped. Day 14. A test sample is

placed on the embryonic membrane and contained within a plastic

ring. Day 17. The chorioallantoic membrane is evaluated for its

response to the test substance, and the embryo is discarded.

SOURCE: J. Leighton, J. Nassauer, and R. Tchao, “The Chick Embryo in Toxicology: An Alternative to the Rabbit Eye,” Food Cherry. Tox/co/. 23:293-298.

Copyright 19S5, Pergamon Press, Ltd.

REPEATED-DOSE TOXICITY TESTS

Repeated-dose toxicity testing involves the re- peated-dose testing, the long-term effects of

peated application of a substance to a biological repeated, sublethal exposure to a substance are

assay system and subsequent measurement of of interest, rather than acute, lethal effects. Cell

many different effects of the substance. In re- cultures may be useful adjuncts for suspected tar-
Ch. 8—Alternative to Animal Use in Testing ● 185

Chick Embryo Chorioallantoic Membrane Assay

Photo credit: Joseph Leighton, Medical College of Pennsylvania

Typical react ion seen 3 days after certain concentrations

of household products have been placed on the 14-dayold chorioallantoic membrane. The thin white plastic ring

has an internal diameter of 10 millimeters. The area of

injury within the ring is well defined with a distinct edge.

All of the cells in the injured area are degenerating or

dead. The severity of this positive lesion is quantified by

measuring its diameter.

get organs or tissues, but they are not a replacement for whole-animal testing. The most promising

alternatives in the near future involve modifications of animal use (for example, by combining

tests), and the use of screening tests and computer

simulation for improved experimental design. The

screening tests with the greatest promise are for

hepatotoxicity and neurotoxicity.

Hepatotoxicity

Several in vitro alternatives for hepatotoxicity

have been developed, including perfused liver

(108), liver cell suspensions (39), and liver cell cultures (39)44). Liver perfusions can only be maintained for a few hours, and with some difficulty.

Cell cultures can retain the special functions of

liver cells with specially prepared culture media

(76,81). However, the cells are viable for only a

limited period of time and do not replicate in a

reproducible manner. Although these techniques

have been used to study mechanisms of liver toxicity, only limited attention has been given to their

use in screening or as alternatives (91).

Neurotoxicity

The development of alternatives for neurotoxicity is more difficult than for hepatotoxicity. The

nervous system is the most complex organ in the

body, both in terms of structure and its function.

Because many neurotoxins affect only one kind

of cell, a battery of in vitro tests would probably

be required to replace whole-animal testing–if

anything could. Substances can also affect various areas differently, partly because of distribution factors, For example, very few substances are

able to enter the brain because of the ‘(blood-brain

barrier.” Thus, pharmacokinetic studies will continue to be very important.

Some in vitro tests (41) and tests using invertebrates (8) seem useful, at least for screening. As

yet, however, the primary use of in vitro techniques has been the elucidation of mechanisms

of known toxic effects (31). Many toxic effects to

neural tissue have been correlated with concentrations of specific chemicals in or around the cells,

thus offering the means for developing in vitro

tests (31).

MUTAGENICITY

Mutation, the change in the DNA sequence of is passed from the mutated cell to its descendants.

genes, is a mechanism by which toxic effects may Mutation can lead to cell death or the gain or loss

be initiated. If the DNA replicates, the mutation of certain functions. When it occurs in germ cells,

38-750 0 - 86 - 7
186 ● Alternatives to Animal Use in Research, Testing, and Education

the gene pool is affected, even if the mutation is

not expressed in the progeny. The mutations that

occur in somatic cells that are of greatest concern

are those that lead to cancer (18).

Recent advances in the techniques of cell biology

have led to an increase in the types and sophistication of mutagenicity tests available. Mutations

can be detected by analyzing DNA or its fragments

or by observing changes in the size, shape, or number of the chromosomes (which contain DNA), as

well as by observing changes in a whole organism

(34). Mutation can also be detected by measuring

the amount of DNA repair.

Micro-organism Tests

The most commonly used test for mutagenicity

is the Ames test for “reverse mutation” in Salnonella typhimurium (3). Mutagenicity is detected

by exposing an already mutated strain to potential mutagens. If the mutation is reversed, the bacteria regain their ability to produce the amino acid

histidine and will proliferate in a histidine-deficient

culture medium.

The Ames test, as well as most other mutagenicity tests involving micro-organisms, does not avoid

animal use entirely, To determine whether the metabolic products of a substance might be mutagenic

even if the substance itself is not, liver preparations from rats or other rodents are used to produce at least some of the likely metabolic products.

Microorganism systems may fail to detector may

overpredict mutagenic changes that could occur

in whole animals or humans. For example, the system provided for metabolism may not be capable

of reproducing conditions in vivo, or in the case

of screening for carcinogenicity, mutation may not

be the initiating event. on the other hand, such

systems may indicate mutagenicity when the DNA

repair system of mammals would reverse the mutation.

.

Other bacterial tests have been developed using

S. typhimurium, Escherichia coli, and Bacillus subtilis. These systems do not seem to offer any particular advantage over the Ames test, although

thorough evaluation is hampered by lack of a comparable database of results (28). Tests have also

been developed for molds (30)) fungi (16), and

yeasts (18,82).

In Vitro Tests

In vitro mutagenicity tests maybe done with cultured mammalian cells that are exposed to toxic

substances, although many mammalian in vitro

tests also have an in vivo variant. Such tests typically measure acquired resistance or lost resistance

to the effects of the toxic substance. Most commonly used are a mouse lymphoma ceil line or hamster ovary cells, but almost any well-characterized

cell can be used. ovary cells are often used because, as germ cells, they have half the number

of chromosomes to be evaluated (18).

A test known as the specific locus test can be

done with Chinese hamster ovary cells. They are

exposed to a test substance and their response to

the normally lethal 8-azaguanine or 6-thioguanine

in cell culture determined. The cell’s ability to survive, requiring the ability to metabolize the 8-

azaguanine or 6-thioguanine, is an indication of

the occurrence of mutation as a result of exposure

to the test substance. This test can also be done

with mouse lymphoma cells exposed to 5-bromodeoxyuridine or trifluorothymidine (23).

The sister chromatid exchange test relies on the

fact that certain substances will cause DNA breakage and reunion. This damage can be observed

by staining the original chromosomes so that any

segments exchanged during replication can be observed. Commonly used cells include human lymphocyte cells and rodent and human fibroblasts

(37). Both the specific locus test and the sister chromatid exchange can also be performed as in vivo

procedures (see ch. 7).

Although the cells are usually derived from animals, there is a considerable net savings in animal

lives when in vitro mutagenicity tests are performed. For example, the rat mast cell assay can

be used to screen severe irritants, and one rat can

supply enough tissue to replace the use of 48 animals in in-vivo procedures (103).

Tests Using Insects

The most widely used insect for genetic studies

is the fruit fly, Drosophila melanogaster (114, 115).

The fruit fly has well-characterized genetics and

is similar to mammals in many key reactions, A

variety of end points can be detected. The most

common, and probably most sensitive, test is the
Ch. 8—Alternative to Animal Use in Testing • 187

sex-linked recessive lethal assay (18). Treated males ured include the loss, gain, or breakage of chroare mated with untreated females, and the progeny mosomes detected by examining germ cells. With

are mated to each other. The number and charac- the availability of mutant strains, the measurement

teristics of the male progeny are evaluated to de- of reverse mutations can be a valuable tool. Eye

termine if lethal mutations (that is, mutations that color is a popular method of following genetic efprevent viability) have occurred. fects in the fruit fly (18).

Other tests involving fruit flies also exist or are

likely to be developed. End points that can be meas -

CARCINOGENICITY

Many assays meant to replace carcinogenicity

testing are designed to detect the initiation of cancer rather than the formation of tumors. First, detecting initiation is faster and easier than detecting cancer. Second, although not all initiation leads

to cancer, certain kinds are considered reliable

surrogates for the disease.

A major problem with evaluating the predictiveness of alternatives to whole animals for carcinogenicity testing is that very few human carcinogens

have been positively identified. Most substances

treated as human carcinogens, although documented to be known animal carcinogens, must be

viewed as probable or suspected human carcinogens. The development of alternatives is somewhat

hampered by a lack of epidemiologic data on humans.

Various molecular and physiochemical properties of substances have been correlated to carcinogenicity. Some structure-activity models developed for families of chemicals have predicted

the carcinogenic properties for 75 to 97 percent

of them. The chemicals modeled include polycyclic

aromatic hydrocarbons (123), nitrosamines (89,99,

121), and aromatic amines (124).

The Ames Test

Because mutation is often the first step in carcinogenesis, the Ames test has been suggested as

a possible screen or replacement for carcinogenicity testing. It has been evaluated for this purpose, both alone and as one in a battery of tests.

Alone, it is less predictive than whole-animal tests.

In a battery, it has been shown to be about as predictive as animal testing for certain families of

chemicals and substantially less predictive for

others for the substances tested. Table 8-1 shows

the predictiveness of mouse and rat bioassays and

the Ames test for some known human carcinogens.

The Ames test has been performed thousands

of times in over 2,000 laboratories throughout the

world and has provided results on over 1,000

chemical substances since it was developed less

than two decades ago. Portions of this large body

of analytical data have been reviewed in over a

dozen evaluation studies with the intent of determining the test ability to predict carcinogenicity

(6,19,66). These evaluations show that the percentage of human carcinogens that are also mutagens

(mutagenic carcinogens) ranges from 50 to 93 percent and is most likely about 80 percent (48). About

20 percent of the human carcinogens were not

mutagens (nonmutagenic carcinogens) in the Ames

test, and it is believed that cancer associated with

these carcinogens is initiated by a mechanism other

than mutation.

A critical analysis of several studies (19) identified several sources of variation. These include

methods of chemical selection, sample coding, use

of a high proportion of chemicals known to work

well or poorly with Ames testing, and differences

in metabolic activation during the test procedure.

The conclusion was that a reasonably careful application of the Ames technique to a nonbiased

group of chemicals would be expected to yield a

predictive accuracy of approximately 80 percent

for mouse and rat carcinogens.

The Ames test tends to be positive for a large

proportion (about 40 percent) of substances that

have not been identified as carcinogens in rodent

bioassays. It should be noted, however, that these
188 ● Alternatives to Animal Use in Research, Testing, and Education

Table 8.1.—The Response of Known Human Carcinogens to

Rodent Carcinogenicity and Bacterial Mutagenicity Assays

Rat Mouse Ames

Chemical bioassay bioassay test

4-Aminobiphenyl . . . . . . . . . . . . . . . . . . . . . . . . .

Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bis(chloromethyl)ether . . . . . . . . . . . . . . . . . . . .

Chromium; some chromium compounds . . . . .

Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . .

Diethylstilbestrol . . . . . . . . . . . . . . . . . . . . . . . . .

Melphalan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mustard gas . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Naphthylamine . . . . . . . . . . . . . . . . . . . . . . . . .

Soot, tars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vinyl chloride.. . . . . . . . . . . . . . . . . . . . . . . . . . .

+—

+—

+

+

+

+

+

+

n.d.

——

+

+—

+

+

+

+—

+

+

+

+

+

+

+

+—

—

+

+

+

+—

+

+

+

+

+

KEY:+ = Positive results (carcinogenic to rodents or mutagenic to bacteria)

– = Negative results (not carcinogenic ornot mutagenic)

n.d. = No data.

SOURCES: From H. Bartsch, L. Tomatis, and C. Malaveille, ’’Mutagenicity and Carcinogenicityof Environmental Chemicals:’

Regu/ Tox/co/. Pharmacoi. 2:94-105, 1982;D. Brusick, devaluation of Chronic Rodent Bioaasays andAmes Assay

Tests as Accurate Modeis for Predicting Human Carcinogens,” Application of Bioiogicai Markets to Carcinogen

Testing, H. Milman and S. Sell (ads.) (New York: Plenum Press, 1963); B.D. Goldstein, C.A. Snyder, S. Laskin et

al., “Myelogenous Leukemia in Rodents Inhaling Benzene,” TcJx/coi. f.ett. 13:169-173, 1962; and J.V. Soderman (cd.),

Handbook of identified Carcinogens and Noncarcinogens, Vols. / and Ii (Boca Raton, FL: CRC Press, 1982),

substances have not been shown to be noncarcinogenic, and many authorities maintain that the information is insufficient to make any statement

about the proportion of noncarcinogens that are

also nonmutagens in the Ames test (4,116).

Use of the Ames Test in

a Battery of Tests

The predictive value of the Ames test, or other

mutagenicity tests, can be improved by combining it with additional short-term assays to form

a test battery. Although no US. regulatory agency

has yet recommended a specific combination, most

authorities recommend that an appropriate battery should include information from a minimum

of three types of tests:

●

●

●

gene mutation (Ames test, mouse Iymphoma

test);

chromosomal mutation (in vivo Chinese hamster ovary cell cytogenetics); and

DNA damage (sister chromatid exchange, —

unscheduled DNA repair).

At least one test should include a mammalian in

vitro cell, tissue, or organ culture assay (4).

In a recent study, 18 Ames tests averaged 66 percent “accuracy” (number of chemicals correctly

identified/number of chemicals tested). Comparative results from six batteries of short-term tests

that included the Ames test increased the accuracy

to 82 to 90 percent (58,111).

CURRENT TRENDS

As long as toxicological data continue to be re- thermore, there are several impediments to develquired by regulators and by the courts to protect opment and implementation:

human health, animal testing will continue for the

foreseeable future. Even major progress in the de- . A large number of scientists have been trained

velopment and implementation of alternatives will to solve health problems and to invent new

not necessarily eliminate whole-animal tests. Fur- products using animal models.
Ch. 8—Alternative to Animal Use in Testing ● 189

●

●

●

Regulatory schemes, product liability law, and

patent law also incorporate notions of animal

models.

A large body of animal testing information already exists that is useful in interpreting new

testing data.

There are substantial costs and delays associated with the development and adoption of

alternatives. One study indicated that it takes

about 20 years for an in vitro test to be developed, validated, adopted, and implemented

(92).

At the same time, there are several factors

facilitating the development and implementation

of alternatives:

●

●

●

●

Rapid progress is being made in techniques

for culturing mammalian cells and organs, in

instruments for detecting and quantifying

cellular and molecular changes, and in the

understanding of the cellular and molecular

processes underlying toxicity. Improved understanding is leading to the ability to predict

long-term effects and carcinogenicity from

short-term biochemical and morphological

changes.

As such advances are made, the research laboratories that have developed the expertise

are often willing to apply it to the development of new testing methods, and can do so

efficiently (42).

Organizations such as The Johns Hopkins Center for Alternatives to Animal Testing and the

Rockefeller University laboratory have been

set up to facilitate and coordinate research

on alternatives (see ch. 12).

Many organizations have been established to

pressure those who conduct animal testing

or use data based on it to adopt alternatives

or conduct research that will lead to alternatives.

Strategies to speed the development and adoption of alternatives will depend on the needs and

resources of the organization involved. The following recommendations encompass a variety of

perspectives. They were promulgated by the Toxicity Committee of the Fund for the Replacement

of Animals in Medical Experiments, which met

from 1979 through 1982 (40). Some involve reassessment of testing needs and priorities; others

involve technical strategies thought to be likely to

lead to better methods, both in testing and in evaluating results:

●

●

●

●

●

●

●

●

●

●

●

●

●

Provide a mechanism for reviewing the need

for a given test.

Investigate the consequences of not requiring or possessing testing data other than what

already exists. Particular attention should be

given to widely used tests such as the LD5O

and skin and eye irritation tests with a view

toward eliminating unnecessary requirements.

Encourage flexible use of testing guidelines

and frequent reappraisal of them in light of

new knowledge.

Strive for broader-based international harmonization and mutual recognition of data

from other countries so that duplicative testing can be avoided.

Encourage detailed publication of all testing

results, particularly for costly or painful tests

or those requiring many animals.

Investigate the possibility of time limits on the

confidentiality of test results.

Make greater use of studies on absorption,

distribution, biotransformation, and excretion

in humans, as well as in test animals, to select

the most relevant exposure conditions, to aid

in extrapolation of results, and to improve the

reliability of test results.

Perform preliminary studies before undertaking long-term studies so that results can be

as useful as possible.

Make greater use of the structural and conformational computer models used in developing drugs for the prediction of toxicity.

Standardize screening tests based on in vitro

and nonanimal tests, both to promote efficient

use of testing resources and to evaluate the

predictiveness of these tests.

Try to predict toxic reactions before testing,

both as a means for improving prediction techniques and to avoid testing highly irritating

substances, particularly in the eye, if possible.

Conduct research on the mechanisms by which

toxic effects occur to facilitate the development of new testing methods.

Develop more accurate, reproducible instrumentation for measuring toxic effects, avoid-
190 ● Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

●

●

●

●

●

ing subjective measurements and reducing

measurement errors.

Make greater use of depositories in standardizing cell lines or strains of micro-organisms

used for testing.

Study the relationship between physiochemical properties and pharmacokinetic properties, as well as between physiochemical and

toxicologic properties.

Develop techniques for detecting nonmutagenic carcinogens.

Develop systematic methods for objectively

evaluating new techniques.

Conduct postmarketing surveillance for adverse effects, noting any discrepancies with

test results from animals.

Substitute very specific tests for the LD5O and

other general toxicity tests, particularly for

substances having specialized uses, such as

drugs.

Use skin irritation testing as a rough screening tool for eye irritation.

Attempt to describe specific effects in eye irritation studies, rather than reporting only

the magnitude of the response.

Investigate specific effects such as neurotoxicity to the extent possible when conducting

general toxicity tests.

●

●

●

●

●

●

●

●

Search for cell lines that retain their special

functions upon replication and develop techniques for culturing them.

Evaluate the statistical precision needed in

various circumstances with a view toward

using the smallest number of animals likely

to be adequate.

Use statistics to maximize the utility of results.

Techniques such as blocking, covariance analysis, and factorial design should be used routinely.

Improve standards of care and diet to reduce

background effects.

Take care that those conducting tests are qualified to do so, including having been trained

in humane handling of animals.

Combine tests wherever possible and keep

them as short as possible, compatible with the

nature of the test,

Place greater emphasis on “no observed effect

levels” than on lethal doses when they have

greater predictive value.

Use more than one species only to answer specific questions, and not for general safety assessments.

SUMMARY AND CONCLUSIONS

There has been a small but significant shift away

from whole-animal testing to in vitro and nonanimal techniques in recent years, partly as a result of advances in biological techniques and partly

in response to political and economic pressures.

Many new methods are being developed for commonly used tests. Most of these are not yet validated, but they already have potential uses for

screening substances for the animal testing they

may eventually replace.

There are several kinds of alternatives. The first

entails the continued, but modified, use of animals-changes in experimental design or data analysis so that fewer animals are needed or changes

in protocols to reduce pain or distress. Living tissues, organs, and cells derived from humans or

animals can sometimes be used instead of whole

animals. These systems require a larger investment

of time and money to develop than do modifications of whole-animal techniques, but their advantages may also be greater. They are usually faster

and often cheaper than the corresponding wholeanimal test, and they have scientific advantages

as well. However, they almost always are less

predictive than whole-animal tests and often fail

to provide reliable dose-response data, information that is critical in estimating potential toxicity

to humans.

Data, both anecdotal and epidemiologic, on toxic

effects in inadvertently exposed humans are sometimes useful. However, these data are often confounded by lifestyle and exposure to other toxic
Ch. 8—Alternative to Animal Use in Testing Ž 191

factors. Another drawback is that human exposure

can be great if there are long delays between exposure and observable effects.

The LD5O, probably the most common and most

criticized toxicity test, is well suited to the limited

use for which it was first developed. The biggest

obstacle to limiting or eliminating use of the LD5O

is institutional: Many regulatory schemes rely on

it for classifying substances. The most promising

alternatives in the short term are testing sequences

that require fewer animals. Cell culture techniques

and computer modeling show some promise, but

they have limited value at this time.

Another common and widely criticized test is

the Draize eye irritation test. Several promising

in vitro alternatives have been developed with cell

cultures. Another technique uses the outer (chorioallantoic) membrane of a 14-day-old chicken embryo. This technique, although it uses a whole animal embryo, is thought to involve no pain because

the membrane has no nerves. These alternatives

may also apply to skin irritation.

Alternatives to carcinogenicity testing and repeated dose toxicity testing are of special interest,

in part because the potential savings in testing costs

and time are quite large, and in part because these

tests require large numbers of animals. The most

promising replacements are batteries of tests involving cell cultures and living, nonanimal organisms. Mutagenicity testing uses many in vitro or

nonanimal protocols. Mutagenicity is of particular interest because mutation can be the first event

in other kinds of toxicity, including carcinogenicity, and because it can permanently affect the human gene pool. The most well known nonanimal

mutagenicity assay is the Ames test. When it is combined with other tests, the Ames shows promise

as an alternative to carcinogenicity testing, but it

is not yet validated for this use.

In general, the development of alternatives is

being facilitated by the rapid development of biological techniques, which are being applied to the

search for- alternatives in many different laboratories. Major contributions to the coordination of

these developments in the United States are being

made by Rockefeller University and The Johns

Hopkins Center for Alternatives to Animal Testing.

The implementation of alternatives is hindered

by various forms of institutional inertia, such as

regulatory schemes (see ch. 7), product liability

law (see ch. 7), and general resistance to change.

Important impediments are the large body of existing information—derived from animals—that is

relied on for the interpretation of new data and

the lack of sufficient information to support the

use of alternatives.

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Chapter 9

Animal Use in Education

and the Alternatives

Any experienced teacher of physiology knows that the ‘Tiling” of a beating heart in the

opened chest of a dog does more to reinforce the lessons about cardiac physiology than any

words he can speak. This is not an argument for unlimited use of animals, but it is a recognition that biology is ultimately about living organisms and that learning about living organisms require some experience with them.

Joel A. Michael

Rush-Presbyterian-St. Luke’s Medical Center

March 4, 1985

Generations of surgeons and veterinary surgeons have been trained without practicing on

live animals and the Government intends future generations to do so as well.

Microsurgery will be the only surgical skill which we at present contemplate permitting

to be practised on living animals.

Scientific Procedures on Living Animals, Command 9521

British Home Office

May 1985
CONTENTS

Page

Patterns of Animal Use in Education . . . . . . . . . . . . . . . . . . . . . . . . .............199

Primary and secondary Education . . . . . . . . . . . . . . . . . . . . . ................199

Animal Use at the Postsecondary Level . ................................202

The Alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............208

Continued, But Modified, Use of Animals in Education ..., . ...............208

Use of Other Living Systems in Education. . . . . . . . . . . . . . . . . . . . . . .........209

Use of Nonliving Systems in Education . . . . . . . . . . . . . . . . . . . . . ............210

Computer Simulation in Education . . . . . . . . . . . . . . . . . . . . . ................211

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...214

Chapter 9 References. . . . . . . . . . . . . . . . . , ..., . . . . . . . . . . . . . . . . . . . . . .......215

List of Tables

Table No. Page

9-1. Sample Policies Governing Animal Use in Primary and

Secondary schools. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

9-2. Courses on Ethics and Animals offered at U.S. Colleges

and Universities, 1983-84 . . . . . , . . . . , . . . . . . . . . . . . . . , . . . . . . . . . . . . , . , . .203

9-3. Instructional Use of Animals in 16 Selected U.S. Medical Schools,

by Discipline, 1983-84 . . . . . . . . . . . . . . . . . . . . . . . . . . ...............,....204

9-4. Animals Used in Laboratory Exercises and Demonstrations in

Medical Education in 16 Selected U.S. Medical Schools, 1983-84 . .........205

9-5. Estimated Animal Use in Medical Education in the United States,

1983-84 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .., ...206

9-6. Animals Used in Veterinary Education in the United States, 1983-84.......207

9-7. Advantages, Disadvantages, and Barriers to Using

Computer Simulations in Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..,.212

Figure

Figure No. Page

9-1. Computer Simulation of Cardiovascular Dynamics for Use in

Teaching Physiology ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........212
Chapter 9

Animal Use in Education

and the Alternatives

Measured by the number of animals involved,

the use of animals is far less significant in education than in research and testing. Yet few students

emerge from the educational system without some

contact with animals in the classroom—an interaction that may range from the observing and

handling of small mammals in grade school to surgical training in medical school. In terms of fostering attitudes, education exerts a vital influence over

the use of animals and the development and implementation of alternatives.

This chapter examines the patterns of animal

use and the prospects for alternatives in primary,

secondary, and college education and in the 127

accredited medical schools and the 27 accredited

veterinary schools in the United States. Replacements, reductions, and refinements of animal use

can today be found at all levels of education. Moreover, principles of humane treatment of animals

are increasingly an integral part of curricula

throughout the life sciences.

PATTERNS OF ANIMAL USE IN EDUCATION

Out of every 1,000 students entering the fifth

grade, 285 will enter college and about 40 will obtain science degrees (2 I). Some of those 40 continue their education to become doctoral scientists and health professionals. As students journey

from elementary school through high school and

then perhaps onto college, universities, and other

postgraduate programs, their educational exposure to animals takes many forms. The elements

of the scientific method and scientific principles

pervade every curriculum. In at least 21 States,

some type of instruction in the value of animals

and humane considerations is required. Acquaintance with animals instills a respect for and appreciation of life and conveys as well the fundamental

principles of biology.

Three distinct educational goals dictate ways in

which animals are used in the classroom:

Development of positive attitudes toward animals. In the best instances, such development

incorporates ethical and moral considerations

into students’ course of study.

Introduction of the concept of “biological models,” by which students learn to single out particular animal species as representative of biological phenomena. Such models vary in the

degree to which they provide general information about a broader spectrum of life.

● Exercise of skills vital to intellectual, motor,

or career development. Familiarity with living tissue, for example, enhances a student’s

surgical dexterity.

Alternatives to using animals in education therefore must satisfy these goals. In addition, the educational use of animals and alternatives can foster

positive attitudes toward alternatives in research,

testing, and education, which may in turn perpetuate the search for such options as these students

themselves become scientists. The sum total of the

educational use of animals and alternatives can

be to reinforce as the guiding principle of the

scientific method the judicious selection of the

most appropriate system to generate the desired

knowledge.

Primary and Secondary Education

Animals in the Classroom

Most students become initially acquainted with

animals and their role in the biological sciences

during primary and secondary education. In primary schools, animals are generally not subject

to experimentation or invasive procedures of any

sort. They are usually present in the classroom

to teach students about care and to observe the

social interactions of people and other animals.

199
.

200 . Alternatives to Animal Use in Research, Testing, and Education

Such interactions provide the vehicle for developing humane attitudes toward animals. In junior high and high school, students begin a more

aggressive pursuit of science, which is reflected

in the patterns of animal use. Dissections and investigational laboratory exercises are introduced

into the curriculum. For most students, high school

provides their last formal science education, in the

form of biology class.

A recent study identified three stages in the development of students’ attitudes about animals (6).

The period from 2nd to 5th grade (ages 6 to 10)

was characterized by an increase in emotional concern about and affection for animals. The years

between 5th and 8th grades (10 to 13 years of age)

were marked by increased factual understanding

and knowledge of animals. From 8th to 1lth grade

(ages 13 to 16), students exhibited broadening

ethical concern about and ecological appreciation

of animals.

Each phase of primary and secondary education

appears to offer varying opportunities for education about animals. The 8th through 11th grades

seem to be the most appropriate times for exercising meaningful influence on the development

of attitudes toward animals (6).

Several national organizations and local school

systems have issued specific policy statements on

the use of animals; these suggest the practices both

permitted and prohibited in the classroom at the

secondary level (see table 9-1). All the policy documents generated by national groups share one distinct limitation: They have neither the power nor

the mechanisms to enforce their provisions. They

are merely guides and statements, not rules.

Science Fairs

Active involvement in the day-to-day aspects of

science and the scientific method is not a usual

component of primary and secondary science education, science fairs provide an opportunity for

some students to enhance their understanding of

science by pursuing independent investigations

and competing with their peers in various local,

Table 9-1 .—Sample Policies Governing Animal Use in Primary and Secondary Schools

Year last

Group revised Description of policy

Connecticut State 1988 Policy urges that no vertebrate animal should be subjected to any procedure that interBoard of Education feres with its normal health or causes it pain or distress. No experiment should be carried out without the personal direction of an individual trained and experienced in approved techniques for such animals.

Alexandria (VA) City 1989 No vertebrate animal used for secondary school teaching maybe subjected to any exPublic Schools periment or procedure that interferes with its normal health or causes it pain or distress. Dissections are not banned; however, they are to be done only with commercially

prepared specimens.

Canadian Council on 1975 Guiding principles apply to animal use in the classroom, not to science fairs. No experAnimal Care imental procedures are permitted on vertebrates that subject them to pain or discomfort or that interfere with the organism’s health.

National Association of 1980 Guidelines for the use of live vertebrates at the pre-university level apply to classrooms

Biology Teachers as well as school-related activities. No experimental procedures should be attempted

that would subject the animals to pain or distinct discomfort. No experimental studies

should be done outside the school. No live vertebrates are permitted in science fair

exhibits. Exemptions to these guidelines maybe granted under limited conditions that

include direct supervision by a qualified research scientist in the field, an appropriate

facility designed for such projects, and the utmost regard for the humane care and treatment of the animals involved in the project. .

National Science 1981 Code of practice applies to the use of vertebrates in schools or school-related activiTeachers Association ties. Experimental procedures conducted should include only those that do not involve

pain or discomfort to the animal. Extracurricular protocols should be reviewed in advance of the start of the work by a qualified adult supervisor, and should preferably be

conducted in a suitable area in the school. This code has been endorsed by the National Academy of Sciences and the American Veterinary Medical Association.

SOURCES: Connecticut State Board of Education, State Board Po//cy on Animals In the School, Feb. 7, 1968. Alexandria City Public Schools, Policy File 3107, Jan.

6, 1%9. Canadian Council on Animal Care (Ottawa), Guiding Principles Governing the Use of Animals in the Classroom at the Pre-Un/versity Levels, May

1975. “National Association of Biology Teachers Guidelines for the Use of Live Animals at the Pre-Unlverslty Level,” Amedcan Biology Teacher 41:426, 1980.

National Science Teachers Association, Code of Practice on Animals In Schoo/s, Washington, DC, 1981.
Ch. 9—Animal Use in Education and the Alternatives . 201

State, and national competitions. The fairs stimulate an interest in science, and they reward active

involvement. Many scientists have taken the first

steps in their career paths by this route. The competitive nature of the fairs encourages budding

scientists to stretch their skills to often sophisticated levels of investigation.

The National Science Teachers Association’s

Code of Practice on Animals in Schools (see table

9-1) applies to science fairs as well as animal use

in the classroom and prohibits experimental procedures that would involve pain or discomfort to

the animal (10). This code governs both projects

conducted by students at schools that adhere to

the policy, and science fairs that have adopted the

standards. Several of the most prominent fairs have

adopted other rules in addition.

The International Science and Engineering Fair

(ISEF) is held annually with several hundred entrants in grades 9 through 12, drawn from many

thousands of participants in local fairs. ISEF rules

require that a Scientific Review Committee consider all research involving vertebrate animals

prior to competition. Criteria include a completed

research plan, evidence of a literature search,

documentation of the type and amount of supervision, use of accepted techniques, demonstrated

skill in such techniques, and compliance with any

required certifications.

ISEF explicitly disallows procedures that would

develop new surgical techniques or would refine

existing ones, as well as research where the animal is not humanely killed (4). Surgical procedures

may not be done at home. Sacrifices of animals

and experiments involving anesthetics, drugs, thermal procedures, physical stress, pathogens, ionizing radiation, carcinogens, or surgical procedures

must be done under the direct supervision of an

experienced and qualified scientist or designated

adult supervisor. Nutritional deficiency studies and

studies of toxic effects may only proceed to the

point where the symptoms appear. Steps must then

be taken to correct the deficiency, or the animals

are to be humanely killed. LD5O experiments (see

chs. 7 and 8) are not permitted.

The Westinghouse Science Talent Search, an annual competition involving more than 15,000 parFinalist, 1985 Westinghouse Science Talent Search

Photo credit: Gary B. Ellis

Louis C. Paul, age 18, Baldwin Senior High School,

Baldwin, NY, with his research project, “Effect of

Temperature on Facet Number in the Bar-Eyed Mutant

of Drosophila melanogaster. ”

ticipants, has since 1970 forbidden experimentation with live vertebrates with the exception of

projects involving behavioral observations of animals in their natural habitat or of human subjects

(17). In 1985, none of the 39 Westinghouse finalists

carried out experiments on nonhuman vertebrate

animals. One entrant studied gene expression in

cultured mammalian cells. Living organisms used

in the winning projects included leeches, butterflies, fruit flies, water fleas, and bacteria.

In Canada, all animal experimentation for science

fairs is subject to Regulations for Animal Experimentation in Science Fairs, the 1975 policy

statement of the Youth Science Foundation of Ottawa, Ontario. Key provisions include:

● Vertebrate animals are not to be used except

for observation of normal living patterns of:

1) wild animals in the free-living state or in

zoos, aquaria, or gardens; or 2) pets, fish, or

domestic animals.

● No living vertebrate animal shall be displayed

in exhibits in science fairs.

Other rules include:

●

●

Chick embryos may be used for observational

studies only.

If eggs are to be hatched, then humane considerations must be met in the disposal of the

chicks.
—

202 ● Alternatives to Animal Use in Research, Testing, and Education

●

●

●

If humane requirements cannot be met, embryos must be destroyed by the 19th day of

incubation.

No eggs capable of hatching maybe exhibited

at science fairs.

All experiments shall be carried out under the

supervision of a competent science teacher.

Enforcement mechanisms for these restrictions

specify that students sign a declaration of compliance, and that this compliance be certified by the

science teacher supervising the project.

Animal Use at the

Postsecondary Level

Animals are used in undergraduate education

for both the acquisition of knowledge and the acquisition of particular skills. Procedures involving animals can, of course, serve both purposes.

Graduate science education (and, in some instances,

advanced undergraduate education) involves an

additional component—the student’s first genuine research experience. The distinction between

teaching and research virtually disappears in graduate school because the student simultaneously

learns the methods and actually conducts research.

The guidelines that dictate practices of animal use

in graduate education are those that govern animal use in research (see ch. 15). Effects of earlier

exposure to humane concerns may manifest themselves in graduate education through the student’s

choice of avenues of research and selection of

model systems for investigation.

BLOOM COUNTY

Because attitudes about animals will almost certainly affect the ways in which students may use

(or not use) animals in education and, later, professionally, it is noteworthy that U.S. colleges and

universities offer about two dozen full-length

courses on ethics and animals, according to a 1983

survey (see table 9-2). These courses cover the bioethical issues surrounding humans’ responsibilities regarding laboratory, agricultural, and wildlife animals. The Scientists Center for Animal

Welfare maintains information on college courses

on ethics and animals and advocates the inclusion

of such courses as a standard component of the

education of all students entering careers in the

biological sciences (18). At virtually all veterinary

schools, lecture material on ethical considerations

of working with animals is included in required

courses as part of the veterinary curriculum.

Determining the number of animals used strictly

for undergraduate and graduate education is difficult because laboratory education is often mixed

with laboratory research. This is especially true

for graduate education. The last survey of animal

use that included questions regarding animals used

for teaching purposes was done for fiscal year 1978

by the National Academy of Sciences/National Research Council’s Institute of Laboratory Animal

Resources (ILAR) under contract to the National

Institutes of Health (23). Respondents that used

animals for educational purposes included 69 medical schools, 10 veterinary schools, 42 additional

health professional schools (e.g., dental, public

health), 65 hospitals, and 149 colleges and univerby Berke Breathed

I

I

Reprinted with permission. © 1985 Washington Post Writers Group.
Ch. 9—Animal Use in Education and the Alternatives ● 203

Table 9-2.—Courses on Ethics and Animals Offered at U.S. Colleges and Universities, 1983.84

Institution Course name (department and course number)

Appalachian State University . . . . . . . . . . . . .

California State University. . . . . . . . . . . . . . . .

Central Michigan State University . . . . . . . . .

Colorado State University . . . . . . . . . . . . . . . .

Eastern Michigan State University . . . . . . . . .

Elmira College . . . . . . . . . . . . . . . . . . . . . . . . . .

Indiana University-Purdue University . . . . . . .

Michigan State University . . . . . . . . . . . . . . . .

Moorhead State University . . . . . . . . . . . . . . .

North Carolina State University . . . . . . . . . . .

Purdue University . . . . . . . . . . . . . . . . . . . . . . .

Stanford University . . . . . . . . . . . . . . . . . . . . . .

State University of New York at Stony

Brook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

University of Connecticut . . . . . . . . . . . . . . . .

University of Maryland . . . . . . . . . . . . . . . . . . .

University of Minnesota. . . . . . . . . . . . . . . . . .

\/irginia polytechnic Institute . . . . . . . . . . . . .

Wagner College. . . . . . . . . . . . . . . . . . . . . . . . .

Washington State University. . . . . . . . . . . . . .

People, Plants, and Animals (Philosophy 3560)

Animal Rights (Philosophy 1941; General Studies 4279)

Religion and Social Issues (Religion 335)

Attributes of Living Systems (Biology 102; Honors)

Moral and Conceptual Issues in Veterinary Medicine (Veterinary Medicine 712)

Introduction to Philosophy (Philosophy 100)

Mankind? We and Other Animals (Humanities 0530)

Ethics and Animals (Philosophy 493)

Ethics and Animals (Philosophy 494)

Perspective in Veterinary Medicine (Veterinary Medicine 517)

Animal Rights (Philosophy 215)

Philosophical Issues in Environmental Ethics (Philosophy 332)

Ethics and Animals (Philosophy 280)

Animal Rights: Issues and Politics (Stanford Workshop on Political and Social

Issues Program 161)

Human/Pet Bonds (Psychology 391)

Problems in Environmental Law: Issues in Animal Rights and Protection (Law 852)

Philosophy and Environmental Ethics (Philosophy 0255)

Perspectives: Animal-Human Relationships and Community Health (Public

Health 5-303)

Special Study, Ethics, and the Treatment of Animals (Philosophy 2980)

Bioethics (Biology 230)

Reverence for Life (Veterinary Anatomy, Physiology, and Pharmacology 499)

SOURCE Scientists Center for Animal Welfare (Bethesda, MD), “College Course on Ethics and Animals, ” Newsletter 5(2):3-6, 1963.

sities. Some of the health professional schools were

included in other categories (e.g., universities with

affiliated professional schools) and thus accounted

for a smaller number of such schools identified

separately than expected.

For this assessment, animal use in medical education and veterinary education was examined in

detail for the school year 1983-84. Comparisons

with the 1978 ILAR survey are inappropriate because of different survey methodology.

Medical Education

Animals are used in many capacities in medical

education. In the basic sciences, they are often used

to illustrate the structure and function of the systems under study and the complex physiologic

interactions within a single organism. They function as intermediaries during a medical student’s

transition from trainee to practicing physician, letting students cultivate their skills on other living

creatures before they actually apply those same

techniques to human patients. Techniques such

as venipuncture, insertion of catheters, and other

procedure-oriented exercises are those cited by

medical educators as needing practice before patients are worked with. The need to practice invasive surgical procedures prior to human surgery

is probably the most compelling use of animals by

medical students.

It is generally held that doctors must learn the

techniques of their profession. And most commentators acknowledge the need for students in the

health professions to subject animals to some practice surgery, albeit closely regulated (17). The issue of animal use in medical education thus seems

more a question of degree and manner of use

rather than one of whether or not animals should

be used at all.

Yet, practicing techniques on animals is not

universally condoned. In the United Kingdom, live

animals cannot be used by students practicing ordinary surgery solely to improve manual dexterity

and technique. (This does not necessarily mean

that medical and veterinary students do not improve their techniques by using live animals, but

such activities must have some other purpose.) Physicians are trained by a process similar to apprenticeship, learning by observation, demonstration,

and example. They assist an accomplished surgeon

and expand their active role only as their abilities

increase.
204 Ž Alternatives to Animal Use in Research, Testing, and Education

In 1985, the British Government relaxed its stricture in order to allow animal use in microsurgical

training (22):

Generations of surgeons and veterinary surgeons have been trained without practicing on

live animals and the Government intends future

generations to do so as well. But the new development of microsurgery—which is surgery performed with miniature instruments under a microscope, for example, to repair blood vessels or

nerves—presents special problems. The delicate

techniques involved cannot be practised satisfactorily on dead subjects. Surgeons at present have

to go abroad or practise on decerebrate animals

which for this purpose is technically complicated

and sometimes more wasteful of animals than

using terminally anaesthetised ones. Microsurgery will be the only surgical skill which we at

present contemplate permitting to be practised

on living animals. The consent of the Secretary

of State will be required in every case, and he

will only give it to qualified surgeons working

on approved microsurgical courses on rodents

which are anaesthetised throughout the procedure and killed before the animal can recover consciousness,

In general, adequate training through staged exercises is regarded as a prerequisite for successful microsurgery (11).

To ascertain patterns of animal use in medical

education during the school year 1983-84, the Association of American Medical Colleges (AAMC) surveyed 16 of the 127 accredited medical schools

in the United States. The 16 schools surveyed were

selected in an effort to achieve balance in three

characteristics: ownership (10 public and 6 private); geographical region (4 each in the Northeast, Midwest, South, and West); and research expenditures (5 high, 5 medium, and 6 low) (2).

The AAMC distributed questionnaires to each

department in the sample schools and followed

up with telephone calls. Because differing curricula made analysis by department problematic,

queries were oriented to each of the disciplines

known to be present in undergraduate and graduate medical education. Anatomy, for example, is

taught by the surgery department in some schools,

but animal use in these exercises was still recorded

in the discipline of anatomy (2).

Anatomy, biochemistry, microbiology, pathology, pharmacology, and physiology are part of the

curriculum leading to the M.D. degree everywhere,

and data for these disciplines were obtained from

all 16 schools. The data for all other disciplines

except family medicine and advanced trauma life

support were obtained from at least 15 of the 16

schools surveyed. Family medicine is offered at

only 10 of the 16 institutions (all responded). Advanced trauma life support, a course for house

staff rather than medical students, is offered at

only 7 of the 16 institutions (all responded) (2).

The use of animals was common in only a few

disciplines (see table 9-3), although all 16 institutions used animaIs in some discipline. Animal use

in medical education was most common in physiology (10 of 16 schools), surgery (10 of 16), and

pharmacology (8 of 16). In other disciplines, no

more than 7 of the 16 medical schools used animals for educational purposes. Advanced trauma

life support involved animal use at all 7 schools

where it was offered (2).

Table 9=3.—instructional Use of Animals in 16 Selected

U.S. Medical Schools, by Discipline, 1983-84

Number of

schools with Use Do not use No

Discipline discipline animals animals response

Advanced trauma life

support . . . . . . . . . . . 7 7 0 0

Anatomy ., . . . . . ., . . . 16 2 14 0

Anesthesiology . . . . . . . 16 2 14 0

Biochemistry . . . . . . . . . 16 3 13 0

Dermatology . . . . . . . . . 16 0 15 1

Family medicine . . . . . . 10 0 10 0

Internal medicine . . . . 16 1 14 1

Microbiology ... , . . . . . 16 4 12 0

Neurology . . . . . . . . . . . 16 0 16 0

Neurosurgery . . . . . . . . 16 5 11 0

Obstetrics and

gynecology . . . . . . . . 16 1 14 1

Ophthalmology ., ., . . . 16 3 13 0

Otolaryngology . . . . . . . 16 2 14 0

Pathology . . . . . . ., . . . 16 0 16 0

Pediatrics . . . . . . . . . . . 16 3 12 1

Pharmacology . . . . . . . . 16 8 8 0

Physiology. . . . . . . . . . . 16 10 6 0

Psychiatry . . . . . . . . . . . 16 1 15 0

Radiology . . . . . . . . . . . 16 0 16 0

Surgery. . . . . . . . . . . . . 16 10 6 0

Surgery, orthopedic . . . 16 4 12 0

Urology . . . . . . . . . . . . . 16 1 15 0

SOURCE: Association of American Medical Colleges, UseofAnima/s in Undergraduate and Graduate Medkd Education (Washington, OC: 1985).
Ch. 9—Animal Use in Education and the Alternatives • 205

Table 9-4 shows the numbers of animals used

by the 16 medical schools. The principal species

used by those surveyed were rats, dogs, and mice.

Most animals (84 percent) were sacrificed either

before or at the end of the demonstration or laboratory, but over half the cats and all the sheep

were allowed to recover. Anesthesiology, psychiatry, and biochemistry were the disciplines most

likely to subject animals to multiple recovery procedures. According to this survey, only slightly

more than 10 percent of the animals used in surgery are allowed to recover at all (2).

The majority of animals used in the 16 schools

surveyed were used in the teaching of surgery (51

percent) and physiology (16 percent). No other single discipline accounts for even 10 percent of all

animals used. Most of the dogs (64 percent) were

used in the teaching of surgery and physiology.

The total of 7,274 animals can be placed in context by noting the number of students taking part

in the laboratory exercises and demonstrations—

approximately 7,900 medical students and 6,700

residents, for a total of approximately 14,600 students at both levels. Calculating roughly from this,

approximately one animal is sacrificed each year

to support the training of two students (2).

The purposes for which animals are used vary,

even within a discipline. Several general surgery

and surgical specialty departments offer their residents a course in microsurgery. Residents learn

microvascular suture techniques that they will

later apply in human surgery designed to restore

circulation. Nearly all small-animal use (i.e., rats,

hamsters, and rabbits) is for such microsurgery

training. Some general surgery departments offer their residents training in major surgery (e.g.,

splenectomy) using dogs, cats, or pigs, with the

goal of recovery of animals. ophthalmology departments use rabbits to teach new residents the

fundamentals of microsurgery of the eye (2).

Table 9-4.—Animals Used in Laboratory Exercises and Demonstrations in Medical Education in

16 Selected U.S. Medical Schools, 1983-84

Kind of animal

Guinea

Discipline Primate Dog Cat Pig Rabbit Rat Mouse pig Hamster Other Total

Advanced trauma life

support . . . . . . . . . .

Anatomy. . . . . . . . . . .

Anesthesiology . . . . .

Biochemistry . . . . . . .

Dermatology . . . . . . .

Family medicine . . . .

Internal medicine . . .

Microbiology . . . . . . .

Neurology . . . . . . . . .

Neurosurgery. . . . . . .

Obstetrics and

gynecology. . . . . . .

Ophthalmology . . . . .

Otolaryngology . . . . .

Pathology. . . . . . . . . .

Pediatrics. . . . . . . . . .

Pharmacology . . . . . .

Physiology . . . . . . . . .

Psychiatry . . . . . . . . .

Radiology. . . . . . . . . .

Surgery. . . . . . . . . . . .

Surgery, orthopedic .

Urology. . . . . . . . . . . .

Miscellaneous/basic

sciences . . . . . . . . .

Other. . . . . . . . . . . . . .

—

—

—

—

—

—

—

—

—

—

—

4 —

—

—

—

—

—

—

10 —

—

—

—

39

—

6

7

—

—

115

—

—

12

52

—

5

—

—

44

490

—

—

612

—

20

365

4

13

—

1 —

—

—

—

—

—

—

—

20

1 —

14

50

—

—

—

151

—

—

16

13

10

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

54

—

—

—

—

—

—

—

—

—

—

—

2

—

6

—

122

—

—

4

—

2

—

—

113

113

—

16

—

—

75

—

—

—

—

—

—

—

100

—

—

5

—

—

264

294

—

—

1,689

279

—

72

—

—

—

—

40

—

—

—

12

—

—

—

—

9

—

—

300

—

—

—

930

20

—

‘ 6

—

—

—

—

—

—

—

9

—

—

—

—

—

—

—

—

—

—

—

27

—

—

—

—

—

—

—

—

—

—

—

3

—

—

—

—

—

—

—

G

—

—

130

—

20

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

327

4

—

—

1 —

72

—

62

75

7

47

0

0

115

26

0

118

52

146

20

0

18

658

1,193

4

0

3,716

413

40

541

23

Total . . . . . . . . . . . . 14 1,771 279 64 378 2.778 1.317 > — 36 233 404 7,274

alncludes frogs, sheep, and Pi9e0ns.

SOURCE: Association of American Medical Colleges, Use of Animals in Undergraduate and Graduate Medical Education (Washington, DC: 1985).
206 . Alternatives to Animal Use in Research, Testing, and Education

Dogs and pigs are used to teach techniques for

incubation (establishing an emergency airway) and

the installation of intravenous/intra-arterial catheters, In the AAMC survey, one anesthesia department used dogs to teach insertion of Swan-Ganz

catheters into the right chamber of the heart, a

common procedure in cardiac intensive care units.

Two otolaryngology departments used dogs to

teach the musculature and innervation of the trachea and oropharynx to ear, nose, and throat residents. One obstetrics and gynecology department

used dogs as models to teach exposure and isolation of the Fallopian tubes from the nearby ureters, and three pediatrics departments use young

cats as models for instruction in incubation of premature newborn babies. All of the techniques

taught in these graduate medical programs must

be learned to achieve competence in the desired

specialty. In those programs that do not use animals, the techniques are mastered through experience with human patients during surgery (2).

The AAMC survey found no relation between

a medical school’s level of research expenditures

(high, medium, or low) and its use of animals in

education. The medium expenditure schools used

the most animals in education, perhaps because

in the more research-intensive schools there is a

greater opportunity for students to observe animal surgery in the course of participation in faculty

research and less need to include such experience

in the curriculum. Most of the schools surveyed

expressed regret that they were not able to use

Instruction in Incubation of Premature Newborn Babies,

Using a Young Cat as a Model

Redrawn by: Office of Technology Assessment.

animals to a greater extent in student instruction,

often citing cost as a factor limiting instruction with

live animals (2).

National estimates of the numbers of animals

used in medical education (see table 9-5) were calculated based on the assumptions that the 16

schools surveyed are typical of the 127 accredited

schools in the United States. The mean number

of animals of each species used in the sample

schools was accepted as the best estimate of the

mean for all schools, and an extrapolation was

made to 127 schools (2).

Rats and dogs are the principal species used in

medical education, accounting for about 70 percent of the estimated 36,700 animals used annually. These figures are very rough—the potential

error inherent in the estimates ranges from 22 and

25 percent for rats and dogs to 100 percent for

pigs and hamsters. The great uncertainty stems

from variability among the 16 institutions in the

sample. One school used 10 primates, for example,

while another used 4, and 14 schools used none

at all. Use of dogs and cats was more general; less

uncertainty is associated with the national estimates of those species’ use (2).

It is unlikely that any of the 127 medical schools

in the United States train physicians without using

any live animals. This is neither surprising nor

alarming, particularly in light of the fact that the

ultimate recipients of medical attention-humans—

are not available for many of the types of educaTable 9-5.—Estimated Animal Use in Medical

Education in the United States, 1983.84

Kind of animal Number useda

Rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Rabbit . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . .

Cat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hamster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Pig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Primate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Guinea pig , . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other b 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14,000

12,000

3,000

1,700

800

200

130

70

4,000

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36,700

aEst/mate /s b-On an extrapolation of a survey of 16 Seiected mSdiC@ schools

evenly distributed by geographic region (Northeast, Midwest, South, or West),

ownership (public or private), and research expenditures (low, medium, or high).

bfncludes frogs, sheep, and Pi9eons.

SOURCE: Association of American Medical Colleges, Use of Anima/s in Undergraduate and Graduate Medical Education (Washington, DC: 1965).
Ch. 9—Animal Use in Education and the Alternatives ● 207

tional exercises that medical students routinely

must perform. It should be noted, however, that

it is possible for a student to complete medical

school without using animals.

Veterinary Education

Being admitted to the profession of veterinary

medicine, I solemnly swear to use my scientific

knowledge and skills for the benefit of society

through the protection of animal health, the relief of animal suffering, the conservation of livestock resources, the promotion of public health,

and the advancement of medical knowledge.

I will practice my profession conscientiously,

with dignity, and in keeping with the principles

of veterinary medical ethics.

I accept as a lifelong obligation the continual

improvements of my professional knowledge and

competence,

The Veterinarian’s Oath

American Veterinary Medical Association

Twenty-seven accredited veterinary schools in

the United States educate and train veterinary

scientists and veterinarians in the basic biomedical sciences and comparative animal health. An

OTA survey of the 27 schools indicated that every

veterinary school uses animals in its curriculum.

As in medical education, the question of the use

of animals in veterinary education is a matter of

degree and practice.

Veterinary students—unlike medical students—

train on models identical to their prospective patients. Animals are used in laboratory exercises

and demonstrations, and students have the additional opportunity to interact with clinical cases

owned by their schools as well as those brought

in by clients. Privately owned pets, domestic livestock, and zoo animals all serve as resources for

the clinical education of veterinary students,

Most animal use occurs in the third year of the

curriculum, when surgical training takes place,

using principally dogs and sheep. In earlier basic

science courses, anatomy involves dissection of

cadavers with live animals present in the lab for

comparison, and physiology exercises involve the

observation of live animals. The fourth year of

veterinary studies is largely clinical apprenticeship.

With cooperation from the Association of American Veterinary Medical Colleges, OTA conducted

a census of animal use in veterinary education in

the 27 accredited veterinary schools in the United

States for the school year 1983-84. The survey

counted only those animals that began an exercise alive and either died or were subjected to

euthanasia during the course of the laboratory session or demonstration. Cadavers or animals subjected to euthanasia prior to educational use were

not counted, and clinical patients were not counted.

Of 16,655 animals used in 1983-84, half (8,020)

were dogs. Mice, rats, and birds accounted for the

bulk of the remaining animals (see table 9-6). No

primates were killed during or after educational

exercises in veterinary schools.

Laboratory-Animal Training

Technicians with specialized training in public

health and animal care are needed at all levels by

public health organizations, research institutions,

pharmaceutical manufacturers, and universities.

During the 1970s, several 2-year training programs

were developed in response to an increasing need

for personnel formally qualified to assist in priTable 9.6.—Animals Used in Veterinary Education

in the United States, 1983-84

Kind of animal Number useda

Dog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8,020

Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,180

Rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,083

Bird . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,323

Reptile. ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

Sheep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Cat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414

Horse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

Rabbit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Goat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Pig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Guinea pig . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

cow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Hamster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16,655

aThis census of all 27 U.S. veterinary schools does not include privately owned

or pet animals used for clinical demonstrations, animals purchased as cadavers,

or those subjected to euthanasia prior to the laboratory exercise. It krcfudes

only those animals that began the course alive and then either died or were

subjected to euthanasia during the course of the laboratory session.

bincludes fish, frogs, and exotic SPecies.

SOURCE: Office of Technology Assessment,
208 • Alternatives to Animal Use in Research, Testing, and Education

vate veterinary practices, biological laboratories,

animal research, food inspection, and other areas

requiring expertise in both science and animal care

and use.

Graduates of these programs are generally referred to as animal technicians. The terminology

may vary slightly among different schools or with

individual State laws and regulations. Many employees of animal care and research and testing

facilities have received training on the job, in secondary schools, or at less than the 2-year college

level. These individuals are commonly referred

to as animal attendants, animal caretakers, or animal health assistants. Two other types of animalsupport personnel are laboratory-animal technicians (whose training has been oriented primarily

toward laboratory animals) and animal technologists (who have had training in a 4-year baccalaureate degree program).

Most accredited animal technician

cover 2 academic years of college-level

programs

study and

lead to an Associate in Applied Science degree or

its equivalent. The core curriculum usually includes animal husbandry, animal care and management, animal diseases and nursing, anesthetic

monitoring and nursing, ethics and jurisprudence,

veterinary anatomy and physiology, medical terminology, animal nutrition and feeding, necropsy

techniques, radiography, veterinary urinalysis,

veterinary parasitology, and animal microbiology

and sanitation (l).

Many States require animal technicians to be registered or certified. The Laboratory Animal Technician Certification Board sponsored by the American Association of Laboratory Animal Science

provides examinations and registry for technicians

who are eligible and employed in laboratory-animal

facilities.

In addition to increasing interest in laboratoryanimal technician degree programs, a number of

graduating veterinary students have begun to seek

additional training and certification in laboratoryanimal medicine. To date, about 700 full-time veterinarians are certified in this field nationwide (see

ch. 15). As more’ laboratory-animal technicians are

trained and as the number of veterinarians specializing in laboratory-animal medicine increases,

the resulting base of skills and knowledge will likely

improve animal care in the laboratory.

THE ALTERNATIVES

Finding alternatives to the use of animals in education is a complex challenge. Alternatives must

satisfy the demands of science education, teaching both the scientific method and the fundamental skills and techniques necessary to carry out

scientific investigation. Yet science education does

more—as it trains aspiring students, it establishes

a framework of values and molds attitudes that

will long influence their work. Therefore, exposure

to alternatives, particularly the concepts underlying animal use and alternative methods, strongly

influences the paths investigators choose to follow in the future. Viewed from this perspective,

the acceptance (or rejection) of a specific alternative method in education assumes an importance

that is, in fact, secondary to the impact it may have

on the development of a student’s overall attitude

toward animal use in research, testing, or education.

Implementing alternative technologies and methods in education does not necessarily mean banishing animals from the classroom or laboratory. As

in research (see ch. 6) and testing (see ch. 8), certain techniques are available that allow for the continued, but modified, use of animals, the use of

living systems, the use of nonliving systems, and

the use of computers. In education, computer simulation stands as a particularly promising alternative.

Continued, But Modified,

Use of Animals in Education

Demonstrations

In contrast to animal experimentation in research and testing, animal use in the educational

laboratory is unlikely to result in novel findings.
Ch. 9—Animal Use in Education and the Alternatives . 209

In education, a traditional laboratory exercise with

a well-known outcome is usually repeated by a new

student or group of students. The process of selfdiscovery and training is generally of greater importance than the specific data being collected.

Under these circumstances, live demonstrations

can often provide experiences that combine the

best of direct student participation in animal laboratories with a reduction in animal use. Such exercises, when carried out by practiced professional

instructors, avoid clumsy errors that students may

make at the expense of laboratory animals. They

also provide a convenient intermediate in the constant tension between active student participation

in the laboratory and the limitations imposed by

large class sizes.

In a variation on the laboratory demonstration,

students may work together in groups on a single

animal, again using fewer animals than if each student worked alone on a single animal. Exercises

based on animal cells, tissues, or organs may be

coordinated such that the minimum number of

animals required can be sacrificed. Or animals may

be subjected to multiple procedures, although if

these involve sequential survival surgeries the

advantage of reducing the number of animals used

stands in conflict with the undesirability of

repeated insults imposed on a surviving animal.

Noninvasive Procedures

observation can give rise to an appreciation of

the diversity of the animal kingdom in general and

important principles of physiology and behavior

in particular. A sense of responsibility and an

understanding of the life processes of animals are

also conveyed when animals are maintained for

observation in the laboratory. Areas for study in

which animals can be used in a noninvasive manner include:

Ž simple Mendelian genetics (e.g., the inheritance of coat color in successive generations

of small rodents);

● reproductive behavior (e.g., behavioral receptivity of a female during estrus);

. normal physiological processes of maturity,

aging, and death (e.g., the relationship between aging and body weight);

● disease processes (e.g., the incidence of spontaneous tumor growth in a population);

Ž biological rhythms (e.g., nocturnal and diurnal feeding and drinking patterns); and

● social interactions (e.g., territoriality and dominance relationships among males).

Reduction in Pain

Reduction in pain and distress may be accomplished with the use of anesthetics, analgesics, and

tranquilizers. In education, this is of primary importance in surgical training, when animals are

anesthetized, operated on, and then subjected to

euthanasia. Principles of pain and pain relief—

common to research, testing, and education—are

discussed in chapters 5, 6, and 8.

Substitution of Species

The substitution of nonmammalian for mammalian species, of cold-blooded vertebrates for

warm-blooded ones, or of nonpet species for companion animals is occasionally possible in education. Swine have replaced dogs in one surgical

teaching and research laboratory (20). The pigs

were especially successful replacements in a basic

operative surgery course offered as an elective t o

medical students. The principal advantages cited

were closely shared anatomic and physiologic characteristics with humans, better health than dogs,

and economic factors.

Use of Other Living Systems

in Education

Invertebrates

The use of invertebrates as an alternative is already widespread in primary and secondary schools.

Most laboratory manuals include common exercises that teach biological principles and introduce

students to the scientific method of inquiry using

organisms such as hydra, planaria (flatworms), annelids (earthworms), mollusks, and a variety of arthropods (e.g., insects and crustaceans). The use

of invertebrates at the college and graduate levels

may also increase as more is known about them.

These deceptively simple systems are valuable resources for the laboratory investigation of sophisticated biological principles.
210 ● Alternatives to Animal Use in Research, Testing, and Education

In Vitro Methods

Like the use of invertebrates, in vitro manipulation and maintenance of animal components such

as cells, tissues, or organs (see chs. 6 and 8) can

illustrate many biological principles. The incorporation of in vitro techniques into students’ education and training also bears potential for shaping

their later attitudes about the utility of in vitro

methods. The stimulus provided by in vitro laboratory exercises can therefore ultimately alter

the general course of research and testing.

One noteworthy endeavor in training researchers in in-vitro methods is the program of the Center for Advanced Training in Cell and Molecular

Biology at Catholic University of America in Washington, DC. With funding from the American Fund

for Alternatives to Animal Research, the American

Anti-Vivisection Society, and the Albert Schweitzer Fellowship, the Center offers courses to students interested in the biomedical sciences and

to professional researchers. In 1985, its third year

of existence, the Center offered:

● Basic Cell and Tissue Culture,

● In Vitro Toxicology: Principles and Methods,

● Tissue Culture Technology in Neuroscience

Research, and

● An Introduction to Tissue Culture and In Vitro

Toxicology.

The first three courses were attended by technicians and Ph.D. and M.D. researchers. The last

course was specifically designed for high school

seniors and college freshmen (9). Activities of this

nature are useful in that they enable professionals

and, particularly, beginning students to become

acquainted with and proficient in in-vitro methodologies and to comprehend the possibilities as

well as the limitations of alternative methods.

The debate about whether or not the training

of medical and veterinary students requires animals has spawned development of an alternative

technique in microsurgery training. The most

prominent use of microsurgery is for reconnecting arteries and veins, for example in restoring

circulation to severed fingers. To reproduce vascular circulation for microsurgical training, a British plastic surgeon connected human placentas to

a pump and an artificial blood supply, thereby

simulating a heartbeat and typical blood pressures.

Because the placenta contains blood vessels of

widely ranging diameters, a single placenta can

provide material for a substantial amount of practice (14).

At present, the human placenta cannot fully substitute for living animals. One of the problems is

that the placenta contains an anti-blood-clotting

agent or mechanism that is not understood and

cannot be controlled. Clotting therefore does not

occur in placental vessels. since learning how to

avoid clotting during repair is a critical aspect of

training, and since students training on placental

tissue cannot detect their errors that cause clotting, the existing system is not fully adequate in

microsurgical training (14).

Use of Nonliving Systems

in Education

Audiovisual presentations bring the abstract

prose of lecture and text one step closer to the

biological reality of living organisms. Films and

videotapes can demonstrate principles and protocols performed with live animals, while sparing

additional animals. They may also present experiments and situations that cannot be performed

live in the average classroom setting. As replacements for animals, however, they lack the living

dimension; most cannot behave interactively. Recently developed computerized videodisks offer

an opportunity for student interaction with an audiovisual program.

When audiovisual aids are used in concert with

animals, they may enhance the value of live animals used in the laboratory. Students may learn

a technique from a taped demonstration, for example, and then build on that experience as they

perform the actual laboratory exercise in vivo.

Medical education substitutes audiovisual techniques for animals in several cases. This has less

to do with educational philosophy than with factors external to the particular laboratory exercise,

Those factors include the costs of animals and the

facilities required to perform quality experiments,

large medical school classes, lack of faculty time,

and competition within a tightly packed curriculum.

Animal cadavers (e.g., frogs, sharks, cats, and

fetal pigs) are currently used at all levels of educa-
Ch. 9—Animal Use in Education and the Alternatives . 211

Use of the Human Placenta for Training in

Microvascular Surgery

Human placenta perfused under dissecting microscope.

Phcto credits: Pau/l LG Townsend, Consultant Plastic Surgeon,

Frenchay Hospita/, Brlstol

Sutures and valves implanted in vessels of human placenta.

tion as models for dissection. Commercially prepared specimens are often used in junior high and

high school education; medical and veterinary

schools are more likely to prepare their own specimens. In some situations, cadavers may provide

adequate replacements where living animals were

once used.

Computer Simulation in Education

Computer simulation offers a variety of alternatives for studying animal and human biology

at all levels of education, and the field is evolving

quickly as experience grows and computer technology advances. Although at this time popular

expectations for computer simulation still outdistance actual performance, the options that simulations present to educators can be expected to

increase. Educational computer simulations fall

into two categories: computer models of biological events and interactive simulations of biological experiments.

Computer simulations of biological events-primarily mathematical models of physiological and

cellular phenomena—present in quantitative form

phenomena that might be difficult or impossible

to study in animals or humans. By altering parameters within the programs and noting results, students learn principles of biology from an ersatz

animal system, the computer program. For example, a dog’s circulatory functions are converted

to a series of mathematical equations, which are

programmed into a computer. As students change

individual values or groups of values, the program

resolves the various equations and reports values

that mimic the effects of altering those parameters of the circulatory system in a living dog. Figure 9-1 depicts a portion of such a simulation.

An array of computer models of physiological

processes are used in undergraduate and graduate laboratory exercises. The range of physiological

simulations includes simulations of blood chemistry, cardiovascular physiology, the digestive system, the musculoskeletal system, respiratory physiology, and renal physiology. Computer simulations

currently used in physiology laboratory exercises

include:

● HUMAN: a comprehensive physiological model (3),
212 ● Alternatives to Animal Use in Research, Testing, and Educatkm

Overview of a computer simulation of the complete

cardiovascular system, showing student-controlled variables

such as heart rate (HR%), total active blood volume (BV%),

and total peripheral resistance (TPR%).

SOURCE: N.S. Peterson and K.B. Campbell, “Teaching Cardiovascular Integrations

With Computer Laboratories,” Physlo/oglst 26(3):159-169, 1965.

●

●

●

●

●

●

●

●

pH regulation and carbon dioxide (24),

pulsatile hemodynamics in the aorta (5),

determinants of cardiac output (16),

effects of medically important drugs on the

circulatory system (25),

simulation of the digestion of a meal (25),

responses of organisms to exposure to high

and low temperatures (25),

influence of hormones on muscle cells (25),

and

renal excretory response to volume and osmolarity changes (12).

Computer simulation of a particularly sophisticated

laboratory exercise—for example, one that is too

difficult for beginning veterinary students to perform-can enable students to carry out laboratory

exercises they otherwise would not have had (13).

Table 9-7 summarizes the advantages, disadvantages, and barriers to substituting computer models of biological systems for animals in education.

Some characteristics apply to one type of computer

application more than another. Viewed as a whole,

the descriptors of computer simulations listed in

table 9-7 illustrate the potential as well as the limiTable 9-7.—Advantages, Disadvantages, and

Barriers to Using Computer Simulations in Education

Advantages:

Quality of teaching material:

●

●

●

●

●

Simplification. Some biological events that are too

complicated or not accessible to human study by vivisection or dissection are better approached through computer simulation.

Quantitative ski//s. Physical mechanisms and mathematical variables that underlie biological events are emphasized.

Emphasis. Student attention is shifted from techniques

to concepts, supporting lecture and textbook material.

Reliability. Strong consistency from experiment to experiment.

Response time. Simulations yield immediate results.

Cost and efficiency:

● Long-range cost reduction. Following initial purchase

of computer hardware, computer laboratory costs are

often lower than relatively high animal laboratory costs.

● Speed and coordination. Increased teaching efficiency

through expeditious testing, drills, and tutorials.

. Laboratory availability. Increased access for students to

laboratories.

Disadvantages:

●

●

●

●

●

Bio/ogica/ complexity. Computers cannot be programmed

to simulate many integrative interactions between internal organs.

Missed experiences. In the view of some teachers, students should have experience with living tissue.

Bioogical variability. Computers do not accurately portray the large degree of uncertainty that arises from biological variability, whereas comparisons of animals do

present this concept.

Publication of results. Developers of computer simulations sometimes find publication of their work in the

usual scientific journals difficult since some simulations

require ponderous documentation; in cases where publications are intrinsic to tenure and other faculty decisions, computer modelers may be discriminated against,

Student attitudes. In some cases, dubious student outlook on computer replacement of animals undermines

teaching of concepts. In other cases, simulations may

unintentionally train students (e.g., medical students) to

ignore the behavior and appearance of patients and to

place unwarranted importance on data from instruments.

Barriers:

●

●

●

●

Incompatibility. Hardware components and software systems often are not interchangeable; this is especially

true of graphic simulations.

Computer /imitations. Some complex digital computer

programs are not fully realistic because they must approximate biological processes that are continuous and

simultaneous by using a series of discrete steps. The

only way to make such a computer approximation more

realistic is to reduce the time the computer takes between steps. This may require more sophisticated

hardware.

Tradition. Widespread lack of training in mathematics

modeling leads many talented people to write textbooks

rather than computer models.

Proprietary considerations. Many of those who are developing programs or catalogs of programs for commercial purposes will only disseminate useful information

about computer simulations if they are paid, restricting

applications.

SOURCE: Office of Technology Assessment
Ch. 9—Animal Use in Education and the Alternatives ● 213

tations of this alternative in a variety of teaching

situations. Several of the disadvantages listed in

table 9-7 underscore the small likelihood that computers can completely replace animals in the classroom. Those who are developing computer simulations are among the most vocal in maintaining

that this technique is not the optimal method in

every teaching situation; in some cases, they say,

animals serve the lesson better (8,13,15,26).

In addition to providing models of biological experiments, computer programs serve in the classroom and laboratory as reusable training devices

to teach specific skills, just as airline pilots train

in flight simulators. These simulations are based

on graphic presentation of the experiments and

involve interaction between the program and trainee.

An interactive videodisk program, for example,

enables students to simulate dissections using photographic images stored on the disks, rather than

animals. Production of such a videodisk can cost

from $60,000 to $200,000 for a 30-minute program

and involves thousands of still photographs, computer overlay, and touch screen interaction. The

sales price of such a videodisk can range from

$1,000 to $5,000.

The most sophisticated types of videodisk programs have not achieved widespread use, largely

because of economic factors. Apart from steep initial production costs, the hardware supporting

videodisk use is expensive.

Computer-linked mannequins and robots currently provide the most sophisticated simulations.

Resusci-Dog, developed at the New York State College of Veterinary Medicine at Cornell University

in Ithaca, NY, is a canine cardiopulmonary resuscitation training mannequin, the equivalent of the

human dummies used in training paramedical technicians. Constructed of plastic, Resusci-Dog can

simulate a femoral artery pulse, and pressure can

be applied to its rib cage for cardiac massage or

cardiopulmonary resuscitation. The first microprocessor-laden canine simulator cost $7,000; the

second $700. Resusci-Dog has replaced about 100

dogs per year in veterinary classes at the New York

school (19).

Despite the widespread enthusiasm for the potential of computer models and interactive simulations in the life sciences, three general problems

Scenes From Interactive Videodisk Laboratory Exercise

—Canine Hemorrhagic Shock

Photo credits: Charles E. Branch and Gregg Greanoff, Auburn University

These photographs were taken from the monitor screen

of a video program on blood flow and hemorrhagic shock

in use at the Auburn University School of Veterinary

Medicine. The interactive video simulated experiment

depicts actual experiments conducted by experts.

Several treatments are videotaped and students then

simulate performing the experiment, testing different

treatments and dealing with the results as if they were

actually performing the study. Top: Anesthetized dog

in experimental setup. Bottom: Response of

dog’s pupil to light.

confront computer-based education in the mid1980s (7,8):

● The rapid advance of computer technology

has resulted in many–frequently incompatible—machines in competition for the same

market. This has limited the transportability

of existing computer-based education materials. Users of different systems cannot eas-
214 . Alternatives to Animal Use in Research, Testing, and Education

Canine Cardiopulmonary Resuscitation Simuiator

(Resusci-Dog) in Use

Photo credit: Charles R. Short, New York State College of Veterinary Meidiine,

Cornell University

ily share or exchange materials. As a result,

there is a serious problem of duplication of

effort, with individuals and institutions devel-

●

●

oping similar teaching programs. Although

ideas are clearly portable, actual computer

programs may not be, and the avenues for

effective dissemination of programs remain

limited.

The resources available to support research

and development in computer-based education are too limited. Few institutions have committed funds for such activity, and much current work is supported by departmental or

individual resources. Many new computerbased education materials are developed by

individuals on their own time out of personal

interest. There is virtually no external funding available to support advances in this field.

In the long run, the most serious problem may

well be the lack of professional academic rewards for faculty members working in this

area. Promotion, tenure, and salary increments

are awarded predominantly for productivity

in the research laboratory, not for efforts to

develop innovative teaching techniques and

materials, with essentially no external grant

support for computer-based education activities and with few refereed high-quality journals in which to publish, two of the measures

by which rewards are apportioned are not

available to developers of novel educational

soft ware. This is a particular problem for junior faculty members, who often must devote

their major efforts to climbing the academic

ladder. Computer-based education seemingly

fails to meet the perception of an academically valid and creditable enterprise.

SUMMARY AND CONCLUSIONS

In elementary school, student exposure to ani- Taken together, the approximately 53,000 animals in the classroom generally takes the form of reals used in accredited medical and veterinary

exercises in humane awareness. Later, involve- schools for education and training make up less

ment in science becomes more active and the role than one-half of 1 percent of the estimated 17 milof the animal as a tool of science is explored. As lion to 22 million animals used annually in the

students advance to and through college, animal United States for research, testing, and education.

use often becomes more invasive during instruc- (No data are available on the number of animals

tion in laboratory techniques. At the highest levels, used in primary, secondary, and college educaespecially in professional and research training, tion.) Yet the development of students’ attitudes

students are expected to attain levels of skill that toward animals during the classroom years overmay be difficult to reach without the use of animals. shadows in importance the actual quantity of ani-
—

Ch. 9—Animal Use in Education and the Alternatives . 215

mal subjects used in education. Each phase of primary and secondary education appears to offer

an opportunity for shaping students’ attitudes

toward animals. Grades 8 through 11 seem to be

the most appropriate times for influencing the development of attitudes toward animals.

Alternatives applicable to different levels of

schooling vary with the educational goals of each

level. whereas classroom demonstrations or noninvasive observation could be appropriate in primary and secondary education to teach the scientific method and aspects of biology, a nonliving

system is inadequate to teach surgical technique

and manual dexterity to medical and veterinary

students. Computer models of biological phenomena and interactive simulations of biological experiments are especially promising alternatives to

animal use, even in sophisticated laboratory physiology exercises. Interactive videodisk programs—

although expensive and not currently widely available-offer particularly realistic training simulations.

CHAPTER 9 REFERENCES

1. American Veterinary Medical Association, Your Ca -

reer in Animal Technology (Washington, DC: January 1981).

2. Association of American Medical Colleges, Use of

Animals in Undergraduate and Graduate Medical

Education (Washington, DC: 1985).

3. Coleman, T. G., and Randall, J. E., “HUMAN: A Comprehensive Physiological Model,” Physiologist 26:

15-21, 1983.

4. International Science and Engineering Fair, Rules

of the 35th International Science and Engineering

Fair (Washington, DC: Science Service, Inc., 1984).

5. Katz, S., Hollingsworth, R. G., Blackburn, J. G., et

al., “Computer Simulation in the Physiolo~ Student Laboratory,” Physiologist 21:41-44, 1978.

6. Kellert, S. R., “Attitudes Toward Animals: AgeRelated Development Among Children, ’’.J. Environ.

Educ. 16:29-39, 1985.

7. Michael, J. A., “Computer-Simulated Physiology

Experiments: Where Are We Coming From and

Where Might We Go?” Physiologist 27:434-436,

1984.

8. Michael, J. A., Associate Professor, Department of

Physiology, Rush-Presbyterian-St. Luke’s Medical

Center, Chicago, IL, personal communication, Mar.

4, 1985.

9. Nardone, R. M., Director, Center for Advanced

Training in Cell and Molecular Biology, Department

of Biology, Catholic University of America, Washington, DC, personal communication, Sept. 4, 1985.

10. National Science Teachers Association, Code of

Practice on Animals in Schools (Washington, DC:

1981).

11. Oelsner, G., Boeckx, W., Verhoeven, H., et al., “The

Effect of Training in Microsurgery, ’’Am. .J. Obstet.

Gynecoi. 152:1054-1058, 1985.

12. Packer, J. S., and Packer, J. E., “A Teaching Aid for

Physiologists—Simulation of Kidney Foundation, ”

The Physiology Teacher 6:15, 1977.

13. Peterson, N. S., Professor, Department of Veterinary and Comparative Anatomy, Pharmacology,

and Physiology, College of Veterinary Medicine,

Washington State University, Pullman, WA, personal communication, Aug. 23, 1985.

14. Progress Without Pain (Lord Dowding Fund, National Anti-Vivisection Society, Ltd., London), “Development of a Dynamic Model Using the Human

Placenta for Microvascular Research and Practice,”

23:6-10, 1985.

15. Randall, J. E., Professor, Medical Sciences Program,

Indiana University School of Medicine, Bloomington, IN, personal communication, Apr. 25, 1984.

16. Rothe, C. F., “A Computer Model of the Cardiovascular System for Effective Learning, ” Physiologist

22:29-33, 1979.

17. Rowan, A. N., Of Mice, Models, & Men: A Critical

Evaluation of Animal Research (Albany, NY: State

University of New York Press, 1984).

18. Scientists Center for Animal Welfare (Bethesda,

MD), “Co]lege Courses on Ethics and AnimaIs, ”

Newsletter 5(2):3-6, 1983.

19. Short, C. E., Chief, Department of Anesthesiology,

New York State College of Veterinary Medicine,

Cornell University, Ithaca, NY, personal communication, March 1984.

20. Swindle, M. M., “Swine as Replacements for Dogs

in the Surgical Teaching and Research Laboratory,”

Lab. Anim. Sci. 34:383-385, 1984.

21. Tarp, J., “Toward Scientific Literacy for All Our

Students,” The Science Teacher 45:38-39, 1978.

22. U.K. Home Office, Scientific Procedures on Living

Animals, Command 9521 (London: Her Majesty’s

Stationery Office, 1985).

23. U.S. Department of Health and Human Services,
216 “ Alternatives to Animal Use in Research, Testing, and Education

Public Health Service, National Institutes of Health, 25. Walker, J. R., “Computer Simulation of Animal SysNational Survey of Labora tory AnimalFacilities and terns in the Medical School Laboratory,” A]terna -

Resources, NIH Pub. No. 80-2091 (Bethesda, MD, tives to Laboratory Animals (U. K.) 11:47-54, 1983.

1980). 26. Walker, J. R., Assistant Director, Integrated Func24, Veale, J. L., “Microcomputer Program for Teach- tional Laboratory, University of Texas Medical

ing pH Regulation and COZ Transport, ” Fed. Proc. Branch at Galveston, TX, personal communication,

43:1103, 1984. Feb. 22, 1984.
Chapter 10

Information Resources and

Computer Systems

One of the biggest harriers to using available information is that most people do not know

how to use existing resources or what systems are available for use.

John S. Wassom

Oak Ridge National Laboratory

March 1985

The best computer programs evolve into large creations. It is rare !v possible to imagine a

very large computer activity at the outset and build it as such.

Charles S. Tidball

The George Washington University Medical Center

March 4, 1985
CONTENTS

P+!@

Sources of Research and Testing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .219

Primary Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . .219

Secondary Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . . ~ ..219

Unpublished Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........219

Information Centers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..220

The Availability of Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......221

Journal Publication Policies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...221

Federal Laws Affecting Unpublished Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ ...221

Barriers to Using Available Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..222

Data Quality and Comparability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...222

International Barriers to Sharing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..223

Retrieving Research and Testing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......223

Abstracting and Citation Services ~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........223

Retrieving Unpublished Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...224

Computer Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........228

Advantages of Computers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .228

Toxicology Data Bank . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............229

Registry of Toxic Effects of Chemical Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,229

On-Line Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .231

Laboratory Animal Data Bank . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . . . . . . . . . . . . . . . . . . . . ..233

Building Phase, 1975-80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................233

Public Accessibility, 1980-81 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... ..235

Reasons for the Failure of LADB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............235

Lessons Learned From LADB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...236

Expanding the LADB Concept: A Computerized Registry of

Research and Testing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . .................237

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............238

Chapter 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . . . . .239

List of Tables

Table No. Page

1()-1 Growth and Publication Frequency of Literature Related to Genetic

Toxicology, Carcinogenicity, Mutagenicity’, and Teratogenicity . . . . . . . . .220

10-2. Examples of Databases Available for Searches of Literature

Involving Animal Research and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .230

10-3. Examples of On-line Databases of the National Library of Medicine. . . . . ..231

List of Figures

Figure No. Pag e

10-1. A Scientific Abstract and Corresponding Index Entry in BIOSIS . ................225

IO-2. Sample Bibliographic Entries in Biological Abstracs/RRM . . . . . . . . . . . . . . . . . . . . ..226

10-3. Promotional Material From Commercial Supplier of Full Texts

of’ Scientific Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .227

10-4. A Typical Substance Entry in the Registry of Toxic Effects of

Chemical Substances (RTECS) . . . . . . . . . . . . . . . . . . . . . ~ . . . . . . . . . . . . . . . . . . . . .. ..232

10-5. A Representative Page of the Eight-Page Data Input Form for the

Laboratory Animal Data Bank . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..234
Chapter 10

Information Resources and

Computer Systems

Earlier chapters have described the quantity and creases information exchange reduces the need

variety of data generated by using animals in re- of other investigators to perform the same expersearch, testing, and education. To assess fully the iments. The pivotal role computers can play in that

alternatives to animal use in these areas, there- process has recently become an important topic

fore, it is important to consider how the data are for consideration and is examined in this chapter.

shared once they are generated. Anything that inSOURCES OF RESEARCH AND TESTING DATA

Primary Literature

One of the most important ways to make data

publicly available is through the “primary literature” in which they are published for the first time

and in greatest detail. A significant form of this

is the scientific journal, the most up-to-date and

ubiquitous of the published sources available. Journal articles that are reviewed by knowledgeable

peers before they are accepted for publication are

considered especially reliable. Most normally contain a description of the methodology of the experiment, the results obtained, the conclusions

drawn by the author or authors, and references

to and discussions of related published and unpublished information.

Other primary sources are published reports

(e.g., of Government-sponsored research), proceedings of technical meetings, or similar collections

of articles. As a rule, reports and proceedings are

not as widely available as journal articles. They

may or may not have been peer-reviewed,

Secondary Literature

Secondary sources contain information drawn

solely from other published material. The most

common forms are books, reviews, and reports.

(A book that contains original material would not

be considered a secondary source.) Handbooks are

a useful secondary source for numerical data and

for citations to the primary literature in which they

were first published. Because secondary sources

draw from primary sources, the information they

report can be somewhat dated, as there is a timelag ranging from months to years between the publication of a primary source and that of any secondary sources that rely on it.

Many reviews and reports are prepared to meet

the specific needs of various organizations. Government agencies, such as the Food and Drug

Administration and the Environmental Protection

Agency (EPA), prepare reports to support regulatory activities. Research institutions, such as the

National Institutes of Health and the Chemical

Industry Institute of Toxicology (CIIT), prepare

reports to announce the results of a particular

study. Other organizations, such as the Chemical

Manufacturers Association and the World Health

Organization, prepare reports to further their

programs.

Unpublished Information

Unpublished information about recent, planned,

and ongoing research and testing can be of even

greater interest than older, published information.

The timelag between submission or acceptance

of data for publication and their actual publication is often a handicap to those waiting to learn

of experimental results. Time lost while waiting

to obtain another investigator’s published research

results can cost a laboratory its claim to priority

in obtaining research results. In testing, proprietary interests create pressure to obtain information as quickly as possible,

One of the oldest sources of unpublished information is networking-that is, the use of personal

219
220 ● Alternatives to Animal Use in Research, Testing, and Education

contacts. Networking is affected by the economic

factors discussed in chapter 11, such as the proprietary value of testing data and the incentives

to make it public. Membership in scientific and

professional societies and attendance at professional meetings facilitates this form of information exchange. Recent test results are often presented at meetings of professional societies, and

valuable information about work in progress is

exchanged by participants.

Unpublished data may not be written in report

form, which makes it difficult to share the information. Although the data are stored in some kind

of organized fashion, the way one person organizes

information may not be useful to someone else.

Thus, even if it is possible to determine that unpublished useful research or testing data do exist,

it is often difficult to share them.

In addition to unpublished material, a separate

category of information that is fairly inaccessible

includes many Government reports, research institute reports, and obscure journals. This information falls into a grey area—’’published” in a literal

sense, but not in a practical one.

Information Centers

Because of the large volume of published and

unpublished information that is generated, special services called “information centers” have been

set up to collect, organize, and disseminate it. An

information center, to be comprehensive, must

have a fairly narrow scope. These centers are a

good vehicle for sharing unpublished information,

although they do not have the resources to seek

it out.

The most well known information center with

holdings of research and testing data is the International Agency for Research on Cancer, in Lyons,

France. The United Nations maintains several collections of published and unpublished data on

chemicals potentially of international interest, e.g.,

through the International Program on Chemical

Safety and the International Registry for Potentially Toxic Chemicals in Geneva, Switzerland.

These agencies have a much broader scope than

a typical information center, although they carry

out many of the same functions. The Oak Ridge

National Laboratory in Oak Ridge, TN, has individual information centers for environmental carcinogens, teratogens, and mutagens. Statistics on

the volume and rate of growth of publications in

the areas for which Oak Ridge has holdings are

given in table 10-1.

Table 10.1 .—Growth and Publication Frequency of Literature Reiated to

Genetic Toxicology, Carcinogenicity, and Teratogenicity

Papers Publication sources

published Increase in papers providing

Subject per yeara

published per yearbinformation

Genetic toxicology. . . . . . . . . . . . . 4,000-5,000 200-300 3,400

In vivo animal carcinogenicity

studies . . . . . . . . . . . . . . . . . . . . . 1,500-2,000 50-100 1,000

In vitro cell transformation

studies . . . . . . . . . . . . . . . . . . . . . 400-500 25-50 500

Teratogenicity. . . . . . . . . . . . . . . . . 2,000-2,800 100-150 3,500

aFi9ureS Would & substantially greater if augmented with unpublished or Inaccessible published materiai.

bNumbers shown are projected increases based on trends cataloged from the literature fOr the period 1979-M.

clncludes journais, books, symposium proceedings, 90VWr7mt3nt reports, and abstracts.

SOURCE:J.S. Wassom, Director, Environmental Mutagen, Carcinogen, and Teratogen Information Program, Oak Ridge National Laboratory, Oak Ridge, TN, personal communication, November 1985.
Ch. 10—information Resources and Computer Systems Ž 221

THE AVAILABILITY

One of the most important incentives to publish, both for people and for organizations, is to

establish a professional reputation. Although “publish or perish” is an enduring part of academic tradition, in nonacademic research and testing sectors there is often little incentive to publish. As

a rule, industry is more concerned with the protection of proprietary information and the conservation of financial resources than with publishing.

Federal organizations are likewise more interested in carrying out missions required by law than

in the publication of research and testing data (unless that is their mission). As a result, many agencies’ reports are never sent to the National Technical Information Service (NTIS) for distribution

and cataloging, or too little time is spent indexing

them in a fashion that facilitates easy retrieval of

the information.

Journal publication Policies

Because of the importance of journals as a source

of testing data, their publication policies are crucial to the effective exchange of information. Some

journal policies (e.g., the limitations on the length

of an article and the amount of detail it contains)

are related to high printing and distribution costs.

others, such as an unwillingness to publish results

that have already been disclosed publicly, are a

result of the stiff competition that exists among

journals.

One of the most frustrating publication policies

from the standpoint of avoiding duplicative research and testing is that most journals (and therefore secondary sources) rarely publish negative

results. It is natural that people would be more

interested in knowing, for example, which chemicals have been found to be hazardous than which

chemicals have not. As a consequence, a certain

number of experimental protocols are repeated

because the negative results of earlier experiments

were not published. This policy is not likely to

change without dramatic alterations in the stance

of journal publishers, the policies of professional

societies, and, indeed, the tradition of scholarly

publication in academia. One notable exception

OF INFORMATION

to this is the journal Mutation Research, which in

1977 made it a policy to also publish negative

results.

Federal Laws Affecting

Unpublished Data

one method available to the Federal Government

for collecting testing data is to require them, either through registration requirements such as

those under the Federal Insecticide, Fungicide, and

Rodenticide Act (Public Law 92-516, as amended

by Public Laws 94-140 and 95-396), or through

reporting rules such as those promulgated under

the Toxic Substances Control Act (TSCA) (Public

Law 94-469). Section 8(d) of TSCA requires manufacturers and processors to submit citations or copies of health and safety studies they have sponsored, or about which they are aware, for specified

chemicals. As of June 1984, EPA had received over

6,000 such submissions, about half of which were

health-effects studies. For the specified chemicals,

when regulatory notices were published in the Federal Register, about one-quarter of the citations

were to data received under Section 8(d) (10).

Some unpublished data are given to Government

agencies voluntarily, either through personal contacts or in response to publicity that the government is working on a particular problem. Much

of the data concern adverse effects, but some concern negative results as well.

Unlike most countries, the United States has a

policy of making information held by the Government as available as possible, consistent with

protecting its proprietary value. Key laws in

implementing this policy are the Administrative

Procedures Act (Public Law 79-404, as amended

by Public Law 89-554), which encompasses the

Freedom of Information Act (Public Law 90-23,

as amended by Public Laws 93-502, 94-409, and

95-454). This act makes all information held by the

executive branch of the Federal Government available to anyone who asks for it, unless the information is specifically exempted or is protected

under another law. The person requesting the information is frequently required to pay search and

duplication costs, but the burden is on the Government to show why information should be withheld.
222 ● Alternatives to Animal Use in Research, Testing, and Education

Under these laws, the public also has access to

collections of published and unpublished nonproprietary data gathered to support administrative

actions such as rulemaking. This ‘(public docket”

contains all reports, literature, memos, letters, and

other information considered in taking the action.

Once information has been obtained by the Federal Government, it may be shared within and

among Government agencies. Often such sharing

is very informal, and with informality comes unpredictability and oversights. Various committees

have been set up to facilitate intragovernmental

networking, such as the Interagency Regulatory

Liaison Group of the late 1970s, the Interagency

Risk Management Council, and the Interagency

Toxic Substances Data Committee. These efforts

increase the amount of information available to

solve particular problems. They also reduce duplicative information requests made of industry.

In 1980, an interagency Toxic Substances Strategy Committee examined the sharing of information, focusing principally on the data held by Federal agencies (20). The Committee noted there were

then more than 200 independent data systems,

mostly incompatible. Barriers to sharing information included diverse methods of identifying chemicals and differing reliability and review of the databases. The Committee noted that coordination of

Federal agencies’ chemical data systems could reduce duplication of information gathering, minimize delay, and, to some extent, decrease uncertainties in decisionmaking. The benefits of such

coordination would likely extend beyond the Federal Government to State and local governments,

industry, labor, public interest groups, academic

institutions, international organizations, and foreign governments.

BARRIERS TO USING AVAILABLE INFORMATION

Data Quality and Comparability

Before data are to be used, the user must be confident of their quality. This judgment is based on

a variety of facts and inferences. People will frequently take into account the professional reputation of the investigator or the investigator’s industrial, academic, or professional affiliation or

organization. If the person has no reputation, good

or bad, many scientists will not rely on that investigator’s data. This phenomenon is most acute with

investigations carried out in foreign countries and

published overseas (14). Further, many scientists

will not (and perhaps should not) trust results that

have not been peer-reviewed. Lastly, some organizations tend not to trust any data that they have

not generated.

It is important to assess the quality of data. Thus,

even though numerical databases are convenient

because they contain data in summary form, often

there is no way to determine from the information contained there how reliable the data are (unless they were peer-reviewed before being put into

the system). This problem has been addressed by

the National Bureau of Standards (NBS), the Chemical Manufacturers’ Association, and others, A

workshop held in 1982 (16) recommended that

computerized databases (discussed at length later

in this chapter) include the following “data quality indicators” that would allow the user to determine reliability for specific needs:

● the method(s) used to obtain the data,

● the extent to which the data have been evaluated,

● the source of the data, and

● some indication of the accuracy of the data.

An important part of evaluating data is comparing them with data obtained using similar methods—that is, validating the data. In deciding, for

example, to rely on a particular test protocol, it

is necessary to be confident not only that the test

is a useful model of the effect of interest, but also

that the results can be trusted, even though they

are unexpected. For many investigators, validation involves repeating at least a portion of an experimental protocol in their own laboratories.

They might also compare the results with those

generated by other procedures with which they

are more familiar.
Ch. 10—information Resources and Computer Systems . 223

International Barriers to

Sharing Information

Animal research and testing is conducted in

many countries (as described in ch. 16). The importance of communicating scientific information

among nations has been recognized in the United

Nations, in the Organization for Economic Cooperation and Development (OECD), and in regional

and bilateral forums. Although much has been

done to facilitate this, many barriers must still be

overcome.

International communications cost more and

take longer than domestic communications. Moreover, there are fewer international personal acquaintances on whom to rely for information than

there are on a national level. Communication problems are exacerbated by institutional differences.

It is difficult for industry-to-industry communications to occur, for example, when one industry

is privately owned and another is governmentowned, because governments typically deal

through diplomatic channels.

Political animosities hinder information exchange. Defense-related information is affected

the most, but all information sharing must suffer

in such a climate. Even political differences cause

problems in sharing information. It is difficult for

agencies within the U.S. Government to obtain information from governments that have close working relationships with their industries, such as Japan, particularly when any information received

would be subject to Freedom of Information Act

requests in the United States.

Language differences are a large problem, both

in the use of written materials and in personal communications. Translation and interpreting are expensive, particularly in the United States, where

the number of people who speak more than one

language has been decreasing. English translation

costs for the four principal languages of science

(French, German, Russian, and Japanese) range

from $40 to $88 Per thousand words. An estimated

$4 billion to $5 billion would be required to translate the current foreign-language holdings of the

National Library of Medicine (NLM), for example,

with an ongoing yearly translation cost of $150

million (9). Duplicative translations are avoided

through the clearinghouse effort of the John

Crerar Library in Chicago, IL. Translations donated

by a variety of sources on a broad spectrum of

topics are made available to others.

Common protocols can also facilitate the international exchange of, for example, testing data.

OECD members decided in 1981 that health-effects

data generated according to OECD test guidelines

should be mutuallv acceptable in all member countries, regardless of where the testing was done (see

app. A) (17). Although this decision has not been

fully implemented, OECD test guidelines are readily

available and are receiving considerable use.

RETRIEVING RESEARCH AND TESTING DATA

The ways data are obtained and the amount

sought are functions of the resources available for

searching, how the data are to be used, the likelihood that the information exists at all, and how

reliable the information is likely to be. Many methods for finding information are available, and most

of them overlap to some extent.

Abstracting and Citation Services

In research and testing, several hundred thousand scientific articles in thousands of journals are

published each year in the primary literature (6).

Abstracting and indexing services and bibliographic services play a vital role in making these

accessible to those who need them. (An index based

on references cited, or citations, permits the user

to follow the literature into the future to locate

pertinent articles. For example, a user with a 1981

article in hand who is seeking related, more recent publications can consult a citation index to

identify 1985 publications that referenced the 1981

article.) Because animals are used for a variety of

research purposes (see chs. 5 and 6), however, and

because testing is interdisciplinary (see chs. 7 and

8), information may be indexed in the fields of

chemistry, biology, pharmacology, medicine, and

so on.
224 ● Alternatives to Animal Use in Research, Testing, and Education

Abstracting and indexing services and bibliographic services have existed since the 17th century and have grown in number and size as published literature has expanded. The first major

services for scientific information were published

by professional societies (e.g., Chemical Abstracts).

Some were sponsored by the Federal Government

(e.g., Air Pollution Abstracts and AGRICOLA) or

by commercial enterprises (e.g., Current Contents

and Environmental Abstracts) (8). Some, such as

the Chemical Information System, originated in

Government and were later converted into commercial enterprises (12).

The largest abstracting and indexing service for

biological and biomedical research is BIOSIS, the

Biosciences Information Service. In 1985, its coverage extended to 440,000 items from over 9)

000

sources worldwide. The file accumulated to date

contains over 6 million items, the largest biological file in the English language. Items covered include abstracts and citations for journal articles

and other serial publications, and citations to

reports, reviews, and scientific meetings (6).

A typical abstract of a journal article and an illustration of how it is indexed by BIOSIS appear

in figure 10-1. Information like this is contained

in the semimonthly publication Biological Abstracts. Another publication, Biological Abstracts/

RRM, contains bibliographic entries for research

reports, reviews, meetings, and books (see fig.lo2). BIOSIS also offers several computer-based services that provide citations tailored to the customer’s information needs. All of these resources are

regularly used by scientists. As the figures illustrate, however, it is often difficult to tell from a

title, or even from an abstract, whether a particular article would satisfy a reader’s needs.

Once a citation has been obtained, it is easy to

acquire the full text of a research report. Most

libraries have the necessary services available, or

the inquirer can write to the author and ask for

a reprint. In addition, some commercial vendors

offer to supply by mail the full text of virtually

any article (see fig. 10-3).

A recent comparison of databases for literature

on 10 pesticides illustrates the problem of overlap (15). Eight databases had to be searched in order to get 90 percent of all data relevant to a particular regulatory decision. The share of citations

produced by these databases that were not relevant ranged from 11 to 27 percent. Used together,

the four most consistently relevant databases—

TOXLINE, CAB Abstracts, BIOSIS, and Chemical

Abstracts—produced 25 to 91 percent of all relevant citations, with an average of 69 percent.

These statistics illustrate the fragmentation that

may accompany a literature search. Although the

number of databases that need to be searched may

be small for some fields, questions of an interdisciplinary nature require substantial resources for

a complete literature search.

Retrieving Unpublished Information

Citation services are available for some unpublished data and testing in progress. Federal databases and publications include the Bioassay Status

Report and Tox-Tips of the National Toxicology

Program (NTP), the EPA Chemical Activity Status

Report, the Current Research Database of the National Institute for Occupational Safety and Health,

NTIS’s Federal Research in Progress, and the Smithsonian Science Information Exchange (no longer

active). There are also many small databases used

to keep track of specialized data, such as information used in the implementation of a specific law.

Similar citation services to unpublished data or

ongoing testing exist on an international level. The

International Agency for Research on Cancer,

which has substantial U.S. support, coordinates

the sharing of information about current carcinogenicity testing in laboratories around the world

and publishes an information bulletin, Survey of

Chemicals Being Tested for Carcinogenic Activity.

The International Program on Chemical Safety of

the United Nations Environment Program (UNEP)

is establishing a database for Chemicals Currently

Being Tested for Toxicological Effects. This database is designed for long-term or otherwise expensive studies other than those on carcinogenicity.

Participants in both programs include governments, industry, academia, and research institutes.

In addition, Infoterra, a service of UNEP, publishes

a directory through which experts in numerous

subject areas can be located. Assistance is also provided by national representatives. The U.N.’s International Registry of Potentially Toxic Chemi-
Ch. 10—information Resources and Computer Systems ● 225

Figure IO-l.—A Scientific Abstract and Corresponding Index Entry in BIOSIS

ABSTRACT FORMAT

TOXICOLOGY- Major Headlng

ENVIRONMENTAL AND INDUSTRIAL ~ Subheadlng

Authors

/ \

Author

Roforsnco Address

Number ~ 23330. CARSONS, JOANNE N and JOHN O. GOULDEN (Arch=

Oceanogr. Inst., Phila., Pa. 19103, USA.) The effects of chlorine Article

pollutlon on growth and respiration rates of larval lobsters ~ Titl e

(Homarus americanus). BIOL RES 11(12): 1433-1438. 1985. The -

length, dry weight and standard respiration rate of Iarval lobsters

(H. americanus) were measured following 20 days Immersion In

coastal waters surrounding a power plant. Significantly lower

increases in dry weight (P<. 05) and significant reductions in standard respiration rates (P<. 01) were measured in exposed

organisms when compared to control organisms. Water samples

taken from the immersion site contained high concentrations of

free Cl.

BIOSIS’ INDEXING SYSTEM

AUTHOR INDEX (Personal or Corporate Names)

Author Index NAME REF. NO. NAME REF. NO.

CARSONS J N 23330+ ELL A W 26787

(Personal or Corporate Names) CASEY N 29606 FINEMAN C 26884

DAVIES R 24001 GOULDEN J O 23330

BIOSYSTEMATIC INDEX (Taxonomic Categories)

Biosystematic index ARTHROPODA. . . . . . . . . . . . . . HIGHER TAXONOMIC CATEGORY

Crustacea. . . . . . . . . . . . . . . . . .

. Malacostraca. . . . . . . . . . . . . I

LOWER TAXONOMIC CATEGORIES

(Broad Taxonomic Categories) Environmental and Industrial Toxicology. . . . . . . . . . . . . . MAJOR CONCEPT

23330 23572 25352 . . . . . . . . . . . . . REFERENCE NUMBERS

GENERIC INDEX (Genus-species Names)

Generic index GENUS-SPECIES MAJOR CONCEPT REF. NO.

(Genus-species Names) HOMARUS-AMERICANUS TOXIC INDUS 23330

WILDLIFE AQU 24063

MICROCERUS- BERONI CRUSTAC SYST 19145’s

SUBJECT INDEX (Specific Words)

Alphabetic POSITION

Subject index SUBJECT CONTEXT KEYWORD REF. NO.

GHT/ THE EFFECTS OF CHLORINE POLLUTION ON GROWTH 23330

(Specific Words) TOBACTER/ EFFECT OF SUBSTITUTION ON THE 26575

LORINE POLLUTION ON GROWTH AND RESPIRATION RATES 2333 0

GERMINATION RADICAL BARRIER TEMPERATURE 27304

SOURCE: The 1985 8/0S/S Information Catalog (Philadelphia, PA’ Biosciences Information Service, 19S5).
226 Ž Altematives to Anirnal Use in Research, Testing, and Education

Figure 10=2. -Sampie Bibliographic Entries in Blological Abstracts/RRM

EXAMPLES OF BIBLIOGRAPHIC ENTRIES IN BA/RRM:

CONTENT SUMMARY FORMAT

SOURCE: The 1985 EUOS/S Information Catalog (Philadelphia, PA: Biosciences Information Service, 1985).
Ch. 10—information Resources and Computer Systems • 227

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228 . Alternatives to Animal Use in Research, Testing, and Education

cals sometimes refers information requests among per month would be referred to some combinamember countries through its national corre- tion of government agencies, industry, academia,

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.

lished data relevant to the request, The mecha- A recent U.S.-led project of the OECD, generally nisms for referring&quests on the national level referred to as “Switchboard,” has also addressed

the problems of obtaining information from other and the enlistment of various organizations, either

as requesters or responders, is the responsibility countries. Unpublished information may be requested through the Switchboard system for use of Switchboard’s national focal point. This project

in risk assessments or to otherwise protect health

and the environment. A pilot system is to be run

in which two requests per participating country

will begin on a small scale and will be monitored.

If appropriate, it could be expanded (18).

COMPUTER

Computers have two applications as an alternative to using animals in research, testing, and education. First, they can be used to model or simulate biological, chemical, and physical systems. In

this way, a computer could be used as a direct

replacement for some number of animals used in

laboratories. This form of computer use is discussed in chapters 6,8, and 9. Second, computers

are used to disseminate information that has been

generated from prior use of animals in research

and testing, thus avoiding the needless repetition

of a procedure by other scientists. It is this role

of computers as information disseminators that

is discussed in the rest of this chapter.

Advantages of Computers

Biological testing (see ch. 7) can be described as

the repetitive use of a standard biological test situation, or protocol, employing different chemicals

or different test parameters (e.g., species or biological end points). Because the protocols in testing are more stereotyped and less varied than those

in research, biological testing is more amenable

than research to the institution of a computerized

data retrieval system. In fact, testing emerged in

the 1970s as the first discipline in which such a

system was developed.

If a comprehensive, computerized registry of biological research or testing data were established,

certain benefits might accrue. These benefits are

predicated on the inclusion in the computerized

registry of both control and experimental data,

and of both positive and negative results. (Data

SYSTEMS

obtained from testing fall into two broad categories: those derived from untreated (control) subjects, and those from treated (experimental) subjects. Data obtained from treated subjects may

either show an effect from the treatment (“positive results”) or no effect (’(negative results’’).) Furthermore, the advantages of such a registry depend on the acceptance by working scientists of

the data contained in it—acceptance that seems

possible only with the imprimatur of peer review

of the data. The anticipated benefits of a computerbased registry of research or testing data include:

●

●

Decreased Use of Animals in Research or

Testing. In some instances, an investigator

would locate the exact data desired, possibly

from a previously unpublished source, thus

avoiding unintentional duplication of animal

research or testing. Baseline data could permit the selection of a dose, a route of administration, or a strain of animal without the need

for new animal experiments to establish these

factors. Efficiencies could also include the use

of fewer doses on smaller numbers of animals.

Conceivably, the number of animals required

for control groups could be reduced, although

many experimental protocols require the use

of concomitant control subjects, rather than

of data from a pool of control subjects, in order to achieve statistical significance.

A Check for Genetic Drift. Certain experimental results can change over a span of many

generations due to subtle, progressive changes

in the underlying genetic constitution of the

strain of animals ((’genetic drift”). The regis-
Ch. 10—information Resources and Computer Systems ● 229

●

try would provide baseline data within specified time frames of measurement, and make

it easy to check for the possibility of genetic

drift.

New Perspectives on Old Data. By performing statistical comparisons across data sets and

identifying relationships not already obvious,

unforeseen relations could be established

without animal experimentation.

The scientific community makes use of a number of computerized literature retrieval services

to obtain bibliographic citations and abstracts to

the published literature. Most abstracting and indexing services started as publications, but most

are now available on-line as well. Others, such as

AGRICOLA, are only available on-line.

Many handbooks and other numerical databases

are also available on-line. Several numerical databases are sponsored by the Federal Government.

The most comprehensive, the recently terminated

Laboratory Animal Data Bank, is reviewed in detail in the next section. Two current systems, the

Toxicology Data Bank and the Registry of Toxic

Effects of Chemical Substances, are discussed in

some detail here. Table 10-2 lists a number of databases available for searches of the research and

testing literature. Table 10-3 lists some widely used

databases of the NLM.

Toxicology Data Bank

The Toxicology Data Bank (TDB) was made public

by NLM in 1978. It is designed to address some

of the needs of the testing and regulatory communities for toxicity information. TDB is organized

by individual chemicals or substances, now totaling

more than 4,000. Its fixed format includes:

●

●

●

data on the production and use of each

chemical;

a description of the physical properties of each

chemical; and

the results of pharmacological and biochemical experiments, and information on toxicological testing.

TDB is based on conventional published sources

and does not include unpublished data. Thus, baseline data on control animals, which might be used

in place of a control group, could not be included

because so little has been published.

The most valuable feature of TDB is the fact that

all the data it contains are peer-reviewed. As a consequence, its data summaries are acceptable to

most users (5). (Another database containing only

peer-reviewed data is the Environmental Protec -

tion Agency’s Gene-Tox.)

Registry of Toxic Effects

Chemical Substances

o f

The Registry of Toxic Effects of Chemical Substances (RTECS) has been published annually since

1971 by the National Institute for Occupational

Safety and Health, under Section 20(a)(6) of the

Occupational Safety and Health Act of 1970 (Public Law 91-596). RTECS is a compendium, extracted

from the scientific literature, of known toxic and

biological effects of chemical substances. RTECS

does not evaluate the data it cites, leaving that

responsibility to the reader. An example of the information contained in a typical substance entry

in RTECS is given in figure 10-4.

By congressional mandate, those data that indicate a toxic effect of a chemical are to be included

in RTECS; those that show no toxicity are to be

excluded. Thus, RTECS does not include negative

results. Moreover, a chemical might not be included in the registry for a variety of reasons, including the following:

●

●

●

The test results could not be cited because

the protocol of the study did not meet the

RTECS selection criteria.

The substance has not yet been tested or the

results have not yet been published.

The substance has been tested and the results

published, but the information has not yet

been entered into the RTECS file.

The exclusion of negative results from RTECS and

its incompleteness for these other reasons may

lead to the repetition of toxicity testing of essentially nontoxic substances.

The production of RTECS costs approximately

$500,000 per year. The current quarterly update

includes a total of 68,000 compounds, and it continues to grow steadily toward the estimated 100,000

unique substances for which toxicity data may be

available. If RTECS were expanded to include all

results of whole-animal toxicity testing, including
230 . Alternatives to Animal Use in Research, Testing, and Education

Table 10.2.—Examples of Databases Avaiiabie for Searches of Literature Involving Animal Research and Testing

Database Description

First year

covered

AGRICOLA Worldwide journal and monograph literature on agriculture and related subjects; from 1970

the National Agricultural Library

AQUACULTURE

AQUALINE

ASFA (Aquatic Sciences

and Fisheries Abstracts)

BIOSIS Previews

CA Search

Comprehensive

Dissertation Abstracts

Conference Papers Index

CRIS (Current Research

Information System)

Enviroline

Environmental

Bibliography

Excerpta Medica

INSPEC

I PA (International

Pharmaceutical

Abstracts)

IRL Life Sciences

Collection

ISI/BIOMED

ISI/COMPUMATH

ISI/lSTP&B

LISA (Library Science

Abstracts)

Microcomputer Index

NIMH

Oceanic Abstracts

Pollution Abstracts

Population Bibliography

Psychological Abstracts

SCISEARCH

Growth requirements, engineering, and economics of marine, brackish, and freshwater

organisms; from National oceanic and Atmospheric Administration

Abstracts from world literature on water, waste water, and aquatic environments; from

Water Research Centre, Stevenage, U.K.

Life sciences of seas and inland waterways plus legal, political, and social implications of aquatic life; from UNESCO

International coverage of life science research; from Biological Abstracts

International coverage of chemical sciences; from Chemical Abstract Service

Author, title, and subject guide to nearly all American dissertations since 1861 and

many from foreign countries; abstracts added beginning in July 1981; from Xerox University Microfilms

Records of scientific and technical papers presented at major regional, national, and

international meetings each year; from Data Courier, Inc.

Research in agricultural sciences; from U.S. Department of Agriculture’s State Research

Service

International coverage of biology, chemistry, economics, geology, law, management,

planning, political science, and technology of environmental issues; from Environment

Information Center, Inc.

Atmospheric studies, energy, general human ecology, land resources, nutrition and

health, and water resources; from Environmental Studies Institute

Worldwide citations and abstracts from 3,500 biomedical journals; from Excerpta

Medica

Coverage of literature in computers, electrotechnology, and physics; from the American Institute of Electrical Engineers

Literature on drug development and use of drugs; from the American Society of Hospital Pharmacy

Worldwide coverage of life sciences including conferences; from Information Retrieval,

Ltd.

Index of 1,400 biomedical journals; from the Institute of Scientific Information

Covers literature in computer science, mathematics, statistics, operations research,

and related areas; from the Institute for Scientific Information

Computerized version of Scientific and Technical Proceedings and Books. Covers 3,000

proceedings and 1,500 books annually; from the Institute for Scientific Information

international coverage of library and information science literature; from Learned information, Ltd.

Subject and abstract guide to 21 microcomputer journals; form Microcomputer information Services

Mental health literature from 950 journals, symposia, government reports, and other

sources; from the National Institute of Mental Health

International literature on geology, governmental and legal aspects of marine resources,

marine biology, marine pollution, meteorology, and oceanography; from Data Courier,

Inc.

Literature on the sources and control of environmental pollution; from Data Courier, Inc.

international coverage of population research: abortion, demography, family planning,

fertility studies, and migration; from Carolina Population Center, University of North

Carolina

Worldwide coverage of literature in psychology and related social-behavioral literature; from the American Psychological Association

International literature of sciences and technology; from the institute for Scientific

Information

1970

1974

1978

1969

1967

1861

1973

1974

1971

1973

1974

1969

1970

1978

1979

1976

1978

1969

1981

1969

1964

1970

1966

1967

1974
Ch. 10—Information Resources and Computer Systems Ž 231

Table 10-2.—Examples of Databases Availablea for Searches of Literature

Involving Animal Research and Testing (Continued)

First year

Database Description covered

SOCIAL SCISEARCH Worldwide coverage of social and behavioral sciences literature; from the Institute 1972

for Scientific Information

TELEGEN Covers literature on biotechnology and genetic engineering in 7,000 sources includ- 1973

ing conference and symposia papers, government studies, periodicals, and the popular press; from Environment Information Center, Inc.

Zoological Record Covers zoological literature from 6,000 journals; from Biosciences Information Serv- 1978

ice and the Zoological Society of London

aThe~~ d~~aba~~~ are available bY tel~~h~n~ ~On”~Ctl~n to one or more of the following: Lockheed Information System DIALOG, SyStem Development Corp ‘S ORBIT,

and Bibliographic Retrieval Service, Inc.

SOURCE Adapted from R,V. Smith, Graduate Research (Philadelphia, PA: ISI Press, 19S4).

Table 10-3.—Examples of On-Line Databases of the National Library of Medicine

Number of records

Name Description (average length) Type of record

MEDLINE 1966-present. Bibliographic citations and abstracts from 3,300,000 Bibliographic

primary biomedical literature (1,250 char.)

TOXLINE 1965-present. Abstracts from primary toxicological literature 1,400,000 Bibliographic

(1,050 char.)

CHEMLINE Dictionary to chemicals contained in TOXLINE and other MED- 500,000 Chemical compound

LARS data bases (275 char.)

RTECS Brief summaries of toxicity results from primary literature 68,000 Chemical compound

(1,000 char.)

TDB Detailed chemical, pharmacological, and toxicological data and 4,000 Chemical compound

extracts from monographs and handbooks (17,000 char.)

SOURCE: Office of Technology Assessment

negative results, its size would be increased by an

estimated 10 to 15 percent (11). RTECS is available in hard copy (19), on microfiche, on magnetic

tape, and on-line from both the MEDLINE service

of NLM and the Chemical Information System, a

joint resource of several Federal agencies that is

managed by EPA.

On-Line Literature

The research community makes use of a number of computerized literature retrieval services

to obtain bibliographic citations and abstracts from

primary literature. Among these, for example, is

NLM’s MEDLINE database, a bibliographic file now

exceeding 3,300)000 entries. In the private sector,

Biosciences Information Services prepares hundreds of thousands of abstracts each year, providing access to essentially the entire published

biological research literature. However, the research community is not presently served by a

computerized database that includes comprehensive descriptions both of experimental protocols

and of the resulting data.

Movement toward on-line delivery of the full text

of scientific publications has begun in the private

sector. For example, Mead Data Central (Dayton,

OH) offers MEDIS, a medical literature database.

In 1985, the MEDIS service included about 70 publications, with some stored journal articles going

back to 1980. MEDIS includes the full text of the

Journal of the American Medical Association (since

1982), Archives of Internal Medicine, and some

textbooks and newsletters. In 1984, Bibliographic

Retrieval Services (Latham, NY) joined with publisher W.B. Saunders Company to offer the full

text of the New England Journa/ of A4edicine and

several other journals on-line. A serious limitation

to any current full-text literature retrieval system

is the inability to retrieve graphs, photographs,

and other images (7).
232 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 1O-4.—A Typical Substance Entry in the Registry of Toxic Effects of Chemical Substances (RTECS)

Q

4

7

6

MOLFM: C. Re-S-Te

“ TSL (06 S.)

- AMIHB C

AMIHBC

PNASA6

10,61,64

10,61,64

72,513.75

MUREAV4,53,67

TXAPA9 23,288,72

GISAAA 42(1),32,77

TJADAB 19.41A,79

NTIS*” AD-900-000

TOXID9 1,125,81

29ZUA8 -,183,80

JTEHD6 - [SUPPL.2;,69,77

BJCAAI 16,275,62

AIHAAP 23,95.62

MarJV# 26 Apr 76

FCTXAV 17(3),357.79

WQCHM” 2,-.74

IARC 20,151,80

PLMJAP 6(1),160,75

DTLVS* 4,368,80

DTLVS” 4,358.80

FEREAC 39,23540,74

FEREAC 41,57018,76

NTIS**

STATUS. SELECTED BY NTP FOR CARCINOGENESIS BIOASSAY AS OF SEPT 1982

STATUS: NTP SECOND ANNUAL REPORT ON CARCINOGENS, 1981

STATUS: NIOSH MANUAL OF ANALYTICAL METHOOS, VOL 3 S255

STATUS: NIOSH CURRENT INTELLIGENCE BULLETIN 41, 1980

STATUS: REPORTED IN EPA TSCA INVENTORY, 1962

STATUS: EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION

FINAL RULE

FEREAC 47,26992,82
Ch. 10—Information Resources and Computer Systems ● 233

Key to Figure 10-4

A. RTECS accession number, a sequence number assigned to each substance in the Registry.

1.

2.

3.

4.

5.

6.

8.:

9.

10.

11.

12.

13.

14.

15.

16.

17.

Substance name.

Date when substance entry was last revised.

American Chemical Society’s Chemical Abstracts Service unique identification number for

the substance.

Molecular weight of the substance,

Molecular or elemental formula of the substance.

Synonyms, common names, trade names, and other

Skin and eye irritation data.

Mutation data.

Reproductive effects data.

Tumor-causing data.

Toxicity data.

chemical names for the substance.

Acronyms for the references from which the data and other citations were abstracted.

Aquatic toxicity rating.

Reviews of the substance.

Standards and regulations for the substance promulgated by a Federal agency.

A Criteria Document supporting a recommended standard has been published by NIOSH.

Status information about the substance from NIOSH, EPA, and the National Toxicology

Program.

SOURCE: US. Department of Health and Human Services, National Institute for Occupational Safety and Health, Registry of Toxic

Effects of Ctremica/ Substances, R.L, Tatken and R,J. Lewis, Sr. (eds.) (Cincinnati, OH: DHHS (N IOSH) Pub. No. 83-107, 1983).

LABORATORY ANIMAL DATA BANK

The Laboratory Animal Data Bank (LADB) is a

computerized set of records of baseline data of

physiological, histological, and other biological

properties of mammalian species (largely rodents)

used in research and testing. The data contained

in LADB were derived from both research and testing, and are relevant to both areas of animal use.

Although LADB exists today only as an archival

reference, and is no longer publicly available online, it is of great historical interest in a consideration of computer-based information resources.

In 1970-73, as the carcinogenesis bioassay program of the National Cancer Institute (NCI) was

developed, NCI’s Division of Cancer Cause and Prevention anticipated needing better access to baseline data for experimental animals. In 1973-74, NLM

helped formulate the concepts leading to LADB.

The major contributor of funding for LADB was

NCI.

Data for LADB were derived from published and

unpublished reports. Only control, or baseline,

data from groups of animals were included. The

data were collected and entered into LADB via a

standard, eight-page form (reproduced in ref. 2)

that surveyed 306 variables, including:

●

●

●

●

●

●

name and manufacturer of the animals’ feed,

vaccinations given to the animals,

organs or tissues routinely examined at autopsy,

blood variables that were analyzed,

detergent used in washing cages, and

source of the animals.

The first page of that form s reproduced in figure 10-5.

Building Phase, 1975-so

Battelle Laboratories (Columbus, OH) was awarded

an NLM contract in 1975, after a competitive procurement, and began detailed design activities in

1975-76. Methods for obtaining data were developed, and the data file was designed to permit interactive access, or time-sharing, by users. Sufficient

data were entered to permit initial study by NLM

staff in 1976, and in the following year 13 outside

users were allowed to test the system.

In June 1976, NLM requested the Institute of Laboratory Animal Resources (ILAR) of the National

Academy of Sciences to provide advice on scientific and technical aspects of LADB. A Committee

on Laboratory Animal Data was formed by ILAR
234 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 1O-5.—A Representative Page of the Eight-Page Data Input Form for the Laboratory Animal Data Bank

Animal Group Environment and

Husbandry Conditions [

FOR INTERNAL LADB USE ONLV

LADB Animal Group Number

+

Related Animal Group Numbers

Carnivores

Now go to qtitlori 3s 1 Now(pJLoquowbon35

Iv

● Includes ❁●● ❁■❉❍❁●▲ postquarantine and under onwonmwntal condtmns pnOI to voatmwnt roglmrn

SOURCE: P.L. Altman and K.D. Fisher, Review of Standards Related to the Laboratov Animal Data Bank—lnlerirnF7eporf (Bethesda, MD: Federation of American Societies for Experimental Biology, 1980),
Ch. 10—information Resources and Computer Systems ● 235

to advise NLM. It met in 1977 and 1978 to consider reports from the NLM and Battelle staff and

to respond both to specific requests for guidance

concerning LADB developmental aspects and to

feedback from the 13 outside users. The NLM staff

further requested ILAR to review the basic concept, purpose, scope, validation of data, and utility of LADB.

In 1978, ILAR prepared such a report and recommended that peer review of data for inclusion

in LADB be performed, together with peer examination of the criteria for data acceptability (13).

NLM contracted with the Life Sciences Research

Office (LSRO) of the Federation of American Societies for Experimental Biology (FASEB) to organize

an ad hoc LADB User Assessment Panel to review

data descriptors and coverage of various disciplines

by LADB.

In 1979, each member of the LSRO ad hoc panel

had a computer terminal with unlimited access

to the LADB database. The resulting hands-on experience provided the basis for an objective assessment of the data descriptors and the scope of

coverage of LADB. The ad hoc panel’s report, published in 1980 (2), made some 20 suggestions for

improving LADB. The recommendations focused

on increasing the data coverage, ensuring the quality of the data included, and facilitating statistical

comparisons of data within LADB. The panel’s principal recommendations were:

●

●

●

●

●

put the individual animal data files on-line with

the grouped animal data files;

standardize diagnostic terms for pathology

data, by using a system such as Systematized

Nomenclature of Medicine;

add new data elements to LADB for growth,

development, reproduction, and teratology;

provide capability for on-line statistical analysis for determining relationships between

different data sets; and

adopt new acceptance criteria for data submitted to LADB.

Public Accessibility, 1980-81

LADB first became available on-line to the public in April 1980, via the Battelle computer in Columbus, OH. Some 100 subscribing organizations

logged 96 billable hours over the first 6 months

of public availability. This usage was far lower than

that of other databases operated by NLM, even

in their beginning stages. The paucity of user

hours, coupled with other financial considerations

(see following section) led NLM to stop LADB filebuilding in January 1981. Slightly more than 1 million animal measurements were contained in LADB

at this point, mainly obtained from 30,000 rats and

mice. A small amount of data came from cats, dogs,

hamsters, minipigs, monkeys, and tree shrews (2).

Approximately 80 to 85 percent of the total was

obtained from investigators holding contracts

awarded by the National Cancer Institute, under

its cancer treatment and bioassay programs. When

the collection of data was halted, 44 organizations

and 15 Federal contractors had contributed data,

and 9 other sources had agreed to do so. The Federal commitment to LADB from 1975 through 1980

totaled slightly over $3 million.

Battelle continued to make the file available to

the public, but usage did not increase sufficiently

to make the project self-sustaining. In early 1982,

just 2 years after becoming available on-line, LADB

was taken off -line. The file was turned over to the

National Technical Information Service for public distribution via licensing. One copy of LADB

has been licensed by NTIS to date, to Pergamon

International Information Corporation. In 1985,

Pergamon, in a joint venture with FASEB, published

hard-copy data books created from LADB records

(l). There are no plans to add data to the existing

file, or to make it publicly available on-line.

Reasons for the Failure of LADB

Financial Considerations

As mentioned, only 96 on-line hours were logged

by about 100 LADB users over the first 6 months

of public availability. This total was far too small

to provide any useful base for self-sufficiency—

one of the initial goals for the system. When the

Federal Government was vigorously seeking ways

to reduce its long-term financial commitments in

late 1980, NCI dropped its major financial support

in December, and other agencies of the Department of Health and Human Services declined to

pick up the slack, under pressure from the Office

of Management and Budget to reduce expenses.

The LADB contract with Battelle was terminated

in early 1981 for lack of funding.
236 . Alternatives to Animal Use in Research, Testing, and Education

User Friendliness and User’s Needs

The interactive software used in LADB was designed in 1975. As such, it predated many major

software developments that have emphasized “user

friendliness . ’’The users the system was aimed at–

biologists–found it hard to retain procedural

familiarity with infrequent use.

Another problem with the use of the LADB data,

according to the FASEB ad hoc panel (2), was the

inability to perform on-line statistical comparisons

between different data sets. This limitation, which

makes some desirable statistical comparisons difficult to perform, arose from inadequate design

and would probably not be a problem with today’s

soft ware.

User Community

LADB was publicly available for too short a time

to permit many conclusions to be drawn about

the users. By definition of the content, its users

would be expected to be pharmacologists and toxicologists concerned with toxicity testing, particularly chronic toxicity testing. This community,

numbering about 3)

000 to 5,000 scientists, is far

smaller than the community of basic biological

scientists (about 200,000). The pool of prospective

users of LADB, therefore, seems too small to sustain it.

Peer Review of LADB Design and Data

Although the Institute of Laboratory Animal Resources of the National Academy of Sciences evaluated LADB in 1978, it had not been involved in the

original design considerations. Similarly, FASEB

entered the review process in 1979—too late to

have substantial impact on the design and most

of the file-building process. The March 1980 FASEB

review (2) pointed out several major design problems, including lack of on-line availability of the

individual animal data files. The LADB records that

are searchable on-line are composites from groups

of animals. Failure to include data on individual

animals prevents users from performing statistical comparisons between different data sets.

Lessons Learned From LADB

The acceptance of a biology data bank by the

user community and its success in supplying useful research and testing data are actually determined well in advance of the collection or dissemination of data. The first step in assembling a

computerized data registry should be the clear definition of its potential users and their specific needs.

No adequate study of this nature was performed

prior to the original design of LADB. The results

of a preliminary feasibility study should identify

the various users, their needs, and their desire (or

lack thereof) to use and support the proposed database (3).

A 1981 FASEB report, “Guidelines for Development of Biology Data Banks” (4), emphasized three

important steps in planning and developing a data

bank of biological information. First, the stimulus

for establishing a research and testing data bank

may be the realization by a scientist, a government

agency, or a private organization that the required

information is not readily accessible from published, unpublished, or on-line resources. Nevertheless, the need for such an information resource

must be determined independently. Most appropriately, this is done by an organization unrelated

to the proposing institution. Determination of need

involves answering the following questions:

●

●

●

●

●

How many institutional, organizational, or individual users would find the database useful?

How many would be willing to subscribe, and

to what extent would cost be a factor in subscribing?

How many institutions, organizations, or individual scientists could supply data? How

many would?

How are potential users distributed among

disciplines?

How much unpublished and presently inac -

cessible data could be made available to investigators by developing a data bank?

If the responses to these questions indicate a solid

foundation of perceived need, then the establishment of the data bank is probably justified.
Ch. 10–information Resources and Computer Systems Ž 237

Second, the collection of descriptive data on those

scientists interested in the proposed database and

on their disciplinary specialties provides a basis

for matching the scope of the database to the

breadth of disciplinary interest. Specifically, the

scope and design of the database depend on the

range of purposes for collecting the research and

testing data, the size of the prospective audience,

and the needs of the users. It is essential to recognize that the needs of any user audience are dynamic and subject to change. A feasibility study

should include an analysis of current trends in user

application as a basis for inclusion of sufficient flexibility to permit later modification.

In identifying the potential user community, the

following considerations are key:

● Can a model be developed to estimate with

a high level of accuracy the number of potential users?

● Can a projection of the number of potential

donors be made from a similar model?

● To what extent will the user community sup-

●

port assessment of operational charges to defray costs?

What will it cost to collect, systematize, store,

and retrieve the data for a computerized, online system?

Third, critical to the acceptance and success of

a registry of research and testing data is peer review by experts, at all levels of database development. These levels include:

●

●

●

●

●

system design;

definition of data elements;

establishment of standards for data acceptance;

compilation and building of data files; and

post-hoc evaluation of the system (i.e., feedback resulting from experience gained by actual use of the system).

The peer-review process assures that experienced researchers have judged the design, standards, and data to be used. The process enhances

quality control, although it imposes the penalty

of high costs and slow input of data.

EXPANDING THE LADB CONCEPT: A COMPUTERIZED REGISTRY

OF RESEARCH AND TESTING DATA

The concept behind the LADB could be expanded

in at least two important dimensions. First, the

scope could be broadened beyond baseline results

to include experimental results from research and

testing. How great an increase in size would this

be? For every measurement obtained from a group

of control animals, measurements are obtained

from an estimated one to nine groups of experimental animals. This makes a registry of control

and experimental data from 2 to 10 times the size

of a registry of baseline data alone.

Second, the coverage could be enlarged beyond

principally rodents to all vertebrate species. How

great an increase would this entail? Several hundred vertebrate species could be involved. The

number of species would increase by a factor of

more than 100. Yet the bulk of the results would

still be derived from rats and mice, since rats and

mice account for 12 million to 15 million of the

17 million to 22 million animals used annually in

the United States (see ch. 3). Increasing the scope

from rats and mice to all vertebrates would therefore likely enlarge the size of the data registry by

a factor of 1.5 (17 million to 22 million animals

divided by 12 million to 15 million rats and mice).

The creation and maintenance of a computerized registry of baseline and experimental results

from all species of vertebrate animals would represent an enterprise 3 to 15 times more complex

than the unsuccessful Laboratory Animal Data

Bank.

The factors that led in the 1970s to the assignment of the LADB project to the NLM remain valid

today should a similar project be undertaken. NLM

has related experience in handling substance-oriented databases (as detailed in table 10-3), such as

the TDB and RTECS. NLM also operates much larger

databases, such as TOXLINE and MEDLINE, that

are bibliographic rather than substance-oriented.
238 . Alternatives to Animal Use in Research, Testing, and Education

Other entities that could be considered for operating a centralized registry of research and testing data include:

● National Toxicology Program. NTP never

had as its mission the development of a data

bank, and it is not presently equipped to do

so. The scope of NTP’s mission would have

to be redefined if it were to undertake this

responsibility.

● National Bureau of standards. Although

NBS specializes in physical, chemical, and engineering databases, it has never been involved

in a biological database operation. NBS does

not appear to be a viable candidate.

● National Agricultural Library (NAL). Unlike

NLM, NAL has not developed any specialized

computerized biological data registry systems.

It does not appear to be a viable candidate for

operating a centralized registry of research

and testing data. The 1985 amendments to the

Animal Welfare Act (see ch. 13) directed NAL–

in cooperation with NLM—to provide information that could prevent unintended duplication of animal experimentation, and information on improved methods of animal experimentation.

● Chemical Industry Institute of Toxicology.

Unless the chemical industry chose to increase

funding to CIIT for this express purpose, it

could not support this activity. Also, CIIT lacks

personnel experienced in large-scale database

development and operation,

● Pharmaceutical Manufacturers’ AssociaSUMMARY AND

The sharing of information on research and testing is vital to scientific progress. There are a variety of ways in which such information can be

shared.

Published materials, especially articles appearing in scientific journals, are an indispensable

source of information on the results of completed

research and testing, Unfortunately, a substantial

body of information is not published, although

some of it is publicly available.

Publication is a means of establishing a reputation in the scientific community. This is especially

important to academics. For scientists in industry, however, the efforts required for publication

tion(PMA). PMA is not independent of direction by its members (as is CIIT, for example).

Further, PMA is not engaged in large database

efforts, making it an unlikely candidate.

Federation of American Societies for Experimental Biology. FASEB has published

handbooks of biological data and is currently

embarked on a venture to extract some data

from LADB files. However, because of limited

resources for data-base development and operation, FASEB’s most appropriate role might

be as the coordinator of peer-review groups.

Chemical Abstracts Service of the American Chemical Society, and Biosciences Information Services Each of these services

annually prepares hundreds of thousands of

abstracts that report biological research and

testing results. These files are documentoriented and indexed systematically. However, the detail of the abstracts published does

not begin to approximate the depth of information found even in LADB. Both services

could conceivably undertake the development

and operation of a computerized data registry, particularly with NLM supervision.

In summary, it appears that virtually no existing private or public entity, save the NLM, has the

resources and expertise to design, develop, and

maintain a computerized registry of research and

testing data. If NLM were to undertake such a task,

it would probably rely on contractors from the

private and nonprofit sectors.

CONCLUSIONS

compete with other demands on resources, as well

as with the need to keep information with some

proprietary value confidential.

Much data generated by the Government are

published, Yet, when an agency’s mission is regulatory, less attention is given to publication than

to other concerns.

Because of the importance of journals, their publication policies have a great impact on the kinds

of information available. The most troublesome

policy is the tendency to publish only results that

show an effect, Thus, protocols that yield negative results may be unintentionally duplicated in

subsequent experiments.
Ch. 10—information Resources and Computer Systems . 239

Federal Government agencies have access to

some of the unpublished information held by industry, through reporting rules promulgated under the Toxic Substances Control Act, for example, and through registration requirements of the

Federal Insecticide, Fungicide, and Rodenticide Act.

This information is used for a variety of regulatory activities and is frequently available to the

public under the Freedom of Information Act. It

may also be added to databases.

There are several barriers to using available information. One is that users who wish to base important decisions on data need to know how reliable the data are. In assessing reliability, scientists

will consider not only the protocol used but also

the professional reputation of the scientist, the

journal in which the article is published, and where

the research or testing was done. If the format

of the data (e.g., a numerical database) does not

allow the quality to be assessed, the data may have

little value. The imprimatur of peer review is an

additional factor when assessing data quality.

International barriers to sharing information include language, the delays and expense of communication, the lack of personal acquaintances

who could facilitate net working, and political and

institutional differences.

Hundreds of thousands of research and testing

articles are published each year. Most of these articles and other resources are available through abstracting and indexing services and through bibliographic services. No service, unfortunately, is

so comprehensive that it can be relied on as a sole

source. However, when multiple sources are used,

there can be a great deal of overlap. Another problem is that the summary information may be inadequate to judge whether the complete article

should be obtained. Citation services also exist for

unpublished data and ongoing experiments, some

on an international level.

Computers are quite valuable in obtaining access to information. Many of the abstracting and

indexing services and bibliographic services are

available on computer. Recently, the full text of

some scientific journals-except for graphs and

images—has become available on-line. In principle, a computer-based registry of research and testing data could reduce the use of animals in research

and testing. In practice, the best design of such

a computerized database remains uncertain.

One attempt toward a modest, well-defined data

registry, the Laboratory Animal Data Bank, failed.

Any new effort to establish a comprehensive database that includes descriptions of experimental

protocols, control and experimental results, and

peer review will benefit from the lessons learned

from LADB. The creation and maintenance of a

computerized registry of baseline and experimental results from all species of vertebrate animals would be 3 to 15 times more complex than

the defunct LADB.

The initial step towards assembling a computerized data registry is the clear definition of both

its potential users and their specific needs. The

acceptance of a new biological data bank by the

user community and the registry’s success in supplying useful research and testing data are closely

linked to how well the databank meets user needs.

Thus, the probable success or failure of a new data

bank can be predicted in advance of the collection or dissemination of the data,

CHAPTER 10 REFERENCES

1. Altman, P.L. (ed.), Patiolo~ofbborato~~ Mke and

l?ats (New York: Pergamon Press, 1985).

2. Altman, P.L., and Fisher, K,D.,l?eviewofData Standards Related to the Labora tory Animal Data Ilank —

Interim Report (Bethesda, MD: Federation of American Societies for Experimental Biology, 1980).

3. Altman, P. L., and Fisher, K. D., Assessment of the

Laboratory Animal Data Bank in Meeting Needs of

Users (Bethesda, MD: Federation of American Societies for Experimental Biology, 1980).

4. A]tman, P. L., and Fisher, K. D., Guide~ines for Det~e]opment of Bjo]ogv DaIa Banks (Bethesda, MD:

Federation of American Societies for Experimental

Biology, 1981).

5. Ahman, P. L., and Fisher, K. D., A User Assessment

of the Toxicolo&VData Bank (Bethesda, MD: Feder-
. .

240 c Alternatives to Animal Use in Research, Testing, and Education

ation of American Societies for Experimental BiolOgy, 1982).

6. BIOSIS (Biosciences Information Service), “The 1985

BIOSIS Catalog,” Philadelphia, PA, 1985.

7. Cohen, M. F., and Flagle, C, D., “Full-Text Medical

Literature Retrieval by Computer) ’’JA&O-t 254:2768-

2774, 1985.

8. Cooper, M., “Secondary Information Services in

Science and Technology: A Wide-Angle View, ” J,

Am. Soc. Info. Sci. 33:152, 1982.

9. Cummings, M. M., Consultant, Council on Library

Resources, Inc., Washington, DC, personal communication, April 1985.

10. Davidson, J., “The Scope of Biological Testing

Today,” paper presented at the Annual Meeting of

the Society for Information Science, Annual Meeting, Philadelphia, PA, October 1984.

11. Fang, J., Tracer Jitco, Inc., Rockville, MD, personal

communication, June 1984.

12. Fox, J. L., “News and Comment)” Science 226:816,

1984.

13. Institute of Laboratory Animal Resources, Committee on Laboratory Animal Data, Review and Evaluation of the National Librartiy of Medicine Laboratory Am”mal Data Bank (Washington, DC: National

Academy Press, 1979).

14. Loosjes, Th.P,, On Lhcumentation ofScientifi’cLiterature (London: Archon Books, 1967).

15. Meyer, D. E., Mehlman, D. W., Reeves, E. S., et al,,

“Comparison Study of Overlap Among 21 Scientific

Databases in Searching Pesticide Information,” Online Review, 7(1):33, 1983.

16. National Bureau of Standards, Workshop on Data

Quality Indicators, Gaithersburg, MD, Feb. 10-12,

1982.

17. Organization for Economic Cooperation and Development, “Decision on the Mutual Acceptance of

Data in the Assessment of Chemicals,” [C(81)30 (Final)], addenda 1 to 4, adopted May 12, 1981.

18, Organization for Economic Cooperation and Development, “Improved Access to Unpublished Inforrlla -

tion,” Report of the Expert Group (Paris: 1984).

19. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health,

Registry of Toxic Effects of Chemical Substances,

R.L. Tatken and R.J. Lewis, Sr. (eds.), DHHS (NIOSH)

Pub. No. 83-107 (Cincinnati, OH: NIOSH, June 1983).

20. US, Executive Office of the President, Council on

Environmental Quality, Toxic Substances Strategy

Committee, Toxi”c Chemicals and Public Protection

(Washington, DC: U.S. Government Printing Office,

May 1980).
Chapter 11

Economic Considerations

It would not be reasonable to make decisions on alternatives to animal use without having

some idea of the consequences to the health and welfare of the public.

Kennerly H. Digges

National Highway Traffic Safety Administration

U.S. Department of Transportation

March 20, 1985
CONTENTS

Pag e

How Much Does Animal Use Cost? . . . . . . . . . . . . . . . . . . . . . .................243

Costs and Benefits in Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245

Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........245

Supporting Patent Claims , . . . . . . . . . . . . . . . . . . . . . . . . . . ..................247

Costs and Benefits in Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ..248

Testing pesticides for Toxicity. . . . . . . . . . . . . . . . . . . . . . ....................248

Testing and Product Liability. . . . . . . . . . . . . . . . . . . . . . . ...................249

Testing Costs of Animals and the Alternatives . . . . . . , . . . . . . . . ., . . . . . . . . . .249

National Expenditures for Research and Testing . . . , . . . . . . . . . . . . . . . . . . . . . . .250

Toxicological Testing Services . . . ., . . . . . . . .“. . . . . . . . . . . . . . . . . . . . . . . . . , , .251

Government Toxicological Research and Testing . . . . . . . . . . . . . . . . . . . . .. ...251

Protecting Proprietary Interests , . . . . . . . . . . . . . . . . . . . . . . . .................252

Cooperative Research and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........252

Toxicity Testing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............252

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...253

Chapter 11 References. . . . . , , . . . . . . . . . . . . . . . . , . . . . . . . . , . . . . . . . . . . . . . ..254

List of Tables

Table No.. Page

11-1. Total Savings Attributable to Biomedical Research . . . . . . . . . ............246

11-z. Estimated Biomedical Research Outlays, Selected Years, 1900-75” . . . . . . , . .247

11-3. Selected Federal Expenditures Related to Toxicological Testing

and Research, 1984-86 . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . .251

List ofFigures

Figure No, Page

11-1. Relation Between Number of Animals Used and Cost of Animal Use . . . . . .244

11-2. Development of a Typical Pesticide for Agriculture , . , . , . . . . . . . . . . . . . . .249
Chapter 11

Economic Considerations

Economic considerations play an important role

in decisions on the use of animals in research, testing, and, to a lesser extent, education. It is demonstrable that many valuable techniques, pharmaceuticals, pesticides, and other products have

been developed or tested using animals. Yet animal use is often very expensive and time-consuming. A new pesticide, for example, may require

$5 million worth of testing with animals before

it can be registered. Even higher animal costs may

be incurred in developing a new drug. Large incentives thus exist to find alternatives that reduce

the cost and time involved in animal research and

testing while maintaining the ability to improve

human health, assess and manage the risks of

toxic substances, and acquire fundamental new

biomedical knowledge. Considerable investments

are required to develop and validate such alternatives before they can be implemented with confidence.

This chapter examines costs and benefits surrounding animal use and the development, validation, and implementation of alternatives in

research and testing. Data are provided for biomedical research as it relates to human health and

disease, but a precise determination of costs and

economic benefits of animal use within biomedical research is elusive. Several aspects of using

animals in toxicological testing are examined,

including the development of pesticides, the economic incentives to develop and validate nonanimal

tests, and the extent of liability a manufacturer

might incur for insufficient product testing.

In education, it is hard to put a price tag on the

use of animals. At the college and graduate levels,

benefits of animal use include the training of biologists, psychologists, toxicologists, physicians,

and veterinarians. Education involving animals

contributes indirectly to research and testing by

training those who eventually carry out this work.

The benefits of using animals in primary and secondary education include increasing students familiarity with animal behavior and care (see ch. 9).

HOW MUCH DOES ANIMAL USE COST?

In either research or testing, the principal cost

associated with animal use is that of human labor. Animals must be fed, watered, and have their

cages cleaned. They require attendant veterinary

care and are housed in facilities needing laborintensive sanitation. Such labor costs are the major component of both the expense of producing

animals in breeding facilities and the cost of maintaining them in laboratory facilities prior to and

during research and testing.

The total cost of animal use is the sum of the

cost of acquisition of the animals and that of maintaining the animals prior to and during their use.

Acquisition expenses vary widely among species.

Mice, for example, cost on average about $2

apiece, hamsters about $5, and guinea pigs about

$19. Dogs range in price from $5 for a pound animal to several hundred dollars for a purpose-bred

animal. Primates can cost from $400 to more than

$2,000. The actual cost for a particular species

varies with the sex, strain, weight, age, quantity

ordered, method of shipping, and distance shipped.

Maintenance costs also vary. Maintaining a

mouse, for example, costs about 5 cents per day,

a hamster about 11 cents per day, and a guinea

pig about 40 cents per day. The actual cost varies

among different laboratory facilities, depending,

for example, on accounting practices and local labor costs. The total maintenance cost of an animal

is directly related to its length of stay in the laboratory. It is important to note that maintenance

expenses can quickly exceed and even dwarf acquisition costs. A 2-month-old hamster costing $5,

for example, used in research until the age of 10

months costs $26 to maintain.

Figure 11-1 illustrates the relation between the

number of animals used in research and testing

243
244 ● Alternatives to Animal Use in Research, Testing, and Education

Figure 11-1 .—Relation Between Number of Animals Used and Cost of Animal Use

Acquisition Maintenance Total

i . .h

II

+ ‘x

I

The total cost of animal acquisition and maintenance equals the sum of the acquisition cost and the maintenance cost.

maintenance cost depends-on the animal’s length of stay in the animal facility.)

Acquisition Maintenance

I Number of

animals

used

x

I

+

Number of

animals

used

x

Total

I

—

(The

Using fewer animals will yield a decrease in the total cost of animal acquisition and maintenance, but the proportionate savings ‘will be less than the decrease in the number of animals used. Both the price of each animal and the cost of maintenance

per animal can be expected to increase to support the operating costs of breeding facilities and animal facilities.

SOURCE: Office of Technology Assessment.

and the total cost of animal use. Although the

numbers and species of animals used (see ch. 3)

and the price per animal can be estimated, it is

currently impossible to estimate with any accuracy the laboratory lifetime-and hence the total maintenance costs-of animals used in the

United States. Therefore no actual dollar figure

can be affixed to the cost of animal acquisition

and maintenance in research and testing. Beginning in 1986, the Public Health Service (PHS) will

require reports on the average daily census of all

species housed in PHS-funded facilities (see app.

C). These data may permit an estimate of the total cost of animal use in a sizable portion of animal research—namely, that conducted in PHSfunded facilities.

The relationship shown in figure 11-1 emphasizes several aspects of the economics of animal

use. If the number of animals used is reduced,

the total cost of animal acquisition and maintenance will decline. But the proportional decrease

in total cost will not match the proportional decrease in the number of animals used. Reducing

animal use by 15 percent, for example, will not

effect a cost savings of 15 percent; the savings

will be somewhat less, for two reasons, First, if

the number of animals used decreases, the cost

of acquiring each animal can be expected to increase somewhat. (A temporary drop in price for

some species that are in immediate oversupply

may occur, but this would last only through the

laboratory-useful lifespan of animals already on
Ch.11 -Economic Considerations Ž 245

hand and ready for sale.) With reduced demand, would have to spread the cost of operation over

vendors would have to raise prices to cover their fewer animals. In both breeding and laboratory

overhead. Second, if the number of animals used maintenance of animals, there are economies of

decreases, the expense of maintaining each re- scale such that breeding and maintenance of marmaining animal in a laboratory facility can be ex- ginally fewer animals does not yield a correspondpected to increase. Laboratory-animal facilities ing decrease in costs.

COSTS AND BENEFITS IN RESEARCH

The many important economic contributions of

research with animals are difficult to characterize. First, research does not lend itself to such

analysis. Normally, one experiment will draw

from many others and contribute to future research, making allocation of costs and benefits to

a particular activity virtually impossible. Second,

the outcome of each experiment is uncertain, and

the experiences in one program would not necessarily apply to others. Third, the delay between

research and commercialization is long, reaching

a decade or more, with payoff taking even longer.

Thus, it is not possible to evaluate with any reasonable confidence the costs and benefits of current or even recent animal and nonanimal research practices,

Biomedical Research

This section discusses biomedical research in

general, which unavoidably averages many diverse research experiences. Biomedical research

is of interest because it is a major user of animals,

because it affects human health, and because it

affects an important sector of the economy—the

health care industry. As with most areas of research, many of the contributions are indirect and

many are not easily quantified in economic terms

(see ch. 5). Most benefits are realized in the health

care industry, which in 1983 accounted for $355.4

billion (10.8 percent) of the gross national product (9). Drugs, which require both biomedical research and toxicological testing in their development, have annual sales of about $30 billion and

contribute about 20,000 jobs to the economy (29).

The first medical discovery that was largely a

result of research with animals was diphtheria

antitoxin at the end of the 19th century. Its use

reduced the likelihood of death for those contracting diphtheria from 40 to 10 percent (28). Animals eventually came to be used in all phases of

biomedical research and in the development of

medical products such as drugs and devices and

of services such as surgery and diagnostic techniques.

Research with animals that leads to practical

applications can last from a few days to many

years. It may involve inexpensive equipment or

hundreds of thousands of dollars’ worth of instrumentation, may be performed by a laboratory

technician with little supervision or by a team of

highly educated scientists, and may be done with

fruit flies or with primates. The costs will vary

accordingly.

The benefits and rates of return on a given experiment vary widely. The rate of return for a

given research program can only be determined

reliably many years after commercialization. In

the case of products with high research and testing costs and long lead times to commercialization, which applies to many of the products of biomedical research, the lag can be several decades.

A 1972 study on the rates of return for six large

pharmaceutical companies for research they conducted in 1954 through 1961, when animals were

widely used, estimated the pretax private rate of

return to be 25 to 30 percent (2). The social rate

of return—the benefits to the public, was estimated to be at least twice as high (20).

Another approach to gauging costs and benefits involves looking at expenditures from 1900

to 1975 and comparing them with the benefits

of medical advances in preventing sickness and

death in the work force over the same period (4).

All data were adjusted to 1975 conditions. Analogous comparisons were made for 1930 to 1975.
246 . Alternatives to Animal Use in Research, Testing, and Education

Of course, this approach ignores both the costs

of research before 1900 (or 1930) that contributed benefits after those years and any research

conducted before 1975 for which the benefits had

not fully accrued. The latter is more confounding because much more research was done in the

last decade of the study than any other, so the

benefits could not be fully counted. Undervalue

also occurs because it is impossible to measure

the value of not being ill. Yet, other assumptions

in the study may overvalue the benefits by neglecting changes in nutrition, lifestyle, and working conditions.

Benefits exceeded costs in this study by factors

ranging from 4 to 16, depending on the assumptions made in calculating benefits and whether

the time period is from 1900 to 1975 or 1930 to

1975. Expressing the results in another way, the

savings in health-related costs due to the increase

in knowledge was estimated to be $115 billion to

$407 billion (4,20).

Savings were also calculated for various disease

categories. As can be seen in table 11-1, research

costs in certain areas have exceeded benefits accruing over the same period (as indicated by a

minus sign). Table 11-2 provides related information about levels of funding in selected years,

showing how funding grew during the same

period. The research budget for 1975 corresponded

to almost 9 percent of the costs associated with

neoplasms (data not shown in tables), whereas all

other budget-to-cost ratios were below 1.4 percent (20).

Although economic and financial data such as

these are useful in making policy judgments, most

decisions about using animals are more complicated and take into account political and technical

considerations, as well as economic ones. Monetary costs and benefits must be balanced with factors such as scientists’ desire to be certain and

society’s desire to have animals treated in a humane fashion. Economic analysis focuses on only

part of the equation, and cannot be the sole basis

for decisions.

one example of the tension between financial

and other criteria is exemplified by the question

of whether pound animals should be used in laboratory studies. A recent survey indicates that

about three times as many dogs and cats are obtained from pounds and dealers (who often purchase from pounds) as are purpose-bred for laboratory use (18). Scientists have argued that

Table 11=1.—Total Savings Attributable to Biomedical Researcha (in billions)

Disease categorv - . 1900-75 simulation 1930-75 simulation

Totalb . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $299.37 to $479.83 $145.65 to $167.76

Infective and parasitic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Endocrine, nutritional, and metabolic diseases . . . . . . . . . . . . . . .

Diseases of the blood and blood-forming organs . . . . . . . . . . . . .

Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the nervous system and sense organs. . . . . . . . . . . .

Diseases of the circulatory system . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the respiratory system . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the digestive system, oral cavity, salivary glands,

and jaws. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the genitourinary system . . . . . . . . . . . . . . . . . . . . . . .

Complications of pregnancy, childbirth, and postpartum . . . . . . .

Diseases of the skin and subcutaneous tissue . . . . . . . . . . . . . . .

Diseases of the musculoskeletal system and

connective tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Congenital anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Certain causes of perinatal morbidity and mortality . . . . . . . . . . .

Svmptoms and ill-defined conditions . . . . . . . . . . . . . . . . . . . . . . . .

Accidents, poisonings, and violence . . . . . . . . . . . . . . . . . . . . . . . .

aMinus signs indicate costs exceeded benefits.

%otals may not add due to rounding.

118.35

–2.66

0.28

0.76

9.20

14,76

10.68

71.75

12.96

23.58

4.59

0.93

to 174,16

to –3.17

to 0.95

to 1,27

to 21.88

to 24.31

to 18.11

to 116.38

to 21.62

to 37.28

to 7.88

to 1.76

to 14.59

to 10.08

to 3.73

to 19.80

to 9.39

63.15

– 1.17

– 1.57

5.22

3.73

–3.32

–6.42

23.44

23.53

9.27

10.92

2.98

6.19

7.56

2.80

14.46

4.08

– 11.04

– 1.41

4.38

–2.10

26.05

to 69,23

to – 1.40

to –0.99

to 5.45

to 3.72

to –2.70

to –4.91

to 27.56

to 26.53

to 10.96

to 11.62

to 3.04

to – 10.98

to –1.11

to 6.58

to – 1.67

to 26.86

SOURCES: 1900.75 slmulatlon: S.J. Mushkin, Biomedical Research: Costs and Benefits (Cambridge, MA: Ballinger Publishing Co., 1979); 1930.75 simulation: A. Berk

and L.C. Paringer, Econornlc Costs of Illness, 1930-1975 (Washington, DC: Public Services Laboratory, Georgetown University, 1977).
Ch. 11-Economic Considerations . 247

Table 11-2.—Estimated Biomedical Research Outlays, Selected Years, 1900-75 (in millions)

Disease category 1900 1930 1963 1975

Total a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

------ ------ - -. --- - --- -- -

Infective and parasitic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Endocrine, nutritional, and metabolic diseases . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the blood and blood-forming organs . . . . . . . . . . . . . . . . . . . . .

Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the nervous system and sense organs. . . . . . . . . . . . . . . . . . . .

Diseases of the circulatory system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the respiratory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the digestive system, oral cavity, salivary glands, and jaws .

Diseases of the genitourinary system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Complications of pregnancy, childbirth, and postpartum . . . . . . . . . . . . . . .

Diseases of the skin and subcutaneous tissue . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the musculoskeletal system and connective tissue . . . . . . . .

Congenital anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Certain causes of perinatal morbidity and mortality . . . . . . . . . . . . . . . . . . .

Symptoms and ill-defined conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Accidents, poisonings, and violence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

aTOtalS may not add due to rounding.

$0.1570

0.0476

0.0195

0.0006

0.0003

0.0005

0.0072

0.0039

0.0305

0.0060

0.0129

0.0009

0.0002

0.0006 —

0.0085

0.0096

0.0068

$l0.0180

1.0329

2.8291

0.2775

0.0701

0.0461

0.2164

0.9136

1.0609

0.7273

0.9338

0.1142

0.0160

0.0240

0,1092

0.4448

0.2725

0.9377

$1,561.0

17.2

847.6

33.2

4.5

4.1

14.2

252.4

96.5

62.3

25.8

1.2

1.9

3.3

18.4

50.0

19.4

109.0

$4,640.0

37.6

2,464.8

109.0

12.5

22.7

41.3

876.0

261.7

175.4

66.8

0.9

4.6

12.1

32.0

68.7

74.2

379.6

SOURCEDatafrom S.J. Mushkin, Biomedica/ F?esearch:CosM and Benefits (Cambridge, MA’ Ballinger Publishing Cov 1979)

pound animals are much cheaper than purposebred ones and that it would be wasteful to destroy them when they could be used. The difference in price between a purpose-bred and a

pound dog ranges from $200 to $500 per animal.

Estimates of the impact on research of a ban on

using pound animals range from a tenfold increase in costs to effectively`stopping research

in Los Angeles County (25). Others have argued

that pound animals are poorly suited to most laboratory work because they are often in poor

health and their genetic background is usually uncertain (25).

It may seem ethically desirable to make use of

animals that would be killed anyway, but an animal that had been a pet may find laboratory conditions more stressful than a purpose-bred animal would. Other nonpecuniary considerations

are that people may hesitate to bring their animals to a pound if they oppose laboratory use of

pound animals and that those using pound animals will see them as cheap, disposable experimental tools that need not be conserved (22).

Supporting Patent Claims

Data derived from animal research have proprietary value and are often used to support patent applications for drugs or devices for humans.

Patents give the inventor an exclusive right to

make and sell the patented invention, thus providing an incentive to invent, which in turn fuels

a growing economy. Thus, animal use can have

important economic consequences in addition to

improvement in health.

To obtain a patent, an inventor must show that

the invention is novel and useful and must disclose how to make it and use it. Data from studies

with humans are normally obtained to support

a patent on an invention to be used by humans,

but data on animals can provide evidence of utility as well (12,15). And because they are normally

obtained before research is done on humans, such

data sometimes play a crucial role in determining the date of an invention, which could determine who gets the patent in the case of two competing inventors.

Utility can be demonstrated with animal studies,

but only if the data would convince someone of

ordinary skill in the art that the same effect would

be observed in humans (14). The character and

quantity of evidence needed to show utility depend, in part, on whether the results agree with

established beliefs (13). Courts recognize that an

animal may respond differently than a human

would (16), and in demonstrating the utility of an

invention it is not necessary to demonstrate safety

(11)17).
248 ● Alternatives to Animal Use in Research, Testing, and Education

In vitro experiments are sometimes sufficient

to demonstrate utility for patent purposes. In one

recent case (7), in vitro tests showed that the

chemical to be patented, an imidazole derivative,

inhibited thromboxane synthetase in blood platelets. The activity of thromboxane synthetase was

thought to be related to hypertension, pulmonary

vasoconstriction, and other cardiovascular diseases, and the demonstration of the chemical’s

ability to inhibit it was sufficient to show utility.

Data showing therapeutic use were not required

in showing that an invention had taken place. In

another case, the fact that the inventor had given

a detailed description of how the substance to be

patented would behave was enough to support

a showing of utility, thus fixing the date of invention (24).

Although the use of alternatives to support patents is interesting, it does not have much practical effect on the use of animals in developing medical products because safety and efficacy must be

demonstrated to satisfy regulatory requirements

(see ch. 7). These patent cases might have some

application, however, in demonstrating the sufficiency of alternatives in other areas.

COSTS AND BENEFITS IN TESTING

There are several major economic benefits to

using animals in toxicological testing. Drugs, food

additives, pesticides, and many consumer products are tested for toxicity or other kinds of hazards before they can be marketed and begin to

generate income for the manufacturer. This is

often done to meet regulatory requirements, but

the tests are also done to avoid marketing unsafe

products. In addition, testing is done to confirm

that a product does in fact confer a benefit.

Testing Pesticides for Toxicity

Over a billion pounds of pesticides are used in

the United States annually, corresponding to over

$4 billion in sales. About 130 firms produce the

active ingredients in pesticides. Thirty of these

produce common products in high volume; the

others tend to produce specialty pesticides. Most

of the pesticides are used in the agricultural sector. About 7 percent are purchased by consumers

for home and garden use, while industrial and

institutional use account for about 20 percent (31).

Because pesticides are designed to be biological poisons, they are among the most toxic substances commercially available. Most of the hazards result from chronic, low-level exposure.

Exposure and the risk of it are widespread. About

2 million commercial farms in the United States

use pesticides, some of which remain in or on the

food and are eventually consumed. About 40,000

commercial applicators use pesticides to treat

structures and facilities. The Environmental Protection Agency (EPA) estimates that 90 percent

of all households regularly use or have used pesticides in the home, garden, or yard (31). The results of tests on animals are used by EPA to identify hazards and to develop acceptable exposure

levels and safe handling and disposal practices (see

ch. 7). Thus, animal testing plays an important

role in the protection of virtually the entire U.S.

population.

Acute poisonings have been estimated to cost

over $15 million annually (1980 dollars), excluding the value of saving lives or avoiding suffering. The estimated cost of each death due to pesticide poisoning is $112,000, whereas the average

cost of a nonfatal poisoning is $200 (23,31). The

costs of cancer, the most important chronic effect, is over $34 billion in 1980 dollars, with each

cancer costing $52,000 (31). One research goal is

to find new pesticides that are less toxic and more

effective than those now in use, a search that entails animal testing.

There are over 48,000 registered pesticide formulations, with an estimated 1,400 to 1,500 active ingredients (5). There are between 5 and 20

new registrations for active ingredients issued annually, each requiring a complete toxicological

evaluation based on animal testing and other data.

Another 1,500 to 2,000 new formulations or uses

are also registered annually (5,31). These require

little additional testing, as a rule, and often rely

on data in EPA’s files.
Ch. 11—Economic Considerations Ž 249

Testing costs vary with the product and its uses.

Pesticides intended for food crops require much

more testing than those for other uses. Some of

the required testing depends on results obtained

in screening tests. The cost of testing can range

from $2 million to $5 million for a new active ingredient. This represents a small fraction of the

total developmental expenses, which may approach

$100 million (31). Testing costs are incurred primarily in the beginning of the developmental

cycle (see fig. 11-2). As the figure illustrates, testing with animals-during testing for toxicity—is

an integral part of the development of a new pesticide.

Testing and Product Liability

Toxicological testing of consumer products

helps keep unsafe products off the market, It also

may sometimes allow liability for injuries to be

avoided. The cost of product liability litigation can

be enormous, and companies are tending to drop

risky products, as the current situation with vaccines illustrates.

Most States have “strict liability, ” in that a

manufacturer is liable for whatever injuries its

products cause. In most jurisdictions, there are

exceptions, such as when the technology for determining that a product is unsafe does not exist. There are also exceptions when the product

is known to be dangerous but also to confer a

great benefit. Such is the case for rabies vaccine.

A few jurisdictions merely require that a manufacturer not be negligent (see ch. 7.) Manufacturers are unlikely to adopt alternatives to animal tests until they believe such methods offer

a level of assurance of product safety equal to that

offered by animal testing.

Testing Costs of Animals

and the Alternatives

An estimated 80 percent of the cost of testing,

whether whole-animal or in vitro, is for labor (6).

Testing costs vary widely with the assay used and

somewhat with the facility. The cheapest, such

as for eye or skin irritation, can be done for un-

\ Figure 11 ”2.—Development of a Typical Pesticide for Agriculture

(Note the integral role of animal toxicity testing in pesticide development, shown in boldface.)

~ Year “:” . “ ~ o - 

~ ~ $: “ i g .$: & . 8

* ,&pH t

”’ ;,. ,: : ‘ ., -t

I

: m ; ~ ~ f ~ $

7 .

-@& , ~ .,,, ‘

;

J 4 ;?*

. ~ ,,. . -

‘“ T- “--” , ““ { .? Full

Commercialization

..

SOURCE: Off Ice of Technology Assessment, adapted from Haskell Laboratories, El. du Pent de Nemours & Company, Wilmington, DE, 1984.

38-750 0 - 86 - 9
250 ● Alternatives to Animal Use in Research, Testing, and Education

der $1,000. An LD5O test can be performed for

less than $2,000. Subchronic toxicity tests can cost

under $100,000, and those for long-term toxicity or carcinogenicity for two species can be done

for less than $1 million, and perhaps for under

$500,000 (10,31). As a rule, the cheaper tests require fewer animals, but more importantly they

take far less time at each of three stages—planning, execution, and analysis. Another reason for

large variations in testing costs is the species used,

with maintenance costs approximating $0.05 per

day for a mouse, $4 for a dog, and $11 for a chimpanzee. Most of the cost of maintaining animals

is attributable to labor expenses.

Various short-term in vitro tests for mutagenicity have been developed over the past 15 years

in an effort to replace the more costly and timeconsuming carcinogenicity test (see ch. 8). The

most popular mutagenicity test, and one of the

first to be introduced, is the Salmonella typhimurium/microsome plate mutation assay (the Ames

test), costing $1,000 to $2,000 (10). This assay has

the most extensive database thus far (1). Used

alone, it does not appear to be as predictive of

human carcinogenicity as are animal tests.

If the Ames test, some yet-to-be developed test,

or a battery of tests proves to be more predictive of carcinogenicity than testing with animals,

the savings could be enormous. A battery of tests

that might indicate carcinogenicity has been suggested by the National Toxicology Program (30)

and has shown some promise in preliminary

evaluations (see ch. 8). Most testing laboratories

could conduct this particular battery of tests for

under $50,000, and costs would probably decline

as the tests become more commonplace (10).

NATIONAL EXPENDITURES FOR RESEARCH AND TESTING

Research and testing in the United States are

financed and conducted in a variety of ways. The

sources of research funding are Government and

industry. Some Government research funds support Government laboratories, but a larger share

support research in academia. Industry research

is done primarily at in-house industry laboratories, with some funds contracted to other laboratories and to academia.

Most testing is conducted by industry. The

chemical industry is the sector most directly affected by regulatory policies concerning toxicological testing. In 1982, this industry (Standard

Industrial Classification Code 28) had shipments

worth over $170 billion and employed 866,000

people, which represented 8.7 percent of all industry shipments in the United States and 4.5 percent of the employees.

Drugs, soaps and toilet goods, and agricultural

chemicals account for the greatest use of animals

in testing, and constitute almost a third of their

use by the chemical industry. The rest of the chemical industry, in order to satisfy transportation,

disposal, and occupational health requirements,

does simple tests such as the LD5O for substances

for which the potential exposure is high (see ch. 7).

Corporate research and development (R&D) in

the chemical industry is large and concentrated

in the industrial chemicals and drug sectors. Expenditures by the industry totaled $7.6 billion in

1984 (8), a figure that includes in-house toxicological testing, research involving the use of animals, and many other activities. It has been estimated that the toxicological testing industry

accounts for just under 10 percent of the R&D

expenditures in the chemical industry (27), making testing an estimated $700 million expenditure

in 1984. An unknown percentage is spent on research involving animals.

In the past 10 years, industry’s R&D expenditures have grown at about 13 percent per year,

following a slight decline in the early 1970s. R&D

expenditures for drugs, as a percentage of sales,

are twice as high as the industry average, and

have grown at a slightly higher rate (8). Animal

use could be growing at a similar rate, although

survey estimates (see ch. 3) and other factors (see

ch. 8) do not support this notion.

The Federal Government also plays a major role

in animal research and testing, with almost $6 billion obligated for research in life sciences for

1985. University research in the life sciences,

which is funded largely by Government and some-
Ch. n-Economic Considerations ● 2 5 1

what by industry, will cost an estimated $2.9 billion (8).

Projections of future expenditures depend on

a number of factors, including the growth of the

chemical industry and of R&D within it; the areas

of R&D (e.g., new substances, new uses for old

substances, new processes for making old substances); regulatory policies, both domestic and

foreign; the growth of the overall economy; tax

policy; and further developments in nonanimal

tests.

International developments can have economic

repercussions. For example, Swiss voters defeated

in 1985a referendum virtually banning all animal

testing (see ch. 16). A number of companies have

facilities in Switzerland, and such a change could

have shifted testing to another country. whether

U.S. labs could compete for that business depends

on the strength of the dollar.

Toxicological Testing Services

In 1984, the toxicity testing industry in the

United States was estimated to be worth about

$650 million per year (27). Sixty-five percent of

the testing is done by corporations in-house. The

remaining 35 percent (about $225 million annually) is conducted by commercial laboratories,

universities, and other organizations. Although

there are over 110 U.S. laboratories that sell testing services, most specialize in a small number

of assays and are not ‘(full service. ” Hazelton is

the largest of the full-service labs, with domestic

sales of $36 million in 1983. Except for Hazelton

and several other large commercial labs, the industry is a dispersed one, with the many small

commercial firms accounting for approximately

two-thirds of the value of domestic sales (10).

The industry expanded its facilities in the 1970s

in response to Federal regulatory changes and the

passage of the Toxic Substances Control Act. Testing did not increase as much as expected, however, and in the early and mid-1980s the industry was operating at 60 to 70 percent capacity (27).

This has led to fairly level prices over the past

few years and, in some cases, price cutting to

maintain market position. Because of this competition, current prices reflect the actual costs of

testing. Testing laboratories often do not quote

set prices for some testing procedures or for particular batteries of tests, preferring to negotiate

on a case-by-case basis.

Government Toxicological

Research and Testing

The U.S. Government programs with strong ties

to toxicological testing are EPA, the National Center for Toxicological Research in the Food and

Drug Administration, the Centers for Disease Control, and the National Institutes of Health (see table

11-3). other programs are not identified with separate budget line items and are dispersed among

various agencies and departments.

Table n-3.-Selected Federal Expenditures Reiated

to Toxicoiogicai Testing and Research, 1984-86

(in thousands)

1984 1985a 1986a

Environmental Protection Agency:

Program expenses . . . . . . . $327,145 $380,341$376,074

Toxic substances . . . . . . 34,484 39,341 38,660

Pesticides. . . . . . . . . . . . . 32,772 37,805 36,948

Research and

development. . . . . . . . . 144,903 195,449 212,061

Toxic substances . . . . . . 12,327 14,450 26,358

Pesticides. . . . . . . . . . . . . 1,738 5,121 6,938

Interdisciplinary. . . . . . . . 18,522 22,423 14,876

Food and Drug Administration:

National Center for

Toxicological Research . 21,132 21,575 22,284

Drug program ., . . . . . . . . . . 138,248 153,112 152,430

Food program . . . . . . . . . . . 115,541 109,538 113,907

Devices and radiologic

products . . . . . . . . . . . . . . 62,568 67,081 68,368

Centers for Disease Control:

Occupational safety and

health research . . . . . . . . 54,740 54,863 57,645

Research on chronic and

environmental disease . . 25,953 28,568 23,726

National Institutes of Health:

National Cancer Institute:

Cause and prevention. . . 276,075 301,655 285,844

Detection and

diagnosis . . . . . . . . . . . 63,182 70,524 66,839

Treatment . . . . . . . . . . . . . 340,041 367,940 351,683

National Institute of Environmental and

Health Sciences:

Characterization of

environmental

hazards . . . . . . . . . . . . . 19,152 21,136 21,601

Applied toxicological

research and testing. . 57,781 57,303 56,737

Intramural research . . . . . . . 48.643 55.051 52.536

aEstimates.

SOURCE: U.S. Executive Office of the President, Office of Management and Budget, Budget of the United States Government, Fiscal Year IQ% (Washington, DC: U.S. Government Printing Office, 1985),
252 ● Alternatives to Animal Use in Research, Testing, and Education

PROTECTING PROPRIETARY INTERESTS

In commercializing a particular product, animal

use may be limited to toxicity testing, but many

products rely on animals in the initial research

phase as well. These research and testing results

have proprietary value that is sometimes protected

by secrecy, other times by obtaining a patent. The

value of data that lead to a particular product may

depend more on the size of the market and its profitability than on the cost of obtaining them, particularly when it takes a long time to generate the

data.

Cooperative Research and Testing

Two major competing factors influence the

sharing of research and testing costs— the desire

to keep information that has proprietary value

secret and the desire to share the very large expenses that may be involved in generating it.

These business decisions are only slightly influenced by Government policies. Another factor is

antitrust law, however, which is greatly affected

by such policies.

In considering the role of antitrust law, it is important to recognize that the results of research

and testing enable society to use resources efficiently. Antitrust laws help ensure that these

efficiencies benefit consumers, by preventing

manufacturers, for example, from colluding to

maintain high prices. However, these statutes

have sometimes been applied in a way that impedes technological development (3) by making

it difficult for companies to pool resources for

research so expensive that none would undertake

it alone.

In recent years, antitrust policies have been

changed or clarified so that resources can be

pooled more easily (19). One component of this

is the National Cooperative Research Act of 1984

(public Law 98-462). The Sherman and Clayton

antitrust acts still apply, but damages in private

suits are reduced from three times the value of

the unfair advantage to the actual value. This will

certainly lower the risks involved in collaborating, and probably the likelihood of being sued as

well.

Testing costs can be most equitably shared if

potential participants can interact before testing

begins rather than after it is completed, because

a party who has already tested may have an unfair advantage (or disadvantage) in negotiating

compensation. It is easiest to identify potential

sponsors for a particular chemical when testing

is required by a regulatory agency, because it is

known that testing will take place and who is required to test. When industry forms testing consortia to share costs, it is most easily done through

existing trade associations, such as the Chemical

Manufacturers Association. Cooperative testing

is also conducted by industry through the Chemical Industry Institute of Toxicology.

Many testing consortia have been put together

to negotiate agreements in anticipation of required testing under Section 4 of the Toxic Substances Control Act. Such negotiations were ruled

invalid in a recent case (2 I). Despite this ruling,

testing consortia will continue to have appeal so

long as testing is expensive and the results have

little or no proprietary value other than in fulfillment of regulatory requirements.

Toxicity Testing Data

Many companies begin making other financial

commitments to the commercialization of a product before testing is completed. Plant design and

small-scale production may coincide with longterm toxicity testing. The practical costs of fulfilling lengthy testing requirements may greatly

exceed the costs of testing. Thus, it is advantageous to be able to use any existing data generated by another laboratory in order to avoid the

delays and uncertainties of testing. Conversely,

this provides an incentive to prevent data from

being made available to competitors.

The protection of pesticide testing data has been

the subject of much litigation and several amendments to the Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA). The most recent changes

provide that data submitted after September 30,

1978, are protected from uncompensated use for

15 years. There are two kinds of protection. One
Ch. 11-Economic Considerations ● 2 5 3

requires that data be shared as long as compensation is offered. The terms of the compensation

are subject to arbitration if the parties cannot

agree. The other protection only applies to new

pesticides (new active ingredients), not to new formulations of old ingredients. It gives exclusive use

of the data to the data owner for 10 years unless

the data owner explicitly agrees to sell the right

to use the data.

The Supreme Court recently decided in Ruckelshaus v. Monsanto (26) that these provisions of

FIFRA are constitutional. For data submitted before 1972 or after 1978, there is no expectation

of a proprietary interest, thus nothing is taken;

for data submitted between those years, the compensation and arbitration provision, in combination with the Tucker Act, provides adequate compensation. (See also the Environmental Protection

Agency’s regulations at 40 CFR 1984 ed. 152; 40

FR 30884.)

Congress has recognized the important business

interest in keeping information from competitors,

but it also supports the public’s ‘(right to know”

and the Federal Government’s need to know. An

important barrier to the sharing of confidential

business information among agencies is the differing standards and procedures for handling it. The

ad hoc interagency Toxic Substances Strategy

Committee, coordinated by the Council on Environmental Quality, thought it would be necessary

to pass legislation permitting the sharing of confidential data between health and environmental

agencies (32). Such legislation would establish a

need-to-know standard, require uniform security

procedures for the data to be shared, impose uniform penalties for disclosure, and provide for

notification of the data submitted by the data

holder at least 10 days prior to transfer.

SUMMARY AND CONCLUSIONS

The total dollar cost of animal acquisition and

maintenance is directly related to the length of

time animals stay in the laboratory. With no accurate source of data on various species’ length

of stay, it is impossible to calculate the total cost

of animal use. Analysis of the factors involved in

the costs of animal acquisition and maintenance

indicates that a reduction in animal use will be

accompanied by a reduction in cost—although the

proportionate savings will be less than the proportionate decrease in the number of animals used.

Many of the issues involved with using animals

in research and testing have economic implications, although they do not lend themselves well

to rigorous quantitative economic analysis because many considerations are nonmonetary. A

highly contested concern, for example, is the

propriety of using unclaimed pound animals in

laboratory studies.

An area of animal use that is of major economic

importance is biomedical research, which contributes to health care through the development of

drugs, medical devices, diagnostic techniques, and

surgical procedures. Health care accounts for

over 10 percent of the Nation’s gross national

product, or $355 billion in 1983. The results of

research with animals might also reach the public through patented products. Although data on

humans may also be required, and although

nonanimal or in vitro methods are sometimes

sufficient, many such patent applications use animals to show that the invention is useful.

Another use of animals with economic importance is toxicological testing, used to ensure that

new products are sufficiently safe. One type of

product for which such testing is of major consequence to public health is in the development

of pesticides, which affect virtually all Americans

through the production and contamination of

food. The Environmental Protection Agency has

estimated that 90 percent of all households use

some pesticide product.

Whole-animal tests can be far more costly than

in vitro and nonanimal alternatives, largely because they are labor-intensive. The incentives to

find alternatives to the LD5O and Draize tests are

primarily nonmonetary, however, as these tests

can be performed for $1,000 to $2,000. This is
254 . Alternatives to Animal Use in Research, Testing, and Education

in the price range of the cheaper, currently available in vitro and nonanimal replacements.

Most research and testing in the United States

is financed by Government or industry. The

chemical industry, including the production of

drugs, has annual sales of over $170 billion and

spends over $7 billion on research and development. An unknown fraction is spent on research

involving animals and about $700 million is spent

on toxicity testing.

The Federal Government sponsors much biomedical research and testing involving animals

(see ch. 12). An unknown amount leads to the development or use of alternatives. The Government

also has many programs related to testing, including the evaluation of testing data generated in

other sectors. Agencies with significant budgets

for such activities include the Environmental Protection Agency, the Food and Drug Administration, the Centers for Disease Control, and the National Institutes of Health.

The Federal Government also has a special role

in the sharing of data derived from animal use,

as the data have proprietary value. First, antitrust

laws and policies affect industry’s ability to share

data and the costs of generating it. Such sharing

is facilitated by the passage of the National Cooperative Research Act of 1984. It is also facilitated under the Federal Insecticide, Fungicide,

and Rodenticide Act and the Toxic Substances

Control Act.

CHAPTER 11 REFERENCES

1. Auletta, A., Genetic Toxicologist, U.S. Environmental Protection Agency, Washington, DC, personal communication, 1984.

2. Baily, M. N., “Research and Development Costs and

Returns, the U.S. Pharmaceutical Industry, ’’.l. Po]it.

Econ. (Jan. -Feb. ):7O-85, 1972.

3. Baxter, W .F., “Antitrust Law and Technological Innovation,” 1ss. Sci. Tech. 1(2):80-91, 1985.

4. Berk, A., and Paringer, L.C., Economic Costs of Wness, 1930-1975 (Washington, DC: Public Services

Laboratory, Georgetown University, May 1977).

5. Bishop, F., Chief, Registration Support and Emergency Response Branch, Office of Pesticide Programs, U.S. Environmental Protection Agency,

Washington, DC, personal communication, 1985.

6. Brusick, D.J., Director, Molecular Sciences Directorate, Litton Bionetics, Kensington, MD, personal

communication, 1984.

7. Cross v. Izuka, 224 USPQ 745, 1985.

8. Chem. Engin. News, “Facts and Figures for Chemical R&D,” 53(29):28, 1985.

9. Gibson, R. M., Levit, K. R., Lazenby, H., et al., “National Health Expenditures, 1983,” Health Care Finan. Rev. 6(2):1-29, 1984.

10. Hertzfeld, H. R., and Myers, T.D., “Economic and

Policy Considerations,” contract report prepared

for the Office of Technology Assessment, U.S. Congress, 1985.

11, In re Anthony, 56 CCPA 1443,414 F.2d 1383, 162

USPQ 594 (1969).

12. In reBergeZ, 48CCPA 1102, 292F.2d 955, 130USPQ

206 (1961).

13. ~n re Chihnvsky, 43 CCPA 775, 229 F.2d 457, 108

USPQ 321 (1956).

14. In re Irons, 52 CCPA 938, 340 F.2d 974, 144 USPQ

351 (1965).

15. In re Jo]]es, 628 F.2d 1322, 206 USPQ 885 (CCPA

1980).

16. In re Krimmel, 48 CCPA 1116, 292 F.2d 948, 130

USPQ 215 (1961).

17. In re Watson, 517 F.2d 465, 186 USPQ 11 ([Cust.

and Pat. App.1 1975).

18, Institute of Laboratory Animal Resources, National

Survey of Laboratory Animal Facilities and Resources (Washington, DC: National Academy of

Sciences, 1980).

19. McGrath, J. P., Remarks at the 18th Annual New England Antitrust Conference, Boston, MA, Nov. 2,

1984.

20. Mushkin, S.J., Biomedical Research: Costs and Benefits (Cambridge, MA: Ballinger Publishing Co., 1979).

21. Natural Resources Defense Council v. EPA, 595

F. Supp. 1255 (S.D.N.Y., 1984).

22. Payton, N., Massachusetts Society for the Prevention of Cruelty to Animals, Testimony in Support

of H1245, Boston, MA, February 1981.
Ch. n-Economic Considerations ● 2 5 5

23.

24.

25.

26.

27.

28.

Pimentel, D., Andow, D., Dyson-Hudson, R., et al.,

“Environmental and Social Costs of Pesticides: A Preliminary Assessment,” Oikos 34:127-140, 1980.

Rey-Bel]et v. Englehardt, 493 F.2d 1380, 181 USPQ

453 (1974).

Rowan, A. N., Of Mice, Models, & Men: A Critical

Evaluation of Am”mal Research (Albany, NY: State

University of New York Press, 1984).

Ruckelshaus v. Monsanto, 104 S. Ct. 2862 (1984).

Stock Market Surveuy for Hazelton Labs (New York,

NY: Silverberg, Rosenthal, and Company, Apr. 9,

1984).

Turner, J., Reckoni~ With the Beast: Animals, Pain

and Humam”ty in the Victorian ~“nd (Baltimore, MD:

Johns Hopkins University Press, 1980).

29. U.S. Department of Commerce, 1982 Census of

Manufactures, Drugs (Washington, DC: U.S. Government Printing Office, 1985).

30,

31.

32.

U.S. Department of Health and Human Sert~ices,

Public Health Service, Food and Drug Administration, National Toxicology Program, Board of Scientific Counselors, Draft Report-Ad Hoc Panel on

Chemical Carcinogenesis Testing and E~raluation

(Bethesda, MD: Feb. 15, 1984).

U.S. Environmental Protection Agency, Regulatoqt~

Impact Analysis: Data Requirements for Registering Pesticides Under the Federal Insecticide, Fungicide and Rodenticide Act, EPA 54019-82-013 (Washington, DC: 1982).

U.S. Executive Office of the President, Council on

Environmental Quality, Toxic Substances Strategy

Committee, Toxic Chemicals and Public Protection

(Washington, DC: U.S. Government Printing Office,

1980).
Chapter 12

Public and Private Funding

Toward the Development

of Alternatives

The most authoritative source for information on alternatives to the use of live animals in

research is the NIH itself.

Eleanor Seiling

United Action for Animals, Inc.

April 18, 1984

Cutting the NIH appropriation and eliminating this Federal agency will be an excellent

place to start trimming waste from the Federal budget.

Helen Jones

International Society for Animal Rights, Inc.

July 1984

I become very suspicious when I see a grant for $5,664 or a grant for $22,000. What can

a researcher accomplish with $22,000?

Sen. Alfonse M. D’Amato (R-NY)

Senate Hearing

October 2, 1984
CONTENTS

Page

Funding Toward Alternatives in Research , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .259

Public Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................259

Private Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................263

Funding Toward Alternatives infesting . . . . . . . . . . . . . . . . . . . . . .............264

Public Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . 264

Private Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... 265

Funding Toward Alternatives in Education. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..268

Related Types of Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............269

Animal-Facility Improvement Grants . . . . . . . . . . . . . . . . . . . . , . . . . ...........269

Researching Animal Health and Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..270

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

Chapter 12 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......271

List of Tables

Table No. Pag e

12-1. Approaches Used in National Science Foundation Research Grants,

Fiscal Year 1983 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................262

12-2. Alternative Tests Under Development at the Food and Drug

Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .266

12-3, Alternative Tests in Use at the Food and Drug Administration. . . . . . . . . . .266

12-4. Selected Research Projects Supported by The Johns Hopkins

Center for Alternatives to Animal Testing . . . . . . . . . . . . . . . . . . . . . . . .. ...267

List of Figures

Figure No. Page

12-1. Trends in NIH Research Subjects, 1977-82, as

Percentage of Research Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....261

12-2. Trends in NIH Research Subjects, 1977-82, as

Percentage of Research Dollars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......261

12-3. Funding Levels of National Toxicology Program Activities,

Fiscal Year 1985 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................265
Chapter 12

Public and Private Funding Toward

the Development of Alternatives

Attempts to find alternatives to using animals

in research, testing, and education are so diverse

that it is difficult to cite firm figures on funding

levels. An investigation of public and private funding practices does make it clear, however, that no

single policy covers such research and development (R&D). Much of the work that could lead to

the replacement, reduction, or refinement of animal use is not even considered R&D of alternatives by the body that funds it.

Research is seldom targeted toward alternatives

as ends in themselves. Few projects are initiated

with this specific goal. Consequently, confining the

inquiry to only those cases where development

of an alternative method is the desired result, such

as programs to find in vitro substitutes for the

Draize eye irritancy test, drastically narrows the

category of funding classified as supporting alternatives. In addition, it is especially difficult to examine funding policies related to reductions and

refinements, because these considerations generally enter into the construction of any protocol.

This chapter covers targeted as well as incidental cases of research into alternatives—investiga -

tions directed toward the development of alternatives as well as those pursued for other reasons

but that lead to or use alternatives. Also considered are research into laboratory-animal health

and some types of pain research that may increase

knowledge about the mechanisms of pain and improve methods of alleviating distress. Resources

allocated to upgrading animal facilities are closely

related, since inadequate facilities may skew experimental results, thereby requiring that more

animals be used.

FUNDING TOWARD ALTERNATIVES IN RESEARCH

Developing replacements for the use of animals

in research is far more likely to be incidental than

targeted. Refinements and reductions may be incidental developments as well, but they are more

likely to result from conscious efforts on the part

of the investigator. Areas in which alternatives,

especially replacements, are discovered will often

be those in which animals are not used at all. This

type of development is exemplified by basic research in cell biology that resulted in improved

cell culture capabilities, and work in basic physics

that led to noninvasive imaging techniques. Identifying funding in this area is particularly difficult:

Few agencies view these projects as alternatives

to animal use or label them as such, even though

the methods may yield techniques and systems that

could replace animals, reduce the numbers used,

or refine the protocols. (Most testing-related research has been deliberately excluded from this

category.)

In an attempt to obtain a rough indication of expenditures on alternatives, OTA examined the

range of models in use, identifying the number

of projects and amount of research money in each

system area. Of course, not every nonanimal method evolves into an alternative to animal use. Yet

research in specific techniques, such as biostatistics, may have broad or unanticipated applications

across many areas of research and testing.

Public Funding

Two major granting agencies, the National Institutes of Health (NIH) and the National Science

Foundation (NSF), account for most of the basic

biomedical research sponsored by the Federal Government. Neither agency currently funds alternatives as a targeted goal. In few cases is the development of a replacement a major objective of the

research that produces one. However, considera259
260 ● Alternatives to Animal Use in Research, Testing, and Education

tion of models of all types, and the selection of a

research model appropriate to the problem under investigation, occurs with every grant. Other

scientific and ethical considerations may lead to

reductions and refinements within protocols during the grant review process (see ch. 15).

National Institutes of Health

In fiscal year 1985, national expenditures on

health R&D exceeded $12.8 billion (24). Of this total, industry accounted for the largest portion (39

percent), followed by the National Institutes of

Health (37 percent), other Federal research, and

other funding groups (24). Of health R&D supported by the Federal Government, NIH has funded

approximately 90 percent in recent years (13).

About 60 percent of the research funded by NIH

can be characterized as basic (25). NIH basic research has accounted in recent years for about

40 percent of all Federal basic research conducted

(18).

Until recently, NIH had no concerted program

under which it pursued the development of alternatives in research, as opposed to any such methods that may occur as byproducts during investigations. However, the new Biological Models and

Materials Resources Section within the Division

of Research Resources may assume this function.

This office was created in February 1985 and

its function was mandated (Public Law 99-158) in

November 1985 to address the need to explore and

support the use of nonanimal models in biomedical research, Its missions include developing the

use of cell systems, lower organisms, and nonbiological systems (mathematical and computer models) for biomedical research and actually providing biological materials that serve as critically

important resources to the biomedical research

community, such as those just mentioned (28).

The office intends to implement some of the recommendations offered in the recent report of the

National Academy of Sciences’ Committee on Models for Biomedical Research:

● As favorable systems are identified, the NIH

should strive to make them readily available

●

●

to the research community by providing support to supply organisms for research, maintaining stock centers for mutant strains and

for cell lines, facilitating access to computer

programs for biomedical modeling, maintaining databases like those for protein and DNA

sequences, and providing long-term support

for collections of cloned genes and useful vectors or collections of monoclinal antibodies.

NIH should consider supporting proposals

whose objective is the development of model

systems for specific research areas. Indeed,

funds might be targeted for the development

of new model systems that appear to be particularly promising.

NIH should encourage interest in nonmammalian systems through postdoctoral fellowships, symposia, and direct support of model

development (12).

The office today tracks the use of model systems

in research supported by NIH and serves as NIH’s

focal point for the exchange of information with

individuals, organizations, and institutions concerning the use of model systems in biomedical

research. In addition, the Biological Models and

Materials Resources Section serves as the new

home of four previously existing resources:

●

●

●

●

The American Type Culture Collection:

Support for this collection of cultured cells,

$600,000 in fiscal year 1985, was recently

transferred from the NIH Director’s office.

The Massachusetts Institute of Technology

Cell Culture Center This facility produces

animal cells in large quantities tailored to specific investigator needs; 85 percent of its users

are NIH grantees. Funding is in the process

of being taken over from NSF in fiscal year

1985 (NIH contribution: $165,000) and will be

complete in fiscal year 1986.

Caenorhabditis elegans Genetics Center

This resource serves as a repository for

nematodal mutants and a clearinghouse for

the mapping of the C. elegans genome. It is

supported jointly with the National Institute

of Aging ($15,000 in fiscal year 1985).

National Diabetes Research Interchange:

This information resource is supported jointly

with the National Institute of Arthritis, Dia-
Ch. 12—Public and Private Funding Toward the Development of Alternatives ● 261

betes, and Digestive and Kidney Diseases with

funds ($25,000 in fiscal year 1985) provided

through the General Clinical Research Centers

Program (28).

An analysis of research systems within various

projects and subprojects funded by NIH provides

some idea of the patterns of subjects and models

used overall for NIH; it may also indicate national

patterns because NIH supports more than onethird of the health-related R&Din the United States

(24). Use of both human subjects and mammals

(expressed as the percentage of research projects

using each) was essentially stable from 1977

through 1982 (see fig. 12-1). At the same time there

was a slight increase (approximately 5 percent) in

the percentage of research dollars being spent on

mammalian systems and a corresponding decrease

in the percentage of research dollars spent on research involving human subjects (see fig. 12-2). The

data in these figures do not indicate, of course,

the number of individual animals used; they only

illustrate the relative percentages of projects

funded and dollars spent among several types of

research subjects.

NIH-supported research uses many models.

Three widely used ones are in vitro cells and tissues, invertebrates, and mathematical and computer simulations, all commonly referred to in dis -

Figure 12-1 .-Trends in NIH Research Subjects,

1977=82, as Percentage of Research Projects

1977 1978 1979 1980 1981 1982

Fiscal year

SOURCE: J.D. Willett, “Biological Systems Used as Research Models in NIH Programs,” Animal Resources Program, Division of Research Resources,

National Institutes of Health, Bethesda, MD, Sept. 24, 1984.

Figure 12-2.—Trends in NIH Research Subjects,

1977.82, as Percentage of Research Dollars

w h~ -

1977 1978 1979 1980 1981 1982

Fiscal year

SOURCE: J.D, Willett, “Biological Systems Used as Research Models in NIH Programs,” Animal Resources Program, Division of Research Resources,

National Institutes of Health, Bethesda, MD, Sept. 24, 1984.

cussions about alternatives. In fiscal year 1981,

12 bureaus, institutes, or divisions (BIDs) of NIH

supported 378 research projects that used human

cells or tissues, for a total commitment of over $32

million (27). The projects included studies of cellular aging, in vitro studies of immune response

and regulation of antibodies, the cellular basis of

disease, and the mechanisms of DNA repair. A further 381 projects and subprojects used cells and

tissues from sources other than humans in the

course of their investigations. These accounted for

nearly $34 million, directed toward research into

models for diseases such as herpes, leprosy, and

parasitic diseases; hormonal effects on the control and function of differentiated cells; differences

between tumors and normal tissues; and other cellular and biochemical mechanisms. Invertebrates

used in fiscal year 1981 included annelids, aplysia,

cephalopods, crustaceans, Drosophila, echinoderms, gastropod, helminths, horseshoe crabs,

mollusks, nematodes, platyhelminths, and protozoans, accounting for 608 subprojects and over

$46 million.

Mathematical models were used by 8 BIDs, in

23 projects and subprojects for nearly $1.2 million, to analyze renal flow and neural networks,

to model biological waves and kinetics, to model

clinical trials, to predict fetal outcomes, and to support mathematical biology. Computer simulations
262 ● Alternatives to Animal Use in Research, Testing, and Education

were supported by 10 BIDs to study a range of

research questions including computer analyses

of cellular differentiation and homeostatic control

mechanisms, modeling of bladder cancer and

structure-activity relationships in drugs, simulations of renal function, imaging reconstruction and

display of biological surfaces, and the modeling

of artificial intelligence. These 54 projects accounted for close to $6 million in awards.

Nonanimal models, including invertebrates and

nonmammalian vertebrates in addition to those

described above, account for approximately 26

percent of NIH’s projects and an average of 29 percent of the funds in any given year. Mammalian

systems account for slightly more than 43 percent

of the projects and about 46 percent of the dollars

spent. Many projects use several systems at once.

National Science Foundation

NSF considers project proposals for support in

all fields of science. Among its programs are eight

that have potential to support alternatives-related

research:

●

●

●

●

●

●

●

●

Behavioral and Neural Sciences,

Biotic Systems and Resources,

Information Science and Technology,

Mathematical and Computer Sciences,

Cellular Biosciences,

Molecular Biosciences,

Research Instrumentation and Equipment,

and

Science and Engineering Education (21).

The National Science Foundation normally does

not support clinical research either with humans

or animals, the development of animal models for

specific diseases or conditions, or the development

of drugs or other therapeutic procedures. For the

most part, it supports only what can be classified

as basic research.

The character of research projects and models

used in investigations funded by NSF varies widely.

Table 12-1 indicates the distribution of the approaches proposed in NSF research grants for fiscal year 1983. In the categories that include living

organisms, only those projects involving actual experimentation manipulations have been included.

Thus the data do not include studies on animals,

plants, or micro-organisms that are observational

or descriptive in nature; these might be ecologic

studies, population dynamics, and studies of field

behavior, for instance. However, field studies that

included the actual capture of animals, involved

invasive or noninvasive placement of electric tracking devices, or used physiological sampling were

included.

In addition, NSF supports three additional

awards that relate to the use of animals in research,

although these projects do not directly use animals, The first is a grant to the Institute of Laboratory Animal Resources of the National Academy

of Sciences for its activities in developing and making available to the biomedical community scientific and technical information on laboratory-animal science resources. The other two, related to

research on ethical issues surrounding the use of

animals, originate in the Ethics and Values in

Science and Technology (EVIST) program in NSF’s

Directorate for Biological, Behavioral, and Social

Sciences.

Table 12.1.—Approaches Used in National Science Foundation Research Grants, Fiscal Year 1983

Number of Range of award sizes

Approach used awards (in thousands) Total expenditure

Whole nonhuman primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 $9-$135 $ 1,875,958

Whole nonprimate vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2-289 32,872,503

Culture of animal-derived components (cells, tissues,

organs, or embryos) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 6-250 8,368,526

Mathematical modeling as an adjunct to animal use. . . . . . . . 22 9- 100 747,079

Mathematical modeling without animal use . . . . . . . . . . . . . . . 9 25- 176 657,000

Invertebrates ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 5- 266 18,451,785

Micro-organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 7- 250 21,440,070

Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 9“ 250 20,288,332

Total ... , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,906 $2-$289 $104,701,251

SOURCE: B.L. Ummlnger, Deputy Director, Division of Cellular Biosciences, National Science Foundation, Washington, DC, personal communication, 19S4.
Ch. 12—Public and Private Funding Toward the Development of Alternatives . 263

Although many of the projects listed in table 12-1

involve the culture of animal derived components,

invertebrate animals, micro-organisms, plants, or

mathematical modeling, the intent of NSF-funded

investigations usually is not the development of

alternative methods to experimentation with live

animals. Nevertheless, the outcome of some of

these projects may lay the groundwork for the subsequent development of alternative techniques.

The Biological, Behavioral, and Social Sciences

Directorate houses most of the work related to

alternatives. NSF’s total basic research budget is

approximately $1.5 billion in fiscal year 1986, including approximately $260 million for this division. If past patterns continue, the bulk of these

funds will not be spent on animal research but

on a much broader group of projects,

Small Business Innovation Research

The Small Business Innovation Act (Public Law

97-2 19) requires agencies of the Public Health Service and certain other Federal agencies to reserve

a specified portion of their R&D budgets for the

Small Business Innovation Research (SBIR) program. The stated goals of this project are to “stimulate technological innovation, use small businesses

to meet federal research and development needs,

increase private sector commercialization of innovations derived from federal R&D, and to foster and encourage participation by minority and

disadvantaged persons in technological innovation”

(26). The NIH set-aside for the SBIR program totals $18.2 million, NSF retains a similar SBIR setaside pool equal to 1.25 percent of its budget in

fiscal year 1986.

Small businesses seeking to commercialize alternatives can take advantage of these funds for product research and development. The grants are

generally in the range of $35,000 to $100,000, depending on how quickly commercialization is likely to follow the research. For fiscal year 1983, NIH’s

SBIR program funded many projects that might

be related to alternatives, such as:

● phase I structure activity relationship estimation of skin and eye irritation,

● an interactive teaching system for medical

students,

●

●

●

●

●

●

●

●

CAT scanning for carcinogenesis bioassay in

rodents,

cell growth chambers for chemotherapeutic

drug screening,

continuous cell culture for monoclinal antibodies,

a new method to detect immune complexes,

synthetic peptides as animal vaccines,

bacterial/laser bioassay to detect environmental pollutants,

rapid methods to monitor genetic damage in

humans, and

development of mammalian cell culture aneuploidy-assay.

Although not all of these will develop as replacements, reductions, or refinements of animal use,

some may eventually produce commercially viable alternatives.

Private Funding

Private funding in research, especially basic research, is most difficult to evaluate and classify

according to its applicability to alternatives. And

because most basic biomedical and behavioral research is sponsored by the Federal Government,

it is through public sector funding that alternatives in research are most likely to develop.

Private foundations and research institutes support biomedical research internally as well as extramurally. Although some of this research may

pertain to alternatives, it is not often the case unless the mission of the institution is specifically related to animal welfare. Disease-oriented foundations conduct research on aspects of a particular

system or affliction and support a variety of research approaches, animal as well as nonanimal.

Though some of these initiatives may indeed qualify as alternatives, examining this research on a

project-by-project basis is beyond the scope of this

assessment.

In 1985, the Nation’s first professorship in humane ethics and animal welfare was established

at the University of Pennsylvania School of Veterinary Medicine with the an endowment of $1.25

million from Marie A. Moore. One goal of the endowed professorship will be to investigate alter-
264 ● Altematives to Animal Use in Research, Testing, and Education

natives to animal experimentation in medical research (15).

Several foundations have animal welfare as their

primary mission or included as a principal goal.

Since 1981, the Geraldine R. Dodge Foundation has

disbursed over $450,000 in grants related to alternatives (7). The foundation awards grants in several categories, including that of animal welfare.

Research grants include a 2-year contribution of

$115,409 to the Baker Institute for Animal Health

of Cornell University for the development of a cell

hybridization laboratory to enhance diagnostic,

therapeutic, and disease prevention capabilities.

Dodge has also contributed $63,000 to the Center

for Alternatives to Animal Testing (CAAT) at The

Johns Hopkins University to help cover the costs

of publishing the center’s newsletter. Additionally,

the Scientists’ Center for Animal Welfare (Bethesda,

MD) has received over $90,000 to date.

FUNDING TOWARD ALTERNATIVES IN TESTING

Funding of R&D on alternatives in testing is in

many ways the support most easily identified, especially when the alternative is intended to replace

a test that currently uses animals. This applied R&D

draws on basic research from other areas, incorporates it into a testing methodology, and then validates the new test. Developing an alternative requires that the alternative system be shown to

correlate with the effect that is of interest. Narrow efforts such as these contrast markedly with

the broader goals of basic research, and the development of alternatives is correspondingly easier.

Public Funding

Public funding of research toward alternatives

in testing stems from the Federal Government’s

role as regulator and guardian of safety. Federal

agencies conduct toxicological and other tests on

many substances and devices in order to establish effects as well as standards for safety (see ch.

7). The greatest impetus for Federal funding of

replacements for animal tests would be a strong

indication that an alternative could be found that

would be superior to the comparable conventional

assay with animals. This has not yet occurred in

terms of technologies that would totally replace

the use of animals, nor is it likely to in the near

future, although promising areas like in vitro assays may someday replace some whole-animal

tests. It is more likely that short-term in vitro tests,

functioning primarily as screens, will reduce the

number of substances run through the complete

battery of tests with animals (see ch. 8).

Toxicological Testing

The National Toxicology Program (NTP) was

chartered in 1978 as a cooperative effort by the

Department of Health and Human Services (DHHS),

involving four principal groups— the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences (NIEHS), both of which

are part of NIH; the National Center for Toxicological Research (NCTR) of the Food and Drug Administration (FDA); and the National Institute for

Occupational Safety and Health (NIOSH) of the Centers for Disease Control (CDC). Fiscal year 1985

funding for the NTP totaled $76.7 million, drawn

from contributions by the DHHS member agencies that were negotiated after each agency received its congressional appropriation. NIEHS provides approximately 86 percent of the program’s

resources (8).

The stated goals of the NTP include the expansion of toxicological information obtained on chemicals nominated, selected, and tested; the expansion of the number of chemicals to be tested, within

the constraints of funding; the development, validation, and coordination of tests and protocols to

match regulatory needs; and the communication
Ch. 12—Public and Private Funding Toward the Development of Alternatives ● 265

of program plans and results to the public (22,23).

Figure 12-3 illustrates the relative priorities of these

activities and their components with reference to

spending in fiscal year 1985. Testing activities consume by far the largest share of resources. Within

each of the three divisions, efforts are divided into

four major areas: mutagenesis (cellular and genetic

toxicology), carcinogenesis, toxicological characterization, and fertility and reproduction (reproductive and developmental toxicology).

According to the NTP’s “Fiscal Year 1984 Annual

Plan” (22), planning activities are directed toward

reducing the number of chemicals that require

chronic testing through the development, validation, and application of more efficient and more

sensitive testing systems. It is in this area—estab -

lishing new batteries of tests and subsequently

validating them—that the development of alternatives is most likely to occur.

NIEHS directs between $18 million and $20 million toward testing and research related to alternative test systems, especially short-term indicators of intoxication. Approximately 85 percent of

this money is channeled through NTP in the form

of grants for research and testing, R&D contracts

for testing and development, and in-house research. These funds cover the actual testing in addition to methods validation and evaluation of alternatives. Test systems receiving the bulk of attention

include bacteria, yeast, insects, and cultured cells

from mammalian tissues including humans (10).

Figure 12.3.—Funding Levels of National

Toxicology Program Activities, Fiscal Year 1985

(dollars in millions)

/

Methods development $13.2

Carcinogenesis . . . . . . . . . . . . 2.0

. .

. .

. . . .

. . . .

. . . .

. . . .

. . . .

4.2

5.5

1.5

$5.0

0.6

1.5

0.9

2.0

$54.5

Carcinogenesis ., . . . . . . . . . . 28.4

Toxic characterization. . . . . . . 17.0

Mutagenesis. . . . . . . . . . . . . . . 6.9

Fertility and reproduction . 2.2

SOURCE: L.G. Hart, Assistant to the Director, National Toxicology Program,

Research Triangle Park, NC, personal communication, July 1985.

Beyond NCI, NIEHS, NCTR, and NIOSH (the four

constituent agencies of NTP), DHHS support for

research related to toxicology is also found within

the Alcohol, Drug Abuse, and Mental Health Administration, CDC, FDA, and NIH. Substantial Federal support for toxicological research and testing

is also provided by the Environmental Protection

Agency (see ch. 11, table 11-3).

Food and Drug Administration

FDA conducts primarily mission-oriented, applied research. Its interest in alternatives derives

from FDA requirements for product testing. Although intramural funds are not allocated on a

project-by-project basis, the agency has tried to

estimate expenditures on the basis of person-years

involved in the work (4). Assuming a person-year

is $40,000 (salary, overhead, and benefits), intramural research into alternatives to testing with

animals was estimated at 35 person-years, an expenditure of roughly $1.2 million. Extramural

work consists of one project, valued at $87,000,

to develop an in vitro model as a primary screen

to detect active agents against Dirofilaria immitis

larvae (a heartworm found in the dog, wolf, and

fox) and microfilariae (the prelarval stage of a parasitic roundworm). For the most part, these in vitro

models have been developed elsewhere, and these

projects involve the application to FDA-regulated

products. Tables 12-2 and 12-3 list alternative tests

currently under development and in use at the

Food and Drug Administration.

Private Funding

private sector motivation to develop alternatives

in testing ranges from scientific concerns through

economic and political ones. Investors in this sector account for perhaps the most diverse group

of supporters of this type of research.

Trade and Industrial Groups

The development of alternatives in testing is supported by trade groups and industry for several

reasons, mostly linked economically to the financial health of the company or industry. Commercial concerns find alternative methods generally

take less time and labor and are therefore less expensive to perform than standard animal-based
—

266 ● Alternatives to Animal Use in Research, Testing, and Education

Table 12=2.—Alternative Tests Under Development

at the Food and Drug Administration

Tabie 12=3.-Aiternative Tests in Use

at the Food and Drug Administration

. Genetic probes for toxigenic strains of Campylobacter

jejuni

. Genetic probes for invasive Escherichia coli

. In vitro invasiveness test based on siderophore avidity

for iron

● Enzymatic and chemical in vitro evaluation of infant

formula protein quality

● Development of an assay for genetic transposition in

bacteria

● Cultures of rat embryos to detect agents that cause

developmental toxicity and to determine the

mechanism by which effects are produced

● Porcine kidney explant cultures for screening

potentially nephrotoxic agents

. In vitro macromolecular biosynthesis as an index of

potential tissue damage by chemical agents

. In vitro determination of effects of chemical agents of

T- and B-lymphocyte function

● Improved procedures for use of unscheduled DNA

synthesis for genotoxic effects

. In vitro use of renal cortex tissue to determine

biochemical correlates for evaluating toxicity of

natural toxicants

● In vitro assays to assess biological vaccine potency

and safety (diphtheria antitoxin, rabies, polio vaccines)

● I n vitro assays to assess drug potency (gonadotropin,

Iactogenic hormone, corticotropin, oxytocin, insulin)

● In vitro methods to determine percutaneous absorption

of hydrophobic compounds

● In vitro immunoassay methods (RIA, ELISA) for

assessment of immunotoxic effects of drugs and

environmental pollutants

● Liquid and thin-layer chromatographic methods for

ciguatera and paralytic shellfish toxins

. In vitro immunoassay methods (RIA, ELISA) for

assessment of seafood toxins

SOURCE: A.P. Borsetti, Staff Scientist, Office of Science Coordination, Food and

Drug Administration, U.S. Department of Health and Human Services,

Rockville, MD, personal communication, 1985.

testing protocols. A desire for improved tests and

responsiveness to public concern over animal use

also drive the search for alternatives. As public

relations tools, nonanimal methods have proved

valuable in reassuring the public that these corporations share their concern about animal use

and are exploring other systems, while being careful not to jeopardize public health and safety.

In 1980, Revlon Research Center, Inc., awarded

a 3-year, $750,000 grant to Rockefeller University

to establish the Rockefeller Laboratory for In Vitro

Toxicology Assay. Revlon’s investment was the first

serious, publicly taken step by industry in the

search for alternatives. The Revlon award has been

extended into a fifth year and totals more than

$1.25 million (5). The laboratory employs four

scientific staff, working on projects including alter-

● Genetic probes for heat-labile and heat-stable

enterotoxin of Escherichia coli

● Genetic probes for invasive strains of Yersinia

enterocolitica

● Genetic probes for classical 01 cholera toxin

● Genetic probes for pathogenic organisms (01 and

Non-01 Vibrio cholerae, Vibrio parahemolyticus, Vibrio

vulnificus)

● In vitro tests for percutaneous absorption of cosmetic

ingredients

● In vitro cell transformation assay

● Unscheduled DNA synthesis in primary rat hepatocytes

● Salmonella microsome assay for gene mutations

• Limulus amebocyte Iysate test for pyrogenicity of

drugs and biologics

● Sister-chromatid exchange for assessing mutagenic

potential

● Use of primary myocytes and endothelial cells from

neonatal rat heart ventricles for identification of

potential cardiotoxic agents

Ž High-performance liquid chromatography as a screen

for the vitamin D assay (used for products other than

infant formula)

● Instrumental analysis assay for potency of three

anticancer drugs for batch release (Dactinomycin,

Doxorubicin hydrochloride, and Plicamycin)

. Instrumental analysis assays to determine the potency

of biological vaccines

● Genetic probes for invasive Shigella

● In vitro assays for tumor-producing potential (HL 60

differentiation, V-79 metabolic cooperativity, and

Epstein-Barr virus activation

. Assays for detection of mycotoxins (mass

spectrometry, instrumental methods, brine shrimp

assay)

SOURCE: A.P, Borsettl, Staff Scientist, Office of Science Coordination, Food and

Drug Administration, U.S. Department of Health and Human Services,

Rockviile, MD, personal communication, 1985.

natives to the Draize eye irritancy test and other

animal cell culture applications. Prior to the establishment of this facility, there were no laboratories

committed to alternatives research.

The Johns Hopkins Center for Alternatives to

Animal Testing has committed $2.1 million to the

search for alternatives since 1981, funding 30

grants for research (19). The Center has both an

information program (consisting of a regularly

published newsletter, symposia, and a book series)

and a research program (focused on in vitro acute

and chronic toxicity testing and acute irritancy of

the skin and eye). The center’s enabling sponsor,

the Cosmetic, Toiletry, and Fragrance Association

(CTFA), is joined by other corporate donors, including the Bristol Myers Company, as well as by

consumer and industrial groups and private individuals. CAAT solicits projects from scientists by
Ch. 12—Public and Private Funding Toward the Development of Alternatives ● 267

Solicitation for Proposals by The Johns Hopkins

Center for Alternatives to Animal Testing

REQUEST FOR PROPOSALS

REQUEST FOR PROPOSALS

The Johns Hopkins Center for Alternatives to Animal Testing is soliciting proposals. These research

proposals should provide the fundamental knowledge base to develop alternative methods to whole

animals for the safety evaluation of commercial

products.

The center is specifically interested in the use of

human cells and tissues. Funds are available for

studies of skin and eye irritation, inflammation,

acute toxicity, and other organ specific toxicity. At

the present time funds are unavailable for mutagenicity and carcinogenicity.

Grants will normally be funded up to a maximum of

$20,000 per year including 15 percent overhead or

actual costs, whichever IS less. All grants will be on

a yearly basis with continuation funding dependent

upon an acceptable continuation of proposal.

Abstract deadline: 30 March 1985.

Application deadline: 30 May 1985.

Application instructions can be obtained by contacting: Joan S. Poling, Secretary to the Director, Room

2306, School of Hygiene and Public Health.

Taken from Science 227:212, 1985. Copyright 1985 by the

American Association for the Advancement of Science.

circulating requests for proposals either for a

broad, nonspecific area or for specific, investigatorinitiated projects. In the first stage of a two-stage

peer review, a group of scientific experts judges

the proposal on the quality of the science proposed

and its relevance to the mission of CAAT. Second,

the advisory board votes on which projects to fund.

The voting membership of the organization is academic, although nonvoting members do represent

the sponsors, government, and animal welfare

groups. Table 12-4 lists examples of some of the

projects funded by The Johns Hopkins Center.

The Soap and Detergent Association is supporting work at the University of Illinois to develop

alternatives to eye irritancy tests with a 3-year

grant of $218,596. The program is designed to develop a mathematical model that would correlate

the responses to a series of in vitro tests with the

test material’s potential to irritate the human eye

(17). The Fund for Replacement of Animals in Medical Experiments (FRAME) reports that it is collaborating with both the Rockefeller and Illinois

groups, providing chemicals for use in blind trials

on alternative methods (3).

These various examples of private funding illustrate the variety of mechanisms to provide supTable 12-4.—Selected Research Projects Supported

by The Johns Hopkins Center for Alternatives

to Animal Testing

Condition and organ/Project description

Irritation and inflammation:

Vagina: Tests for vaginal products

Eyes: Corneal cultures for tests

Corneal cultures—plasminogen activator as an

indication of irritation

Skin: Human umbilical cord cells

Fibroblast damage by chemicals

Development of artificial skin

Phototoxic chemicals and skin

Architecture of skin in vitro

Biological change/toxic response

Cytotoxicity and acute toxicity:

Liver Response to toxins in solution

Cells: In vitro production of metallothionein

In vitro production of peroxisomes

Effects of culture media on cells

Chemicals’ effects on protein synthesis

Organ specific effects:

Heart, lung, kidney: Mechanistic data—acute and chronic

organ toxicity

Other projects:

Nerves: Neurotoxicity/neuronal cell culture

Teratology: Fruit fly assays

Botulism: Evaluation of contamination of foods

SOURCE: A.M. Goldberg, Director, The Johns Hopkins Center for Alternatives

to Animal Testing, Baltimore, MD, 1985.

port for the development of alternatives. The first,

the Rockefeller Laboratory, is a case in which a

corporation endows a single laboratory facility and

funds the work of scientists within that group. The

research conducted in the lab is closely allied with

the products manufactured by the sponsor and

with the testing required by those products.

The second model, exemplified by The Johns

Hopkins Center, is a central clearinghouse established to collect and disseminate funds in a wider

variety of research areas. The source of the funds

is also varied. The grants distributed within this

structure are small (under $20,000) and not strictly

comparable to the support accorded to the Rockefeller lab, but The Johns Hopkins Center funds

many more grants.

The third example, the Soap and Detergent Association, shows a single project within a university

funded by an industrial concern. In this case the

association draws funds from its constituent members and then acts as their proxy in distributing

them.
268 ● Alternatives to Animal Use in Research, Testing, and Education

Both the Animal Protection Institute and the Institute for the Study of Animal Problems have surveyed corporations that do animal research and

testing (2,14). Many companies indicated that they

were taking steps to promote alternatives. Support often took the form of membership in a trade

association (e.g., CTFA) that sponsors research into

alternatives. Others indicated that investigations

were being undertaken within their own research

programs. Responses and levels of commitment

varied greatly among corporations.

Animal Welfare Groups

Groups such as the American Fund for Alterna -

tives to Animal Research (AFAAR), the American

Anti-Vivisection Society, the New England AntiVivisection Society, the Animal Welfare Foundation of Canada, the Lord Dowding Fund in Great

Britain, the Millennium Guild, and the Muriel Lowrie Memorial Fund have supported research in the

United States aimed at replacing animals in testing protocols. These grants range in size from a

few thousand to several hundred thousand dollars.

AFAAR, for example, has provided some $130,000

in grants between 1977, when it was founded, and

1985 (l). Included among these are a grant of

$25,905 to develop a test system to determine the

nutritive value of protein in foodstuffs, using Tetrahymena (ciliate protozoans) in place of weanling mammals. This test enables food producers

to provide correct diet supplements or therapeutic

diets. In addition, a grant of $45,000 was awarded

to develop a replacement for the Draize eye irritancy test using the chorioallantoic membrane

of the chick embryo. Additional funding for this

project has been supplied by other animal welfare

groups (a total of $148,500 from the Lord Dowding Fund, the American Anti-Vivisection Society,

the Muriel Lowrie Memorial Fund, and the Animal Welfare Foundation of Canada) and by the Colgate-Palmolive Company. In 1985, AFAAR joined

three other animal welfare groups in awarding

an additional $133,987 to develop procedures for

toxicology testing using monolayer cell cultures

in gradients of oxygen tension and temperature (l).

The Millennium Guild has offered $500,000 to

encourage the development and implementation

of testing methods that will replace or significantly

reduce the use of animals (11). There is a breakthrough award of $250)000 for nonanimal replacements for the Draize eye, the Draize skin, or the

LD5O tests for any scientist or team of scientists

who develops a cost-effective test or battery of tests

that can be validated and accepted by a U.S. regulatory agency. An equal sum is available to promote innovation and to reward the rapid reduction of widely used animal tests, These incentive

awards have been granted in areas such as uses

of liver culture, quantitative structure activity relationships, cell culture bioassays, and the use of protozoans as indicators of eye irritancy.

Foundations and Research Institutes

Foundations and research institutes often devote in-house and other private funds to research

into alternate testing methodologies and systems.

Battelle Columbus Laboratories (Columbus, OH),

for example, is pursuing the development of many

alternatives. Its efforts fall into two major divisions,

mammalian and nonmammalian systems. The basic areas of system development include cell and

organ culture, in vitro teratology, and neurotoxicity. A figure of $500,000 has been conservatively

estimated as the investment in this area. The funding comes primarily from private sources and includes both internal and external funds. Some of

the projects now under way are cell culture initiatives, including microphage work, and teratology research using rat embryo and frog embryo

cultures (16),

FUNDING TOWARD ALTERNATIVES IN EDUCATION

Funding of research toward alternatives in edu- education. Alternatives in education also often origcation, especially within the public sector, stems inate as research simulations, and then move back

more from a renewed emphasis on science and into the classroom. Exceptions to this are projects

math education and on computers than from sub- undertaken for the express purpose of developstantial concerns with methods of animal use in ing replacements for animals in the classroom, or
Ch. 12—Public and Private Funding Toward the Development of Alternatives ● 269

programs developed in order to cultivate attitudes

conducive to the further development and implementation of alternatives (see ch. 9). Some of these

other initiatives, such as those funded by groups

interested in issues pertaining to animal use, have

developed from concerns related to humane education.

The Health Professions Educational Assistance

Amendments of 1985 (Public Law 99-129) authorized the Secretary of the Department of Health

and Human Services to make grants to veterinary

schools for work related to alternatives. These

grants can support the development of curricula

for:

Ž training in the care of animals used in research,

● the treatment of animals while being used in

research, and

● the development of alternatives to the use of

animals in research.

Since 1981 the Geraldine R. Dodge Foundation

has given over $240,000 toward education-related

alternatives programs including:

● $25,000 to the Biological Sciences Curriculum

Study to support the development of materials

at the high school level relating to animal welfare as a legitimate consideration in biology;

●

●

●

more than $50,000 to the National Association for the Advancement of Humane Education to support the development of People and

Animals, an interdisciplinary humane education guide for preschool through sixth-grade

teachers;

$50,000 to the American Society for the Prevention of Cruelty to Animals to broaden and

strengthen its humane education component,

particularly through four 15-minute humane

education television programs for elementaryschool children developed in cooperation with

the New York City Board of Education; and

$30,000 toward the development at Cornell

University of Resusci-Dog, a canine cardio-pulmonary resuscitation mannequin (see ch. 9);

this is the first of a series of simulators, including one that will demonstrate irregularities in heartbeat rhythm (7).

The American Fund for Alternatives to Animal

Research supports a series of intensive training

sessions on in vitro toxicology for students planning a biomedical career to promote the development of scientists who are well trained in the uses

and limitations of replacement techniques. This

$39,000 grant supports courses that cover the theory and practice of cell and tissue culture, in vitro

mutagenesis, transformation, and cytotoxicity (20).

RELATED TYPES OF FUNDING

Three additional categories of funds maybe considered in conjunction with efforts to develop alternatives. These types of projects are more likely

to contribute to reductions and refinements than

to replacements. Grants to improve animal facilities, research in animal health, and research into

pain can have broad implications for research, testing, and education.

Animal-Facility Improvement Grants

Research support through grants to improve facilities for housing animals is not specifically designed to promote the development of alternatives,

but it may assume that role nonetheless. The quality of animal care provided directly affects the

health of experimental animals. Those maintained

within a more controlled environment are less likely to exhibit variations stemming from exposure

within that environment, And if they are kept under conditions better suited to their individual

needs, they are less likely to exhibit symptoms of

stress. These negative effects, all resulting from

the intrusion of external stimuli, may skew the results of an experiment. Less reliable results may

in turn demand that more animals be used for each

protocol, perhaps a needless addition under better conditions.

To address this problem, the Division of Research

Resources within NIH is offering grants for the

development and improvement of animal facilities

so that institutions can comply with the Animal

Welfare Act and with DHHS policies on the care

and treatment of animals. Eligibility is open to any

nonprofit institutions engaged in research supported by NIH. Two programs currently exist. The

first, an ongoing program, has funded from two to

four proposals each year for the past several years.
270 ● Alternatives to Animal Use in Research, Testing, and Education

Funds for alterations and renovations are limited

to $100,000, although requests for funds for equipment may push the total above this amount.

The second program draws from a one-time pool

of $5 million. Support for new construction is not

available, and funding for alterations and renovations is limited to $500,000 for each award, Recipient institutions are required to match these funds

dollar for dollar. As in the ongoing program, funds

may be requested for equipment in addition to this

amount. More than 100 applications have been received; of these, only 12 requested the maximum

funds for renovations and alterations. Many, however, exceeded $700,000 in their total request. The

applications averaged in the $300,000 to $400,000

range. Some 12 to 15 projects are likely to be

funded, and grants will probably range from $65,000

to $750,000 (9).

It is important to note that at least two other

sources of funding for improvement of animal facilities are available to NIH grantees. First, an institution’s maintenance of facilities is an allowable indirect cost of research. Second, the National

Cancer Institute is allowed to make awards for facilities renovation (6).

Groups other than NIH are also devoting resources to improvements in animal facilities. Industry laboratories, contract laboratories, and

universities are mustering both internal and external funds to improve their facilities. For commercial groups, a longer term economic advantage is recognized in these efforts. Contract testing

labs, in particular, have special incentives to maintain the highest laboratory standards in order to

attract clients.

Research in Animal Health and Pain

Funding devoted to research in animal health

can function in an analogous fashion to efforts to

improve animal care facilities. It creates the scientific base on which improvements in facilities and

practices may be based, The larger the knowledge

base on animal research grows, the more exact

and focused research using animals can become

and, ultimately, the smaller the number of animals

included in individual protocols.

Parallel with this, research into the mechanisms

of pain and pain perception can contribute knowledge that allows researchers to alleviate pain in

experimental protocols. This can include research

on the detection of pain and distress, for example,

that would allow an investigator to detect these

phenomena with greater sensitivity. Advances in

analgesics and anesthetics may produce less distortion in some protocols and allow animals a greater degree of comfort.

As an example, Humane Information Services,

Inc., awarded $184,000 in research grants during

1984 to support eight agricultural research projects

directed toward the alleviation of animal suffering. Included were studies on the behavioral effects of several types of housing for pigs and

chickens, studies of electronic immobilization, and

projects aimed at reducing the stress of weaning

and pre-slaughter handling. Similar efforts could

be undertaken in testing and research to maximize

the information obtained from protocols while

minimizing pain and suffering for the subjects.

SUMMARY AND CONCLUSIONS

Measuring the funding of alternatives is inex- The development of alternatives, especially react at best. Funding of replacements is easiest to placements, is likely to be the result of multidiscimeasure, while the data are poor for reductions plinary efforts, executed over relatively long peand refinements. The easiest type of research to riods of time. The results of research can be

recognize and categorize as related to alternatives transferred across the sciences—as has happened,

is targeted research. Such work is most often asso- for example, with the noninvasive imaging techciated with technique development—for example, nologies developed by physicists that are now used

the effort to replace whole-animal testing assays in the biomedical sciences.

with in vitro tests, as with the Draize eye irritancy

test.
—

Ch. 12—Public and Private Funding Toward the Development of Alternatives . 271

Three types of grants can augment the development of alternatives. Funding to improve animal

facilities can result in healthier, less stressed animals and can free research from the confounding

variables bred by a less well defined or inferior

environment. Grants to investigate improvements

in animal health in general can have the same effect. And research into the mechanisms governing pain may spare animals some measure of suffering when the techniques are incorporated into

other protocols.

The development of alternatives in research is

funded largely by incidental means through the

support of basic biomedical research by the National Institutes of Health and the National Science

Foundation plus a few targeted efforts that are

supported privately. In a climate of finite research

resources, research and development of alternatives to animal use take their place in the competition among research priorities. A noteworthy effort by NIH was the creation of the Biological

Models and Materials Resources Section within the

Division of Research Resources. With funding, this

office may serve as a focal point for the exchange

of both nonvertebrate biological materials and information about the use of model systems in biomedical research.

In testing, a solid organizational structure for

R&D of alternatives is in place, best illustrated by

the National Toxicology Program and the Food and

Drug Administration in the public sector and by

the Rockefeller Laboratory for In Vitro Toxicology Assay and The Johns Hopkins Center for Alternatives to Animal Testing in the private sector. Any

strong indication that an alternative test method

would be superior to a comparable conventional

animal assay is likely to attract funding readily.

CHAPTER 12 REFERENCES

1. American Fund for Alternatives to Animal Research, “Presentation of Grant Awards by AFAAR

at the Center for Advanced Training in Cell and Molecular Biology,~ Washington) DC, June 1985.

2. Animal Protection Institute, “The Product Testing

Update: Who’s Using Animals and Who’s Not, ” response to “A Day That Counts” program, Sacramento, CA, January 1985.

3. Balls, M,, Chairman of Trustees, Fund for the

Replacement of Animals in Medical Experiments,

Nottingham, UK, personal communication, Mar. 4,

1985.

4. Borsetti, A. P., Staff Scientist, Office of Science Coordination, Food and Drug Administration, US. Department of Health and Human Services, Rockville,

MD, personal communication, 1985.

5. Brauer, E. W., Vice-President, Revlon Research Center, Inc., Edison, NJ, personal communication, January 1985.

6. Fed. Proc., “NIH’s McCarthy Discusses New Animal

7

8

9

Policy” 44(10 ):10a-12a, 1985.

Geraldine R. Dodge Foundation, “Annual Reports, ”

Morristown, NJ, 1981-85.

Hart, L. G., Assistant to the Director, National Toxicology Program, Research Triangle Park, NC, personal communication, July 1985.

Holman, J., Director, Laboratory Animal Sciences

Program, Division of Research Resources, National

Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, personal

communication, July 1985.

10,

11,

12.

13.

14.

15.

16.

17.

18.

McKinney, P., Administrative Officer, Toxicolog-v

Research and Testing Program, National Institute

of Environmental Health Sciences, Research Triangle Park, NC, personal communication, July 1985.

Millenium Guild, “Half Million Dollar Rewards to

Get Rid of Lab Animal Suffering,” press release, New

York, Apr. 13, 1982.

INational Research Council, Models for Biomedical

Research: A New Perspective (Washington, DC: National Academy Press, 1985).

National Science Board, Science Zndica tors 1982

(Washington, DC: National Science Foundation,

1983).

Nethery, L. B., and McArdle, J. E., Animals in Product Development and Safety Testing: A Survey

(Washington, DC: The Institute for the Study of Animal Problems, Humane Society of the United States,

1985).

Resovsky, E. M., Director of Development, University of Pennsylvania School of Veterinary Medicine,

Philadelphia, PA, personal communication, Oct. 1,

1985.

Sabourin, T.D., Battelle Columbus Laboratories, Columbus, OH, personal communication, February

1985.

Shadduck, J. A., “Alternative Testing Methods: A

Proposal for the Development of Alternatives to

Ocular Irritancy Tests,” Grants and Contracts Office, University of Illinois at Champaign-Urbana,

Nov. 24, 1982.

Shapley, W., “Special Analyses, ’’AAAS Report X: Re-
272 . Alternatives to Animal Use in Research, Testing, and Education

search and Development, Fiscal Year 1986 (Washington, DC: American Association for the Advancement of Science, 1985).

19. The Johns Hopkins Center for Alternatives to Animal Testing, “New Grants Support Research to Simulate Human Exposure” 3(3):6, 1985.

20. Thurston, E., Director, American Fund for Alternatives to Animal Research, New York, personal

communication, Apr. 25, 1985.

21. Umminger, B. L., Deputy Director, Division of Cellular Biosciences, National Science Foundation,

Washington, DC, personal communication, February 1985.

22. US, Department of Health and Human Services

(DHHS), National Toxicology Program, “National

Toxicology Program: Fiscal Year 1984 Annual Plan,”

NTP-84-023 (Research Triangle Park, NC: DHHS,

February 1984).

23. U.S. Department of Health and Human Services

(DHHS), National Toxicology Program, “Review of

Current DHHS, DOE, and EPA Research Related to

Toxicology,” NTP-84-024 (Research Triangle Park,

NC: DHHS, February 1984).

24. U.S. Department of Health and Human Services

(DHHS), Public Health Service, National Institutes

of Health, NIH Data Book (Bethesda, MD: DHHS,

1985).

25. U.S. Department of Health and Human Services

(DHHS), Public Health Service, National Institutes

of Health, “NIH Federal Funds Data Submitted to

NSF,” Office of Program Planning and Evaluation

(Bethesda, MD: DHHS, April 1985).

26. U.S. Department of Health and Human Services

(DHHS), Public Health Service, Omnibus Solicitation

of the public Health Service for the Small Business

Innovation Research Grant Applications PHS Pub.

No. 86-1 (Bethesda, MD: DHHS, 1985).

27. Willett, J.D., “Biological Systems Used as Research

Models in NIH Programs,” Animal Resources Program, Division of Research Resources, National Institutes of Health, Public Health Service (Bethesda,

MD: DHHS, Sept. 24, 1984).

28. Willett, J.D., Project Officer, Biological Models and

Materials Resources Section, Animal Resources Program, Division of Research Resources, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda,

MD, personal communication, July 1985.
Chapter 13

Federal Regulation of Animal Use

There is a debate as to what is the right of a mouse. Why are we wasting time in

Washington with taking seriously this business?

James D. Watson

Cold Spring Harbor Laboratory

As quoted in Science 228:160, 1985
CONTENTS

Page

Federal Laws and Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

The Laboratory Animal Welfare Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

The Health Research Extension Act of 1985 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Other Federal Laws and Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

Agency Guidelines and Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

The Public Health Service Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Interagency Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Specific Agency Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Criticisms of the Present System of Federal Regulation . . . . . . . . . . . . . . . . . . . . 297

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Chapter 13 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

List of Tables

Table No. Page

13-1. Requests for Appropriations, Actual Appropriations, and Staff-Years,

USDA Animal and Plant Health Inspection Service, FiscaI Years 1980-85. . 287

13-2. Distribution of Research Facilities, by State, Registered With

USDA/APHIS Under the Animal Welfare Act.. . . . . . . . . . . . . . . . . . . . . . . . 288

13-3. Licensing, Registration, and Reporting Activity of Registered

Research Facilities Under the Animal Welfare Act, Fiscal Years 1978-83. . 289
Chapter 13

Federal Regulation of Animal Use

This chapter describes Federal law, as enacted

and currently interpreted, that directly governs

and regulates the acquisition and use of laboratory

animals for research and testing. Federal laws and

regulations governing the purchase, sale, handling,

or transportation in commerce of animals for exhibition, domestic, or other purposes unrelated

to research, testing, and education are not examined. Federal laws and regulations that have been

interpreted to require testing with certain methodologies or protocols are considered in chapter

7, and appendix B describes regulations promulgated and guidelines issued by specific Federal

agencies, pursuant to statutory authority, to regulate laboratory-animal use in required or sponsored research and testing.

FEDERAL LAWS AND

Long before passage of the Laboratory Animal

Welfare Act (Public Law 89-544) in 1966, Congress–following a trend against cruelty to animals

that had manifested itself in some States throughout the 19th century-in 1873 passed the first

Twenty-Eight Hour Law (Act of Mar. 3, 1873). Action was taken by the national legislature under

its powers to regulate interstate commerce because

of the toll exacted in animal flesh, literally, by inhumane conditions of rail transport for meat-producing livestock. The law barred confinement of

livestock in rail cars for longer than 28 hours,

Continuing expressions of concern led to repeal

of the original act and the passage in 1906 of the

Twenty-Eight Hour Law still in effect today (45

U.S.C. 71-74). (In the intervening three decades,

22 States passed general anticruelty statutes (13).)

Since enactment of the 1906 act preceded the rise

of interstate motor traffic, its provisions regulating length of confinement and conditions of treat -

ment during shipment do not apply to trucks (39).

Similar concerns about needless suffering undergone by food-producing animals led Congress to

pass the Humane Slaughter Act (public Law 85-

765) in 1958, permitting slaughter only by “humane” means.

After 1966, concerns about animals led to Federal protection of:

● Horsesl with the passage in 1970 of the Horse

Protection Act (public Law 91-929), against an

unesthetic physical practice on animals to

produce a physical appearance aesthetically

●

●

REGULATIONS

appealing to humans (“soring” the ankles to

produce a high-stepping gait);

marine mammals as a class (whales, porpoises, seals, and polar bears, for the most

part), with the passage in 1972 of the Marine

Mammal Protection Act (Public Law 92-522)

against extinction or depletion from indiscriminate taking, including hunting, harassment,

capture, and killing (permitted takings, including for subsistence and research purposes,

must be accomplished humanely, with “the

least degree of pain and suffering practicable

to the animal”); and

endangered and threatened species, with

the passage in 1973 of the Endangered Species Act (Public Law 93-205), making it unlawful to buy, sell, or transport in interstate or

foreign commerce any species found to be endangered and closely regulating commerce in

any species threatened with extinction.

Thus, Congress has acted on several occasions

over the past century to protect animals, both as

individuals and as species (i.e., marine mammals

and endangered species). The degree of commitment to protection of animals through proscription, regulation, and enforcement varied, with

Congress exhibiting a tendency toward stricter

controls beginning in the 1970s. Similarly, recent

exercising of the constitutional authority of the

Federal Government over interstate commerce

seems to be based on interests broader than the

welfare or treatment of individual animals -e.g.,

saving a species from extinction.

275
276 ● Alternatives to Animal Use in Research, Testing, and Education

Congressional handling of humane treatment for

experimental animals, discussed in this chapter,

is an interesting mixture: It professes to protect

the individual animal (e.g., the experimental subject), but it establishes classifications that favor

some animals over others. It uses Federal authority over interstate commerce to regulate the procurement and housing of laboratory animals, but

it does not use it to the same degree as for other

animals in other circumstances. Though Congress

has found less-than-humane treatment of laboratory animals to be worth exercising authority over

interstate commerce in order to control, it has not

judged the burden on commerce to be serious

enough to preempt the regulatory field. By a cautious exercise of its power, Congress has acknowledged implicitly that there is some intrinsic public value in animal experimentation and that the

uniqueness of the process of experimentation requires a deliberate approach, in order to achieve

one policy objective without sacrificing the other.

The Laboratory Animal Welfare Act

The 1966 Act

Finding increasing evidence that dogs and cats

owned as pets were being stolen by unscrupulous

dealers, moved across State lines, and resold to

research institutions to satisfy a demand for experimental subjects, Congress enacted the Laboratory Animal Welfare Act in 1966. The act sought

to head off these abuses by requiring dealers and

research facilities that handle, care for, treat, or

transport certain animals “in commerce” to follow standards to be developed and issued by the

U.S. Department of Agriculture (USDA). The purposes of the act were:

●

●

●

“In

to protect the owners of dogs and cats from

theft of such pets;

to prevent the use or sale of stolen dogs or

cats for purposes of research or experimentation; and

to establish humane standards for the treatment of dogs, cats, and certain other animals

by animal dealers and medical research facilities.

commerce” meant interstate commerce between States, the District of Columbia, territories,

and possessions; between points within a State,

the District of Columbia, a territory, or a possession, but through an outside point; or within the

District of Columbia, a territory, or possession.

Thus, to be covered by the act a dealer or research

facility would have to acquire, for a use covered

by the act, a regulated animal that had moved, or

at some point would move, “in commerce.”

Although “animal” was defined to include nonhuman primates, guinea pigs, hamsters, and rabbits, recordkeeping requirements were restricted

to dogs and cats. Humane treatment was required

on the premises of animal dealers, in transit, and

at research institutions. The act established a system for licensing dealers and registering research

facilities, with monitoring by Federal regulators.

The Secretary of Agriculture was vested with the

power to promulgate and enforce standards for

humane care, treatment, and housing of protected

animals. The act provided for the suspension of

the license of any dealer violating its provisions

and, upon conviction, imprisonment of not more

than 1 year and a fine of not more than $1,000.

The law’s reach extended to transportation of regulated animals by the supplier, but not by common

carriers. The Secretary was authorized to cooperate with State and local officials to prevent theft

of dogs and cats, apprehend pet thieves, and administer the previsions of the act. In addition, the Secretary was directed to establish rules for inspections of premises and of the required records of

licensed dealers and registered research facilities,

primarily to expedite the search for stolen pets.

As applied to research, the act’s reach was short.

Research facilities to be regulated were limited by

definition to those that:

. used or intended to use dogs or cats in experiments, and

● either purchased them “in commerce” or received any Federal funds for research, tests,

or experiments.

Covered facilities were required to register with

the Secretary rather than be subject to more stringent licensure requirements. Research-animal suppliers were subject to the new law’s requirements

only if they bought, sold, or transported dogs or

cats and if the dogs or cats supplied were used

for research by the client institution. In other

words, research facilities could continue to procure experimental animals from farms, munici-
Ch. 13—Federal Regulation of Animal Use . 277

pal pounds and shelters, and ‘(duly authorized

agents of local governments, ” rather than having

to acquire animals only from licensed dealers. Research facilities were defined to include ‘(major

research facilities and exclude the thousands of

hospitals, clinics, and schools which use other animals for research and tests, ” though research or

experimentation included use of animals as teaching aids in educational institutions associated with

major research facilities.

A specific and unequivocal exemption from

newly devised standards for humane treatment

for actual research activities was included. USDA

jurisdiction over research activities was confined

to care and treatment of research animals in an

institution’s holding facilities. The drafters of the

bill were careful to point out that the exemption

of research procedures was not to be compromised. The conference report stated the legislation’s intent was (38):

. . . to provide protection for the researcher in

this matter by exempting from regulation all animals during actual research or experimentation,

as opposed to the pre- and post-research treatment. It is not the intention of the committee to

interfere in any way with research or experimentation . . . [T]he Secretary is not authorized

to prescribe standards for the handling, care, or

treatment of animals during actual research or

experimentation by a research facility. The important determination of when an animal is in

actual research so as to be exempt from regulations under the bill is left to the research facility,

but such determination must be made in good

faith.

Regarding the power to require regular recordkeeping and to inspect premises to assure compliance, the committee intended:

. . . that these inspectors will be employees of the

U.S. Department of Agriculture. . . [and that] inspectors not be permitted to interfere with the

carrying out of actual research or experimentation as determined by a research facility. . . [and]

that inspection. . . be specifically limited to searches

for lost and stolen pets by officers of the law (not

owners themselves) and that legally constituted

law enforcement authorities means agencies with

general law enforcement authority and not those

agencies whose law enforcement duties are limited to enforcing local animal regulations. It is not

intended that this section be used by private citizens to harass or interfere in any way with the

carrying out of research or experimentation. Such

officers cannot inspect the animals when the animals are undergoing actual research or experimentation.

Unlike dealers, research facilities were subject only

to civil penalties (a fine of up to $500 for each offense) for violation of the act.

In the Senate committee’s report on its version

of the bill leading to the act, comments from relevant executive agencies were included. The Departments of Commerce and the Treasury and the

Federal Aviation Administration deferred to the

views of USDA and the Department of Health, Education, and Welfare (DHEW). The Under Secretary

of DHEW opposed licensure for research facilities

and restrictions on procurement by them of experimental subjects from other than licensed sources.

Noting that the agency charged with enforcing the

new law would be USDA, the letter expressed support “for sound legislation to alleviate abuses which

now exist in the transportation, purchase, sale,

and handling of animals intended for use in research laboratories .“ The Secretary of Agriculture

responded as follows (38):

This Department conducts programs in research related to animal production and animal

diseases. In addition, it is charged with the administration of programs for the control and eradication of infectious, contagious, and communicable diseases of livestock and poultry; for the

prevention of the introduction and dissemination

[in] the United States of such diseases; and for

the prevention of the exportation of diseased livestock and poultry. It also administers laws regarding the humane slaughter and treatment of

livestock.

. . . There are many State laws covering [illicit

traffic in family pets] and licensing requirements

pertaining to dogs are common. Since the operating methods of people who steal family pets and

the commercial aspects of the purchase and transfer of dogs and cats in commerce are not areas

as to which this Department has expertise, we

are unable to evaluate the effectiveness of existing State laws. In respect to animals, the functions of this Department relate basically to livestock and poultry, Accordingly, there is a question

as to whether it would not be desirable that a law

such as that in question be administered by a Fed-
278 ● Alternatives to Animal Use in Research, Testing, and Education

eral agency more directly concerned and having

greater expertise with respect to the subject than

this Department.

USDA estimated that administration of the act

would cost approximately $2 million per year. It

was authorized to assess “reasonable” fees for

licenses issued. Judging that the exact cost was

undeterminable, because it was not known how

many new dealers would be licensed, Congress

included a general authorization for appropriations (38).

1970 Amendments

Continued allegations of poor treatment of animals by unregulated parties and expressions of

concern for experimental animals besides dogs and

cats prompted Congress to pass the Animal Welfare Act of 1970 (Public Law 91-579) to cover a

broader class of animals, including those exhibited

to the public and sold at auction, and to regulate

anyone engaged in those activities.

The amendments broadened the 1966 act’s coverage beyond dogs, cats, monkeys, guinea pigs,

hamsters, and rabbits to protect all warm-blooded

animals as the Secretary of Agriculture may determine are being used for research, testing, experimentation, exhibition, or as pets. Excluded specifically from the new definition were horses not

used for research and other livestock, poultry, and

farm animals used for food or fiber production

(7 U.S.C. 2132@). The 1970 amendments define

the word “animal” as:

. . . any live or dead dog, cat, monkey (nonhuman

primate animal), guinea pig, hamster, rabbit, or

other such warm-blooded animal, as the Secretary may determine is being used, or is intended

for use, for research, testing, experimentation,

or exhibition purposes, or as a pet.

The act does not appear to give the Secretary

the discretion to determine that a warm-blooded

animal used for experimentation is not an “animal” for purposes of the act. The act gives the Secretary the authority to determine only whether

or not a warm-blooded animal is being used or is

intended for use for experimentation or another

named purpose. If the warm-blooded animal is

judged as being used in that way, it is an “animal”

under the act’s coverage (6).

In 1977, the Secretary promulgated regulations

that specifically excluded rats, mice, birds, and

horses and other farm animals from the definition of “animal” (9 CFR I. I(n),(o)). The introductory

comments published by the Secretary upon issuing the regulation did not discuss the basis for this

exclusion (42 FR 31022) (6).

The Secretary’s 1977 regulatory exclusion of rats

and mice from coverage by the act appears to be

inconsistent with the language of the 1970 amendments. The exclusion of rats and mice from the

definition of “animal” appears to frustrate the policy Congress sought to implement in 1970 and consequently to be beyond the Secretary’s statutory

authority (6).

The Secretary’s enforcement powers over the

expanded classes of licensees and registrants were

broadened by adding to the definitions of “commerce” and “affecting commerce.” These expanded

concepts made it plain that the act extended to

trade, traffic, commerce, and transportation among

States and, further, that Congress considered any

activity leading to the inhumane care of animals

used for purposes of research, experimentation,

exhibition, or held for sale as pets as constituting a

burden, obstruction, or a substantial effect on the

free flow of commerce. Penalties exacted against

persons convicted of interfering with, assaulting,

or killing Federal inspectors were increased, and

the Secretary’s authority to obtain adequate information to sustain administration was augmented

by broadening discovery procedures. A new provision was added, establishing a legal agency relationship between a covered entity and any person acting for or employed by that entity, essentially to

ensure that the Secretary could hold licensees and

registrants to account for the acts, omissions, and

failures of their agents or employees.

The definition of research facility was amended

to include those using covered live animals, not

just live dogs and cats, but the Secretary was given

the authority to exempt institutions not intending

to use live dogs or cats, unless other animals would

be used in “substantial numbers.” Regulation of

covered research facilities was increased to require

annual reporting and to add civil penalties for any

refusal to obey a valid cease and desist order from

the Secretary.
Ch. 13–Federal Regulation of Animal Use ● 279

The amendments announced a commitment to

the humane ethic that animals should be accorded

the basic creature comforts of adequate housing,

ample food and water, reasonable handling, decent sanitation, sufficient ventilation, shelter from

extremes of weather and temperature, and adequate veterinary care, including the appropriate

use of pain killing drugs. Besides adding handling

to the basic categories of care, treatment, and transportation of covered animals, the standard of “adequate veterinary care” was broadened to include

the appropriate use of anesthetic, analgesic, or

tranquilizing drugs, when the use of such drugs

is considered proper in the opinion of the attending veterinarian at a research facility.

The prohibition on interference with research

was qualified in 1970 with a proviso that every

covered research facility must show, at least annually, that professionally acceptable standards

of animal care, treatment, and use are being followed by each research facility during actual research or experimentation. However, the intent

regarding the continued prohibition on interference in experimentation itself was clear (35):

. . . it is the intention of the committee that the

Secretary neither directly nor indirectly in any

manner interfere with or harass research facilities during the conduct of actual research or experimentation. The important determination of

when an animal is in actual research is left to the

research facility itself.

Similarly, the House Committee on Agriculture’s

report on this bill stated that the inspection section applies only to agencies with general law enforcement authority and is not intended to "be used

by private citizens or law enforcement officers to

harass research facilities and in no event shall such

officers inspect the animals when the animals are

undergoing actual research or experimentation .“

In summarizing these provisions, the report said

that “the research scientist still holds the key to

the laboratory door. This committee and Congress,

however, expect that the work that’s done behind

that laboratory door will be done with compassion and with care” (35).

The committee report included a letter from the

USDA Under Secretary indicating the Department:

●

●

●

was doing everything possible to carry out its

assigned responsibilities under the act within

the limitations of available resources of a fiscal year 1970 appropriation of $337)000;

agreed with the objective of the legislation concerning the need for humane care and handling of laboratory animals during actual research and experimentation, but believed “that

the Department of Health, Education, and Welfare is the appropriate agency to administer

such an activity. We would expect to work

with that Department to help assure consistency of standards and make other necessary

arrangements to promote the objectives of

both [laws]”; and

suggested that regulating the humane care and

handling of animals by exhibitors should be

the responsibility of State and local agencies,

rather than the Federal Government.

The committee’s report, noting that license fee

collections and appropriations in fiscal year 1971

were expected to total $376,600, projected that

the responsibilities added by the 1970 amendments

would increase related program costs by approximately $1.2 million annually. The report responded

to research facilities’ concerns that compliance

with higher standards for adequate veterinary care

would require substantial expenditures for new

plants, equipment, and better trained personnel

by urging “that adequate funds from Federal

sources be made available for those research facilities which depend to a large extent on support

derived from both State and Federal sources for

laboratory facility improvements” (35).

1976 Amendment s

Amendments to the Animal Welfare Act in 1976

(Public Law 94-279) enlarged its provisions to define more sharply and to simplify the regulation

of animals treated inhumanely during transportation affecting interstate commerce and to combat ventures involving animal fighting. In brief,

the amendments having an effect on experimentation:

● added a specific finding that activities or animals regulated by the act are in interstate and

foreign commerce and do, in fact, burden or
280 . Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

●

●

●

●

●

substantially affect the free flow of commerce,

making regulation necessary to relieve those

burdens;

reordered the statement of policy to reflect

Congress’ desire to:” 1) insure that animals intended for use in research facilities or for exhibition purposes or for use as pets are provided

humane care and treatment; 2) to assure the

humane treatment of animals during transportation in commerce; and 3) to protect the

owners of animals from the theft of their animals by preventing the sale or use of animals

which have been stolen’’—in that order;

simplified the definition of “commerce” by

eliminating the definition of “affecting commerce)” and substituting a definition of “State”

(the conference committee resisted an attempt

to narrow the definition of “commerce” by

adopting a provision from the Senate-passed

bill that would have done so with an amendment that retained the act inclusion of commerce between intrastate points but through

a place outside the State);

extended required “dealer” licensure by redefining “dealer” to include persons who negotiate the purchase or sale of protected animals for profit;

broadened the definition of animal to correct

a then-existing interpretation that hunting,

security, and breeder dogs did not fall within

the act’s protection;

required carriers and intermediate handlers

of animals, not otherwise required to be licensed, to register with the Secretary;

extended the agency relationship, recordkeeping, and other existing regulatory requirements to carriers and intermediate handlers;

increased the Secretary’s options for enforcement and collections by revising the section

on penalties and appeals and by increasing

the daily civil penalty for violation of cease

and desist orders from $500 to $1,000 for all

classes of regulated parties;

extended to Federal research facilities the existing requirement to demonstrate at least annually that professionally acceptable standards governing the care, treatment, and use

of animals are being followed; and

required the Secretary to consult and cooperate with other Federal departments, agencies, or instrumentalities concerned with the

welfare of research animals, where transportation or handling in commerce occurs.

USDA estimated that the enlarged responsibilities for establishment and enforcement of humane

transportation standards and certification practices and the oversight of compliance by carriers

and intermediate handlers would increase its annual operating costs by $565,000 in fiscal year 1977

and $385,000 per year thereafter. (The decline in

required outlays in future years was attributed

to a reduced need for training and orientation.)

The Congressional Budget Office (CBO) estimated

a total startup cost in fiscal year 1977 of $968,000—

some $570,000 for transport standards and certification enforcement and $398)000 for investigation

of animal fighting ventures. That estimate projected a gradual increase in each segment of new

enforcement outlays for 5 years, with total costs

for these new responsibilities rising to $1,304)

000

by fiscal year 1981. CBO questioned USDA’s estimates of declining costs, pointing out that USDA

had factored in neither anticipated higher salary

costs in the future nor the total anticipated cost

of enforcing the new Federal ban on animal fighting. Neither agency projected any offsetting increase in miscellaneous receipts, since newly covered carriers and intermediate handlers would not

be required to become licensed. Reflecting uncertainty about the total costs of the new effort to

regulate animal transport, House and Senate conferees agreed to remove the House-passed funding

ceiling of $600,000 per year, though the annual

ceiling for enforcing animal-fighting prohibitions

was fixed at $400,000 (36).

1985 Amendment s

With the enactment of the Food Security Act of

1985 (Public Law 99-198), Congress amended the

Animal Welfare Act for the third time. The amendments, effective December 1986, strengthen standards for laboratory-animal care, increase enforcement of the Animal Welfare Act, provide for the

dissemination of information to reduce unintended

duplication of animal experiments, and mandate

training for personnel who handle animals. For

the first time, the Department of Health and Human Services is brought into the enforcement of

the Animal Welfare Act, as the Secretary of Agri-
Ch. 13—Federal Regulation of Animal Use . 281

culture is directed to “consult with the Secretary

of Health and Human Services prior to the issuance of regulations” under the act.

The statute requires the Secretary of Agriculture to issue minimum standards for all aspects

of the veterinary care of animals, including standards for the exercise of dogs and a physical environment adequate to promote the psychological

well-being of primates. The Secretary shall require

that no animal be used in more than one major

operative experiment from which it is allowed to

recover, except in cases of scientific necessity or

by determination of the Secretary.

Each research facility covered by the Animal

Welfare Act—including Federal facilities—is required to appoint an institutional animal committee that includes at least one doctor of veterinary

medicine and one member not affiliated with the

facility. The latter is intended “to provide representation for general community interests in the

proper care and treatment of animals.” Any member of the committee revealing confidential information is subject to a fine of up to $10,000 and

three years’ imprisonment. The committee must

inspect all animal study areas at least twice a year.

USDA shall inspect each facility at least once a year,

and each facility is required to report at least annually to USDA that the provisions of the act are

being followed. (Committees in Federal facilities

will report not to USDA, but to the head of the

Federal entity.)

This provision for institutional animal committees, taken in concert with similar provisions in the Health Research Extension Act of

1985 (Public Law 99-158) and the policy of the

Public Health Service (see app. C), brings the

overwhelming majority of experimental-animal users in the United States under the oversight of a structured, local review committee.

USDA is directed to establish an information service at the National Agricultural Library (NAL). The

service, in cooperation with the National Library

of Medicine, shall provide information that could

prevent the unintended duplication of animal experimentation, reduce or replace animal use, minimize animal pain or distress, and aid in the training of personnel involved with animals.

The law requires research facilities to provide

for scientists, animal technicians, and other personnel involved with animal care and treatment

training on:

● the humane practice of animal maintenance

and experimentation;

● methods that minimize or eliminate the use

of animals or limit animal pain or distress;

● the utilization of the NAL information service; and

● the way to report deficiencies in animal care.

Current Provisions Governing Research

In addition to the provisions of the 1985 amendments, there are 14 key provisional of the Animal

Welfare Act, as amended, that affect research facilities:

● Definition of “Research Facility. ” The act

defines “research facility” to cover any individual, institution, organization, or postsecondary school that uses or intends to use live

animals in research, tests, or experiments and

that purchases or transports live animals in

commerce or receives Federal funds for research, tests, or experiments. Exemptions may

be granted where dogs or cats are not used,

except where the Secretary determines that

substantial numbers of other types of warmblooded animals are used and the principal

purpose of the entity covered is biomedical

research or testing [7 U.S.C.A. 2132(e)]. For

these to be a violation under this provision,

it must be established that Federal jurisdiction extends to the particular facility—either

that some connection exists between animals

acquired or used and interstate commerce,

or that Federal funding support is received

for the contemplated research. Research facilities that receive no Federal support for experimental work and that either purchase animals

IPertinent previsions of the act are discussed in the order they

appear in the U.S. Code, with cross-references where appropriate.

A]] parenthetical references in this section are to current provisions

of chapter 54 of Title 7 of the Code, which can be found in Title

7, “Agriculture,” IV.S. C’ode Annotated, $52131-2152 (St. Paul, NIN:

Wrest Publishing Co.), 1973 Edition (126-139) and 1984 Supplement

(126-139).

38-750 0 - 86 - 10
282 . Alternatives to Animal Use in Research, Testing, and Education

●

●

●

●

within their own State or maintain intramural

breeding colonies are not “research facilities”

under this definition.

Registration Requirement. Research facilities not otherwise required to be licensed as

a dealer or exhibitor are required to register

with the Secretary [7 U.S.C.A. 2136]. Most U.S.

research facilities covered by the act are thus

required only to register, rather than to pay

license fees and submit to more stringent compliance requirements and criminal penalties.

A “dealer” is someone engaged in interstate

trade of regulated animals for research, teaching, or exhibition, or for companion, hunting,

breeding, or security purposes. ‘(Exhibitors”

include carnivals, circuses, and zoos touching commerce in some way, excluding “retail

pet stores, organizations sponsoring and all

persons participating in State and county fairs,

livestock shows, rodeos, purebred dog and

cat shows, and any other fairs or exhibitions

intended to advance agricultural arts and

sciences)” as determined by the Secretary [7

U.S.C.A. 2132(h)],

Acquisition of Dogs and Cats. Covered research facilities (including Federal agencies

[7 U.S.C.A. 2138]) may not purchase dogs or

cats from anyone other than a person holding a valid license, unless the seller is not required to be licensed by the act, or an operator of an auction sale [7 U.S.C.A. 2137], who

may also need a license [7 U.S.C.A, 2142], Only

dealers and exhibitors who meet the act’s definitions for those activities, and auction sellers who sell dogs or cats “affecting commerce)”

must be licensed.

Responsibility for Employees and Agents.

A principal-agent relationship between research facilities and their agents or employees concerning any “act, omission, or failure”

is created by statute [7 U.S.C.A. 2139]. This

provision creates a legal presumption that a

covered research entity knows about, and is

responsible for, transgressions of the act by

its employees or authorized agents.

Recordkeeping for Animals Research facilities must make and retain records only with

respect to the purchase, sale, transportation,

identification, and previous ownership of live

dogs and cats [7 U.S.C.A. 2140].

●

●

●

●

Animal Marking Requirements. Generally,

the act requires that all animals delivered for

transportation, transported, purchased, or

sold, in commerce by a dealer or exhibitor be

marked or identified as required by the Secretary. Research facilities need only mark or

identify live dogs and cats (7 U.S.C.A. 2141].

Compliance With Auction Sale Rules. Research facilities involved in purchase, handling,

or sale of animals in commerce at auction sales

must comply with humane standards and rec -

ordkeeping requirements established by the

Secretary to regulate those activities [7

U.S.C.A. 2142].

Standards of Care and Treatment. The general grant of rulemaking authority to the Secretary for establishing minimum requirements

for handling, housing, feeding, watering, sanitation, ventilation, shelter from extremes of

weather and temperature, adequate veterinary care (including appropriate use of anesthetic, analgesic, or tranquilizing drugs, when

such use would be proper in the opinion of

the research facility’s attending veterinarian),

and separation of species when necessary may

not be construed as authorizing the Secretary

to promulgate rules, regulations, or orders

with regard to design, outlines, guidelines, or

performance of actual research or experimentation by a research facility as determined by

such research facility. But the Secretary must

require every facility to show annually that

professionally acceptable standards governing animal care, treatment, and use, “including appropriate use of anesthetic, analgesic,

and tranquilizing drugs, during experimentation are being followed by the research facility during actual research or experimentation” [7 U.S.C.A. 2143(a)].

‘Animal Certification Requirements. Research facilities may not deliver for handling

or transportation in commerce any dog, cat,

or other designated animal without a certificate of inspection, executed by a licensed

veterinarian not more than 10 days prior to

delivery, for freedom from infectious diseases

or physical abnormalities that would endanger the animal or other animals or endanger

public health. The statute permits the Secre -

tarv bv regulation to exempt from this require-
Ch. 13—Federal Regulation of Animal Use . 283

●

●

●

●

●

ment animals shipped to research facilities for

purposes of research, testing, or experimentation requiring animals not eligible for such

certification [7 U.S.C.A. 2143(b)].

Minimum Age for Transport. Research facilities may receive dogs, cats, and other designated animals younger than the minimum

age requirement for transportation in commerce established by the Secretary pursuant

to the act [7 U.S.C.A. 2143(c)].

Federal Facilities Federal agencies with laboratory-animal facilities are required to comply with regulations for humane treatment in

commerce as they apply to nongovernmental

research facilities [7 U.S.C.A. 2144].

Inspections Research facilities are required

to grant inspectors reasonable access to their

places of business, facilities, animals, and records. Inspectors are empowered to confiscate

or destroy in a humane manner any animal

found to be suffering as a result of a failure

to comply with the act, its regulations, or

standards, if such animal is held by a research

facility and is no longer required by such research facility to carry out the research, test,

or experiment for which such animal has been

utilized [7 U.S.C.A. 2146(a)]. Research facilities

engaged in the purchase, handling, or sale of

animals are also required to permit inspections

by legally constituted law enforcement agencies in search of lost animals [7 U.S.C.A. 2147].

Penalties, Hearings, and Appeals. For any

violation of the act, its regulations, or standards, a research facility maybe assessed a civil

penalty up to $2,500 for each day of noncompliance. Knowing failure to obey a cease and

desist order can result in an additional penalty of $1,500 for each day of noncompliance.

Research facilities are not subject to criminal

penalties for violations [7 U.S.C.A. 2149(b),

(c),(d)].

Annual Report to Congress. Each March,

the Secretary of Agriculture is required toreport to Congress the identification of all research facilities that are required or choose

to be licensed, the nature of all investigations

and inspections conducted and reports received, and the Secretary’s suggestions for

legislative changes to improve the administration of the act. The annual enforcement report

cannot be released to non-Federal entities until

it has been made public by a congressional

committee [7 U.S.C.A. 2155].

Regulations

Congress intended that the broad statutory framework it had erected in the Animal Welfare Act be

fleshed out to achieve the law’s general objectives.

USDA received common grants of discretionary

power and ministerial duties, giving the Secretary

both latitude to exercise judgment in enforcing

the law and the obligation to execute a number

of distinct duties.2

Responsibility for administration was delegated

by the Secretary to the Administrator of the Animal and Plant Health Inspection Service (APHIS).

Ministerial and enforcement duties are the province of the APHIS Deputy Administrator for Veterinary Services, and initial collection of records and

supervision and assignment of inspectors are done

by Veterinarians-in-Charge, based in APHIS’s State

offices in each of five geographic regions throughout the United States. Except for the Northeast region (served centrally by a Boston office), every

State has an APHIS office, usually in the capital

[7 CFR 371.2(a),(d); 9 CFR l.l(a)-(j)l. Inspectors

known as Veterinary Services Representatives perform investigative tasks in consultation with an

attending veterinarian or with a three-member

committee employed by a registered research facility (one of whom must be a licensed veterinarian), which is responsible for evaluating the type

and amount of anesthetic, analgesic, and tranquilizing drugs used on animals during actual research,

testing, or experimentation where appropriate to

relieve all unnecessary pain and distress in the subject animals [9 CFR l.l(ee)].

“Animal” includes ‘(any live or dead dog, cat,

monkey (nonhuman primate mammal), guinea pig,

hamster, rabbit, or any other warm-blooded animal, which is domesticated or raised in captivity

or which normally can be found in the wild state,

ZPertinent provisions are discussed in this section in the order in

which they appear in the published regulations, with cross-references

where appropriate. All parenthetical references are to Title 7, Part

371, and Title 9, Parts 1-4, of the U.S. Cocfe of Fecfera/ Regulations

(Washington, DC: General Services Administration, 1984).
284 ● Alternatives to Animal Use in Research, Testing, and Education

and is being used, or is intended for use, for research, testing, experimentation or exhibition purposes, or as a pet” [9 CFR I. I(n)]. By regulation,

this definition excludes birds, rats, mice, and horses

and other farm animals intended “for use as food

or fiber, or livestock or. . . [for] improving animal

nutrition, breeding, management, or production

efficiency, or for improving the quality of food or

fiber” [9 CFR 1.l(n),(o)l. The definition of “dog” is

enlarged to include those used for hunting, security, or breeding purposes [9 CFR l.1(1)-(n),(q)]. The

farm-animal exemption and expanded dog definition reflect changes in the act made in 1970 and

1976. The only warm-blooded animals, other than

those specified in the act, that the Secretary has

chosen to designate are marine mammals.

A research facility not otherwise required to be

licensed must register with APHIS by completing

a standard registration form and filing it with

the office in the State of its principal place of business. The registrant receives a copy of the form

and “applicable standards” from APHIS and is required to acknowledge their receipt and agree to

comply with the standards by signing a form [9

CFR 2.25-2.26].

Each “reporting facility” (each segment of a registered facility using experimental animals and for

which an attending veterinarian has responsibility, including departments, agencies, and instrumentalities of the United States) must file an annual report, signed by a legally responsible official,

showing that professionally acceptable standards

governing the care, treatment, and use of animals,

including appropriate use of anesthetic, analgesic, and tranquilizing drugs, during actual research, testing, or experimentation, were followed

by the facility. The report, due by December 1 and

covering the preceding Federal fiscal year (Oct.

l-Sept. 30)) must include:

● the location of the facility where animals were

used;

. common names and approximate numbers of

animals on which research, experiments, or

tests were conducted involving:

(a) no pain, distress, or use of pain-relieving

drugs;

(b) accompanying pain or distress to the animals, for which appropriate anesthetic,

●

analgesic, or tranquilizing drugs were used;

and

(c) pain or distress to the animals for which

the use of appropriate anesthetic, analgesic, or tranquilizing drugs would adversely

affect the procedures, results, or interpretation of the research, experiments, or tests

and a brief statement explaining the reasons for the same (in all three cases, routine procedures—injections, tattooing, and

blood sampling–need not be reported);

and

certification by the attending veterinarian or

institutional committee that the type and amount

of anesthetic, analgesic, and tranquilizing

drugs used on animals during research, testing, or experimentation was appropriate to

relive pain and distress for the subject animals (9 CFR 2.28).

Research facilities must observe certain requirements for maintaining identification of dogs and

cats either received from or consigned for delivery into commerce. Live dogs and cats so consigned

must bear either the original tag or tattoo, or a

tag, tattoo, or collar supplied by the facility, that

identifies each animal by description or number

[9 CFR 2.50e)].

Records on acquired dogs or cats must be kept

and maintained to disclose the name and address

of the person from whom the animal was acquired;

the official tag number or tattoo; a description of

each live dog or cat, including species, sex, date

of birth or approximate age, color and distinctive

markings, and breed or type; and the number assigned to the animal by the facility.

Facilities that transport, sell, or otherwise dispose of a live dog or cat must maintain on forms

furnished by APHIS, in addition to the above information, the name and address of the person

into whose custody the animal is delivered, the

date of delivery, and the method and identification of mode of transportation.

Research facilities may not destroy or dispose

of required records without the written consent

of APHIS, and records must be held for longer

where necessary to comply with any other Federal, State, or local law (9 CFR 2.100). Research
Ch. 13–Federal Regulation of Animal Use ● 285

facilities (like dealers, exhibitors, and auction operators) must open their records to APHIS requests

for information and inspections related to the act’s

enforcement as well as their facilities, during ordinary business hours, and they must be willing

to have the facility’s name published in a periodic

list of registered facilities (9 CFR 2.126-2.127). They

must also open their premises to inspection by police or legally constituted law enforcement agencies with general law enforcement authority (other

than agents whose sole authority is to enforce local animal regulations) for inspections for missing animals, where the authority provides a description of the animal and the owner’s name and

address and agrees to abide by institutional policies concerning spread of disease and animal

escape, but such searches cannot be extended to

animals undergoing actual research or experimentation, as determined by the facility (9 CFR 2. 128).

An APHIS inspector can act to confiscate and

destroy an animal found to be suffering as a result

the

●

●

●

of a research facility’s failure to comply with

act, its regulations, or its standards only:

if the animal suffering through such failure

is no longer required to carry out the research,

test, or experiment for which it has been

utilized;

if the inspector has made a reasonable effort

to notify the facility and request that the responsible condition be corrected or appropriate veterinary care be given, and the facility

refuses to comply; or

if the inspector is unable to locate or notify

a representative of the facility, in which case

a local law enforcement officer may be contacted to accompany the inspector to the

premises to either provide veterinary care or

confiscate and destroy the suffering animal.

Costs of care or destruction are to be borne by

the violator facility. If the animal to be destroyed

is an endangered species, the Deputy Administrator is required to consult with the Department of

the Interior and the International Union for the

Conservation of Nature and Natural Resources [9

CFR 2.129].

Research facilities are required to comply with

detailed standards for humane care and treatment,

except that nothing in the rules, regulations, or

standards may affect or interfere with the design,

outlines, guidelines, or performances of actual research or experimentation by a research facility

as determined by such research facility (9 CFR

2.100(a)).

Part 3 of the regulations details specific standards for humane care and treatment according

to category of defined animal—dogs and cats,

guinea pigs and hamsters, rabbits, nonhuman primates, marine mammals, and warm-blooded animals other than the above species-under three

headings:

●

●

●

Facilities and Operating Standards (general,

indoor, and outdoor facilities and primary enclosures);

Animal Health and Husbandry Standards

(feeding, watering, sanitation, employees, classification and separation, and veterinary care);

and

Transportation Standards (consignment to

carriers and intermediate handlers, primary

enclosures used for transport, primary conveyances [motor vehicle, rail, air, and marine],

food and water requirements, care in transit, terminal facilities, and handling).

Although specific environmental requirements

differ by category of defined animal, the pattern

of each set of standards is quite similar. The primary difference with respect to research facilities

pertains to the veterinary care standards for each

animal, which contain the following common provisions: “Programs of disease control and prevention, euthanasia, and adequate veterinary care

must be established and maintained under the supervision and assistance of a doctor of veterinary

medicine. ” Specifically, research facilities must:

● include the appropriate use of anesthetic, analgesic, or tranquilizing drugs in their programs

of veterinary care, when such use would be

proper in the opinion of the attending veterinarian. The use of these three classes of drugs

shall be in accordance with the currently accepted veterinary medical practice, as cited

in appropriate professional journals or reference guides, which shall produce in the individual subject animal a high level of tranquilization, anesthesia, or analgesia consistent with

the protocol or design of the experiment;
286 . Alternatives to Animal Use in Research, Testing, and Education

● provide guidelines and consultation to research personnel regarding type and amount

of the three classes of drugs recommended

as being appropriate for each species of animal, through the animal care committee or

attending veterinarian; and

● assure that the use of the three classes of drugs

effectively minimizes the pain and discomfort

of the animals while under experimentation

[9 CFR 3.10, 3.34, 3.59, 3.84, 3.110, 3.134].

Few petitions for changes in existing regulations

have been made. No person or organization has

used the formal rulemaking process to seek to add

any classes of warm-blooded animals. In 1982, the

Humane Society of the United States filed a petition for rulemaking and collateral relief that,

among other things, sought definitions of the terms

‘(pain,” “distress,” and “routine procedures” and

a requirement that research facilities explain in

adequate detail why pain-relieving drugs are withheld from animals used in experiments acknowledged to cause pain and distress (12).

In summary, USDA’s approach has been literal

and cautious with regard to research facilities. This

position can be traced to two influences. First, both

the act itself and its legislative history make clear

Congress’ desire to avoid any entanglement in the

actual conduct of research. Second, both the legislative and executive commitments of funds and

personnel for enforcement have never lived up

to the expectations of those who believe the primary mission of the existing law to be the prevention or alleviation of experimental-animal suffering.

Enforcement

The responsibilities of APHIS in enforcing the

Animal Welfare Act fall into three main categories:

. making, implementing, and enforcing policies

and rules for national and international programs to protect the health of US. livestock

and poultry resources, assuring quality and

safety of veterinary biologics, and providing

for the welfare and humane treatment of certain animals;

● cooperating and providing technical assistance

to State and local governments regarding international quarantines and exotic animal disease programs; and

● providing professional development and training for APHIS personnel and training for foreign visitors in veterinary service programs.

Nineteen public laws outline APHIS’s duties in

the first area, including the Animal Welfare Act,

the Horse Protection Act, and the Twenty-Eight

Hour Law (49 FR 26674). By far, the most timeand resource-consuming APHIS objective is protecting domestic plants and livestock from diseases

and pests, Of 841 pages in the code of Federal Regulations on APHIS duties and programs, only 100

are devoted to animal welfare activities under the

relevant acts (7 CFR 1984 ed. 371.2). Port-of-entry

inspections by APHIS seek to prevent the introduction of insects, plant diseases, nematodes, and animal pests and diseases harmful to crops and crop

products. Plant exports are controlled through a

certification system administered by APHIS, and

cooperative programs with States are conducted

to eradicate domestically established plant pests.

The APHIS mission, then, is traditionally bound

to certification, inspection, and cooperative assistance programs that govern agricultural activities,

devoted almost exclusively to protecting plants and

animals used to produce food and fiber.

The APHIS Assistant Deputy Administrator for

Animal Health Programs, under the Deputy Administrator for Veterinary Services, is responsible for directing enforcement activities through

four regional offices, located in Scotia, NY; Tampa,

FL; Englewood, CO; and Fort Worth, TX (50 FR

31341). (Prior to 1985, five regional offices existed

but this was changed in response to a review of

APHIS activities by the General Accounting Office

(GAO).) Licensing, registration, and inspection of

all regulated entities-dealers, exhibitors, research

facilities, carriers, intermediate handlers, and auction sales—are handled by a field force directed

by Veterinarians-in-Charge in the APHIS offices

in 45 State capitals. Field officials conducting animal welfare work include veterinary medical officers, compliance officers, and animal technicians.

Six veterinarians trained in laboratory-animal husbandry procedures coordinate animal welfare activities among the four regions (43), APHIS has 286

Veterinary Medical Officers (inspectors), who

spend approximately 6 percent of their time inspecting research facilities (25).
Ch. 13—Federal Regulation of Animal Use ● 287

Table 13-I summarizes funding and staff support dedicated to animal welfare activities, compared with the total APHIS budget and equivalent

staff-years, for Federal fiscal years 1980-85. As a

percentage of the total budget for APHIS activities, animal welfare has consistently constituted

less than 2 percent.

Animal welfare appropriations have remained

virtually constant since fiscal year 1982, despite

gradual reductions in APHIS’s overall budget.

(Some of the decline in regular appropriations can

be traced to increases in fees collected for a variety of activities, though program-specific reductions have occurred (4),) The total number of staffyears spent on APHIS activities (calculated from

work -years available from authorized positions for

which general appropriations are made) declined

steadily from fiscal year 1980 through fiscal year

1985. That decline is reflected proportionately in

animal welfare activities, but the percentage of

staff -years devoted to those activities has remained

constant and, as a percentage of the total staff time,

is slightly higher than that of appropriated funds.

As of March 1985, a total of 1,286 research facilities had registered with APHIS as using covered

animals, as having acquired them in commerce,

or as receiving related Federal funding support.

Sixty-four percent of the principal registered research facilities (RRFs) are located in just 10 populous States (California, New York, Pennsylvania,

Ohio, Massachusetts, New Jersey, Texas, Illinois,

Michigan, and Florida; see table 13-2); most facilities are close to urban centers. These numbers

are for the principal registrants only, not the total

number of research sites. A university campus system, for example, is only required to register once

under the act, though it may have a number of

sites where research or tests are performed. The

location of licensees (dealers and exhibitors), other

registrants (carriers and intermediate handlers),

and violators of the act animal-fighting prohibition may not, of course, exhibit a similar distribution. Given APHIS’s traditional and overarching

duties to protect food-and fiber-producing plants

and animals as well as the Animal Welfare Act’s

exemption from coverage of most agricultural research, it seems that not even the major share of

animal welfare enforcement resources could be

targeted toward monitoring the care and treatment of experimental animals.

As the most widely used experimental subjects—

mice and rats—have been excluded by USDA regulation from the act’s coverage (9 CFR l.l(n),(o)),

current regulations probably do not affect a substantial percentage of animals used for experimental purposes. This can be tested in a crude way

by comparing the 1984 Directory of Toxicology

Laboratories, compiled by Chemical Times and

Trends (CT&T), with APHIS’s 1984 List of Registered Research Facilities. Sixty-eight of 112 testing facilities, or 61 percent, listed in the CT&T

directory also appear by name in the APHIS registration list; 39 percent are not registered. This implies no wrongdoing on the part of unregistered

toxicity testing labs, since they may not fall under

any of the definitional requirements for compliance with the act. The number of unregistered

facilities is conservative, however; for purposes

of comparison, it was assumed that all universityaffiliated testing sites are covered by the parent

institution’s principal registration and that any

nonuniversity lab whose name approximates that

of another registrant is also covered. If rats and

Table 13.1 .- Requests for Appropriations, Actual Appropriations, and Staff-Years,

USDA Animal and Plant Health Inspection Service, Fiscal Years 1980-85

1980 1981 1982 1963 1984 1985

Total appropriation, APHISa (in thousands) . . . . . . . . . . . . . $249,098 $282,385 $281,967 $275,115 $263,238 $267,558

Executive request, Animal Welfare (in thousands) . . . . . . . $ 3,594 $ 4,355 $ 4,402 $ 1,509 $ 1,568 $ 3,655

Total appropriation, Animal Welfarea (in thousands). . . . . . $ 4,128 $ 4,291 $ 4,882 $ 4,886 $ 4,865 $ 4,865

Proportion (percent) of total appropriation . . . . . . . . . . . . 1.7 1.5 1.7 1.8 1.9 1.8

Total staff-years, APHISb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5,286 5,099 5,069 4,637 4,416 4,440

Staff-years, Animal Welfare Act enforcement . . . . . . . . . . . 150 137 137 120 119 120

Proportion (percent) of total . . . . . . . . . . . . . . . . . . . . . . . . 2.8 2.7 2.7 2.6 2.7 2.7

%11 appropriations are actual (excluding pay SUPPlf3merrtalS). bstaff.years are ~alCUlat~ from available ~ork.years for authorized positions (appropriated funds only). All figures are actual, except for fiscal year 19S5, which iS projected.

SOURCE: Office of Technology Assessment.
288 ● Alternatives to Animal Use in Research, Testing, and Education

Table 13-2.—Distribution of Research Facilities,

by State, Registered With USDA/APHIS

Under the Animal Welfare Act

Number of

registered

research Percent Rank

State/jurisdiction facilities of total out of 52

Alabama. . . . . . . . . . . . . .

Alaska ... , . . . . . . . . . . .

Arizona. . . . . . . . . . . . . . .

Arkansas . . . . . . . . . . . . .

California. . . . . . . . . . . . .

Colorado . . . . . . . . . . . . .

Connecticut . . . . . . . . . .

Delaware . . . . . . . . . . . . .

District of Columbia . . .

Florida . . . . . . . . . . . . . . .

Georgia . . . . . . . . . . . . . .

Hawaii ... , ... , . . . . . . .

Idaho . . . . . . . . . . . . . . . .

Illinois . . . . . . . . . . . . . . .

Indiana. , . . . . . . . . . . . . .

Iowa . . . . . . . . . . . . . . . . .

Kansas . . . . . . . . . . . . . . .

Kentucky . . . . . . . . . . . . .

Louisiana . . . . . . . . . . . . .

Maine ....,.... . . . . . . .

Maryland . . . . . . . . . . . . .

Massachusetts. . . . . . . .

Michigan . . . . . . . . . . . . .

Minnesota . . . . . . . . . . . .

Mississippi . . . . . . . . . . .

Missouri . . . . . . . . . . . . . .

Montana . . . . . . . . . . . . . .

Nebraska . . . . . . . . . . . . .

Nevada . . . . . . . . . . . . . . .

New Hampshire . . . . . . .

New Jersey ..., . . . . . . .

New Mexico . . . . . . . . . .

New York. . . . . . . . . . . . .

North Carolina . . . . . . . .

North Dakota . . . . . . . . .

Ohio . . . . . . . . . . . . . . . . .

Oklahoma . . . . . . . . . . . .

Oregon . . . . . . . . . . . . . . .

Pennsylvania. . . . . . . . . .

Puerto Rico . . . . . . . . . . .

Rhode Island . . . . . . . . . .

South Carolina . . . . . . . .

South Dakota . . . . . . . . .

Tennessee, . . . . . . . . . . .

Texas . . . . . . . . . . . . . . . .

Utah . . . . . . . . . . . . . . . . .

Vermont . . . . . . . . . . . . . .

Virginia . . . . . . . . . . . . . .

Washington . . . . . . . . . . .

West Virginia . . . . . . . . .

Wisconsin . . . . . . . . . . . .

Wyoming . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . .

12

;

3

175

25

17

8

8

47

12

4

63

21

11

18

6

12

11

33

69

49

19

3

27

3

10

1

4

68

11

120

19

3

72

13

18

90

10

9

5

2

11

67

10

23

18

5

19

4

1,286

0.9

0.1

0.7

0.2

13.6

1.9

1.3

0.6

0.6

3.7

0.9

0.3

0.3

4.9

1.6

0.9

.05

0,9

0.9

2.6

5.4

3.8

1.5

0.2

2.1

0.2

0.8

0.1

0.3

5.3

0.9

9.3

1.5

0.2

5.6

1.0

1.4

7.0

0.8

0.7

0.4

0.2

0.9

5.2

0.8

0.3

1.8

1.4

0.4

1.5

0,3

100

24

51

34

46

1

13

22

36

37

10

25

41

42

8

15

27

19

38

26

28

11

5

9

16

47

12

48

31

52

43

6

29

2

17

49

4

23

20

3

32

35

39

50

30

7

33

44

14

21

40

18

45

SOURCE: U.S. Department of Agriculture, Animal and Plant Health Inspection

Service, Anirrra/ kVe/fare:List off?egisteredfacillfies, Fiscal Year19S5.

mice used in testing and testing-related research

merit the same coverage as other warm-blooded

animals, and if inhumane treatment of such anireals that are not part of interstate commerce is

as much a burden on oraffects commerce as much

as the animals that are part of such commerce

this disparity assumes greater legislative and regulatory significance.

Table 13-summarizes annual registration and

reporting activity as recorded by APHIS for fiscal

years 1978-83. The total number of licensees and

registrants covered by the act-all classes of regulated parties, from dealers through intermediate handlers-decreased slightly, and the total at

the close of fiscal year 1983 remained smaller than

in 1978. Increases in the number of RRFs over the

preceding year occurred in 4 of the 6 years. The

number of registered research facilities classified

as “inactive” by APHIS (i.e., reporting no use of

regulated animals for 2 consecutive years) has risen

steadily but it remains below 7 percent of the total. As a class, RRFs rose from 15.8 percent of the

total in fiscal 1978 to 19.3 percent in fiscal year

1983, due mainly to a simultaneous decrease in

the number of licensed dealers.

APHIS indicated in its 1981 and 1982 Annual Enforcement Reports that the failure of qualified research facilities to register and report was a significant enforcement problem and stated that it

“currently had no effective system for detecting

research facilities that use laboratory animals without being registered.” During 1981, one research

facility was prosecuted for failure to register, resulting in registration and entry of a cease and desist order by an administrative law judge (41).

Three cases were filed against registrants who had

failed to report in 1981; in one case, a fine of $1,000

was assessed, the first time a research facility had

been fined for failure to report (41,42).

A number of reports are late or not filed by actively registered research facilities either through

inattention, ignorance of the law, lack of penalties with sufficient deterrent value, some incompatibility between the calendar or fiscal years of

facilities and the established Federal fiscal year for

reporting, the inability of APHIS to analyze and

compile all reports to meet the congressionally
Ch. 13—Federal Regulation of Animal Use ● 289

Table 13-3.—Licensing, Registration, and Reporting Activity of Registered Research Facilities

Under the Animal Welfare Act, Fiscal Years 1978.83

1978 1979 1980 1981 1982 1983

Total licensees/registrants . . . . . . . . . . . . . . . . . . . . . .........6,902 6,389 6,585 6,492 6,297 6,447

Licensed dealers . . . . . . . . . . . . . . . . . . . . . ...............4,501 3,982 3,886 3,664 3,439 3,490

Exhibitors:

Licensed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924 978 1,101 1,168 1,237 1,266

Registered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 239 170 130 106 101

intermediate handlers/carriers . . . . . . . . . . . . . . . . . . . . . . . . . 66 139 274 312 339 346

Registered Research Facilities (RRFs)

Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........1,057 1,051 1,092 1,169 1,113 1,166

Inactive a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 — 62 49 63 78

New RRFs added . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 71 43 70

RRFs asproportion of total percent) . . . . . . . . . . . . . . . . . . . . 16

—

17 18 19 19 19

Reports received from RRFs . . . . . . . . . . . . . . . . . . . . . . . .. ..1,092 NA 1,061 1,111 968 1,127

Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ............1,072 1,061 857 919 885 1,005

Negative c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — 169 138 143 73 73

Late or no report filedd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 NA 66 49* 10 49

aMean~ “O ~eporfed US* Of regulated anirnalS for two cOnsecUtlVe Years.

bEXCludeSrepoflSfrofrl Federal factiitles.

CM*anS no US* Of regulated animals during r*pOrtinfJ Year.

dMeanS no Annual Repo~ re~el”ed bY@C*rnber 1 of reportlngyearforinclusion inApHls’Anlf’rlalwelfareErlfOrC*nl*nt Report tO Congress for that year

*LXtrepoflingYe~rforwhich lateornoffllngscould becalcularedfrorninforrnatlon given in AnnUal AnimalWdfare Enforcement RePort. Later fiwressuwlied bYApHls.

NA = Not available.

SOURCE: Office of Technology Assessment

established deadline for annual enforcement reports, or some combination of all these factors.

The method used by APHIS for monitoring compliance with the act’s and its own standards is

“regular,unannounced’’ inspections of licensee and

registrant premises. For research facilities, the

most important standard is that adequate veterinary care or, more particularly, “professionally

acceptable standards” of relief of pain and distress

are observed during and after experimentation,

except where administration of anesthetics or pain

relievers would interfere with the purpose of the

experiment. Major inspections are characterized

as:

●

●

●

●

recurring compliance inspections, performed to “spot-check” active licensees and

registrants for continued compliance with

established standards;

inspections to investigate complaints of

noncompliance or substandard treatment;

status searches, undertaken to determine

whether a business (principally potential

dealers) should be licensed; and

inspections to investigate apparent violations that have come to the attention of inspectors (43).

Though a multi-sited facility may be required

to register only as a single entity, obviously all sites

where covered animals are held must be inspected

on a regular basis if standards are to be enforced

adequately. The precise number of sites of animal

use in experimentation in the United States is unknown; it likely falls between 5,000 and 10,000.

In 1985, GAO completed a study for the Chairman of the Subcommittee on Agriculture, Rural

Development and Related Agencies, Senate Committee on Appropriations, on USDA activities under the Animal Welfare Act. GAO focused on:

● the training and guidance given to USDA’s inspectors;

● how USDA schedules its inspections of licensees and registrants and the frequency of

those inspections; and

● the followup action USDA takes when inspectors find unsatisfactory conditions (32).

GAO reviewed animal welfare inspection activities at the APHIS area offices in California, Iowa,

Kansas, Missouri, New York, and Texas. These

offices accounted for 45 percent of the 19,473 recurring compliance inspections made in fiscal year

1982.
290 ● Alternatives to Animal Use in Research, Testing, and Education

Regarding the training and guidance of inspectors, GAO found that 57 out of 73 inspectors had

attended formal training courses. However, 43 of

the 57 had received no training in recent years.

The last training course for the 17 inspectors in

Texas was given in 1979.

Although USDA personnel and planning documents state that four inspections a year per site

is desirable, GAO found that the 3,379 sites in the

six States were inspected, on the average, 1.7 times

during fiscal year 1983. In California and New York,

each site averaged 0.7 inspections per year. Between 6.4 percent (in Kansas) and 51.7 percent

(in California) of the registered facilities in a given

State were not inspected at all during fiscal year

1983.

When looking at followup action taken by USDA

for unsatisfactory conditions, GAO reviewed inspection reports of 114 sites where major deficiencies were found. In general, GAO found that the

APHIS offices complied with the Service’s policy

and met the timeframe goals for the various steps

in the process. Only 17 of the 114 sites did not follow the prescribed procedure.

While conducting the review, GAO noted some

additional matters affecting the APHIS Animal Welfare Program. First, there was no specified program or procedure to oversee the quality of inspections. Three of the six States surveyed did not

have any program for monitoring inspection quality. Second, GAO found inconsistencies in the reporting of inspections. Finally, GAO found that

funding of inspections for 1983 had been based

on 1982 work levels rather than on estimates of

current potential workloads and the severity of

expected problems.

USDA is subject to the provisions of the Freedom of Information Act (FOIA) (public Law 90-23),

a Federal law that generally requires most Federal agencies to release to interested persons information in its possession, unless it is classified

or meets one of the other exceptions established

by Congress and interpreted by the courts. Congress, concerned about the potential for “harassment” of research facilities through the use and

publication of their required inspection forms and

reports, specified in the final sentence of Section

25 of the 1966 Animal Welfare Act that USDA could

not release any such information (except to other

agencies) “unless and until it [was] made public

by an appropriate’’ congressional committee (Public Law 89-544).

Requests for information under FOIA have increased steadily since fiscal year 1979. Humane

groups have usually made about half the petitions

for information. In fiscal 1978, they accounted for

53 of 98 requests—54 percent (40). For fiscal years

1981-83, the proportions were 50,53, and 52 percent (41,42,43). The highest numbers of documents

released were in fiscal year 1981 and calendar year

1984, which coincided with renewed lobbying for

amendments to strengthen the Animal Welfare Act

or for new legislation increasing the Federal regulatory presence in research. No data are available on the proportion of requests for research

facility records for prior years, but 1984 records

show that 58 percent of total requests concerned

research facilities, 62 percent of all documents released affected research, and 50 percent of all regulated parties affected were registered research

facilities. The Animal Welfare Institute, a Washington, DC, organization interested in the act application to research, entered most of the requests

affecting such institutions (19). Documents most

often requested are copies of inspection reports,

reporting forms, records, and forms used to apply for licenses or registrations (43).

Litigation

No cases can be found where a Federal court

has had to interpret the provisions of the Animal

Welfare Act requiring humane care and treatment

of research animals. Though some State courts

have considered the act’s provisions when interpreting the effect of other laws (see ch. 14), their

decisions cannot affect the constitutionality of a

Federal law’s application under the Federal Constitution. In the only case where the U S. Supreme

Court considered any of the act’s provisions, “exemplary” language in the 1970 amendments extending judicial enforcement powers to the Federal district courts was cited to sustain review

jurisdiction asserted under another, similar provision in Federal law (14),

Three Federal appeals courts have had occasion

to examine the language of the act, though none
Ch. 13–Federal Regulation of Animal Use Ž 291

of the cases involved registered research facilities

(11,21,27). One case is nevertheless germane because it is the only time the courts have had to

examine the language and the intent of Congress

in passing the act, In a 1976 decision denying a

professional dog-and-pony-show owner’s claim

that he was not covered by the act, the U .S. Court

of Appeals for the District of Columbia indicated

the likelihood of a favorable judicial response to

attacks on the act and of a liberal interpretation

of the legislation. Quoting from the House report,

the Court stated that (11):

As the evolution of the Animal Welfare Act

manifests, Congress has chosen a cautious approach to regulation in this area, increasing governmental intervention as the national interest

seemed to warrant. . . . From the small beginning

in 1966--confined to a few animals, and only

when they were devoted to research purposes—

the present legislation further, though still modestly, “implement[s] a statutory mandate that

small helpless creatures deserve the care and protection of a strong and enlightened public.” We

perceive nothing in the Constitution outlawing

this commendable “effort to demonstrate America’s humanity to lesser creatures. ”

The U.S. Supreme Court refused to review the decision (11). Thus, the case’s value rests in using

it to support the notion that the highest court refused to disturb a lower court’s decision upholding the reasonableness of Congress’ effort to protect animals from inhumane treatment, including

in research. The D.C. Federal appeals court has

cited provisions of the act on three other occasions,

once in support of judicial review of the delegated

powers of the Secretary of Agriculture (29) and

twice without comment (1,28).

At the district court level (the Federal system’s

usual courts of first resort, or ‘(trial” courts), several cases have been brought in which the act’s

provisions have been raised (3,5,9, 10), but no court

has fully considered or decided any case invoking

the act against a research facility.

A review of reported and unreported cases involving the Animal Welfare Act indicates that what -

ever case law has been developed bears little relation to the act’s regulation of research activities.

This can be traced to a single major factor. Congress–very deliberately, it appears, fearing harassment of research facilities—gave no party other

than APHIS any statutory right to enforce the act

or regulations promulgated pursuant to it. The degree of circumspection toward research evident

in Congress’ consideration of the act and its amendments must be seen as an obstacle to private enforcement of its standards through the courts,

since at least one Federal court has held that humane groups have standing to sue on behalf of

animals under another law enacted for humane

objectives, the Marine Mammal Protection Act (2).

Lack of standing—i.e., proof to a court that a claimant’s stake in the accomplishment of the policy objectives of a statute is significant and the effect

on the claimant’s interests is real if those objectives are frustrated (see ch. 14)—makes it impossible to attain enforcement of laws from the bench.

The Health Research Extension Act

of 1985

In 1985, Congress amended the Public Health

Service Act (Public Law 78-184) by enacting the

Health Research Extension Act of 1985 (Public Law

99-158), which contained provisions for the care

and treatment of animals in research funded by

the Public Health Service (PHS), including the National Institutes of Health (NIH). The act provided

statutory authority for and recognition of certain

elements of the PHS Policy on Humane Care and

Use of Laboratory Animals by Awardee Institutions

(see app. C).

The act also contained provisions for the development of alternative research methods. Thus, the

concept of alternatives to animal use was explicitly

described for the first time in Federal law in 1985.

(The concept of alternatives first appeared in Federal law earlier in 1985, in fact. Public Law 99-

129, The Health Professions Educational Assistance

Amendments of 1985, also mentions the development of curriculum for veterinary students on

alternatives to the use of animals. It is described

in ch. 12.)

Care and Treatment of

Animals in Research

The act requires that each entity receiving PHS

support for research with animals establish a committee to monitor care and treatment of animals
292 • Alternatives to Animal Use in Research, Testing, and Education

used in research. These committees shall consist

of at least three members, of which one must be

a veterinarian and one an individual having no association with the institution. The act thus specifies

more modest requirements for the committees

than does the PHS policy. The PHS policy requires

a minimum of five committee members, and the

veterinarian must have training or experience in

laboratory-animal science or medicine.

The animal care committees are responsible for:

1) reviewing at least semiannually the care and

treatment of animals in all animal study areas and

facilities for compliance with NIH guidelines, 2)

keeping appropriate records of such reviews, and

3) certifying to NIH that such reviews have been

conducted. In requiring a minimum of two inspections per year, the law is more stringent than the

PHS policy, which requires at least one per year.

The act requires applicants for NIH funds to file

assurances with NIH indicating both that the applicant will meet the NIH guidelines for the care

and treatment of animals and that the applicant’s

institution has an animal care committee. Applicants must also assure NIH of the availability of

instruction at their institutions in the humane practices of animal care and in research methods that

minimize the use of animals and limit animal distress. All applications for NIH funds must include

a statement of the reasons for using animals in

the research. If NIH determines that a research

entity is not meeting the guidelines, and if no action is taken after notification of the noncompliance, the act provides that the NIH Director shall

suspend or revoke funding.

Research on Alternatives

The act directs NIH to establish a plan for research into methods of biomedical and behavioral

experimentation that do not require the use of animals, that reduce the number of animals used, or

that produce less pain and distress than methods

currently in use. NIH is further directed to develop

plans for evaluating the validity and reliability of

such methods, proceeding with development of

methods found to be valid and reliable, and training scientists in the use of such methods. The law

instructs NIH to disseminate information to investigators about alternative methods that are found

to be valid and reliable, and to establish an internal

coordinating committee (made up of the directors

of each NIH institute) to assist in developing the

NIH plan, which must be prepared by October 1,

1986. With the creation in 1985 of the Biological

Models and Materials Resources Section (see ch.

12), NIH appears poised to respond to this legislative mandate.

Other Federal Laws and Regulations

Beyond the Federal laws and regulations that

either directly require or have been interpreted

to require the use of certain animals in testing or

research and guidelines adopted pursuant to general statutory authority, several other Federal laws

and regulations establish duties for research facilities concerning the acquisition and general care

of animals used for experimentation.

Good Laboratory Practices

In the 1970s, concern at the Food and Drug

Administration (FDA) about faulty toxicological

data based on animals, generated both internally

and externally (18), led to the promulgation of regulations requiring all regulated parties conducting nonclinical laboratory studies that test for

safety or effectiveness to conduct, keep records

about, and permit audits on all such tests in a specified manner. In 1978, FDA adopted Good Laboratory Practices (GLP) rules (43 FR 59986) and began a laboratory audit and inspection program.

In 1984, FDA published a notice proposing some

changes in these regulations primarily to streamline recordkeeping, data storage and retrieval, and

reporting practice (49 FR 43530). Further action

may occur in early 1986,

Drawing on the FDA experience and mindful of

its responsibility to collect and analyze substantial

amounts of testing data for approval of new chemicals and registration of pesticides, the Environmental Protection Agency (EPA) defined its own

approach to GLPs (44FR 27362). In 1978, EPA executed a Memorandum of Understanding to permit

FDA to inspect toxicity testing labs and audit pesticide data submitted in support of registration applications (43 FR 14124). After much consideration—and the discovery by FDA of the submission

of hundreds of fraudulent test results by one in-
Ch. 13—Federal Regulation of Animal Use ● 293

dependent laboratory (22)–in 1983 EPA issued its

own final GLP rules for its toxic substances control (48 FR 53922) and pesticides (48 FR 53946)

programs.

The GLPs for FDA and EPA are similar. Both address all areas of laboratory operations, delineating

requirements for the establishment of a Quality

Assurance Unit to conduct periodic internal inspections and keep records for audit and reporting purposes; Standard Operating procedures (SOPS) for

all aspects of each study and for all phases of laboratory maintenance; a formal mechanism for evaluation and approval of study protocols and their

amendments; and inclusion in reports of data in

sufficient detail to support conclusions drawn from

them. FDA performs four kinds of inspections in

US. toxicology labs (8):

●

●

●

●

GLP compliance, including examination of

an ongoing study as well as a completed study

(once every 2 years);

data audit as needed, to verify that information submitted to the agency accurately reflects the raw data;

directed, when prompted by questionable

data, an informer’s tip, etc.; and

followup, to observe for correction of previously discovered deficiencies.

Inspections are conducted by investigators, who

visit each facility and are given access to all parts

of the premises where covered studies are performed and to all pertinent personnel and documentation. The Final Report and a more detailed

Establishment Inspection Report are prepared after an audit is concluded; both can be obtained

under FOIA. One (or more) of three sanctions can

be imposed in cases of noncompliance: refusal to

consider a study in support of an application; disqualification of the testing facility; or, in cases of

alleged fraud, recommendation for criminal prosecution.

Provisions relating to care and housing of test

animals are identical in both agencies’ GLP rules.

Both regulations provide that, where animals are

housed, “facilities shall exist for the collection and

disposal of all animal waste and refuse or for safe

sanitary storage of waste before removal from the

testing facility. Disposal facilities shall be so provided and operated as to minimize vermin infestation, odors, disease hazards, and environmental

contamination. ” Finally, each GLP has a full section on animal care, specifying SOPS for housing,

feeding, handling, and care, with additional standards on separation, disease control and treatment,

identification, sanitation, feed and water inspection, bedding, and pest control (21 CFR 1984 ed.

58.43,58.45,58.49, 58.90; 40 CFR 1984ed. 792.17,

792.43, 792.45, 792.90).

One chemical-industry representative summarized the benefits and problems of GLPs as follows:

● Benefits:

1) promotion of good science through good

documentation;

2) credibility–’’clean bill of health”; and

3) self-assurance through knowledge-reducing chances of mistakes due to ignorance

or use of shortcuts.

● Problems:

1) duplication—possibility of six distinct audits in the animal care operation—FDA,

EPA, USDA/APHIS, American Association

for the Accreditation of Laboratory Animal

Care (if accredited), State, and internal Quality Assurance Unit;

2) adversarial climate—”guilty until proven innocent”;

3) confidentiality and accessibility—inadvertent disclosure of confidential business information or compromise of client confidentiality;

4) time and cost—in larger facilities, single

audits may occupy several hours per day

for several weeks (7).

Noting that the GLP compliance record has been

good, the commentator suggests that some duplication can be avoided by instituting a self-audit

compliance program, using the Guide for the Care

and Use of Laboratory Animals of the National Institutes of Health (47).

If consideration is given to broadening USDA’s

enforcement of the Animal Welfare Act to reach

more testing facilities that may not now be covered—either by extending coverage to include rodents beyond only hamsters and guinea pigs or by

increasing covered facilities compliance duties—

the problems of cost and duplication assume more

significance. One indication of the cost of increas-
294 ● Alternatims to Animal Use in Research, Testing, and Education

ing an animal facility’s compliance duties comes

from a study commissioned by EPA to estimate

the compliance costs for its new GLPs. That study

concluded that additional costs to industrial laboratories would be $15 million ($80,000 per laboratory for 185 laboratories) (48 FR 53946).

Military Research and Training

In 1973, Congress prohibited the use of dogs for

research and development of chemical or biological weapons (public Law 93-365). At that time, Senate and House conferees stated that they did not

support the use of dogs for research on chemical

or biological agents whose only function was to

destroy life. They believed it essential, however,

that research to improve and save human and animal lives be continued, including establishing immunologic levels, occupational safety hazard levels,

and other “vital medical research designed to improve and save lives.”

Continued concern about this issue prompted

a request for a GAO investigation of the U.S. Army’s

Edgewood Arsenal (Edgewood, NJ). The Comptroller General reported that the Army had complied

with the restriction in fiscal year 1975 and, further, that compliance would continue. He responded to congressional concern about APHIS’s

lack of jurisdiction to inspect Federal facilities with

the finding that, although dogs being used in toxic

exposure research were treated well during experimental procedures, their housing facilities

were deficient and needed physical improvements.

He stated that legislation would be required to accomplish that purpose (33). Meanwhile, to implement the new restrictions, the Secretary of Defense issued three policy documents, in 1976 (44),

1982 (46), and 1984 (44), defining the types of investigations in which animals could be used.

In 1983, publicity about the use of dogs and pigs

at the Uniformed Services University of Health Sciences (Bethesda, MD) to train military surgeons

to treat wounds led to prohibitions on the expenditure of Department of Defense (DOD) funds in

fiscal years 1984 and 1985 (Public Law 98-473) for

the training of surgical personnel in treating

weapon-produced wounds in dogs and cats (26).

The Assistant Secretary of Defense for Health Affairs issued a memorandum in 1984 that explained

the reach of the new limitation and superseded

old policy directives (45):

. . . effective October 1, 1983, dogs or cats will

not be purchased or otherwise used for the purpose of training Department of Defense students

or other personnel in surgical or other medical

treatment of wounds produced by any type of

weapon. In addition, the standards of such training with respect to the treatment of animals shall

adhere to the Federal Animal Welfare Law and

to those prevailing in the civilian medical community.

Current DOD policies and their effect on intramural and extramural defense research are examined in more detail in appendix B.

Animal welfare groups have expressed dissatisfaction about substitution of other animals for dogs

and cats in ballistics training, and pressure on Congress to prohibit animals’ use in this type of research is expected to continue (15).

Endangered Species, Public Health,

and Import Legislation

Research facilities that plan to import, take, or

otherwise use nonhuman primates or other animals protected by national or international laws

and agreements must comply with provisions

found in several laws. Besides prohibiting or controlling acquisition of some types of animals, these

laws and agreements generally require, at a minimum, a permit or authorization from one or more

Federal agencies. Relevant legislation includes:

●

●

●

●

●

Section 7 of the Endangered Species Act of

1973, as amended (16 U.S.C. 1531 et seq.), and

regulations administered by the Research Division of the Fish and Wildlife Service [50 CFR

10-24];

Public Health Service Act regulations governing importation of nonhuman primates, both

to control the spread of animal-borne disease

(42 U.S.C. 264; 42 CFR 71) and for use in producing and testing viral vaccines (42 U.S.C.

262; 21 CFR 620 et seq.);

the Airline Deregulation Act of 1978 and the

Tariff Schedules of the Civil Aeronautics Board;

Convention on International Trade in Endangered Species of Wild Fauna and Flora Treaty

of 1973 [see app, E); and

certificates of need for importing rhesus monkeys (a 1955 agreement between the United

States and India, resulting in the Indian Rhesus Monkey Certification Program).
Ch. 13—Federal Regulation of Animal Use • 295

AGENCY GUIDELINES AND ACTIVITIES

Besides providing general assurances to USDA

that intramural research activities involving warmblooded animals meet the general requirements

of the Animal Welfare Act, various Federal agencies have adopted general animal use guidelines

or have taken steps to review relevant intramural

and extramural policies. Most policies are confined

to measures governing humane care and treatment

of animals in testing and research-establishment

of standards, review, and enforcement. Some policies mention the actual conduct of experimentation.

The Public Health Service Policy

Pursuant to a delegation of authority from the

Secretary of the Department of Health and Human

Services (DHHS), NIH is responsible for implementing the public Health Service Policy on Humane

Care and Use of Laboratory Animals by Awardee

Institutions (PHS Manual, chs. 1 through 43). Each

institution that receives Federal support from PHS

for research involving live vertebrate animals is

subject to the policy, including agencies of the PHS

itself (NIH; FDA; the Alcohol, Drug Abuse, and Mental Health Administration; the Centers for Disease

Control; and the Health Resources and Services

Administration). Provisions of the PHS policy, revised in 1985, are discussed in detail in chapter

15 and the policy is reproduced in appendix C.

Interagency Activities

Governmentwide Standards

Representatives from 14 Federal entities3 involved in animal use sit on the Interagency Research Animal Committee (IRAC) formed in recognition of the need for an interagency committee

knowledgeable about the use, care, and welfare

of research animals.

3USDA, Department of Defense, DHHS, Department of Energy, Department of State, Departmentof the Interior, EPA, the National Aeronautics and Space Administration, the National Science Foundation,

and the Veterans’ Administration. Components of the Public Heahh

Service within DHHS that are represented on the committee include

the Alcohol, Drug Abuse, and Mental Health Administration; the

Centers for Disease Control; FDA; NIH; and the Office of International Health.

Staffed and sponsored by NIH, IRAC was established by the Assistant Secretary of Health in 1983

as an outgrowth of the Interagency Primate Steering Committee that had been established within

NIH in 1974 to assure both short- and long-term

supplies of primates critical to biomedical research,

testing, and vaccine development programs (48).

Along with regular meetings to discuss current

issues and needs, the Committee has undertaken

two principal projects to date: serving in an advisory capacity to U.S. observers to the Council of

Europe, which considered a draft convention on

laboratory-animal use (see app. E), and writing the

“Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and

Training” (see box A). Developed and issued at the

request of the Executive Office of Science and Technology Policy, the principles are intended to serve

as a model for Federal agencies developing specific policies on the use of animals. The IRAC principles incorporate nine distinct injunctions on

proper care and treatment of research animals,

based primarily on similar principles promulgated

by the Council for International Organizations of

Medical Science (see app. E).

These statements on establishment, review, and

enforcement of standards of humane care and

treatment are part of the NIH Guide for the Care

and Use of Laboratory Animals and are explicitly

endorsed in the PHS Policy on Humane Care and

Use of Laboratory Animals by Awardee Institutions (47).

Memorandum of Understanding

In 1983, APHIS, NIH, and FDA executed a Memorandum of Understanding and agreed to exchange

information on animal welfare concerns and compliance with policies. Each has appointed liaison

officers to serve on a standing committee to meet

at least annually. Specifically, APHIS, NIH, and FDA

have agreed to:

●

●

share information contained in the registry/

inventory/listing of establishments that fall under the purview of each;

send to one another, each quarter, a listing

of establishments that have been inspected
or site-visited, to be used to avoid redundant

evaluations;

share information on significant adverse find- ●

ings concerning animal care and welfare revealed by inspections or site visits and on followup actions taken;

inform each other of evidence of serious non- ●

compliance with required standards or polwith PHS policies) in establishments that fall

under the authority of each agency;

request from each other comments and advice on regulatory or policy proposals involving animal care and welfare under consideration; and

provide to each other resource persons for

scientific seminars, speeches, and workshops.

icies for care and use of laboratory animals The agreement remains in effect indefinitely, may

(including defective assurances of compliance be modified by mutual consent, and may be ter-
Ch. 13—Federal Regulation of Animal Use ● 297

minated by any agency on 90-day advance writ- fiscal year 1983 (see ch. 3). In addition, extramural

ten notice to the other two agencies (37). research is conducted by many of these departments, Two departments, Commerce and TransSpecific Agency Activities portation, conduct almost all research extramurally

and so have no specific policy regulating animal

Six departments and four agencies within the use other than the PHS policy (1 7,23). For a detailed

Federal Government do intramural research in- discussion of the regulation of animal use within

volving animals. At least 1.6 million animals were Federal departments and agencies, see appendix B.

used by these branches for such research during

CRITICISMS OF THE PRESENT SYSTEM OF FEDERAL REGULATION

The operation of the Animal Welfare Act, as applied to research, has been criticized since its passage. In addition to obvious shortcomings—lack

of coverage for actual research practices and inadequate resources for enforcement-critics have

questioned the presumption that researchers know

best how to care for experimental animals (20,49)

and the choice of APHIS as the primary enforcement agency (16,24). Complex recordkeeping requirements imposed on APHIS inspectors and

other field enforcement staff have been decried;

the process of noting, investigating, and evaluating violations for prosecution, and the attendant

rights of suspected violators that can result in delay in disposition of cases, are viewed by some as

too cumbersome and bureaucratic (20). Some question the expertise and the will of APHIS, pointing

out its traditional reluctance to accept broader

responsibilities under the act. Indeed, USDA remains opposed to its further extension (34,37). A

1982 review of the APHIS reporting system by the

Humane Society of the United States concluded

that the present system, as it is administered (24):

. . . fails to achieve its primary statutory objective: it does not provide APHIS with information

sufficient to demonstrate that researchers have

used pain-relieving drugs “appropriately” and in

accordance with “professionally acceptable standards.’’ The chief reasons for this failing are: 1) regulations and guidelines do not define “pain” or

“distress, ” 2) regulations and guidelines do not

adequately define “routine procedures, ” and 3)

regulations and guidelines do not require meaningful explanations for the withholding of painrelieving drugs in procedures acknowledged to

cause pain.

The Reporting System, as presently administered, for the same reasons also fails to achieve

a secondary—but nonetheless important —objective: it does not generate reliable and meaningful

information to the public about the use of animals in research.

Humane groups have used the Freedom of Information Act with increasing frequency to obtain

copies of inspection and annual reports in attempts

to demonstrate their claims that the system does

not work. Members of the research community

opposed to the act extension defend existing practices as adequate (16,34)37).

Could the Secretary of Agriculture require greater

proof that “professionally acceptable” standards

of care are being followed, require more detailed

explanations of the use and withholding of anesthetics and pain relievers, and more effectively audit annual reports? The law permits such greater

discretion. Several competing factors, however,

are worth noting. First, consistent with Congress’

enumerated powers to spend and to regulate interstate commerce, the objectives for the regulation

of research are more limited than is often admitted by the critics. The remarks of congressional

sponsors of the first bills, in the record of debates

on the 1966 conference report, recognize that only

a fraction of research animals would be covered

(30) and that the new act was “nothing more than

a very small first step toward the elimination of

cruelty, mistreatment, and abuse of laboratory animals .“ The absolute power that remained with the

experimenter to determine the nature of experimentation prompted the remark that “animals that

are under research or experimentation for sev-
 ✒✙✘● Altematives to Animal use in Research, Testing, and Education

eral years will have absolutely no protection under

this law” (31). Subsequent amendments added

more specific requirements but left the intraresearch exemption undisturbed, retaining a posthoc, audit-style enforcement system.

Second, creating an agency whose sole purpose

is to regulate experimentation, or infusing more

authority and funds into APHIS, are options that

Congress has not chosen to exercise, even in the

face of a lukewarm commitment to enforcement

by existing executive agencies. Third, these choices

have not been made because a consensus on the

preferable mode and extent of control has never

been apparent. Some regulation advocates, it appears, will settle for some degree of tinkering with

the act; others will not rest until research on animals is done away with (27). Those differences have

strong roots and are likely to persist.

There are important statutory and regulatory

considerations regarding any attempt to modify

existing law in order to effect replacements, reductions, or refinements of animal use. Statutory

changes would reflect judgments on:

●

●

●

●

●

●

whether the jurisdiction of enforcing agencies should be expanded to enforcement of

adequate care, treatment, and use standards

during actual conduct of experimentation;

whether the scheme of regulation of experimentation should be scaled to a higher

level of compliance responsibility, as is now

the case for dealers and exhibitors;

whether penalties for violations of research

standards should be enacted that are commensurate with those assessed against other regulated parties;

whether voluntary assurances or simple certifications of compliance are adequate;

whether coverage of existing classes of animals is statutorily adequate to achieve even

existing policy objectives; and

whether proposed changes take into account

the operation of other, overlapping laws that

have different policy objectives.

Regulatory changes would involve judgments of:

● whether existing enforcement agencies are

appropriate (and willing) to continue to fulfill

current responsibilities and assume others;

●

●

●

whether enforcement agencies should be

given increased discretion in formulating and

enforcing professionally acceptable standards

of care, handling, treatment, and use of research animals;

whether additional requirements for research

regulation will be susceptible to consistent

interpretation by inspection and enforcement

agents in the field, in light of existing availability of training resources and aids for field

inspectors; and

whether efficient assignment of funds and enforcement resources on a state-to-state basis

is likely to occur.

In addition, statutory or regulatory change would

reflect a judgment of:

●

●

●

whether funds authorized and appropriated

will be adequate in relation to contemplated

enforcement duties;

whether regulated research institutions have

sufficient financial resources and institutional

and independent veterinary resources to effect meaningful compliance with a strengthened law, while avoiding any compromise of

research or testing objectives; and

whether strengthening existing laws will promote resolution of or enhance differences between the research and animal welfare communities.

Finally, the Animal Welfare Act is often criticized—inappropriately—for excluding mice and

rats from its coverage. In fact, the act, as amended

in 1970, covers all warm-blooded animals that the

Secretary of Agriculture determines are being used

or intended for use in research or for another

named purpose. The Secretary does not appear

to have the discretion to determine whether or

not mice and rats are warm-blooded animals, only

whether or not they are used in research. No

amendment to the act is therefore necessary to

bring mice and rats under its scope. The exclusion of mice and rats (and birds) from the definition of “animal” by USDA regulation in 1977 (9 CFR

1.1 (n),(o)) appears to frustrate the intent of Congress and to be beyond the Secretary of Agriculture’s statutory authority (6).
Ch. 13—Federal Regulation of Animal Use ● 299

SUMMARY AND

The Animal Welfare Act and its amendments represent a cautious and deliberate attempt by Congress to improve care and treatment of research

animals. Initially, the act was designed to regulate

interstate traffic in dogs and cats used for research,

with the goal of halting the use of stolen pets. This

was accomplished by requiring Federal licenses

for dealers, requiring research facilities to register, and instituting inspection and recordkeeping

requirements for both. Enforcement responsibility was vested in the Animal and Plant Health Inspection Service of the U.S. Department of Agriculture, an agency not aligned with traditional,

nonagricultural research interests. Three times

the act was amended; twice the amendments extended interstate regulation to exhibition, transportation, and auction sales of covered animals

(which, as enforced, now includes dogs, cats, rabbits, hamsters, guinea pigs, and nonhuman primates), The oversight of animal use by committees at every research facility was mandated in

the most recent amendments.

A legislative reluctance to invade the actual conduct of research is clear. The Secretary of Agriculture is forbidden to enact any regulation that

could be so construed. The closest the law comes

is to require the Secretary to establish and enforce

standards for care and treatment of experimental

animals outside the laboratory door, and to require

covered research facilities to certify that professionally acceptable standards of care, treatment,

and use are being followed in the laboratory, including “appropriate” use of anesthetics and pain

relievers, except when their use would interfere

with experimental objectives. In addition, large

classes of experimental animals—principally mice

and rats—are not covered by the act as it is currently enforced by the Department of Agriculture,

and the law’s provisions remain weighted toward

traffic in pet species. Since interstate regulation

constitutionally requires some connection to interstate commerce, research institutions that use aniCONCLUSIONS

reals protected by the act but that receive no Federal funds and that maintain their own breeding

colonies cannot be regulated. To date, there has

been no significant judicial test of the provisions

regulating research.

The Health Research Extension Act of 1985

amended the Public Health Service Act with provisions for the care and treatment of animals in

PHS-funded research. The 1985 act also contained

provisions for the development of alternatives to

research methods using animals.

In addition to the Animal Welfare Act and the

Health Research Extension Act of 1985, there is

regulation of the use of laboratory animals at the

Federal agency level. The Interagency Research

Animal Committee was formed to provide a knowledgeable source about all vertebrate animal use

in testing, research, and training within the Federal Government. It has developed the U.S. Government’s “Principles for the Utilization and Care

of Vertebrate Animals Used in Testing, Research,

and Training” at the request of the Executive Office of Science and Technology Policy. The IRAC

principles are endorsed by the Public Health Service, are part of the widely used NIH Guide for the

Care and Use of Laboratory Animals, and are used

by some Federal agencies in their own policies on

animal use.

Six Federal departments and four Federal agencies conduct animal experimentation within Federal facilities (see app. B). Only the Departments

of Commerce and Transportation, which use few

animals, have no specific guidelines. The other entities all have some type of policy for such intramural research. In general, the more research

conducted by an agency, the more extensive are

its animal care guidelines. In addition, departments

in which animal treatment has been targeted by

animal welfare groups or spotlighted by the media tend to have more substantive guidelines.
300 ● Alternatives to Animal Use in Research, Testing, and Education

CHAPTER 13 REFERENCES

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(D.C. Cir. 1978).

2. Animal Welfare Institute v. Kreps, 561 F.2d 1002,

1007 (D.C. Cir. 1977).

3. Barnes, P., “Animal Advocates Are No Friends to

Lawyer, ’’New Haven (C7’)Regikter, p. 17 (COIS. 1-6),

Aug. 17, 1984.

4. Becker, G., ‘(The U.S. Department of Agriculture’s

FY 85 Budget, ” Issue Brief No. IB84043, Congressional Research Service, U.S. Congress, Washington, DC,

Mar. 9, 1984.

5. Californians for Responsible Research, Inc. v. Block,

et a]., (N.D.Calif., 1983).

6. Cohen, H., “Two Questions Concerning the Animal

Welfare Act,” Publication No. 85-927A, Congressional Research Service, U.S. Congress, Washington, DC, Aug. 7, 1985.

7. Conine, D., “Laboratory Audits: An Industry View,”

Chem. Times Trends 7(3):13-16, 1984.

8, Ford, D., and Mackler, B., “Good Laboratory Practices: A Perspective for Research Scientists,” BioTechniques Jan./Feb. 1984:48-49.

9. Friends of Animals, Inc. v. U.S. Surgical Corpora10.

11.

12.

13.

14.

15.

16.

17!

tion, Civ. No. B81-643 (D. Corm., Feb. 17, 1982).

Friends of Animals, Inc. v. U.S. Surgical Corporation, Civ. No. B82-744, Plaintiff’s Motion to Dismiss

With Prejudice (D.Corm., Aug. 23, 1984).

Havikmd v. Butz, 543 F,2d 169,177 (D.C. Cir. 1976),

cert. denied, 97 S.Ct. 95, 429 U.S. 832 (1976).

Holzer, H. (cd.), ‘(Animal Welfare Act: Rulemaking

Petition, ’’Anim. Rights Law Rep. (Int. Soc. for Anim.

Rights, Clarks Summit, PA) July 1982:14.

Leavitt, E., and Halverson, D., “The Evolution of

Anti-Cruelty Laws in the United States)” Animals

and Their Legal Rights, E, Leavitt (cd.) (Washington, DC: Animal Welfare Institute, Third Ed., 1978).

Marshall v. Bar/ow3, Inc., 436 U.S. 307,98 S.Ct. 1816

(1978).

McArdle, J., Assistant Director, Institute for The

Study of Animal Problems, Humane Society of the

United States, Washington, DC, personal communication, Dec. 13, 1984.

Morrison, L., and Levey, G., “Animals and Research:

Labs Already Take Steps to Protect the Anima]s’

Health and Welfare,” L.A. Daily J., p. 4, June 29,

1983.

Mosed, R., Executive Director for Oceanic and

Atmospheric Administration, National Oceanic and

Atmospheric Administration, U.S. Department of

Commerce, Rockville, MD, personal communication, Se~tember 1984.

,

18.

19.

20,

21.

22.

23.

24.

25,

26,

27,

28,

29,

30,

Murray, C., “FDA-Proposed Lab Practice Regulations Scored,” Chem. Eng. News 55(9):18, 1977.

Poore, S., Freedom of Information Act Coordinator, l’eterinary Services Branch, Animal and Plant

Health Inspection Service, U.S. Department of Agriculture, Washington, DC, personal communications, Jan. 11 and 18, 1985.

Rikleen, P., “The Animal Welfare Act: Still a Cruelty to Animals, ’’Boston CoIl. Environ. Aff. La w Z?ev.

7:129-142, 1978.

Robinson v. United States, 718 F.2d 336 (lOth Cir.

1983).

Schneider, K., “Faking It: The Case Against Industrial Bio-Test Laboratories, ’’Amicus .J. 4(Spring):14-

26, 1983.

Schultz, C., Chief, Sciences Branch, Technology Division, Office of Hazardous Materials Regulation,

Materials Transportation Bureau, Research and

Special Programs Administration, U.S. Department

of Transportation, Washington, DC, personal communication, September 1984.

Solomon, M., and Lovenheim, P., “Reporting Requirements Under the Animal Welfare Act: Their

Inadequacies and the Public’s Right to Know, ” .J.

Stud. Anim. Problems 3:210-218, 1982.

Stewart, W,, “Legal Standards for Humane Care:

The Animal Welfare Act, ” Lab Anim. 13(6):33.41,

1984.

Time, “In the Doghouse: Protest Halts Animal Killings,” 122:38, Aug. 8, 1983.

Union County Jail Inmates v. DiBuono, 718 F.2d

1247 (3rd. Cir. 1983).

United States v. Fraley, 538 F.2d 626 (D.C. Cir. 1974).

United States v. Hill, 694 F.2d 258,264, n. 19 (D.C.Cir.

1982).

U. S., Congressional Record, 112:19559, 19608, Statements of Reps. Rogers and Pepper (1966).

31. U. S., Congressional Record, 112:19785, Remarks of

Sen. McIntyre (1966).

32. U.S. Congress, General Accounting Office, Report

to the Chairman, Subcommittee on Agriculture, Rural Development and Related Agencies, Committee

on Appropriations, United States Senate: The Department ofAgriculturek Am”mal Welfare Program,

GAO/RCED-85-8 (Gaithersburg, MD: May 16, 1985).

33. U.S. Congress, General Accounting Office, Use of

Dogs in Experiments at Edgewood Arsenal, Maryland: Department of the Army, GAO Rep. No. PSAD76-80 (Washington, DC: Mar.12, 1976).

34. U.S. Congress, House of Representatives, Committee on Agriculture, Subcommittee on Department

Operations, Research, and Foreign Agriculture, Im -
Ch. 13—Federal Regulation of Animal Use ● 301

proved Standards for Laboratory Animals, Hearing on H .R. 5725, hearings Sept. 19, 1984, Seria] No.

98-086 (Washington, DC: U.S. Government Printing Office, 1984).

35. U.S. Congress, House of Representatives, Committee on Agriculture, Report to Accompany H.l?.

19846, H. Rpt. 91-1651 (Dec. 2, 1970), reprinted in

U.S. Code Congressional and Administrative News,

1970:5103-51 13.

36. U.S. Congress, House of Representatives, Committee on Agriculture, Report to AccompanuVH.R. 5808,

H. Rpt. 94-801 (Jan. 29, 1976), and Conference Committee, Report to Accompany S. 1941, Conf. Rpt.

94-976 (Mar. 29, 1976), reprinted in U.S. Code C’ongressionaland Administrative Arews, 1976:758-797.

37. U.S. Congress, Senate, Committee on Agriculture,

Nutrition, and Forestry, Improved Standards for

Laboratory Animals, Hearing on S. 657, hearings

July 20, 1983, Serial No. 98-470 (Washington, DC:

U.S. Government Printing Office, 1983).

38. U.S. Congress, Senate, Committee on Commerce,

Report to AccompanyH.R. 13881, S. Rpt. 1281 (June

15, 1966) and Conference Committee, Reports to

Accompany H.R. 13881, Conf. Rpt. 1848 (Aug. 11,

1966), reprinted in U.S. Code Congressional and

Administrative News, 1966:2635-2658.

39. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, “First Federal Law to Prevent Cruelty to Animals, ” Animals and Their Legal

&“ghts, E. Leavitt (cd.) (Washington, DC: Animal Welfare Institute, Third Ed., 1978).

40. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, AnimaZ Welfare Enforcement, FY 1978: Report of the Secretary of Agriculture to the President of the Senate and the Speaker

of the House of Representatives (Washington, DC:

March 1979).

41. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, Animal Welfare Enforcement, FY 1981: Report of the Secretar~~ of Agriculture to the President of the Senate and the Speaker

of the House of Representatit~es (Washington, DC:

March 1982).

42. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, Animal Welfare Enforcement, FY 1982: Report of the Secretaqv of Agriculture to the President of the Senate and the Speaker

of the House of Representatives (Washington) DC:

March 1983).

43. U.S. Department of Agriculture, Animal and Plant

Health Inspection Service, Animal Vt’elfare Enforcement, FY 1983: Report of the Secretary of Agricult ure to the President of the Senate and the Speaker

of the House of Representatives (Washington, DC:

March 1984).

44. U.S. Department of Defense, “Clinical Investigation

Program)’) DOD Directive 6000.4, Washington, DC,

Apr. 16, 1976.

45. U.S. Department of Defense, Assistant Secretary

of Defense for Health Affairs, “Memorandum to the

Secretaries of the Uniformed Services, President

of the Uniformed Services University of the Health

Sciences, and Directors of Defense Agencies, ” Washington, DC, Jan. 4, 1984.

46. U.S. Department of Defense, “The Use of Animals

in DoD Programs, “ DoD Instruction 3216.1, Washington, DC, Feb. 1, 1982.

47. U.S. Department of Health and Human Services,

Public Health Service, National Institutes of Health,

Guide for the Care and Use of Laborato<v Animals,

NIH Pub. No. 85-23 (Bethesda, MD: National Institutes of Health, 1985).

48. Wolfle, T., ‘(The Interagency Research Committee

[HL4CI,” mimeo, National Institutes of Health, Bethesda, MD, 1984.

49. Zurvalec, L., “Use of Animals in Medical Research:

The Need for Governmental Regulation, ” L1’a.vne

Law Rev. 24(5):1733-1774, 1978.
Chapter 14

State Regulation of Animal Use

John E. McArdle

Humane Society of the United States

Physiologist 28(2):71, 1985
CONTENTS

Page

Anticruelty Laws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

General Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

Enforcement . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Constitutionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Judicial Interpretation of Applicability of Anticruelty Statutes to Research . . 310

Criticisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Recent Initiatives in Anticruelty Laws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Right to Take Legal Action on an Animal’s Behalf . . . . . . . . . . . . . . . . . . . . . . . . . 314

Past Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

Recent Initiatives to Create Legally Enforceable Rights for Animals . . . . . . . . 315

Regulation of Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

Past Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

Recent Initiatives in Research Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Pound Release Laws. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Past Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Recent Initiatives in Pound Release Laws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Animal Use in Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . 321

Past Trends . . . . . . . . . . . . . . . . . . . . .; . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Recent Initiatives in Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

Case Study: Friends of Animals, Inc. v. U.S. Surgical Corporation. . . . . . . . . . . . 323

The Parties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

The Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

The Lawsuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..., . . . . . . . . . . . . . . 325

Discussion of the Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

Chapter 14 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

List of Tables

Tab!e No. Page

14-1. Laws on Research and Animal Cruelty, by Jurisdiction . . . . . . . . . . . . . . . . 307

14-2. Laws on Pound Animal Use, by Jurisdiction . . . . . . . . . . . . . . . . . . . . . . . . . 319
Chapter 14

State Regulation of Animal Use

States have enacted a bewildering array of laws

governing animals-their control, their ownership

and disposition as human property, the responsibilities and liabilities of their owners, and the

duty of care that is owed animals, including freedom from unnecessary and unjustified suffering.

State laws in the last category are the most venerable; many predate any congressional action

on the subject. These laws take several general

forms, including the regulation of animal use in

experimentation and the delegation of authority

to local governments to regulate animal use and

treatment (33). With Federal entry into the field,

the potential for conflict and duplication arises.

This chapter summarizes State laws affecting

the use of research animals and examines the potential for conflict or duplication with current

Federal law. The analysis is restricted to laws with

some bearing on the conduct of research and

where some potential for conflict or duplication

may exist. Examples of types of local laws or ordinances are cited to illustrate the contexts in which

local law has affected research, but no attempt

is made to describe such legislation independent

of the operation of State law.

ANTICRUELTY LAWS

At common law, animals were entitled to no intrinsic right of protection, reflecting the prevailing belief that they were mere human instrumentalities. Two classes of animals existed, domestic

and wild, with domestic animals considered the

property of their owners and legally protected

only as possessions. An owner could treat an animal in any manner, as long as no public nuisance

was created. Abuse of an animal owned by another

created liability in the abuser only for resulting

damage to the economic value of the animal (2,4).

This means that any legal right or duty owed

to animals by humans must have a statutory basis (33). Every U.S. jurisdiction has in place a statute prohibiting cruel treatment of some types of

animals. These statutes generally apply criminal

penalties (usually lower class misdemeanors) and

civil sanctions for specified violations (74). Most

of the original State anticruelty statutes were

enacted prior to the turn of the century and have

common, continental roots as offshoots of general societal concern for humane treatment. The

first such statute, known as an “override, overdrive” law because it outlawed riding or driving

farm animals beyond reasonable limits, was passed

in the Massachusetts Bay Colony in 1641. It provided that “No man shall exercise any Tyranny

or Cruelty towards any Brut Creatures which are

usually kept for the use of man” (19).

The principal social goals promoted by the imposition of criminal or economic penalties for

cruel or inhumane treatment of animals are threefold (3,33):

● protecting the interests of society and promoting morality by deterring conduct considered wanton or offensive, such as willful

mistreatment of animals;

● protecting the interests of animals and preventing neglect by establishing enforceable

minimum standards of care for animals; and

● protecting the economic interests of animal

owners by shielding animals against treatment that invades or damages the owner’s

economic interest (including companionship

and enjoyment).

Most anticruelty statutes serve the first two goals

by prohibiting and punishing active cruelty to animals (beating, burning, castrating, shooting, pouring acid on hooves, or overworking) and, in some

cases, passive cruelty occasioned by neglect, such

as failure to provide basic necessities (food, water,

shelter, or appropriate care) (36). Since most State

anticruelty statutes combine elements of both ac305
306 . Alternatives to Animal Use in Research, Testing, and Education

tive and passive cruelty, these concepts are discussed under this single rubric. Special duties of

care, such as those imposed in some States on animal carriers, pet stores, and others, generally do

not affect research facilities (39).

Genera] Provisions

State anticruelty statutes often incorporate prohibitions on both active cruelty and failure to

meet a generally described duty of care. Under

these laws, several elements must be proved to

sustain a conviction and penalty:

●

●

●

●

●

The mistreated animal must come under the

statute’s coverage.

The person charged with infliction or neglect

must similarly be subject to the reach of the

law, as must the conduct complained of.

The act complained of must not be the subject of any exceptions to the statute.

There must be no statutory defenses that can

be sustained against the act complained of.

The prescribed level of human knowledge or

intent must be present if required by statute. Most States, however, do not require culpability to be proven (33).

Culpability depends on the presence of a specified state of mind at the time of the commission

of the act. Except for statutes that create liability without culpability, conduct must generally

fall into one of the following categories to result

in the commission of an offense:

● Intentional, Knowing or Willful The individual must be conscious of his or her conduct, intend his or her voluntary actions or

failure to act, and know or should know the

actual consequences.

● Recklessly Negligent: This lesser level applies to an individual who is aware of and

consciously disregards a substantial and unjustified risk to another interest (the animal’s

interest in avoiding cruel treatment).

● Negligent: This lowest level of culpability,

also known as criminal negligence, applies to

an individual who fails to perceive a substantial and unjustified risk incurred by his or

her action or inaction. The standard applied

in cases of criminal negligence is proof of a

gross deviation from the standard of care observed by a reasonable person in similar circumstances.

Many statutes incorporate more than one level

of culpability (33,36).

The other type of criminal statute, often combined with those that prohibit specified acts of

cruelty, deals with nonfeasance or omissions.

These laws establish a minimum duty of care

toward an animal by making it a crime to fail to

meet that duty in some specified way. Their objective is general care of covered animals, rather

than protection from immediate harm. If no degree of culpability is required, defenses applicable under active statutes are not available. Nonetheless, if words like “willfully,” “intentionally,”

or “knowingly” are used, then the appropriate degree of culpability must be proved. The most comprehensive “duty-of-care” statute is Virginia’s Animal Welfare Act, which requires all companionanimal owners to provide adequate food, water,

shelter, and space, as well as humane care and

treatment and veterinary care necessary to prevent suffering. The maximum penalty upon conviction is a fine of $100 (117).

The variability of the basic elements of anticruelty statutes is demonstrated by a recent review by the Animal Welfare Institute of laws in

the 50 States, the District of Columbia, Puerto

Rico, Guam, the Virgin Islands, and the Canal

Zone. The Institute found the following:

●

●

●

Definition of “Animal”: Twenty-nine anticruelty laws protect “any animal,” including

all living creatures except humans. Nineteen

others provide no definition at all, and others

apply the word to domestic animals, captive

animals, or warm-blooded creatures.

Culpability Thirty-two jurisdictions have

prohibitions on specified types of cruelty

with no qualifying phrases—i.e., no requirement for proof of a particular state of mind

on the part of the person charged. The other

23 have one or more of the qualifying phrases

described above.

Food, Water, and Shelter Statutory prohibitions against failure to provide for basic animal survival vary in both definition and interpretation. Thirty-two jurisdictions have laws
Ch. 14–State Regulation of Animal Use Ž 307

●

●

●

●

requiring food and water, with no qualifying phrases. Twenty-three others qualify the

duty of care to provide food and water with

some requirement to prove at least a high degree of neglect; the word used most often as

a qualifier here is “unnecessarily. ”

Other Living Conditions: Requirements for

adequate exercise or space, light, ventilation,

and clean living conditions are found in some

statutes. Eight jurisdictions require fresh air.

Exercise or adequate space is required by 11.

One requires sufficient light, and two laws

mention clean living conditions.

Abandonment General anticruelty statutes

in 42 jurisdictions prohibit the abandonment

of animals. In several cases, abandonment is

restricted to willful, cruel, or intentional

abandonment, to abandoning animals to die,

to abandoning disabled animals, or to abandoning domestic animals.

Humane Transport: Thirty-eight jurisdictions incorporate provisions prohibiting cruel

or inhumane transport of various classes of

animals. Minnesota’s statute is most specific,

applying to “any live animal” and defining in

detail requirements for humane transport.

In most jurisdictions, however, laws governing humane transportation are much more

general, often consisting of no more than a

single section incorporating undefined or

vaguely defined terms.

Poisoning: Twenty-four jurisdictions prohibit or restrict the use of poison to inflict

injury or death on an animal. Some statutes

are modified with terms such as “needlessly,”

and others are found outside general anticruelty law, intended to apply primarily to

livestock or other animals held and kept for

specific purposes, usually related to their economic value in a given activity, such as racing or hunting (74).

Some statutes acknowledge the potential application of general anticruelty statutes to research

facilities. Twenty-three jurisdictions specifically

exclude experimental animals from the reach of

criminal anticruelty statutes; 25 others make no

mention of any possible relation (89) (see table 14-

1). Interpretation of these statutes is discussed

later in this chapter.

Table 14.1.—Laws on Research and Animal Cruelty,

by Jurisdiction

Research No mention

State/jurisdiction exemption in law Other

Alabama. . . . . . . . . . . . . .

Alaska . . . . . . . . . . . . . . .

Arizona. . . . . . . . . . . . . . .

Arkansas . . . . . . . . . . . . .

California. . . . . . . . . . . . .

Colorado . . . . . . . . . . . . .

Connecticut . . . . . . . . . .

Delaware . . . . . . . . . . . . .

District of Columbia , . .

Florida . . . . . . . . . . . . . . .

Georgia . . . . . . . . . . . . . .

Hawaii . . . . . . . . . . . . . . .

Idaho . . . . . . . . . . . . . . . .

Illinois . . . . . . . . . . . . . . .

Indiana. . . . . . . . . . . . . . .

Iowa . . . . . . . . . . . . . . . . .

Kansas. . . . . . . . . . . . . . .

Kentucky . . . . . . . . . . . . .

Louisiana. . . . . . . . . . . . .

Maine . . . . . . . . . . . . . . . .

Maryland . . . . . . . . . . . . .

Massachusetts . . . . . . . .

Michigan . . . . . . . . . . . . .

Minnesota . . . . . . . . . . . .

Mississippi . . . . . . . . . . .

Missouri. . . . . . . . . . . . . .

Montana. . . . . . . . . . . . . .

Nebraska . . . . . . . . . . . . .

Nevada. . . . . . . . . . . . . . .

New Hampshire . . . . . . .

New Jersey . . . . . . . . . . .

New Mexico . . . . . . . . . .

New York. . . . . . . . . . . . .

North Carolina . . . . . . . .

North Dakota . . . . . . . . .

Ohio . . . . . . . . . . . . . . . . .

Oklahoma . . . . . . . . . . . .

Oregon. . . . . . . . . . . . . . .

Pennsylvania. . . . . . . . . .

Rhode Island. . . . . . . . . .

South Carolina . . . . . . . .

South Dakota . . . . . . . . .

Tennessee. . . . . . . . . . . .

Texas . . . . . . . . . . . . . . . .

Utah . . . . . . . . . . . . . . . . .

Vermont. . . . . . . . . . . . . .

Virginia . . . . . . . . . . . . . .

Washington. . . . . . . . . . .

West Virginia . . . . . . . . .

Wisconsin . . . . . . . . . . . .

Wyoming . . . . . . . . . . . . .

. . . . . . . .

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aExempts “veterinary practices.”

bExpre55[y intends for animals used for “scientific or medical aCtMty” to be PrOtactad from “intentional cruelty” but exempts “normal human activities to which

the infliction of pain to an animal is purely incidental and unavoidable. ”

cprohibits entry or search to enforce the law “where SC)eIWC research is behw

conducted by or under the supervision of graduates of reputable scientific

schools or where biological products are being produced for the care or prevention ot disease. ”

SOURCE: National Association for Biomedical Researchj State Laws Concerrring the Use of Animals in Research (Washington, DC: Foundation for

Biomedical Research, 1985).
308 Ž Alternatives to Animal Use in Research, Testing, and Education

Most of the laws that do address the issue exempt “scientific experiments” or “investigations”

entirely. In Alaska, one defense to prosecution is

that the defendant’s conduct “conformed to accepted veterinary practice [or] was part of scientific research governed by accepted standards”

(l). Maine allows proof of “accepted veterinary

practice or bona fide experimentation for scientific research” as an affirmative defense to a

charge of cruelty as well, so long as the animal’s

destruction, if required, is not “unnecessarily

cruel unless directly necessary to the veterinary

purpose” (89). Florida’s 59-year-old law states that

cruelty “shall be held to include every act, omission, or neglect whereby unnecessary or unjustifiable pain or suffering is caused, except when

done in the interest of medical science” (34). Georgia is more direct in establishing a connection between the exemption and the interest protected

by it: “The killing or injuring of an animal for humane purposes or in the furtherance of medical

or scientific research is justifiable” (53). Others

contain specific provisos that the statutes not be

construed to prohibit or interfere with scientific

research, if done by qualified persons in a humane manner (18)30). The majority simply exempt

“acceptable veterinary practices” and “bona fide

experiments” or research “governed by accepted

standards” (89).

Three other anticruelty statutes, all amended

within the last 3 years, are equivocal. The Indiana Code was amended in 1983 to exempt “veterinary practices” from the general anticruelty statute (63). In Pennsylvania, neither an exemption

nor a provision interpreting the statute as excluding scientific use is included in the law. The general grant of authority to police or humane society agents to enter premises for the purpose of

seizing and destroying exploited animals prohibits

entry or search “where scientific research work

is being conducted by or under the supervision

of graduates of reputable scientific schools or

where biological products are being produced for

the care or prevention of disease” (97).

The Maryland General Assembly, in a 1984

amendment, expressed its intention that “all animals . . . under private, local, state, or federally

funded scientific or medical activity . . . be protected from intentional cruelty” but provided that

no person is to be held liable for criminal prosecution due to “normal human activities to which

the infliction of pain to an animal is purely incidental and unavoidable.” Authorized enforcement officers otherwise permitted to take possession of animals to protect them from neglect or

cruelty cannot do so without prior review and

recommendation from the Division of Veterinary

Medicine in the Department of Health and Mental Hygiene. Reports to the State’s attorney for

the county in which the facility is located must

be made by the Division within 48 hours of receipt of a complaint (75).

Of greatest concern to those engaged in testing and research are older, general anticruelty

statutes that prohibit cruelty to all animals without requiring proof of a culpable state of mind.

Many of these statutes do not generally exempt

scientific inquiry from the prohibitions, and those

statutes that attempt to do so often fail to define

“animal” or “science” or contain vague definitions

of the terms. Virtually none of the statutes surveyed attempts to define what activities constitute scientific research, nor do they establish separate classifications for experimental animals.

Enforcement

Like Congress, State legislatures delegate enforcement to the executive branch of government, which is authorized to promulgate regulations and enforce them under authority of an

enactment. The exercise of the police power to

control and protect animals has been sustained

in a variety of areas, including controlling migration of animals into a State, requiring registration

and licensing of animals, controlling contagious

and infectious diseases borne by animals, and

compensating private parties for the destruction

of animals in furtherance of anticruelty laws (33).

Because criminal penalties are imposed for violations of anticruelty statutes, primary enforcement responsibility generally rests with “duly constituted” law enforcement authorities-police and

sheriff’s departments. Most State legislatures,

however, recognize the difficulty of ensuring enforcement of anticruelty statutes on the local level

and have also delegated limited police powers to

private, not-for-profit organizations, principally
Ch. 14–State Regulation of Animal Use Ž 309

humane societies or societies for the prevention

of cruelty to animals (74). These limited grants

of authority are most frequently extended to seizure of animals found to be cruelly treated, neglected, or abandoned, in violation of an applicable State law. In some States, officers or agents

of these groups possess specific powers for intervention, inspection, or the procurement of warrants or summonses or the ability to be deputized

by local law enforcement officials for such purposes. In New York, for example, lawfully appointed agents of the American Society for the

Prevention of Cruelty to Animals (ASPCA) have

been judicially recognized as “peace officers” and

are therefore authorized to issue summonses for

violations of anticruelty laws. Another New York

State case allowed the ASPCA to seize without a

warrant and impound animals held in violation

of cruelty statutes.

In States where no powers are specified or implied, societies formed for this purpose have developed investigative programs on which State or

local law enforcement officers rely for preliminary investigative activities. There appears to be

some movement away from statutory grants of

authority to nongovernmental agencies for this

purpose. Several States have repealed prior grants

and others have left undisturbed laws with no

mention of them. Beyond enforcement through

specific grants of police power, many anticruelty

groups initiate criminal investigations by filing

complaints or resorting to civil actions against

agencies or facilities to enjoin alleged

animals (33,36).

Constitutionality

cruelty to

Several State anticruelty statutes have been attacked on grounds that they are unconstitutionally vague, either because the statute allegedly

fails to give a person of ordinary intelligence fair

notice that a contemplated act is forbidden or because the statute as drafted encourages arbitrary

arrests and convictions. In almost all instances,

both active cruelty and duty-of-care provisions

have survived constitutional challenges based on

vagueness, even though their breadth and lack

of definition and specificity makes them susceptible to such attacks (9,62).

Cruel Acts

An Arizona statute outlawing cockfighting was

found to be unconstitutionally vague in its use of

the terms “animal” and “needless suffering,” and

two convictions were overturned (104). Disparate

results were reached in cases brought for convictions for the same activity in Kansas and Hawaii (86,105); the court was able to sustain the

statute in the latter case because statutory definitions of “animals” and “cruelty” helped overcome problems of vagueness. These cases are instructive for another reason. When convictions

have been thrown out, it is because courts have

been unwilling to interpret general statutes to forbid cockfights in the absence of legislative action

making these previously acceptable acts illegal.

Duty of Care

Courts have applied the same general principles of construction used in constitutional challenges to anticruelty statutes in upholding their

components governing minimum husbandry or

humane treatment standards. High courts in at

least two States have sustained legislative establishment of broad standards of care, but judicial

interpretations of the application of those standards varies. For example, a Texas court found,

without explanation, that the duty-of-care statute

“sufficiently informs an accused of the nature and

cause of the accusation against him and that it

is not unconstitutionally indefinite. ” Idaho’s Supreme Court upheld the legislature’s intent to

establish broad standards of care, suggesting that

“proper care” is that degree of care that a prudent person would use under similar circumstances. Virginia’s statute attempts to define the

terms ‘(adequate feed” and “adequate water,” but

ultimately the standard adopted is a “reasonable

level of nutrition,” though it adds nothing to the

law’s specificity. Thus, the duty charged to anyone responsible for animal care is speculative,

though the duty implicitly requires knowledge of

the animal’s requirements (33).

Review of the available case law indicates that

courts are reluctant to accept constitutional attacks even against vague and undefined anticruelty statutes, preferring to limit themselves to

measuring defendants’ conduct against general

statutory provisions on a case-by-case basis.
310 ● Alternatives to Animal use in Research, Testing, and Education

Judicial Interpretation of

Applicability of Anticruelty

Statutes to Research

Historically, those interested in protecting laboratory animals from cruelty have used general

anticruelty statutes against research facilities or

individual researchers, but (at least until 1981) to

little effect. In 1914, for example, the Women’s

SPCA sued six faculty members at a Pennsylvania

medical school for “wanton cruelty,” but no conviction resulted (33).

Two recent cases give some indication how a

modern State court might respond to a confrontation between anticruelty and research interests.

The Taub Decision

The most celebrated and controversial case

in this area is Maryland v. Taub, Montgomery

County police investigated conditions at a laboratory that was performing stroke research on nonhuman primates that was funded by the National

Institutes of Health (NIH). The investigation resulted in seizure of the primate colony. In January 1982, the county’s State’s attorney filed 17

charges against the investigator, Edward Taub,

charging him with violation of Maryland Code,

Article 27, Section 59 (1957, 1976 Repl. Vol.), with

respect to each of 17 primates. Following a trial

in district court, the defendant was found guilty

of failing to provide necessary veterinary care for

6 animals and acquitted of all other charges. On

appeal to the circuit court, a jury hearing the case

de novo found Taub guilty of one charge of failing to provide necessary veterinary care for 1

monkey, known as “Nero” (76).

Taub appealed to the Maryland Court of Appeals, asserting that the law was unconstitutional because the Federal Animal Welfare Act preempted State jurisdiction in the area of federally

funded research, and attacking several of the trial

court’s evidentiary rulings. The Maryland high

court reversed the circuit court’s decision and

remanded the case with instructions to dismiss

the charges (32). Tracing the legislative history

of the Maryland statute from 1890 to its last revision in 1976, the court concluded that the legislature had not intended the statute to apply to

this type of research activity under a Federal program, basing its ruling on three points:

●

●

●

The legislative intent was interpreted as exempting from punishment acts not involving

“unnecessary” or “unjustifiable” pain, given

exceptions for “customary and normal veterinary and agricultural husbandry practices”

and the last sentence of Section 59, which

states:

It is the intention of the General Assembly

that all animals shall be protected from intentional cruelty, but that no person shall be

liable for normal human activities to which

the infliction of pain to an animal is purely

incidental and unavoidable.

The court imputed to the assembly “awareness” of the Federal Animal Welfare Act,

which constituted a “comprehensive plan for

the protection of animals used in research

facilities, while at the same time recognizing

and preserving the validity of use of animals

in research.”

Taub’s laboratory was subject to detailed regulations of the U.S. Department of Agriculture (USDA), which set forth specifications

for humane handling, care, treatment, transportation, and veterinary care. With respect

to the latter, the court noted that Federal law

recognized and preserved the validity of animal research. The court also noted the application of NIH’s grant requirements to the

defendant’s project (32).

The Maryland statute neither generally exempted scientific research from the reach of its

anticruelty law nor regulated experimentation

separately, as some others do. On 1984, the Maryland General Assembly enacted a law that made

the anticruelty statute’s application to research

activities less ambiguous.) The Maryland court’s

disposition of the case illustrates a judicial reluctance to find cruelty in an activity of some recognized social utility. Its value as a bellwether for

other States is limited, however, for several reasons. First, although the case may be cited by

other defendants as a helpful precedent, it is law

only in Maryland. Second, the holding in this case

may be limited to its particular facts. At the trial

that resulted in conviction, a substantial amount

of testimony was heard on the issue of adequate
Ch. 14—State Regulation of Animal Use ● 311

veterinary care in research involving intentional

injury to the research subjects. The court’s opinion did not fully address this issue. Third, the

court relied heavily on its presumption that the

General Assembly of Maryland had been aware

of the Federal Animal Welfare Act when it last

amended the statute, 8 years earlier. Many of the

two dozen or so general anticruelty laws that

contain no research exemption have not been

amended since the 1966 passage of the Animal

Welfare Act.

The Preemption Question

The Taub decision is also relevant to the question of research coverage by general anticruelty

statutes because of what the case did not decide.

On appeal, Taub asserted that his conviction was

invalid for five main reasons, three of which addressed themselves to actions occurring in or

taken by the trial court (sufficiency of evidence,

permitting medical experts to define the term

“veterinary care)” and denial of a fair trial due

to introduction of evidence of Nero’s physical condition more than a month after he had been seized).

But Taub also contended that the Maryland statute was unconstitutionally vague, because the definition of “animal” was excessively broad and because it was unclear as to what was ‘(the most

humane method reasonably available” and what

were included or excluded from “normal human

activities to which the infliction of pain to an animal is purely incidental and unavoidable.” In addition, he claimed that his prosecution was barred

by the Supremacy Clause of the Federal Constitution and that the reach of Maryland’s general

statute was therefore preempted by congressional

passage of the Federal Animal Welfare Act (10).

Thus, the court was presented with two constitutional questions of considerable importance

to the continued enforceability of general anticruelty statutes. First, do the old, nonspecific formulations of cruelty provide sufficient notice of

what conduct is prohibited, under what circumstances, and how violation of the law can be

avoided? Second, has Congress so occupied the

field of research regulation that enforcement of

a similar ”State law would violate the principle that

the Federal Constitution and reasonable Federal

laws enacted under it are the supreme law of the

land? The Animal Legal Defense Fund (ALDF), formerly known as Attorneys for Animal Rights, Inc.,

a nonprofit professional legal group interested in

better laws protecting animals, joined the State

attorney general as a friend of the court in

defending the appeal and briefing the constitutional issues raised by Taub’s challenges (11,66).

Whether a State law is preempted by a Federal

law is a matter of statutory interpretation by a

State or Federal court. (Jurisdiction is concurrent

where these questions arise, since both the State

and the Federal Government have a stake in the

outcome of the question.) Court decisions touching on this question over the years have established two general requirements for Federal

preemption of a State statute. First, the Federal

Government must have the authority to preempt

the State’s enactment. Second, Congress must

have intended to preempt State law (115).

Preemptive authority is found where Congress

legitimately exercises an enumerated power, such

as the constitutional power to regulate interstate

commerce (79,100,112,118). A Federal law may

also be preemptive when, supported by application of the “Necessary and Proper Clause” (111),

it gives effect to an enumerated power, even

though the means used is not expressly enumerated in the Constitution (68). In either of those

circumstances, if the law is found to have a rational basis for regulation and effectuation of an

enumerated power, it is capable of preempting

a State law (90). A Federal law does not have

preemptive capability, however, if Congress uses

its enumerated powers alone to go beyond its

areas of enumerated concerns to achieve a result

that a State could also achieve by the exercise of

its reserved power.

Congress may exercise an enumerated power

to achieve an end extraneous to the effectuation

of that power. Thus, for example, Congress may

exercise its spending power to encourage an extraneous goal such as humane treatment for research animals. As a general principle, however,

if an enumerated power is used to affect an area

not within the Federal “circle” of interests, it cannot compel the States to accept that exercise. In

such cases, concurrent jurisdiction exists (16)68)

110). The ALDF brief relied on this principle in

its assertion that, while Congress’ power to appro-
312 . Alternatives to Animal Use in Research, Testing, and Education

priate funds for the general good may be used

to require Federally funded research facilities to

comply with Federal standards of animal care, this

does not preempt similar State laws. Thus, the

grantee of Federal funds maybe bound to adhere

to any conditions of the grant, but the State cannot be and is not so bound except to the extent

that the State itself accepts Federal research

funds. ALDF argued that denial of preemptive capability would promote valuable public policy by

“preserving to the people of Maryland the right

to determine what constitutes cruelty” (66).

Once a Federal law is shown to be constitutionally capable of preemption, it must be demonstrated against a generally applicable presumption in favor of State laws that Congress either

explicitly or by inference intended for the Federal law to supersede conflicting State enactments

(57,98). Determining legislative intent can sometimes be difficult, especially when Congress avails

itself of more than one enumerated power, against

which different constitutional standards must be

applied (28). When the State law involves the exercise of its traditional police powers—to protect

the welfare of its citizens—preemption will occur

only when there is proof that such was the Federal law’s clear purpose (35). If there is insufficient evidence that Congress intended to totally

occupy the field regulated by the respective laws,

there must be sufficient conflict between them

for the State law to stand as “an obstacle to accomplishment and execution of the full purposes

and objectives of Congress” (57).

Both the State and ALDF argued, first, that exercise of a traditional police power was involved

and, second, that Section 2145(b) of the Animal

Welfare Act made it sufficiently clear that Congress intended to establish a cooperative enforcement scheme rather than a conflicting one, so that

no conflict or obstacle to attainment of Federal

objectives was presented (11,66). (Section 2145(b)

of the act authorizes USDA to cooperate with

State and local governments carrying out “any

State, local, or municipal legislation or ordinance

on the same subject.”) Taub, on the other hand,

pressed the argument that the State law was in

conflict with, and an obstacle to, the congressional

objective of minimizing disruption of research

(10). In any case, the court decided that the matter may be disposed of by the conclusion that the

Maryland statute simply is inapplicable to Dr.

Taub (32).

The decision was not at all surprising, given the

publicity about the case over 2 years (8,73,88).

Reaction was also predictable. One professional

society’s newsletter concluded that the Maryland

court had “wisely recognized” the fact that the

“ultimate goal [of biomedical research] is improvement of the human condition” and claimed that

the decision provided an “important legal precedent that affirms the propriety of the use of animals in biomedical research” (31), One of the attorneys on the ALDF brief called the court’s

decision “opaque)” observing that “one manifestation of the court’s confused reasoning is that attorneys and commentators cannot agree on the

grounds for the decision” (122). Writing in the

New England Journal of Medicine, an attorneyprofessor who reviewed the decision and the resulting commentary reached this sober conclusion (27):

It is now necessary for the Congress to consider whether or not it wishes to address this

question and to remove the uncertainty in the

law by making it clear that the Animal Welfare

Act is intended to be a comprehensive, exclusive

system of control over the use of animals in

experimental facilities and activities in interstate

and foreign commerce and under the National

Institutes of Health research programs, Without

such clarification, investigators and operators of

facilities face the possibility of local criminal

prosecution, seizure of animals, injunctions to

close facilities, and cessation of animal investigations. It should be understood, however, that

this Federal mandate, if accepted, means that the

administrative system for monitoring, including

on-site inspection, must be adequate to insure

continued compliance with national standards

for humane treatment. Otherwise, state-level organizations with a sincere and reasonable concern about the care of animals will be justified

in demanding local enforcement and surveillance

of biomedical research programs involving laboratory animals.

Winkler v. Colorado

Only one other State court case addresses the

question of preemption by the Animal Welfare

Act. In Winkler v. Colorado, that State’s supreme

court considered a preemptive challenge to Colo-
Ch. 14—State Regulation of Animal Use . 313

rado regulations prohibiting the importation of

pets for resale from States with less stringent

licensing laws and regulations covering commercial pet dealers. The court found preemptive capability, holding that Congress used an enumerated

power to effectuate an enumerated power: regulating interstate commerce, The challenge to the

State law was not sustained, however; the court

found that the act not only “clearly did not indicate preemptive intent, but rather, expressly endorsed state-federal cooperation” (119).

Criticisms

Despite the fact that it set the stage for future

collisions between research and animal interests,

the Taub case is not particularly valuable for resolving such conflicts, since the court avoided constitutional questions in reaching its decision. The

decision suggests that when a court is confronted

with a difficult case involving sharply contrasting

but supportable interests and obscure legal principles whose potential impact on a decision far

outweighs their understandability in application,

it will go to extraordinary lengths to avoid that

decision. It is a natural and conservative reaction

for a judge to decline an invitation to make law

that prejudices an existing enforcement system,

however imperfect, when the legislature has

shown no inclination to do so itself. The mixture

of enumerated powers supporting the Animal

Welfare Act, coupled with evidence that Congress

did not intend to preempt the field of research

regulation, are probably sufficient to avoid

preemption. That result, however, cannot be predicted with any confidence.

Animal welfare advocates criticize general anticruelty laws as being ineffective in protecting

animals from harm (19,29,124). The statutes’

vagueness and the frequent requirement for some

degree of culpability both exact high standards

of proof and subject statutes to a greater risk of

ineffectiveness. Other criticisms are that general

anticruelty statutes fail to anticipate and prevent

cruelty or neglect, instead taking effect only when

a sustainable complaint is entered. Enforcement

of these statutes is generally entrusted to local

law enforcement agencies, which for a number

of reasons typically assign them a comparatively

low priority. State regulations and local procedures for investigating and building a criminal

case against a violator are complex, involving complicated rules governing warrants and searches.

Fines are low, as a rule, and criminal violations

comparatively hard to prove. When convictions

are obtained, fines assessed against violators are

generally collected by the State, though humane

societies or SPCAs with limited enforcement authority must spend their own funds to investigate

and prove cases (33,36).

Recent Initiatives in

Anticruelty Laws

Critics of current anticruelty statutes, who have

pressed to extend the laws’ reach to research

activities, have not met with a great deal of success. They insist that two basic changes must be

made if anticruelty laws are to be enforced meaningfully: First, animal welfare specialists must be

trained and used; second, those trained specialists

must be given increased enforcement authority

(81). One situation hailed as a model is Massachusetts’ creation of a private right-f-action and its

delegation to the Massachusetts SPCA and, more

recently, to the Animal Rescue League, of authority to act as agents of the Commissioner of Health

in enforcing the State’s anticruelty laws.

The private right-f-action allows citizens to

bring civil suits to enjoin violations, reap statutory damages, and collect court costs and attorneys’ fees if successful. Massachusetts SPCA officers are commissioned as special State police

officers and given training by the police academy

and the Massachusetts SPCA. They have arrest

and prosecution authority for violations. Inspections are conducted when a problem becomes apparent. The officers can use selective enforcement

procedures that focus on serious violations, which

conserves time, money, and personnel while increasing the law’s deterrent effect (77). Supporters

of this model argue that efficient enforcement of

the type contemplated by it would curtail animal

abuse, including abuse occurring in laboratories.

Skeptics point to the obvious increase in cost entailed by such qualification and training requirements, and they wonder if the research community would accept enforcement of anticruelty

provisions by its chief antagonists (19).

38-750 0 - 86 - 11
314 Alternatives to Animal Use in Research, Testing, and Education

Legislatures that have revised their anticruelty

statutes within the last several years are mindful of the problems in applying and enforcing

older laws. Virginia, for example, totally revised

its Animal Welfare Act. Enforcement powers, duties, and training and skill requirements for “animal wardens” were increased, and local humane

societies were granted limited warrant, search,

and arrest powers (117). Florida, while not considering any animal welfare amendments per se,

upgraded the maximum fine for active cruelty to

animals from $1,000 to $5,000, and the fine for

confinement without food, water, or exercise or

for abandonment from $500 to $5)000 (58). The

Michigan Humane Society has drafted a model

anticruelty bill, as well as publishing a comprehensive guide to enforcement of the existing

Michigan statute and supplements for use in Illinois and New York (69,70,71). (A model statute

is a law proposed for State adoption by a group

of experts, frequently a national conference of

legal scholars, though advocacy groups are increasingly likely to offer model laws incorporating their positions. Although model statutes are

intended to promote uniformity among the States,

a State adopting such a law will often modify it

to some extent to meet its own needs, or it may

only adopt a portion of the model statute.) The

Michigan guide and its supplements detail the

process of investigating suspected cruel conduct

and building a case against the suspected violator.

Another model anticruelty statute (26) includes

provisions regulating research animals by dividing covered animals into three classes, with treatment depending on their classification. Class A

animals are chimpanzees, gorillas, and dolphins.

An experiment that causes a significant amount

of pain to a Class A animal would be prohibited

unless it is performed in a licensed research facility, it causes less suffering than any alternative

experiment that would provide the same scientific information at a reasonable cost, and it is

limited to gaining information about human or

animal disease, injury, or mental disorder. In addition, weapons research on Class A animals would

be banned unless the experiments dealt directly

with counteracting the health effects of weapons.

Furthermore, behavioral research with this group

would be prohibited unless justified by healthrelated reasons.

Class B animals are all other mammals. The

model statute prohibits scientific experiments that

cause suffering to Class B animals unless the same

restrictions that apply to Class A animals are met.

Behavorial research is not prohibited, however.

Class C consists of any other vertebrate. Only

two restrictions would apply to experiments causing pain to Class C creatures: The research facility would have to be licensed, and the experiment

would have to produce less pain than any other

reasonably priced experiment that would produce

the same information.

This model statute provides both criminal penalties and civil damages for violations. The criminal provisions would be enforced by law enforcement officers and the others by any interested

party (see discussion of private enforcement interests in the next section). Recordkeeping by facilities is required, and the records could be inspected at any time. Required entries include the

number and types of animals used, the conditions

under which animals were kept, and a description of the purpose and design of the experiment.

Proponents contend that adoption of this statute

would provide clear standards of research-animal

care, resulting in less abuse. Critics cite the difficulty of classifying species so as to satisfy everyone and the inconsistency of arbitrarily excluding

behavorial research for Class A animals (12,19).

RIGHT TO TAKE LEGAL ACTION ON AN ANIMAL’S BEHALF

Past Trends contexts, such a right is exercised by bringing

against the enforcement agency a legal action

There are two ways a State could allow legaI seeking a court order directing the agency to enaction on an animal’s behalf. First, an anticruelty force the law. Second, a legislature or court could

statute could provide private citizens with a right confer upon private citizens “standing to sue” on

to compel enforcement of the law. In nonanimal an animal’s behalf, such as by allowing citizens
Ch. 14—State Regulation of Anima/ Use 315

to act as legal guardians of an animal’s welfare.

The requirement of standing is satisfied either if

it is conferred by statute or if a court holds that

the plaintiff has a legally protectable and tangible interest at stake in the litigation.

One State trial court was called on in 1982 to

decide whether the Animal Welfare Act or either

or both of two Connecticut laws confer upon a

private citizen a right to compel enforcement of

the statutes against, and the right to seek damages

from, a research entity on behalf of an animal.

In Friends of Animals, Inc. v. U.S. Surgical Corporation, the plaintiffs filed a complaint alleging

that the defendant’s use of dogs in teaching its

technical field representatives how to use surgical staplers violated both the Animal Welfare Act

and the State’s general anticruelty law. The Connecticut anticruelty law is a general misdemeanor

statute with no qualifiers and contains no research exemption. (Similar attempts by this group

to get a Federal hearing on these charges are described in ch. 13. For a complete chronology of

the lawsuits between these parties and a more

detailed examination of the attempted use of the

act and the State’s anticruelty laws against a research enterprise, see the case study at the end

of this chapter.)

The group, claiming for its members “a personal

stake and an intense interest in the prevention

of cruelty to animals)” asserted a private right of

action against the company to enforce the laws

and recover damages. The defendant moved to

strike the complaint for failure to state a claim

on which relief could be granted, a pleading that,

under Connecticut rules of procedure, automatically tests the legal sufficiency of the complaint.

The court struck the anticruelty counts, finding

no legislative intent to create a private right of

action and noting that the plaintiff introduced no

legal authority in support of its contention that

such a right existed.

To support the alleged right under the Animal

Welfare Act, the plaintiff claimed the act was analogous to the Marine Mammal Protection Act (5).

(A Federal court had previously interpreted the

latter to support a private right to sue, as discussed in ch. 13.) The Connecticut court rejected

this analogy. Citing a judicial-review provision in

the latter statute that is not found in the Animal

Welfare Act, the absence of any proof that the

Congress intended to create a private right to enforce the Animal Welfare Act, and the absence

of supporting case law, the judge struck the balance of the Friends of Animals complaint, leaving no issues for trial before the court (45).

Recent Initiatives to Create Legally

Enforceable Rights for Animals

Support is growing in the animal welfare community for establishing independent and legally

enforceable rights for animals, on the theory that

effective enforcement of animal interests will

never occur as long as they are balanced against,

and almost always outweighed by, competing human or social considerations. This reflects a general historical progression toward treating animals as intrinsically valuable and away from

treating them as mere chattels or personal property (7)29).

Interest in this concept is fed by the success of

animal welfare groups in expanding the reach of

statutes like the Marine Mammal Protection Act

by winning the right to sue on behalf of protected

animals, at least in a limited sense (5,120). Acceptance of other statutes with similar objectives, such

as the Endangered Species Act, has led to a widening circle of protected and judicially enforceable

interests for animals (22,29). Conferring standing

to sue on animals would allow humans to sue on

an animal’s behalf (or on behalf of a class of

animals) to protect the interests of the animal.

Groups such as the Animal Welfare Institute have

used their judicially conferred standing to sue the

Federal Government and others under the Endangered Species Act, for example, on behalf of interests they believe are not being protected sufficiently (29).

Standing proposals have led naturally to other

interest-protecting roles for those seeking to protect animals’ rights. In particular, application of

the familiar principles of guardianship is sought.

Under guardianship principles, the legislative

status of animals, especially companion species,

would be changed from property to possessors

of specified rights, while the definition of a guard-
316 . Alternatives to Animal Use in Research, Testing, and Education

ian would be amended to include a person who

“has elected to take responsibility for the care

and well-being” of an animal. Thus, guardianship

would commence on adoption or purchase. Legal

guardians could be appointed by courts to assume

duties as custodians and conservators of a laboratory animal’s rights, including the right to sue.

The relationship could be terminated by judicial

removal for malfeasance or nonfeasance and would

terminate on the animal’s death or the guardian’s

incapacity. The guardian’s ability to protect and

enforce the animal’s interests, by lawsuit if necessary, would afford animals better protection,

it is argued (109).

As discussed, courts have thus far been unwilling to confer standing on human plaintiffs in the

absence of a specific statutory grant. In the U.S.

Surgical case, the Connecticut Superior Court

found no sustainable private right to enforce either the Animal Welfare Act or the State’s anticruelty statute. Even if courts were less conservative about granting standing, and even if the

burden required for standing of showing actual

injury were not as rigorous, the interest being affected still must be cognizable at law. Using the

Endangered Species Act as an analogy, what would

be required at a minimum is conferring the right

to judicial review on “any person” affected by an

action taken under the law containing the right

of review. Thus, the likelihood of legislative, followed by judicial, acceptance of even some minimal version of animal standing is probably not

imminent. Acceptance of novel interpretations of

otherwise familiar concepts of guardianship to

cover animals is likely to be even farther off.

As frustrated as animal advocates have been in

their efforts to secure enforcement of laws protecting animals, they show no sign of abating. Several such cases, instituted or pending at the Federal level, are examined in chapter 13, and the

case study at the end of this chapter discusses

a series of cases, involving the same parties, that

explores a variety of unsuccessful theories. Recently, Actors and Others for Animals and the

Fund for Animals sued the Los Angeles County

Board of Supervisors, alleging their failure to enforce the county’s pound release ordinances,

which require certification of humane treatment

of animals by institutions seeking to purchase

pound animals (108). Common-law theories, such

as nuisance, have been used in these suits, and

environmental statutes have been enlisted as well.

In 1984, a California Superior Court dismissed

a suit brought by a coalition of animal welfare

groups, citing provisions of the California Environmental Quality Act, to include an evaluation

of laboratory-animal use in an environmental impact report for a new, $46 million science building at the University of California at Berkeley (20).

REGULATION OF RESEARCH

Past Trends

Apart from regulating agricultural and other

economically oriented uses of animals, some

States regulate the use of animals for research

●

purposes. Twenty-one jurisdictions regulate research specifically, either in the context of general registration, licensure or inspection laws, or

●

independently:

Four States allow or require regulation of research facilities: California (15,17), Michigan ●

(84), Tennessee (107), and Virginia (117).

Seven States and the District of Columbia require licensing or registration for a research

facility to receive pound animals: D.C. (30),

Illinois (61), Iowa (65), Minnesota (87), Ohio

(95), Oklahoma (96), South Dakota (103), and

Utah (116).

Two States extend an exemption from their

animal cruelty statutes only to research approved or licensed by the State: New Jersey

(92) and New York (93).

Two States require licenses to use dogs or

cats in research: Connecticut (24) and Massachusetts (77).

Five States exempt all research facilities or

federally licensed facilities from State licensing programs: Colorado (23), Kansas (67),

North Carolina (94), Pennsylvania (97), and

Rhode Island (99).
Ch. 14—State Regulation of Animal Use . 317

Most State statutes deal with the procurement

of animals for research. For example, the Michigan statute makes it unlawful to sell animals to

an unlicensed research facility (84). Dogs used in

research must be marked. Animals cannot be sold

to research facilities at a public auction or by

weight, and when an animal is purchased for research, a bill of sale signed by the seller must be

retained. A facility failure to abide by those rules

could result in revocation of its required license

(85). Conditions in animal holding facilities are also

common concerns in these laws. New York facilities must treat research animals kindly and humanely and must feed and house them properly

(93). Animals held in California facilities must receive satisfactory food, shelter, and sanitation

(15,17).

State legislatures have been as reluctant as Congress to go behind the laboratory door. California law provides that the Department of Health

Services is required to promulgate rules for the

control and humane use of animals in specified

types of research (17). The New York statute specifies that:

.

. . . commensurate with experimental needs and

with the physiologic function under study, all

tests, experiments, and investigations involving

pain shall be performed under adequate anesthesia (93).

Under that statute, the Commissioner of Health

has promulgated regulations applicable to research in the State university system to require

ethical review of experimental procedures by the

degree of pain and suffering caused the animal

involved.

Some of the statutes extend their requirements

only to the use of companion animals. Massachusetts requires a license prior to experimentation

on dogs and cats (77), and Connecticut requires

a license for research on dogs only (24). Institutions in Illinois, Iowa, or Oklahoma that plan to

use live dogs or cats may apply for a license to

obtain animals from a pound (61)65,96); in Ohio,

to receive impounded dogs institutions must be

certified by the Ohio Public Health Council as being engaged in teaching or research (95).

State research-regulation laws enacted since the

passage of the Animal Welfare Act are mindful

of the potential for duplication. California specifically exempts some laboratories from its licensure law, such as those regulated by the National

Institutes of Health (17). Facilities in Kansas holding a current Federal registration under the Animal Welfare Act are exempt from State law (67),

as are federally regulated facilities in North Carolina and Rhode Island (94)99). Facilities in Pennsylvania that have undergone a Federal inspection within the past year are exempt from regular

inspections by Commonwealth animal wardens

(97).

With the exception of Massachusetts and Kansas,

inspection and enforcement authorities are Statelevel agencies. The California statute prohibits

delegation of this authority to anyone other than

an employee of the Department of Health Services (17). Conversely, Kansas law allows the Commissioner of Health to appoint county and city

health commissioners as authorized representatives for inspection purposes (67). In Massachusetts, research institutions must apply to the Commissioner of Licenses for a license to “employ dogs

or cats in scientific investigation, experiment or

instruction or for the testing of drugs or medicines,” The Commissioner must investigate the applicant prior to licensure to determine whether

the public interest is served by granting a license

and that the licensee “is a fit and proper institution to receive such license. ” Licenses are revocable, after notice and hearing, and must be renewed annually. Knowing violators are subject

to a fine of up to $100 for each discovered violation of the statute. Local courts are authorized

to enjoin violations “or to take such other actions

as equity and justice require” in enforcing the

licensing law. The Commissioner is given a general grant of rulemaking and inspection authority, and visitation and inspection powers may be

delegated by regulation to the Massachusetts

SPCA and the Animal Rescue League of Boston,

“as agents of the commissioner” (77).

Recent Initiatives in

Research Regulation

Proposals to enactor modify licensing statutes

suggest such changes as increasing control over

the research process; requiring stricter standards
318 ● Alternatives to Animal Use in Research, Testing, and Education

of treatment and care; increasing recordkeeping

and inspection functions; streamlining investigation, complaint, and prosecution procedures; and

providing additional enforcement resources. Other

than these proposals, not many other initiatives

have been put forward to prevent or reduce experimental-animal suffering. The model statute

discussed above has not generated a great deal

of interest (26). Bills routinely introduced in the

legislatures of more populous States require percentage reductions in funds spent on animal research, require consideration and adoption of

alternatives to animal use, or attack the legitimacy

of animal usage in some other way. But none has

yet been taken seriously. Nevertheless, House Bill

742 in Massachusetts would mandate a 5 percent

annual reduction per institution in the number

of animals used in that State’s research laboratories.

POUND RELEASE LAWS

Past Trends

All States have statutes that provide for the seizure, holding, and humane destruction of unowned or unclaimed stray animals (74). These

laws, which are most complex and aggressive in

their application to dogs and cats, attempt to balance the need for protection of the public’s health

and safety from unmanaged animals against the

rights and duties of private animal ownership,

whether for aesthetic or commercial purposes.

To serve the interests of public protection and

welfare, most States provide for the release to research institutions of unowned or unclaimed animals, usually dogs and cats, under certain circumstances or when specified conditions are met,

such as obtaining a license. Such statutes generally provide for a suitable holding period after

collection or seizure, so that owners have an opportunity to claim their animals, and specify procedures to be followed by owners, holding facilities,

and claiming institutions. Many municipalities also

have laws either requiring or authorizing the release of “random-source” animals to research institutions. Definitions of what types of institutions

qualify to claim random-source animals, and at

what level of “scientific research,” vary widely.

As noted, there is little agreement on what legitimate scientific research is. Sometimes this is left

to authorities responsible for regulating research,

independent of general anticruelty laws, and

some types of educational research activities are

proscribed (33,36). These laws are summarized

in table 14-2.

The authority of States to release unclaimed animals to appropriate research facilities has never

been successfully challenged. In 1959, for example, the Supreme Judicial Court of Massachusetts

declined to rule that such a scheme impaired any

rights of petitioning humane societies or pet

owners, or that it called for an unconstitutional

expenditure of public funds or property (78). The

force of the court’s ruling was rendered moot by

the recent passage in Massachusetts of a law, discussed below, prohibiting the release or importation of pound animals for research purposes.

Currently, nine States (Connecticut, Hawaii,

Maine, Massachusetts, New Hampshire, New Jersey, Pennsylvania, Rhode Island, and Vermont)

prohibit the release of dogs and cats from pounds

for research purposes (89). The most far-reaching

of these laws was passed by Massachusetts in

1983 and went into effect in October 1984. Besides repealing the State’s old pound release statute and eliminating all pertinent references in

general pound law, the new statute prohibits the

release by “dog officers” or municipalities of any

animal to any “business or institution licensed or

registered as a research facility or animal dealer

with the United States Department of Agriculture.” A research ‘(institution” is defined as (77):

. . . any institution operated by the United States

or by the Commonwealth or a political subdivision thereof, or any school or college of medicine, public health, dentistry, pharmacy, veterinary medicine or agriculture, medical diagnostic

laboratory or biological laboratory, hospital or
Ch. 14—State Regulation of Animal Use ● 319

Table 14.2.—Laws on Pound Animal Use,

by Jurisdiction

-

Alabama ., . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Alaska . . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Arizona . . . . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Arkansas . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

California . . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Colorado . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Connecticut . . . . . . . . X . . . . . . . . . . . . . . . . . . .

Delaware . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

District of Columbia. . . . . . X . . . . . . . . . . . . . .

Florida . . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Georgia . . . . . . . . . . . . . . . . . . . . . . . . . . . X .,..

Hawaii . . . . . . . . . . . . . X . . . . . . . . . . . . . . . . . . .

Idaho . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Illinois . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X

Indiana . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Iowa. . . . . . . . . . . . . . . . . . . . X . . . . . . . . . . . . . .

Kansas . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Kentucky . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Louisiana . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Maine . . . . . . . . . . . . . X . . . . . . . . . . . . . . . . . . .

Maryland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X

Massachusetts . . . . . . X . . . . . . . . . . . . . . . . . . .

Michigan . . . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Minnesota . . . . . . . . . . . . . . . X . . . . . . . . . . . . . .

Mississippi . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Missouri . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Montana . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Nebraska . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Nevada . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

New Hampshire . . . . . X . . . . . . . . . . . . . . . . . . .

New Jersey . . . . . . . . X . . . . . . . . . . . . . . . . . . .

New Mexico . . . . . . . . . . . . . . . . . . . . . . . X . . . .

New York . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X

North Carolina . . . . . . . . . . . . . . . . X . . . . . . . . .

North Dakota . . . . . . . . . . . . . . . . . . . . . . X . . . .

Ohio. . . . . . . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Oklahoma . . . . . . . . . . . . . . . X . . . . . . . . . . . . . .

Oregon . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Pennsylvania . . . . . . . X . . . . . . . . . . . . . . . . . . .

Rhode Island . . . . . . . X . . . . . . . . . . . . . . . . . . .

South Carolina . . . . . . . . . . . . . . . . . . . . . X . . . .

South Dakota . . . . . . . . . . . . X . . . . . . . . . . . . . .

Tennessee . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Texas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

Utah . . . . . . . . . . . . . . . . . . . . X . . . . . . . . . . . . . .

Vermont . . . . . . . . . . . X . . . . . . . . . . . . . . . . . . .

Virginia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X

Washington . . . . . . . . . . . . . . . . . . . . . . . X . . . .

West Virginia . . . . . . . . . . . . . . . . . . . . . . X . . . .

Wisconsin . . . . . . . . . . . . . . . . . . . . X . . . . . . . . .

Wyoming . . . . . . . . . . . . . . . . . . . . . . . . . . X . . . .

SOURCE: National Association for Biomedical Research,State Laws Corrcerningthe L4eofAn/mals in &search (Washington, DC: Foundation for

Biomedical Research, 19S5).

other educational or scientific establishment

within the Commonwealth above the rank of secondary school, which, in connection with any of

its activities) investigates or gives instruction concerning the structure or functions of living organisms or the causes, prevention, control or

cure of diseases or abnormal conditions of human beings or animals.

Effective October 1, 1986, Section 9 of the law

will forbid the importation of similar animals into

the Commonwealth for research purposes:

. . . no person, institution, animal dealer or their

authorized agents shall transport, or cause to be

transported, any animal obtained from any municipal or public pound, public agency, or dog

officer acting individually or in an official capacity into the commonwealth for purposes of research) experimentation, testing, instruction or

demonstration.

Under the provisions o Section 9, any instltution

obtaining animals before the deadline must have

filed a report with the Department of Public Health

“detailing its plans for discontinuation of the use

of such animals. ”

The impact of recent laws forbidding the acquisition of unclaimed animals for research is uncertain. Research community representatives in

Massachusetts have claimed that the new laws,

when fully in effect, will add perhaps $6 million

to the annual price of research conducted in the

Commonwealth (80,82). The added cost to taxpayers of humanely destroying animals that remain unclaimed at pounds must also be considered, although it could be argued that taxpayers

bear the cost of sacrificing animals in research

as well, however indirectly (81). The effects of the

new Massachusetts laws merit close observation.

Recent Initiatives in

Pound Release Laws

The success of those who wish to repeal pound

release laws or to prohibit the use of stray and

abandoned companion animals in research by

some other means has been spotty. Most of the
320 ● Alternatives to Animal Use in Research, Testing, and Education

laws permitting the use of pound animals in research were passed in the decade following World

War II, when the need for inexpensive research

models began to mount, and the vast majority of

jurisdictions still permit it. As table 14-2 shows,

6 jurisdictions require release of impounded animals for research purposes, 7 permit it, 29 neither expressly require nor forbid release, and 9

prohibit the practice. Most delegate that authority to local animal control officers and authorities

(89). Release repeals have succeeded in larger

areas, which are perceived to have the resources

for less-convenient means of disposition of unwanted animals. Smaller jurisdictions without

those resources are faced with animal and disease control problems that are as persistent as

ever. Thus, a senate committee in Florida reported a bill in 1984 that required more-humane

methods of euthanasia for strays but rejected a

proposal to prohibit city and county shelters from

sending excess animals to the University of Florida

for experimental purposes (114), Similarly, the Humane Society in Larimer County, CO, voted unanimously in May 1983 to sell animals to Colorado

State University for veterinary research in order

to raise funds.

Pound release laws, whether mandatory or permissive, have come under close scrutiny in the

last 10 years at both the State and local level. A

25-year-oldd law in New York requiring the release

of pound animals to State-run research institutions was repealed in 1979 (21). A bill defeated

in the Wisconsin Senate by a vote of 2-97 would

have amended the current law requiring pounds

and shelters to release unclaimed dogs to Stateaccredited institutions, upon proper requisition,

for research purposes (33,121).

A running legislative battle has been taking

place in the California Assembly for several years.

Two major bills dominated the legislative agenda

in 1983 and 1984, but neither received approval.

Senate Bill No. 883, defeated in 1984 in an assembly committee, would have repealed current requirements for pound signs warning owners and

others that animals could be used in research and

would have generally prohibited the release by

local pounds and shelters of live dogs, cats, and

other animals for the purpose of experimentation,

testing, demonstration, or research (14). Assembly Bill No. 1735, left pending in the 1984 assembly session, would have modified the same law

by permitting persons leaving strays to stipulate

that the animal not be used for research purposes.

Further, it would have extended the mandatory

holding period for potential research animals and

prohibited release of any pound animal to a research facility prior to a determination that the

facility meets specified standards of humane animal care (13). (California law currently provides,

in a regulation-of-research statute, that the Department of Health Services may not make any

rule “compelling the delivery of animals for the

purpose of research, demonstration, diagnosis, or

experimentation,” thus leaving the policy to the

discretion of local jurisdictions (17).)

Substantial recent activity has occurred at the

local level, as well. For 3 years, the City of Los

Angeles has prohibited the release of cats or dogs

for research (60). In 1984, commissioners in Jackson County, MI, refused to prohibit the release

of pound animals to research institutions and

educational facilities. Advocates of the measure

subsequently failed in their drive to have the issue placed on a referendum ballot (102). In 1983,

the Society for Humane Ethics and Principles petitioned the Board of Supervisors for Maricopa

County, AZ, to adopt a policy prohibiting the sale

of impounded animals to research facilities, following the State legislature’s rejection of the society’s proposal for a State law with identical restrictions (72)83). The board adopted the proposal

and the policy has been sustained by an opinion

issued by the State attorney general in 1984 (25).

In 1985, 11 influential animal welfare organizations joined in an effort to prevent all use of

pound and shelter animals for scientific purposes.

The new National Coalition to Protect Our Pets

(Pro-Pets), which includes both humane societies

and antivivisection groups, seeks legislation

toward this end (64).
Ch. 14—State Regulation of Animal Use ● 321

ANIMAL USE IN EDUCATION

Past Trends

Of all areas of State and local law dealing with

the humane treatment of experimental animals,

the realm of education is probably the most neglected. Statutes that refer to humane treatment

in grammar and secondary schools usually contain very general terms, leaving the interpretation for instructional and curricular requirements

to local school authorities.

Twenty-one States, in codes governing public

instruction, list requirements for teaching students about the value of animals. These requirements vary widely and correspond to legislative

perceptions of both the morality and utility of humane treatment. Some States, such as Pennsylvania and Wyoming, require a certain amount of

time per week or other designated instruction

period to be devoted to “kindness to” or “humane

treatment of” animals. Others require such instruction, in more general terms, on designated

days of the year—”bird, flower, and arbor day”

in Tennessee, “arbor and bird day” in Wisconsin,

“bird” day in Utah, and “conservation” day in New

York. New York, however, also requires generalinstruction programs in “moral and humane education” and “protection of wildlife and humane

care of domestic animals, ” while Wisconsin mandates such programs regarding “kindness to and

the habits, usefulness and importance of animals

and birds, and the best methods of protecting,

preserving and caring for all animal and bird life.”

California, besides requiring each teacher to “impress upon the minds of the pupils the principles

of morality . . . including kindness toward domestic pets and the humane treatment of living creatures,” requires public elementary and secondary schools to house and care for live animals in

a ‘(humane and safe” manner and prohibits killing or injuring, including anesthetizing, live vertebrates. Illinois and Massachusetts prohibit any “experiment upon any living animal for the purpose

of demonstration in any study” in a public school.

Further, dogs and cats may not be killed for vivisection, nor can any animal provided by or killed

in the presence of a pupil be so used. Dissection

of dead animals is limited to classrooms before

students “engaged in the study to be illustrated

thereby” (74).

Interest is increasing in laws restricting the use

of at least some animals in experimentation below the undergraduate level. Recently introduced

Kansas Senate Bill No. 529 forbids any school principal, administrator, or teacher from allowing any

live vertebrate animal in a school or sponsored

activity to be used as part of a scientific experiment or procedure in which the normal health

of the animal is interfered with or in which fear,

pain, suffering, or distress is caused. Covered experiments and procedures include, but are not

limited to:

. . . surgery, anesthetization, and the inducement

by any means of painful, lethal, stressful, or

pathological conditions through techniques that

include but are not limited to:

(a) administration of drugs;

(b) exposure to pathogens, ionizing radiation,

carcinogens, or to toxic, hazardous or polluting substances;

(c) deprivation; and

(dielectric shock or other distressing stimuli.

Dissection of dead animals would be permitted

if confined to classrooms, and the bill requires

that its provisions not be construed to prohibit

“biological instruction involving the maintenance

and study of living organisms or the vocational

instruction in the practice of animal husbandry.”

Finally, the bill requires live animals in schools

to be housed and cared for in a humane and safe

manner, assigning personal responsibility to the

teacher or other adult supervisor of a project or

study. Violations would be punished as Class A

misdemeanors.

A bill introduced in Florida seeks to set State

policy regarding experimentation with live animals. The bill prohibits biological experiments on

living subjects other than lower orders of life or
322 ● Alternatives to Animal Use in Research, Testing, and Education

anatomical specimens purchased from biological

supply houses. Further, it permits only noninterventional observation of vertebrate animals (59).

A similar bill was introduced in the New York Assembly in 1983 (58).

Only one case has tested the application of a

State’s general anticruelty statute to secondary

school experimentation. For a science fair project,

a New Jersey high school student intentionally inflicted two chickens with cancer and later killed

them for dissection. The court first found that

the State’s general exemption for scientific research was unavailable to the student, since he

was not a licensed institution. The plaintiff, the

New Jersey SPCA, argued that experiments such

as this one were needless and unnecessary. Adopting an expansive view of what constitutes scientific activity, the court found that the experiment

did not violate the New Jersey anticruelty statute, for several reasons, including:

● the student had received proper supervision

and normal protocols had been employed;

● there were general benefits to society in permitting such experimentation; and

● the chickens were given proper care during

the term of the experiment, and it was unclear whether the chickens were in pain during the experiment (91).

Recent Initiatives in Education

Measures continue to be introduced that restrict the use of some types of animals for experimentation, teaching, or demonstration purposes

and that prohibit painful or invasive procedures

of any kind, as outlined above (56). An extreme

example is Massachusetts House Bill No. 742,

which would eliminate the use of animals for

demonstration purposes at medical schools.

There appears to be growing interest among

professional and humane oriented organizations

in establishing standards for animal use in teaching and promoting science to the young that also

encourage humane attitudes. The Scientists’ Center for Animal Welfare (Bethesda, MD), for example, has targeted science fairs (see ch. 9) as candidates for making students more sensitive to the

needs of animals.

SUMMARY AND CONCLUSIONS

Unlike the Federal Animal Welfare Act, most

State anticruelty statutes were enacted prior to

the turn of the century, and they have been interpreted as protecting the interests of society,

the animal owner, and the animal, in roughly that

order. Most forbid both active cruelty (torture,

“overriding”) and failure to satisfy some specific

(food, water, shelter) or nonspecific (“necessary

sustenance”) duty of care owed to animals. Many

incorporate vague or undefined terms, require

some proof of state of mind (culpability) to sustain a conviction, and are subject to a variety of

defenses. Enforcement of most aspects of these

statutes is usually delegated to local police and

to humane societies. The members of humane societies are generally not trained to build criminal cases skillfully, they lack the enforcement

tools to do so, and they are underfunded for the

task.

The application of these statutes to the conduct

of research is unclear, since many State anticruelty laws are general in nature and contain

no specific exemption for research activity. The

only case that offered the ideal forum for resolving conflicting research and animal protection interests at the Federal and State level—and for

deciding whether Congress intended to occupy

the field of laboratory-animal regulation or, rather,

to establish a cooperative system of protection—

was decided without addressing these issues.

Another State court found no preemptive intent

in Congress’ passage of the Animal Welfare Act.

It seems clear enough that the act is intended to

complement, or at least operate concurrently,

with State efforts at research regulation, but

courts’ reluctance to render broad decisions in

cases on animals and the mixture of constitutional

principles represented in the act make prediction

of outcome difficult in any given case.

Twenty States and the District of Columbia regulate research to some extent. Like the Federal

act, however, most address themselves to pro-
Ch. 14—State Regulation of Anirnal Use Ž 323

curement and treatment of animals after experimentation, rather than to specific standards of

care to be observed before and during research.

These laws concern themselves primarily with

dogs and cats, and some merely require or encourage licensing or some other type of certification to enable research facilities to obtain pound

animals. Several States have passed regulatory

laws that complement the Federal act, in the sense

that they exempt facilities from compliance with

certain responsibilities if they fulfill similar requirements under Federal law, regulations, or

guidelines.

All States have laws providing for the control

and disposition of stray and abandoned dogs and

cats. Beginning in the late 1940s, States began

adopting laws requiring or permitting research

facilities to purchase strays from pounds and

shelters. These laws have been the targets of repeal efforts.

All 50 States and the District of Columbia allow

some form of pound animal use for research and

training. To date, 9 States prohibit in-State procurement (although not importation from out-ofState) of pound animals for research and training. Of these, Massachusetts will in October 1986

prohibit the use of any animal obtained from a

pound.

Twenty-one States have some provision in their

codes requiring the teaching of “kindness” or “humanity” toward, or the “value” of, animals. A few

place some restrictions on animal use in grammar and secondary schools.

Advocates of laboratory-animal protection criticize current State and local efforts to assure animals’ humane treatment for several reasons, the

main ones being that compliance schemes are

overly complex and bureaucratic, that training

and resources are inadequate, and that existing

laws are not specific enough in their standards

for care, treatment, and use. One model statute

would regulate research use more closely by

establishing classes of eligible research animals,

based on comparative intelligence, with specific

proofs to be met before animals in any class could

be used in experiments.

Interest is growing in establishing direct, legally

enforceable rights for animals. Some protection

groups have endeavored to protect laboratory animals by seeking enforcement of anticruelty statutes or suing those they see damaging animals’

interests. They have had virtually no success.

Some have advocated conferring standing to sue

on animals by applying the traditional concepts

of guardianship to them.

Reviewing recent trends in each of these fields

of law, it appears certain that animal welfare and

humane groups will continue to press their case

for reform on all fronts. Thus, it is likely that research and animal welfare interests will continue

to collide in all three branches of Government at

the State and local levels. Though some bills have

been introduced that seek to reduce animal use

in experimentation, promote other models, or

eliminate the use of animals entirely, they have

not been given serious consideration.

CASE STUDY:

FRIENDS OF ANIMALS, INC. v. U.S. SURGICAL CORPORATION

Every year, the United States Surgical Com- fact that one of the dealers who supplied them

pany used approximately 900 dogs to train sales with dogs has been convicted of animal cruelty

representatives in the proper use of their [sur- and of receiving stolen animals (101).

gical] staple guns–a tool that is rapidly replacing

conventional stitching of wounds or operation

cuts. The representatives are chosen primarily

for their sales ability and thus may have little or

no medical knowledge. Before being sent out on

the road, they must pass through a six-week

training course. The company is now the focus

for animal welfare protest in Connecticut. Their

position has not been improved by allegations

of animal abuse in a newspaper expose or the

Thus was summarized a dispute between Friends

of Animals, Inc., a major animal welfare organization, and US. Surgical Corporation, a large, private manufacturing interest using dogs to train

its own personnel and customers in the use of

its products. Behind local newspaper headlines

on the case was a running legal battle involving

several distinct lawsuits in Federal as well as State

courts. Regardless of the positions or motives of
324 ● Alternatives to Animal Use in Research, Testing, and Education

the litigants, the cases in which they are parties

provide an interesting view of the perceived roles

that existing Federal and State animal welfare

laws play when such disputes arise.

The Parties

Friends of Animals, Inc.

Friends of Animals, Inc. (FOA), is a not-forprofit, charitable organization incorporated under

the laws of New York, with registered agents in

a number of other States. FOA claims some 100,000

members nationwide, more than 5,000 of whom

live in Connecticut, where these FOA complaints

were filed. FOA is active in defense of all animals’

right to humane treatment—politically, as well as

legally. In the suits, FOA alleged that among its

members are “individuals who are owners of dogs

and . . . who have an intense interest in the proper administration and enforcement” of animal

welfare laws (37).

U.S. Surgical Corporation

Headquartered in Norwalk, CT, U.S. Surgical

Corporation is the leading producer of surgical

stapling devices used for surgical tissue repair and

wound closure. It has been in business for some

18 years and total sales in 1982 were $146 million. Its surgical products, marketed under the

trade name AUTO-SUTURE, are sold in over 40

countries. U.S. Surgical has international subsidiaries in seven European countries and Australia,

and the company employs about 1,900 people,

two-thirds of whom work in Connecticut. Though

it receives no Federal funding to support its product research or development, the company is subject to inspection and licensure by the Animal and

Plant Health Inspection Service (APHIS) as a “research facility” under the Federal Animal Welfare

Act, by the Drug Enforcement Administration

under the Controlled Substances Act, and by the

Departments of Health and Consumer Protection

in Connecticut, which regulate the use and disposal of dogs in research (106,123). U.S. Surgical’s

president has expressed concern about the amendment of the Federal Animal Welfare Act that

would require the company to appoint nonaffiliated persons to internal animal care review committees that have access to confidential business

information (113).

The Controversy

U.S. Surgical’s use of dogs purchased from local animal dealers to provide live-tissue training

for its sales staff, also known as technical field

representatives, in the use of surgical stapling

equipment at the Norwalk teaching facility first

came to the public’s attention with the publication of a newspaper article in November 1981.

That article contained a variety of allegations

about the company’s practices:

●

●

●

●

●

●

●

“Sales personnel with no medical experience

and surgeons destroyed at least 900 dogs at

the Norwalk laboratory between October 1,

1980, and September 30, 1981. Additional

hundreds of dogs are operated on each year

for sales demonstration purposes by the company’s traveling sales staff and at regional and

national sales meetings.”

Anesthesia was “routinely administered to

the dogs by persons with no medical training, including the sales staff.”

U.S. Surgical “failed to comply, for three consecutive years, with federal laws that [required it] to register with the U.S. Department of Agriculture.”

In at least one case, the personnel performing live-tissue training demonstrated the

strength of the staple closure by lifting a dog

by the clamp enclosing the abdominal fascia

and by attempting to sunder the stapled cut.

Some dogs appeared to be inadequately anesthetized, “jumping, jerking, writhing, and moaning” or showing other apparent signs of pain

or distress during demonstrations, and others

died prematurely, apparently from overdoses

of barbiturates used for anesthesia.

USDA officials quoted in the article were of

the opinion that use of dogs for this purpose

was a legal research activity although they

“questioned the validity of sacrificing animals,

especially in such large numbers, for this type

of commercial purpose. ”

One of the federally licensed dealers from

whom the company had acquired dogs had
Ch. 14—State Regulation of Animal Use ● 325

been “convicted in local court [in New Jersey] of receiving stolen dogs, animal cruelty,

failing to keep proper records and failing to

provide animals with adequate shelter from

the cold” (54).

US. Surgical contended that its salespeople are

given hands-on, live-tissue training in the use of

its surgical stapling equipment, principally to “enable [them] to provide technical assistance in the

operating room the first few times a surgeon uses

the stapling instrumentation on a human patient.”

U.S. Surgical’s technical field representatives also

act as instructors, under the supervision of professors of surgery, in the laboratory portion of

surgical-stapling seminars at postgraduate teaching hospitals. The company provides an “intense,

five-week training program” for these purposes,

consisting of instruction in “anatomy, physiology,

surgical terminology, aseptic surgical techniques,

surgical gowning, gloving, and scrubbing, and

operating room protocol, ” in addition to supervised live-tissue training. Refresher courses on

new surgical-stapling procedures are given to all

sales staff at least once each year (106).

U.S. Surgical responded to major charges contained in the 1981 article as follows:

●

●

●

In all, 974 dogs were acquired and used during the period mentioned, but only for ‘(teaching regarding technical application and use

of surgical instrumentation in well-accepted

surgical procedures,” and not for demonstration purposes. The company asserts that only

foam wound and organ models are used for

sales demonstration purposes.

All anesthetic procedures are initiated and

supervised by two “laboratory technicians

trained in animal care and handling and who

have been previously employed in animal laboratories responsible for both survival and

nonsurvival animal research work.”

The company “complied in good faith” with

Animal Welfare Act requirements. U.S. Surgical first applied for registration of its Stamford, CT, facility on June 4, 1976; it was first

visited by USDA-APHIS inspectors in February 1979, and informed that it was not registered under the act. An inspection was conducted under ‘(license-pending” status. The

●

●

●

●

company reapplied for registration on February 20, 1979, and Registration No. 16-28

was issued on March 27, 1979.

“The strength of the staples is tested to demonstrate their benefit when used in human

clinical surgery; however, the methods described lifting dogs by the staples and attempting to pull incisions apart by hand] are

not employed. ”

Although ‘(the level of sedation may vary during the program, ” due to periodic administration of regulated doses to maintain unconsciousness without overdose, “the animal

never regains consciousness or experiences

discomfort.” U.S. Surgical also stated that

multiple teaching procedures are performed

on single dogs in one session, “minimizing the

need to use even more dogs and maximizing

the teaching benefit provided by the animal.”

Expressing no specific opinion about the

statements made by the quoted USDA-APHIS

inspector as to the utility of using dogs for

this purpose, U.S. Surgical noted that they

had been contacted by a USDA veterinarian

who would be writing to substantiate its need

to use live animals.

Dogs used in live-tissue training were acquired only from federally licensed dealers,

their identification tags were checked and

recorded, and their condition was evaluated

prior to acceptance. If, as was stated in the

article, the New Jersey dealer had had its Federal license revoked, then reinstated when

violations had been corrected, the dealer

“must be considered an acceptable source by

the USDA” (123).

The Lawsuits

Friends of Animals filed its first lawsuit against

U.S. Surgical in Federal court in Connecticut on

December 29, 1981, a little less than 2 months after the newspaper article had appeared (37). Alleging that the defendant company, registered as

a research facility as defined in the Federal Animal Welfare Act, had killed 974 dogs to demonstrate its surgical equipment, FOA contended that

the demonstrations:

● were “at times, performed without the proper administration of anesthesia”;
.

326 . Alternatives to Animal Use in Research, Testing, and Education

● did not constitute “experimentation and/or

research, as permitted by . . . the Animal Welfare Act”; and

. violated the Connecticut anticruelty statute.

The FOA complaint also contended that similar demonstrations performed from 1977 through

1979, when the company was not registered under the act, were not permitted experiments or

research and violated the State anticruelty statute. FOA petitioned the court for a jury trial; unspecified compensatory damages; $5 million in punitive damages; interests, costs, and attorney’s

fees; and “other equitable relief .“ On February 8,

1982, U.S. Surgical filed a motion, under Rule 12

of the Federal Rules of Civil Procedure, to dismiss

the suit because the plaintiff had failed to state

a claim on which the court could base any warranted relief (38). Two days later, FOA filed a separate suit in the Superior Court of Connecticut,

alleging the same facts, complaining of the same

acts by the company, and requesting the same

relief (41). On February 12, 1982, FOA filed a motion for voluntary dismissal without prejudice of

the action filed in the Federal court, under Rule

41(a)(l)(i) of the Federal Rules of Civil Procedure,

asserting that the Federal court lacked jurisdiction over the subject-matter of the suit (39). The

court concurred and dismissed the suit without

prejudice (40).

FOA amended the State court complaint on

April 6, 1982, adding three additional counts to

the original two (42). The third count alleged that

the surgical-stapling demonstrations performed

on anesthetized dogs from 1977 through 1981 violated Connecticut Statute 22a-15, which contains

a general declaration of policy on environmental

preservation. Counts Four and Five complained

that the demonstrations constituted a nuisance

and violated the provisions of the Animal Welfare

Act. Thus, in addition to asserting that the company’s complained-f activity violated Federal and

State animal welfare laws, FOA contended that

it amounted to a compensable common-law nuisance and also violated Connecticut’s stated policies concerning protection of the public trust in

natural resources.

US. Surgical countered with motions to strike

the first two counts, on April 12, 1982, and the

last three counts added by amendment, on May

19, 1982. In its memoranda in support of the motions, the company responded to the allegations

as follows:

●

●

●

●

●

●

The Connecticut anticruelty statute, being a

criminal statute, created no private right of

action to seek or compel enforcement of its

provisions. According to U.S. Surgical, the

law was not enacted to specially benefit a particular class and no evidence of legislative intent to create a private right of action could

be found. The company claimed that such a

right would be inconsistent with the statutory scheme of criminal and administrative

enforcement erected by the legislature to

protect both animals in general and dogs

used in research.

FOA lacked standing to sue, both on behalf

of its members and on its own behalf, since

the alleged injury was neither direct nor “distinct from a general interest shared with the

public at large.”

Punitive damages could not be awarded to

FOA since no allegation was made that the

defendant’s acts were committed to intentionally and wantonly violate FOA’s rights or

showed a reckless indifference to the rights

of FOA.

The Connecticut statute articulating the

state’s interest in natural resources as a “public trust” provided no basis for FOA’s challenge to U.S. Surgical’s use of dogs, for three

reasons. First, it authorizes no private right

of action. Second, the State’s declared policy

of protecting the public trust in natural resources does not apply to defendant’s use of

dogs. Third, the environmental statute does

not supersede other State laws governing the

use of dogs in research.

FOA lacked standing to sue on grounds of

nuisance, having suffered no direct and distinct injury of an interest in real property.

The Federal Animal Welfare Act created no

private right of action in favor of FOA, for

the same reasons stated in US. Surgical’s response to the first count (43,44).

FOA filed an opposition to U.S. Surgical’s motion to strike on June 10, 1982, and the court

heard oral arguments on the motion on November 3, 1982 (106).
Ch. 14—State Regulation of Animal Use 327

The superior court entered a decision granting

the company’s motion to strike all five counts of

FOA’s complaint (45). With regard to the alleged

violation of Connecticut’s anticruelty law, the

court construed the criminal-penalty law strictly

and found no evidence of intent to create a private right to enforce its provisions. Although the

Court did find legislative intent to create a private right to seek injunctive relief against pollution, under the Connecticut Environmental Protection Act, it rejected FOA’s contention that dogs

were covered by the statute.

The court also rejected FOA’s charge that U.S.

Surgical’s destruction of dogs for surgical purposes constituted a common-law nuisance because FOA both “failed to set forth allegations that

established a public nuisance” and based its claim

for recovery “upon its peculiar and particular sensitivities and not upon its rights as a member of

the general public.” Additionally, the court rejected FOA’s claim that the Federal Animal Welfare Act created a private right of enforcement

similar to that created by the Marine Mammal

Protection Act. Finally, the court agreed with U.S.

Surgical that FOA could not collect punitive damages unless it pleaded and proved that the company had shown ‘(a reckless indifference to the

rights of others or an intentional and wanton violation of those rights” (45).

On December 21, 1982, before judgment had

been entered on the motion to strike, FOA filed

an amended complaint in Connecticut superior

court, alleging again that U.S. Surgical’s use of

dogs for surgical demonstrations was reckless,

wanton, sometimes without proper anesthetization, and constituted a public nuisance (46). FOA

also claimed that the company’s use of dogs violated a New Jersey anticruelty statute, The revised

complaint added a new party to the proceedings:

Pierre Quintana, a resident of Wilton, CT, who

alleged that his springer spaniel, “George,” was

“stolen by agents or servants or employees of the

U.S. Surgical Corporation and converted to said

owner’s use. ” FOA asked for a trial by jury and

the same relief as earlier. U.S. Surgical, unaware

that a substitute complaint had been filed, the following day filed a motion for early entry of judgment on the motion to strike (47,106).

While the action in State court continued, FOA

refiled its case in Federal District Court on December 29, 1982, again asserting an interest on

behalf of its members in “legally sufficient enforcement of the Animal Welfare Act” (48). Reiterating the allegations of the company’s use of dogs

in 1981, FOA renewed its contention that proper

anesthetics were not used. It further alleged that

U.S. Surgical had purchased live dogs from unlicensed dealers, in violation of the act, and that

the company’s surgery on live animals did not

constitute experimentation and/or research as

permitted by the act and was performed with

“reckless indifference to the lives and well-being”

of the animals.

Almost 4 months later, FOA moved for leave

to amend the renewed complaint, and the motion

was granted (49). In its amended complaint, filed

on April 13, 1983, FOA charged that Rudolph

Varana, a federally licensed animal dealer doing

business as Varana Rabbit Farms, had committed

“criminal acts”—i.e., received a stolen golden

retriever, for which he was convicted under New

Jersey Law—”as agent and servant for the U.S.

Surgical Corporation . . . in direct violation of 7

U.S.C. 2131(3) which states that one of the purposes of the Animal Welfare Act is ‘to protect the

owners of animals from the theft of their animals

by preventing the sale or use of animals which

have been stolen ’.” FOA contended that the company knew or should have known of ‘(its agent”

Varana’s “criminal acts” but continued to purchase dogs from him. As a result of Varana’s

“criminal acts” and US. Surgical’s own negligence,

FOA claimed that it had “been required to expend

substantial amounts of money, [had] diverted substantial corporate resources, and [had] been

forced to restructure [its] activities in order to investigate the criminal activities of said Rudolph

Varana , . . and address the violations of the Animal Welfare Act and regulations enacted thereof

[sic] by the U.S. Surgical Corporation.” (FOA did

not state that the golden retriever had been acquired and used by US. Surgical.)

Meanwhile, the company filed a request to revise the substituted complaint in the State court

action, asserting that the second count of the substituted complaint reiterated allegations of pub-
328 Alternatives to Animal Use in Research, Testing, and Education

lic nuisance that had already been stricken by the

Court (50). Failure by FOA to object to the request

resulted in the request being granted on May 9,

1983, leaving intact the counts concerning the

claimed violation of the New Jersey anticruelty

statute and the alleged theft of Quintana’s dog

(106).

On December 9, 1983, FOA’s lawyer moved to

withdraw as counsel in the Federal case. The request was granted in March 1984. On August 23,

1984, FOA’s new attorney filed a motion to dismiss the Federal complaint with prejudice, and

moved to withdraw the State complaint and to

set aside a judgment of dismissal entered in that

case. Both motions were granted and the lawsuits

were dismissed, not to be filed again (51,52,106).

A newspaper story a week before the dismissal

and withdrawal motions were filed by FOA reported that prior counsel had instituted suit

against FOA for nonpayment of legal fees in the

U.S. Surgical cases and others filed on FOA’s behalf (6).

Discussion of the Case

Almost 3 years of legal sparring over an animal

welfare controversy, conducted in both Federal

and State courts, came to no substantive conclusion on the real issues in disagreement. There was

no examination by a judge or a jury of the evidence to determine whether U.S. Surgical’s use

of anesthetized dogs to train its personnel in the

use of surgical-stapling equipment on human paCHAPTER 14

1. Akiska Statutes, Section 11,61.140(3)(b) (1982

Supp.).

2. American Jurisprudence, 2d. cd., vol. 4, sec. 27

(1982).

3. American Law Reporter, 2d. cd., vol. 82, sec. 794

(1984).

4. American Law Reporter, 2d. cd., vol. 56, sec. 1031

(1984).

5. Aru”maf Welfare Institute v. Kreps, 561 F.2d 1002,

1007 (D.C. Cir. 1977).

6. Barnes, P., “Animal Advocates Are No Friends to

Lawyer,” New Haven (CT) Register, p. 17 (cols.

1-6), Aug. 17, 1984.

tients was cruel or unjustified. FOA’s attempts to

invoke Federal and State animal use, anticruelty,

animal theft, and even environmental statutes to

“punish” or control behavior it deemed cruel or

unjustified accomplished little more than the consumption of substantial amounts of time and judicial resources.

This result can be attributed to a number of

factors, chief among which is a demonstrated

reluctance on the part of judges to permit private

enforcement of laws entrusted by legislation to

administrative and law-enforcement agencies,

Whether FOA decided to abandon its prosecution

of U.S. Surgical as a result of disagreements with

initial counsel or a realization of the unlikelihood

of a victory on the merits is an open question.

Statements attributed to FOA representatives in

published press accounts could support both of

those reasons (6,55).

Connecticut regulates the use of live companion animals (dogs) in research; its general anticruelty statutes make no mention as to whether

its provisions also apply to the conduct of research. The same situation exists in 24 other

States, If the complex and wholly inconclusive legal maneuvering in Friends of Animals, Inc. v. US.

Surgical Corporation is indicative of what might

occur in similar circumstances in other jurisdictions, it is unrealistic to expect a result that settles

anything or satisfies any party with an ideological interest in the treatment of laboratory animals

and the human benefits of animal research.

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7. Bean, M,, Evolution of National Wildlife Law (Washington, DC: Council on Environmental Quality,

1977).

8. l?ioScience, “Taub Animal Cruelty Trial Sparks

Guideline Review,” 32(1):15, 1982.

9. Brackett v. State, 142 Ga. App. 601, 236 S.E.2d

689 (1977).

10. Brief for Edward Taub, Edward Taub v. Maryland, 296 Md. 439, 463 A.2d 819 (1983).

11. Brief for State of Maryland, Edward Taub v.

Maryland, 296 Md. 439, 463 A.2d 819 (1983).

12. Burr, S., “Toward Legal Rights for Animals,” Environ. Aff. 4:205-219, 1975.
Ch. 14—State Regulation of Animal Use ● 329

13

14

15

California, Assembly Bill No. 1735, Legislative

Counsel’s Digest, 1-10, Mar. 4, 1983.

California, Senate Bill No, 883, Legislative Counsel’s Digest, Mar. 3, 1983.

California Adrrzim”strative Code, Title 17, Sections

1150-1151 (1952).

16. California Department of Human Resources Development v. Java, 404 U.S. 121, 125 (1971).

17. California Health and Safety Code, Sections 1650-

1673, 1676-1677 (West Cumulative Pocket Part

1984).

18. California Penal Code, Section 599c (West Pocket

Part 1984).

19. Chambers, K., and Hines, C., “Recent Developments Concerning the Use of Animals in Medical

Research,” J. Leg. Med. 4(1):109-129, 1983.

20. Chron. Higher Educ., “Cal. Judge Dismisses Animal-Rights Case, ” 27(18):6, 1984.

21. Coalition to Abolish Metcalf-Hatch, “Metcalf-Hatch

Fact Sheet,” New York, NY, 1978.

22. Coggins, G., “Wildlife and the Constitution: The

Walls Come Tumbling Down,” Wash. Law Rev.

55:295-358, 1980,

23. Colorado Revised Statutes, Sections 25-4-701 to

25-4-714, 25-4-1101 to 25-4-1109, and 35-42-114,

(1973) as amended by Senate Bill No. 198, June

2, 1983.

24. Connecticut General Statutes Amotated, Sections

22-332a(b), 22-332b (West 1980& Cumulative Annual Pocket Part 1984).

25. Corbin, C,, Attorney General, State of Arizona,

Letter to Hon. C. Walker, June 6, 1984.

26, Council of State Governments, A40del State Law

to Supplement the Federal Laboratory Animal

Welfare Act (Washington, DC: Council of State

Governments, 1970).

27. Curran, W., “Biomedical Laboratories and Criminal Liability for Cruelty to Animals,” N. EngZ. J.

A4ed. 309:1564-1565, 1983.

28. DeCanes v. Bica, 424 U.S. 351, 360 n.8 (1976).

29. Dichter, A., “Legal Definitions of Crueky and Animal Rights, ” Boston Coil. Environ. Aff. Law Rev.

7:147-164, 1978.

30, District of Columbia Code, Sections 22-812, 22-

814 (1892 & Cumulative Annual Pocket Part

1984).

31. Edinger, H., “The Taub Case: A Final Report, ”

Neurosci. Newsletter 15(5):6-8, 1984.

32. Edward Taub v. Maryland, 296 Md. 439,463 A.2d

819 (Ct. App.Md. 1983).

33. Favre, D., and Loring, M., Am”mal Law (Westport,

CT: Quorum Books, 1984).

34. Florida Statutes Annotated, Section 828.02 (1965

& Cumulative Annual Pocket Part 1984).

35. Florida Lime and Avocado Growers, Inc. v. Paul,

373 U.S. 132, 144 (1963).

36. Friend, C., “Animal Cruelty Laws: The Case of Reform,” U. Rich. Law Rev. 8(2):201-231, 1974.

37. Friends of Animals, Inc. v. U.S. Sur#”cal Corporation, No. B81-643, Plaintiff’s Complaint (D.

Corm. filed Dec. 29, 1981).

38. Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, No, B81-643, Defendant’s Motion to Dismiss Complaint (D. Corm. filed Feb. 8, 1982).

39. Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, No. B81-643, Plaintiff’s Motion for Voluntary Dismissal (D. Corm. filed Feb. 12, 1982).

40. Friends of Animals, Inc. v. U.S. Surgical Corpo41

ration, No. B81-643, Memorandum Order Dismissing Plaintiff’s Complaint Without Prejudice

(D. Corm. entered Feb. 17, 1982).

Friends of Animals, Inc. v. U.S. Surgical Corpo -

ration, CV 82-0202829S, Plaintiff’; Complaint

(Corm. Super. Ct. filed Feb. 10, 1982).

42. Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, CV 82-0202829S, Plaintiff’s Motion to

Amend Complaint (Corm. Super. Ct. filed Apr. 6,

1982).

43. Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, CV 82-0202829S, Defendant’s Motion to

Strike and Memorandum in Support of Motion

to Strike (Corm. Super. Ct. filed Apr. 12, 1982).

44. Friends of Animak, Inc. v. U.S. Sur@”cal Corpo -

45,

46.

47.

48.

49.

50.

ration, CV 82-0202829S, Defendant’s Motion to

Strike Amended Complaint and Memorandum in

Support of Motion to Strike (Corm. Super. Ct. filed

May 19, 1982).

Friends of Animals, Inc. v. US. Sur@”cal Corporation, CV 82-0202829S, Memorandum of Decision on Motion to Strike No. 105 and Motion to

Strike No. 107 (Corm. Super. Ct. entered Dec. 7,

1982- Reynolds, J.).

Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, CV 82-0202829S, Plaintiff’s Substituted

Complaint (Corm. Super. Ct. filed Dec. 21, 1982).

Friends of Animals, Inc. v. U.S. Surgical Corporation, CV 82-0202829S, Defendant’s Motion for

Entry of Judgment on Motion to Strike (Corm. Super. Ct. filed Dec. 22, 1982).

Friends of Animals, Inc. v. U.S. Surgical Corporation, B82-744, Plaintiff’s Complaint (D. Corm,

filed Dec. 29, 1982).

Friends of Animals, Inc. v. U.S. Sur@”cal Corporation, B82-744, Plaintiff’s Motion for Leave to

Amend Complaint (D. Corm. filed Apr. 21, 1983).

Friends of Animals, Inc. v. U.S. Surgical Corporation, CV 82-0202829S, Defendant’s Request to

Revise Substituted Complaint (Corm. Super. Ct.

filed May 9, 1983).

51. Friends of Animals, Inc. v. U.S. Surgical Corporation, CV 82-0202829S, Plaintiff’s Request to

Withdraw Complaint and Motion to Set Aside
330 ● Alternatives to Animal Use in Research, Testing, and Education

Judgement of Dismissal (Corm. Super. Ct. filed

Aug. 23, 1983).

52. Friends of Animals, Inc. v. U.S. Surgk”cal Corporation, No. B82-744, Plaintiff’s Motion to Dismiss

with Prejudice (D. Corm. filed Aug. 23, 1984).

53. Gecqp”a Code Annotated, Section 16-12-4(b) (1972

& Cumulative Annual Pocket Part 1984).

54. Grunewald, C., “Firm Performing Surgery on Live

Dogs,” The Hartford (CT) Sunday Advocate, p. Al

(co1. 1), NOV. 8, 1981.

55. Grunewald, C., “Suit Against U.S. Surgical Ended,”

The Hartford (CT) Advocate, pp. Al (co1. 1), A14,

Sept. 8, 1984.

56. Harris, R., “UC Lab’s Use of Monkeys Investigated,” San Francisco Examiner, pp. Bl, B8, Feb.

3, 1984.

57. Hines v. Davidowitz, 312 U.S. 52, 57 (1941),

58. Holzer, H. (cd.), Anim. Rights Law Rep. (Int. Soc.

for Anim. Rights, Clarks Summit, PA), October

1983, pp. 10-11.

59. Holzer, H., (cd.) Anim. Rights Law Rep. (Int. Soc.

for Anim. Rights, Clarks Summit, PA) April 1983,

pp. 7, 9-lo.

60. Holzer, H. (cd.), Anim. Rights Law Rep. (Int. Soc.

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p. 8.

61. Illinois Annotated Statutes, Title 111-1/2, Section

129 (Smith-Hurd 1975 & Cumulative Annual

Pocket Part 1984).

62. In re William G., 52 Md. App. 131, 447 A.2d 493

(1982).

63. Indiana Code Annotated, Section 35-46-3-2(f)

(Burns 1975 & Cumulative Pocket Supplement

1984).

64. International Society for Animal Rights Report

(Int. Soc. for Anim. Rights, Clarks Summit, PA)

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65. lowa Code Annotated, Sections 162.1-162.12 and

351A.1-351A,7 (West 1949& Cumulative Annual

Pocket Part 1984).

66. Joint Brief of Animal Legal Defense Fund and Animal Legal Defense Fund-Boston, Inc., as Amici

Curiae for State of Maryland, Edward Taub v.

Maryland, 296 Md. 439, 463 A.2d 819 (1983).

67. Kansas Statutes Annotated, Sections 21-4310 and

47-1709 to 47-1718 (1977 & Cumulative Pocket

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68. King v. Smith, 392 U.S. 309, 316-318 (1968).

69. La Rene, S., Michigan Humane Society Handbook

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70. LaRene, S., Michigan Humane Society Handbook

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71. LaRene, S,, Michigan Humane Society Handbook

of Animal Cruelty Law: New York Supplement

(Detroit, MI: Michigan Humane Society, 1983).

72. Lab Anim., “Pound Bill Fails,” 13(4):13, 1984.

73. Lauter, D., “Dr. Taub’s Animal House)” Nat. Law

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74. Leavitt, E. (cd.), Animals and Their Legal Rights

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76. Maryland v. Taub (Dist. Ct. Md., Crim. No.

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77. Massachusetts General Laws Annotated, Ch. 140,

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78. Massachusetts Society for the Prevention of Cruelty to Am”ma]s v. Commissioner of Public Health,

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79. McCuhch v. Maryland, 17 U.S. (4 Wheat.) 316,

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80. McDonald, K., “Mass. Law May Cut Use of Dogs

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81. Medlock, A., Executive Director, New England

Anti-Vivisection Society, Boston, MA, personal

communication, Jan. 13, 1984.

82. Melby, E., Dean, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY, letter to A. Haffner, Mar. 14, 1980.

83. Messenger, P., Deputy Attorney, Maricopa County,

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84. Michigan Compiled Laws Annotated, Sections

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(1948, 1975 & Cumulative Annual Pocket Part

1984).

85. Michigan Compiled Laws Annotated, Section

752.21 (1968, 1975 & Cumulative Annual Pocket

Part 1984).

86. Mil/er v, C/airborne, 211 Kan. 264, 505 P.2d 732

(1973).

87. Minnesota Statutes Annotated, Sections 35.7,

346.35-346.44 (West 1972 & Cumulative Annual

Pocket Part 1984).

88. Morrison, A., and Hand, P., “The Taub Case” (letter to the editor), Science 225:878, 1984.

89. National Association for Biomedical Research,

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90. National League of Cities v. Usery, 426 U.S. 833,

842 (1976).

91. New Jersey Society for the Prevention of Cruelty
Ch. 14—State Regulation of Animal Use ● 331

92.

93.

94.

to Animals v. Board of Education of City of East

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New Jersevy Statutes Annotated, Sections 4:22-15

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New York Laws, Article 26, Section 353 (McKinney 1972, 1975 & Cumulative Annual Pocket Part

1984).

North Carolina General Statutes, Section 19A-37

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95. Ohio Revised Code Annotated, Sections 955.16-

955.18 (Page 1958, 1964, 1968, 1969, 1975, 1979

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96. Oklahoma Statutes Annotated, Title 4, Sections

391-399 (West 1958 & Cumulative Annual Pocket

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97. Pennsylvania Statutes Consolidated Annotated,

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98. Ray v. Atlantic Richfield Company, 435 U.S. 151,

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105. State v. Kaneakua, 61 Hawaii 136, 597 P.2d 590

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107. Tennessee Code Annotated, Sections 44-17-109 to

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108. The Fund for Animals, “Fund Sues Los Angeles

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110. Townsend v. Swank, 404 U.S. 282, 292 (1971)

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111. U.S. Constitution, Article I, Section 8, clause 18.

112. U.S. Constitution, Article 1, Section 10, c]ause 1.

113. U.S. Congress, Senate Committee on Agriculture,

Nutrition, and Forestry, Improved Standards for

Laboratory Animals, hearing on S. 657, July 20,

1983, Serial No. 98-470 (Washington, D. C.: U.S.

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New Method for Invalidating State Laws Designed

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268, 1976.

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117,

118,

119.

120.

121.

122.

and 76-9:301 (1981), 1984 Cumulative Pocket Supplement.

Virginia Code, Sections 18.2 -403.1 to 18.2-403.3,

and 29-213.36 to 29.213.100 (1975) as added by

Chapter 492, Acts of 1984.

Wiggins, C., “Federalism Balancing and the Burger

Court: California’s Nuclear Law as a Preemption

Case Study,” U.C. Davis Law Rev. 13(1):1-87, 1979.

Winkler v. Colorado Department of Health, 193

Color 170, 564 P.2d 107 (1977).

Winters, M., “Cetacean Rights Under Human

Laws,” San Diego Law Rev. 21:911-940, 1984.

Wisconsin Statutes Annotated, Section 174.13

(West 1979 & Cumulative Annual Pocket part

1984).

Wise, S., “Law-Medicine Notes: The Use of Animals in Research” (letter to the editor], N. Engl.

J. Med. 311: 337, 1984.

123. Wolsch, R., Memorandum to D. Fisher, U.S. Surgical Corporation, Norwalk, CT, Nov. 9, 1981.

124. Zurvalec, L., “Use of Animals in Medical Research:

The Need for Governmental Regulation,” Wayne

Law Rev. 24(5):1733-1751, 1978.
Chapter 15

Institutional and

Self-Regulation

of Animal Use

The public fears and distrusts science. Regulation-any regulation—ma-y in the end make

them fear it less. But scientists themselves have a duty, I believe, not just to argue their

own case but to argue it in a manner acceptable to society as a whole. . . . [Fear] must be

allayed if at all by scientists and doctors themselves, making their own case and making it

intelligibly in public.

Baroness Mary Warnock

Girton College, Cambridge

Br. Med. J. 291: 187-190, 1985

What’s happening in I+ Washington is a red herring. The issue of the use of animals in research won ‘t be resolved on Capitol Hill. The real action is right here on your front door

step.

William M. Samuels

American Physiological Society

Address given at the University of South Florida Medical Center

March 21, 1984
CONTENTS

Page

Review of Animal Care and Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

NIH Assurance Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Public Health Service Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . 337

Review by Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Animal Care and Use Committees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

Roles and Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

Financial and Procedural Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Membership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

Monitoring the Monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

The AAALAC Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

policies of Scientific and Professional Societies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

American Psychological Association. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

American Physiological Society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

Federation of American Societies for Experimental Biology . . . . . . . . . . . . . . . . . . . . . . . 348

International Association for the Study of Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

Society for Neuroscience. ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ., . 349

Society for the Study of Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

American College of Physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

American Pharmaceutical Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

American Veterinary Medical Association. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., . . . . 350

Association of American Veterinary Medical Colleges . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

Statements of Institutional Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

University of Southern California . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

University of Wisconsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

School of Veterinary Medicine, Purdue University . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352

Statements of Corporate Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352

Summary and Conclusions . . . . . . . . . . . . . . . . . i.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

Table

Table No. Page

15-1. Distribution of AAALAC-Accredited Facilities by Category. . . . . . . . . . . . . . . . . . . . . 344

List of Figures

Figure No. Page

15-1. Example of Acceptable Verification for Grant Submission to NIH. ..., . . . . . . . . . . 339

15-2. Declaration Required for the Presentation of Data at the Annual Meeting

of the Society for the Study of Reproduction, July 1985 . . . . . . . . . . . . . . . . . . . . . . 350
chapter 15

Institutional and Self-Regulation

of Animal Use

The most important check on the proper treatment of animals is the conscience of the individual investigator (23). A person’s view about animal welfare is influenced by many forces; some

of the most formidable include exposure to professional peers, mentors, and formal course work

on animal care or the ethics of animal experimentation.

Beyond individual conscience, the most visible

means of self-regulation is institutional committee review of animal care and use. The use of animals is also overseen by the peer review of scien -

tific colleagues and others outside of the research

facility—an important part of the grants administration process.

In addition, most scientists are members of one

or more professional associations, some of which

have codes of ethics for research with animal subjects. These statements of principles can serve to

inspire ethical behavior and alert researchers to

ethical issues raised by their work. Codes can sometimes provide advice on specific cases and sanctions for violations (reviewed in ref. 21).

REVIEW OF ANIMAL CARE AND USE

All research supported by the Public Health Service (PHS), including that of the National Institutes

of Health (NIH), is subject to the provisions of the

PHS Policy on Humane Care and Use of Laboratory Animals by Awardee Institutions (revision effective Dec. 31, 1985) (44). Each institution so

funded must submit an acceptable assurance to

NIH’s Office for Protection from Research Risks

(OPRR) that commits the facility to active promotion of compliance with the policy and the NIH

Guide for the Care and Use of Laboratory Animals

(42).

The NIH peer-review system can be construed

as external rather than self-regulation (46). Site

visits to determine compliance can occur, and funding can be terminated for lack of compliance with

contractual assurances, as happened in the Taub

case (see ch. 14). In the broadest sense, however,

NIH is fully dependent on grant recipients for effective policing of its provisions.

The enactment in 1985 of Public Law 99-158 (see

ch. 13) provided statutory authority and recognition for some provisions of the PHS policy, requiring, for example, all entities conducting research

with PHS funds to organize and operate institutional animal care and use committees. Also in

1985, amendments to the Animal Welfare Act (see

ch. 13) extended the mandate for institutional committee oversight to research facilities covered by

the Animal Welfare Act and to Federal research

facilities.

NIH Assurance Review

To test the operation of written assurances of

compliance with the PHS policy regarding humane

care and treatment of experimental animals by investigators in the field, and perhaps in response

to congressional and public pressure, the NIH Office of Extramural Research and Training in 1983

conducted site visits to 10 grantee facilities (43).

These institutions were chosen from a stratified

sample of the more than 800 awardees with general assurances on file at the NIH Office for Protection from Research Risks.

The 10 institutions were distributed among those

receiving more than $10 million in annual support

from NIH (3 institutions), between $5 million and

$10 million (3 institutions), and less than $5 million (4 institutions). The sample was further defined by selecting institutions from each of those

categories with valid written assurances on file

335
336 ● Alternatives to Animal Use in Research, Testing, and Education

but lacking accreditation by the American Association for Accreditation of Laboratory Animal

Care (AAALAC). Awardee institutions were notified of the prospective visits by publication of the

selection criteria and the site names (43), and the

NIH chairperson notified the appropriate institutional representative(s) at least 1 month prior to

the scheduled visit.

Site-visit team size depended on the size of the

institution and the complexity of its physical facilities. At a minimum, teams consisted of a veterinarian, a biological scientist engaged in research using

animals, and an NIH scientist/administrator. In

addition, non-Federal consultants were included

“with a view towards ensuring impartiality and

enhancing expertise” (43). Between June and September 1983, the 10 site visits were conducted to

receive information and impressions in order to

answer the following questions:

●

●

●

Is NIH’s current assurance system adequate

for promoting the proper care and use of animals involved in federally funded biomedical

research?

If it is adequate, how can it be further improved?

If it is not adequate, what alternatives should

be considered?

The NIH site visits were generally criticized

within the animal welfare community on three

grounds:

●

●

●

10 institutions may not represent a sizable

enough sample to generate sufficiently representative data on which to base policy;

the l-month advance notification to the institutions to be visited may have skewed the

findings; and

too few smaller institutions were visited, since

the majority of NIH-funded recipients fall into

the unaccredited, less-than-$5-million category.

Despite these potential shortcomings, information

generated by the 10 site visits led NIH to draw conclusions and make recommendations about the

PHS policy regarding laboratory-animal welfare,

In early 1984, NIH reported on the site visits (43).

Based on the finding of these visits, two general

conclusions were reached:

● Reliance upon voluntary compliance with PHS

policy and recommendations in the NIH Guide

●

is a realistic approach to fostering proper care

and use of laboratory animals in biomedical

research. There is no reason to believe that

regular NIH inspections are needed or would

be more effective than the traditional assurance process.

The present assurance system should be

strengthened by modifying the 1979 PHS policy on animal welfare to promote more conscientious involvement by both NIH and its

awardee institutions.

In addition, the report stated that “no incidents

of animal abuse were observed” (43).

From the findings of the site-visit teams, a series

of recommendations concerning the adequacy of

the current policy and its enforcement were made.

The site-visit report recommended that NIH:

●

●

●

●

●

undertake a program for helping institutional

officials, scientists, and responsible veterinarians “understand fully their responsibilities”

for policy implementation;

expand the policy to include ‘(more specific

information regarding responsibilities of the

institution that receives funds for research

involving the use of animals, ” including new

and more specific assurances to be negotiated

with institutions receiving funds “carefully

and promptly”;

modify the policy to define more precisely institutional responsibilities, “particularly the

role of the animal welfare committee,” to which

the appointment of a nonscientist and a person unaffiliated with the institution should be

given serious consideration;

conduct or sponsor a survey to assess whether

the number of veterinarians trained in laboratory-animal science is sufficient to meet the

needs of institutions conducting biomedical

research involving animals; and

conduct further assessments of the assurance

process, including visiting more awardee institutions receiving total annual support of less

than $5 million, since that category of institutions is the largest with assurance statements

on file (43).

In response to the above recommendations and

criticisms, five additional institutions receiving less

than $5 million were visited in 1984. Using the same
Ch. 15—institutional and Self-Regulation of Animal Use ● 337

protocol as before, visits were made to a stratified

sample of institutions without AAALAC accreditation during the months of July and August 1984.

The site-visit teams consisted of a representative

of the NIH Office of Extramural Research and

Training, a scientist or administrator from OPRR,

and two non-Federal consultants (a veterinarian

experienced in laboratory-animal medicine and a

biomedical scientist currently conducting research

requiring laboratory animals) (44).

The conclusions following these additional visits

are almost identical to the earlier ones. The teams

noted that the small institutions were capable of

both meeting the responsibilities of the 1979 PHS

policy and assuming additional responsibilities in

response to changes made in the 1985 PHS policy.

The site visitors did find, however, that these institutions needed to improve the advisory and oversight roles of their institutional animal care and

use committees (IACUCs) and upgrade their veterinary oversight (44).

Public Health Service Policy

In mid-1985, the Department of Health and Human Services (DHHS) released its new PHS Policy

on Humane Care and Use of Laboratory Animals

by Awardee Institutions (44) to replace the 1979

PHS Extramural Animal Welfare Policy (41). (For

the full text of the new policy, see app. C.) This

new policy is a result of the proposed PHS policy

(43), the conclusions from the 15 site visits t. an

imal care facilities by NIH, and 340 written and oral

comments on the proposed policy. It took effect

December 31, 1985, for all potential grantees of

PHS wishing to use animals in experimentation.

This policy has many of the same features as

the 1979 version. It applies to all PHS-supported

activities involving animals in the United States.

Animal is defined as “any live, vertebrate animal

used or intended for use in research, research

training, experimentation or biological testing or

for related purposes.” The public Health Service

includes the Alcohol, Drug Abuse, and Mental

Health Administration; the Centers for Disease

Control; the Food and Drug Administration; the

Health Resources and Services Administration; and

the National Institutes of Health. The policy relies

on the NIH Guide for the Care and Use of Laboratory Animals for the standards for animal care and

treatment. Finally, the PHS policy is based on a

set of overall principles governing animal experimentation. The 1979 policy was based on 12 principles on the use of animals. The new policy implements and supplements the “Principles for the

Utilization and Care of Vertebrate Animals Used

in Testing, Research, and Training” (50 FR 20864)

prepared by the U.S. Interagency Research Animal Committee (see ch. 13, box A). The principles

contained in these two documents are very similar.

Two major requirements form the core of the

PHS policy-the institutional animal welfare assurance to NIH and an institutional animal care and

use committee, Each institution wishing to obtain

PHS funding for a research project involving animals must have on file with NIH’s Office for Protection from Research Risks a written assurance

setting forth compliance with this policy. The assurance must describe in detail the institution’s

program for the care and use of animals in PHSsupported activities including:

●

●

●

●

●

●

●

a list of every branch and major component

of the institution;

the lines of authority and responsibility for

administering the program (each institution

must identify an official who is ultimately responsible for the institution’s animal program);

the qualifications, authority, and responsibility

of the veterinarian who will participate in the

program;

the membership list of the IACUC;

the procedures that the IACUC will follow to

implement this policy;

the health-care practices for personnel who

work with laboratory animals or their facilities; and

the gross square footage of each animal facility (including satellite facilities), the species

housed therein, and the average daily inventory, by species, of animals in each facility.

In addition, each assurance must categorize the

evaluation of its program and facilities as either

accredited by AAALAC or as evaluated by the institution itself. The second category requires that

the IACUC assess its own program every year and

maintain records on the nature and extent of the

institution’s adherence to the NIH Guide and the

PHS policy. This report must also contain justifi-
338 Altematives to Animal Use in Research, Testing, and Education

cations for any departures from the policy. Deficiencies in an institution’s program or facilities

must be reported to NIH and the institution must

adhere to an approved time frame for correction

of the deficiencies.

The animal care and use committee required by

the new PHS policy is specifically structured to

consist of at least five members including:

. . . one Doctor of Veterinary Medicine with training or experience in laboratory animal medicine,

one practicing scientist experienced in research

involving animals, one member whose primary

concerns are in a nonscientific area, and one individual who is not affiliated with the institution

in anyway other than as a member of the IACUC.

New duties of this committee include reviewing

the institution’s program for animal care and use

and inspecting the facilities (including satellites)

at least annually. The policy also authorizes the

IACUC to suspend any activity involving animals

that is found to not be in compliance with the

policy.

A new power of the IACUC is to “review and

approve, require modifications in (to secure approval), or withhold approval of those sections of

PHS applications or proposals related to the care

and use of animals.” The policy gives a detailed

plan for the administrative structure to handle this

task, along with certain specific animal care requirements that must be met by each proposal (e.g.,

minimization of discomfort of animals). Each application or proposal submitted to PHS must verify that the IACUC has approved those sections

of the proposal related to the care and use of laboratory animals. It should be submitted along with

the application but may be sent directly to the executive secretary of the initial review group within

60 days of the original submission. Figure 15-1 is

the example NIH provides of an acceptable verification letter for a proposal. The letter must be

signed either by the institutional official who signed

the institution’s Animal Welfare Assurance or by

another individual authorized by the institution

to provide verification of IACUC approval.

The PHS policy is implemented by the NIH’s Office for Protection from Research Risks, which is

responsible for approving, disapproving, or withdrawing approval of institutional assurances. It

also has the power to evaluate allegations of noncompliance with the policy and to conduct site visits

to selected institutions to check for proper implementation of the policy.

The new PHS policy differs from the 1979 version in the following ways:

●

●

●

●

●

●

Institutions are required to designate clear

lines of authority and responsibility for those

involved in animal care and use in PHS-supported projects, including an institutional officer responsible for the entire program.

The role and responsibilities of the IACUC

have been upgraded. The requirements of specific types of committee members (e.g., a member unaffiliated with the institution or a member in a nonscientific area) are new, as is the

policy that these committees review and approve those sections of research applications

for PHS funding that relate to the care and

use of animals before they are actually funded.

If an institution is not AAALAC-accredited,

stringent standards for self -assurances apply

and more information about animal facilities

must be made available to NIH.

Following the policy is mandatory, as opposed

to the earlier “commitment to comply.”

Recordkeeping requirements for institutions

are explicitly addressed. Records of IACUC

meeting deliberations, assurance forms, accrediting body determinations, and so forth

must be maintained for 3 years and made

accessible for inspection to PHS officials.

OPRR has power to “evaluate allegations of

noncompliance with the policy [and]. . . conduct site visits to selected institutions.”

In general, the Public Health Service now has

a much more structured animal welfare policy that

specifically designates what individual institutions

must do in order to achieve satisfactory compliance. The old policy had many of the same structures (e.g., institutional committees and assurances)

but in a form that allowed different degrees of institutional animal care and treatment responsibility. The new policy defines a minimum standard

animal care and use policy for an institution that

wishes to obtain PHS funding. In 1979, OPRR released a sample assurance that was two pages long

and only required a few specifics from the insti-
Ch. 15–institutional and Self-Regulation of Animal Use . 339

Figure 15.1 –Exampie of Acceptable Verification for Grant Submission to NIH

[Date]

Division of Research Grants

National Institutes of Health

5333 Westbard Avenue

Westwood Building, Room 240

Bethesda, Maryland 20205

Dear Sir:

The following application submitted to the Public Health Service was reviewed and approved by this institution’s Animal Care

and Use Committee on [insert date of approval]:

Title of application:

Name of principal investigator:

Name of institution:

This institution has an Animal Welfare Assurance on file with the Office for Protection from Research Risks. The Assurance

number is [insert old assurance number until a new assurance number is assigned].

As a condition of approval, this institution’s Animal Care and Use Committee required the following modifications to the above

referenced application:

This information is required when the modifications are not reflected in the original grant application or contract proposal.]

[Signature]

[Title]

SOURCE: Adapted from US. Department of Health and Human Services, Public Health Service, National Institutes of Health, “Laboratow Animal Welfare,” N/H Guide

for Grarrts and Contracts 14(8): June 25, 1985.

tution. The new sample assurance, released in

1985, is seven pages long, including two tables (one

on membership of the IACUC and one summarizing the institution’s individual animal facilities, their

square footage, the species within, and the average daily inventory of species), and requires specific detailed data on the institution’s animal welfare program.

REVIEW BY COMMITTEE

Recourse to committees to sort through a thicket

of value questions occasioned by advances in biomedicine, and in particular biomedical research,

is not unique to the area of research with animals.

For example, there has been a recent explosion

of interest in the formation of hospital ethics committees to develop policies and consult in individual cases. According to one newspaper account,

“quietly and without fanfare, hundreds of American hospitals are organizing internal ethics committees that are coming to play crucial roles . . .

involving life and death decisions for thousands

of patients” (24).

Concern in this country about the objects of research—and the link between animal and human

subjects—has been evident for decades. A recently

published historical account describes nontherapeutic research into the cause of syphilis conducted

at the beginning of the century and reviews the

reaction to the use of orphans and hospital patients

who had not given their consent. The result was

a nearly 20-year campaign against “human vivisection” conducted by antivivisectionists who saw the

use of human beings without their consent in nontherapeutic research as the logical outcome of a

science built on animal suffering: “To whomsoever,

in the cause of Science, the agony of a dying rabbit is of no consequence, it is likely that the old

or worthless man which in the cause of learning

may well be sacrificed” (22). A number of State

and Federal legislative initiatives proposed 60 to

70 years ago regarding animal research were

amended to regulate “human vivisection” as well.
340 ● Alternatives to Animal Use in Research, Testing, and Education

Some egregious violations of human rights in the

name of medical research occurred earlier in this

century. The experiments conducted on prisoners

of war during World War II that were revealed

at Nuremberg are the most notorious and wellknown examples; the trials resulted in a code of

ethics to guide future research. Haunted by the

specter of patently unethical and scientifically

unsound research conducted by Nazi physicians,

some commentators began to complain that it was

not only in wartime that the rights of human subjects had been overlooked. In an influential series

of articles by an American physician (12) and a

British physiologist (28), hundreds of experiments

published in major medical journals were reviewed, revealing many instances in which research subjects were abused or misinformed. In

addition, there was concern that certain segments

of the population-blacks, the poor, women, or

the elderly —were bearing a disproportionate

share of the burden of being research subjects.

In response to such revelations about the exploitation of vulnerable populations, a number of inANIMAL CARE AND

Roles and Responsibilities

One commentator has summarized the potential functions for animal care and use committees

as (26):

●

●

●

●

●

●

●

●

●

to ensure compliance with local, State, and

Federal laws and regulations on animal care

and use;

to inspect animal care facilities;

to review protocols for animal welfare issues;

to assess the qualifications of investigators;

to oversee student use of animals;

to advise on institutional needs, costs of animals, and animal procurement policies;

to control allocation of animals within the institution;

to act as a resource on animal welfare issues

and to educate the university community and

the community at large on animal welfare issues; and

to serve as a community complaint forum.

stitutional review boards (IRBs) were setup in the

mid-1960s under Federal regulations to oversee

research with human subjects. of all the committees formed to respond to value questions raised

by medical practice and biomedical and behavioral

research, IRBs have the most obvious parallels to

animal care and use committees. Many of the questions raised now about committees on animals—

whether they can both protect animal subjects and

abet the scientific enterprise, whether they function to minimize pain and suffering in experiments,

or are mere window dressings for public relations

purposes—have been addressed in 15 years of experience with committees on human subjects, This

experience includes not only the establishment of

IRBs within institutions and oversight of the process through the general assurance process monitored by OPRR (31), but also frequent conferences,

a spate of academic literature, and the publication

of a journal devoted exclusively to the humansubjects review process, which includes case

studies reviewing problematic protocols.

USE COMMITTEES

Each IACUC may be mandated to perform all

or some of the above responsibilities. Some committees oversee the care of all the research animals housed in an institution, This may include

ensuring compliance with local, State, and Federal

regulations; inspecting facilities; and advising on

matters of care and feeding, design of facilities,

and resource allocation. Some of the most difficult problems in this regard have been encountered in large institutions with farflung, decentralized facilities that may house only a few animals

for use by individual researchers or small groups

of students. Small, satellite facilities can present

problems in ventilation, sanitation, care, and oversight during weekends and holidays (25). Some

universities have countered this problem by centralizing a procurement system, so that the purchase of an animal by a researcher anywhere in

the university triggers oversight mechanisms (32).

At a minimum, the IACUC must comply with the

PHS policy committee requirements,
Ch. 15—Institutional and Self-Regulation of Animal Use . 341

According to NIH, approximately 26 percent of

existing animal care and use committees review

research protocols (25). Under the new PHS policy, all IACUCS will be required to approve all sections of each research protocol that involves animals. Some committees have established a system

of expedited review where only protocols that raise

questions regarding pain and suffering are considered by the full committee. More innocuous

projects are reviewed perfunctorily by smaller subcommittees. Rating scales have been established

for expedited reviews. One suggestion of such a

scale has five categories, detailing a range of degree of harm inflicted on animals. This proposal,

already in place in some form in a number of institutions, is designed to provide a calculus so that

“ethical risks” can be weighed against ‘(the benefit

in terms of improvement of animal or human

health or other societal good” (27). Other committees have a bifurcated review, with parallel processes for considering animal care and ethical issues (32).

In a broad sense, animal welfare concerns are

by definition inextricably intertwined with scientific issues. The threshold question of the validity

of an animal model approach and the possible availability of alternatives is followed closely by questions of the efficiency of animal use. Is the smallest

number of animals of an appropriate species being used? Would a more sophisticated statistical

methodology assure this is the case? Are genetic

variables manipulated to the extent necessary? Will

the data generated by the experiment be understood and of use to other scientists? Does the research answer an important question and has the

researcher made sure it does not unintentionally

duplicate already published work? Is the researcher qualified to undertake the project? These are

among the questions that raise twin concerns of

scientific and ethical appropriateness.

The dual nature of the scientific and care review

issues were the focus of remarks by one committee proponent (20):

Concern for the reduction or elimination of pain

is inseparable from consideration of the potential scientific value or the benefits to humankind

to be derived from the work. . . Decisions about,

for example, the species and number of animals

to be used, or the necessity for particular invasive procedures, simply cannot be made intelligently without reference to the scientific value

of the work; or without an understanding of the

scientific discipline represented in the proposal.

Research of inferior quality should not be done

on any species, regardless of how humanely it

is done. Concern for humane treatment of animals is not only consistent with good science, but

augments its quality by assuring us of well-maintained and nourished animals that are behaviorally comfortable.

Many people feel that the IACUC is not qualified

to judge the science or ‘(scientific merit” of an experiment. Yet, it maybe impossible to discuss animal care and use issues without some discussion

of the science involved. How does an IACUC draw

the line between discussing and approving the animal care and use issues and the scientific merit,

feasibility, and potential scientific gain of a particular experiment? Depending on the membership of a particular committee or the institution

itself, science issues may or may not be addressed

in the approval process. This may lead to an inconsistent system: A proposal that might be modified in one IACUC could be approved in a different committee depending on whether only animal

care and use issues were addressed.

In addition to the above functions, animal care

and use committees can also play an educational

role. The process by which investigators justify

their research can bean educational one and the

committee can also be used to teach the research

community as a whole. The availability of alternatives, ways to avoid unintentional duplication, and

amelioration of pain are all subjects the committee can discuss. Some committees also monitor animal welfare legislation and advise institutional officials about pending State and Federal initiatives.

Financial and Procedural Issues

A number of questions about how committees

operate involve “housekeeping” details that, as a

practical matter, may be as important as substantive concerns. The operation of the committee in

terms of recordkeeping and voting has important

implications. Whether it operates on a consensus

or majority vote may determine how much influence unaffiliated members have. In addition, some

committees have provisions for investigators to
342 ● Alternatives to Animal Use in Research, Testing, and Education

appeal adverse findings; the rights of investigators in this regard, as well as the legal posture of

the committee (and individual members), are still

open to question. Other concerns include the committee’s ability to monitor current research and

to establish procedures ensuring that its advice

is followed.

There is a paucity of data on operating costs for

animal care and use committees for several reasons. Service on committees is part of the general

responsibilities of salaried faculty or institutional

officials. Additional overhead costs of office space,

support staff, and recordkeeping are also often

factored into general budgets. One cost estimate

comes from Colorado State University, where the

animal research committee costs about $24,000

per year to run, which was 0.43 percent of the

university’s biomedical research budget (35). In

smaller institutions, requirements for more active

committees would likely be a great administrative

and financial burden, especially with a review process entailing prospective review of all protocols

submitted for funding.

The parallel between the institutional review

boards and IACUCs is the strongest when discussing procedural matters. The lessons learned by

individual institutions in setting up, funding, finding administrative staff support, and structuring

IRBs can help IACUCs avoid similar problems.

Membership

Much of the debate about the value of animal

care and use committees has focused on who

should be on them. One commentator, writing

about the use of hospital ethics committees to advise on decisions about seriously ill newborns,

maintained (10):

. . . when it comes to matters of life and death,

our society prefers procedure to substance. Instead of asking, “What is the right thing to do?”

we ask, ‘Who should decide?” The attractiveness

of such committees probably derives in large

measure from their potential for transmuting a

hard question (Who shall live?) into a more tractable one (Who shall sit on the committee?).

For animal care and use committees, however, the

question may not be quite so tractable after all.

Practicing Research Scientists

Until the recent changes in the PHS policy, which

now requires a diverse group of individuals on the

IACUC, many institutional committees consisted

primarily of practicing research scientists involved

with animal research. Their contribution to an

IACUC is important because of their knowledge

on animal models, research protocols and procedures, and the use of animals in research. These

members make sure that the views of the major

users of animals are represented. At the same time,

they have a conflict of interest with some of the

goals of the IACUC since their jobs and livelihood

are involved with research on animals. Ensuring

their objectivity, therefore, is important.

Veterinarians

Having a veterinarian on the committee is essential since in many cases that person is responsible for the institution’s animals. The PHS policy

requires that each IACUC have one Doctor of

Veterinary Medicine with training or experience

in laboratory-animal science and medicine. The

veterinarian must implement the institution’s animal care and use program on a daily basis. The

role of this person on an IACUC is to be the professional-level link between the committee and the

daily operation of the institutional program.

Veterinarians for institutions doing animal research have come from all fields of veterinary medicine. In the late 1950S) veterinarians began to enter

the specialty known as laboratory-animal medicine. To date, approximately 700 full-time veterinarians are certified in this field (out of a total of

about 45,000 nationwide). The two organizations

accrediting practitioners of laboratory-animal

medicine are the American Society of Laboratory

Animal Practitioners and the American College of

Laboratory Animal Medicine. These veterinarians,

along with any others with experience in laboratory-animal science and medicine, fulfill the PHS

requirement on IACUC membership. For small institutions with only a few projects with animals,

it can be difficult and costly to obtain a part-time

laboratory-animal veterinarian as there are so few

of them.
Ch. 15–institutional and Self-Regulation of Animal Use . 343

Unaffiliated Members

Most proposals for institutional animal review

committees require that one or more persons not

affiliated with the research entity (e.g., members

of the local community) be included. This would

be someone who is primarily responsible for representing community concerns regarding the welfare of animal subjects. This person can bring

objectivity to the committee because there is no

financial tie between the person and the institution and therefore no conflict of interest. The PHS

policy requires one such unaffiliated member.

(This person might also fill the nonscientific spot

described below, but need not.) An unaffiliated

member could well be a research scientist at a

different institution.

The unaffiliated members who have generated

the most controversy are representatives of the

animal welfare and animal rights community.

Scientists have feared that the involvement of such

people might delay or derail research projects.

There have also been concerns about confidentiality and unwarranted disclosure of research

ideas in progress, a fear exacerbated in the commercial setting. On the other hand, not unlike individuals with strongly held views opposing capital punishment (who may be challenged during

the jury selection process for a capital case), some

animal welfare advocates have refused to cooperate with these committees at all.

This leads to another problem: How to certify

the bona fides of such a committee member? Is

membership in a local humane society sufficient

or must it be a particular activist group? Some institutions may have difficulty finding members of

the general community, let alone animal welfare

advocates, who are willing to expend the considerable time necessary to participate in the process. Animal welfare proponents have complained

that the fact they are generally not remunerated

for such activities (whereas other committee members maybe devoting salaried time to the committee) tends to greatly discourage their participation.

(This has generally not been a problem in the human subjects area, however.) Paying unaffiliated

members, which some schemes have proposed,

would present a “Catch 22” situation: Payment

would “affiliate” them with the institution and

therefore disqualify them. Even with all these possible problems, many committees have been very

successful at opening their deliberations to unaffiliated members.

Nonscientific Members

The presence of nonscientifically trained people on the IACUC has rankled some scientists;

others have speculated that the need to translate

research questions for nonspecialists “may well

necessitate [the investigator’s] use of a new vocabulary and new patterns of thought, especially if he

is compelled to provide moral justifications for his

use of animals” (34,37). Against the wishes of many

scientists, the PHS policy requires that one member of the IACUC be from a nonscientific area.

Although nonscientific members are often spoken of as lay members, often they are simply professionals with different backgrounds. Lawyers,

members of the clergy, and philosophers with

training in bioethics have all been suggested as able

to bring relevant outlooks to bear. On occasion,

committees may also rely on specialists on an ad

hoc basis to review particular projects. A professional statistician, for example, might be consulted

in a determination of the appropriate number of

animals to be used in a particular protocol.

Animal Care Staff

Many committees include an animal technician

or a member of the technical staff who provide

the daily service, health care, and personal care

of the laboratory animals. Animal technicians,

well trained in animal health care, animal maintenance, and facility design, can represent the view

of the animal care facility on the committee. Animal care committees with technical staff find these

members helpful with issues of protocol review

(including whether the protocol can be done within

the facility), space allocation, and management issues. On some committees, animal technicians act

as full voting members of the IACUC; in others,

they act as ad hoc advisory members without voting privileges.

Institutional Representatives

Representatives of the institutional administration are often members of animal care and use

committees because of the insights they may have
344 ● Alternatives to Animal Use in Research, Testing, and Education

into the overall management of the institution, including the financial constraints under which it

operates. Management personnel can often provide information on the physical plant that may

bear on care and husbandry issues. For the committees to have clout, it is necessary to have a representative of the office of the president, dean,

or provost.

Monitoring the Monitors

How can the successful functioning of animal

care and use committees be determined? Some of

the committee functions just described translate

into fairly accessible benchmarks. The composition of the committees, the number of protocols

reviewed, and the types of experiments given full

review are all factors that can be examined. Yet

even this relatively “hard” data can belie more elusive factors at work. For example, as in the area

of human subjects review, often the process by

which a committee approves a protocol is one of

negotiation, during which an investigator may

justify or change the number of animals, or species, or methods of experimental manipulation—

a process that would not be reflected in a “yes”

or “no” vote.

Since the review process itself is one that is difficult to study, site visits have been relied on to

examine committee functioning. In addition to examining minutes of meetings, the composition of

the committee, and number and types of protocols

approved, site visits can afford the opportunity

to interview scientists, committee members, and

institutional officials and, perhaps, to sit in on a

committee meeting.

THE AAALAC PROCESS

The American Association for Accreditation of

Laboratory Animal Care is a voluntary organization that accredits institutions that conduct animal research. According to the group (2):

. . . [the association] was organized in 1965 to conduct a voluntary program for the accreditation

of laboratory animal care facilities and programs.

The accreditation program is concerned with encouraging high standards for the care and use

of laboratoy animals including appropriate veterinary care, controlling variables that might adversely affect animal research, and protecting the

health of animal research workers.

AAALAC is governed by a Board of Trustees composed of representatives of 27 professional organizations in education and research, including the

American Association for Laboratory Animal

Science, American Veterinary Medical Association,

Pharmaceutical Manufacturers Association, and

American Association for the Advancement of Science. A 16-member Council on Accreditation is appointed by the board to make recommendations.

All the Council members have D.V.M. or Ph.D.

degrees and are actively involved in laboratoryanimal medicine or biomedical science. As of 1985,

a total of 483 institutions had received AAALAC

accreditation (see app. D) (3). Table 15-1 summarizes the types of facilities that have received accreditation.

To become AAALAC-accredited, a facility must

pay a nonrefundable application fee prior to the

Table 15.1.–Oistribution of AAALAC-Accredited

Facilities by Category

Type of facility Percent of total

Veterans’ Administration medical centers . . . 15

Commercial laboratories . . . . . . . . . . . . . . . . . . 14

Medical schools. . . . . . . . . . . . . . . . . . . . . . . . . . 13

Pharmaceutical manufacturers . . . . . . . . . . . . . 9

Nonprofit research laboratories . . . . . . . . . . . . 9

Government laboratories . . . . . . . . . . . . . . . . . . 8

Hospitals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Universities (facilities serving an entire

campus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Combined facilities for health schools . . . . . . 4

Dental schools . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Laboratory animal breeders . . . . . . . . . . . . . . . . 3

Colleges of pharmacy. . . . . . . . . . . . . . . . . . . . . 3

Veterinary schools. . . . . . . . . . . . . . . . . . . . . . . . 1

Colleges of biological science . . . . . . . . . . . . . 1

Colleges of arts . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Universities (programs serving only a

portion of a campus) . . . . . . . . . . . . . . . . . . . . 1

College of engineering . . . . . . . . . . . . . . . . . . . . 1

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

SOURCE: American Association for Accreditation of Laboratory Animal Care,

AAALAC Act/v/t/es Report, vol. 13, New Lenox, IL, Apr. 1, 19S5.
Ch. 15–institutional and Self-Regulation of Animal Use . 345

first site visit. Current application fees range from

$1,050 to $1,650, depending on the size of the facility, and annual fees range from $600 to $900.

AAALAC uses the NIH Guide for the Care and Use

of Laboratory Animals as its primary standard for

evaluating facilities and programs. In addition, the

association recommends these sources about laboratory animal care:

●

●

●

●

●

“Report of the AVMA Panel on Euthanasia”

(19) and subsequent revisions.

NIH Guidelines for the Laboratory Use of

Chemical Carcinogens (45).

Biological Safety Manual for Research Involving Oncogenic Viruses (40).

Classification of Etiologic Agents on the Basis

of Hazard (39) and subsequent revisions.

Laboratory animal management and standards documents developed by committees of

the Institute of Laboratory Animal Resources

(3).

The accreditation procedure involves 11 steps.

First, an application is requested from AAALAC.

The completed application for accreditation is

returned to AAALAC, which reviews it and determines whether the applicant is eligible to seek accreditation. After the application fee is paid, the

Chairman of the AAALAC Council on Accreditation selects the site-visit team. Normally, this consists of one member of the council and one consultant. The institution is notified of the date and

time of the visit and the names of the site visitors

and is asked to have assembled materials ready.

The site-visit team inspects the laboratory-animal

care facility and evaluates all aspects of the animal care program with respect to AAALAC standards. Copies of the report are forwarded to two

members of the council, who evaluate it for completeness and clarity. The final site visit report is

then reviewed by the council during its next scheduled council meeting, and the accreditation status of the applicant is determined. The Board of

Trustees confirms the action of the council. Finally,

the applicant institution is provided with a letter

summarizing the conclusions of the council (3).

After the initial site visit, an institution can be

awarded full accreditation, provisional accreditation, or accreditation can be withheld. For accredited institutions, AAALAC reinspects facilities once

every 3 years and can either decide to continue

accreditation, provide a probationary accreditation while deficiencies are corrected, or revoke

accreditation. Sixty-six percent (483 out of731) of

the institutions applying for accreditation since

1965 have received it.

Although AAALAC is a private, voluntary organization, its decisions carry great weight because

the PHS recognizes AAALAC accreditation as a

demonstration of institutional compliance with

PHS policies. Moreover, the NIH Guide for the Care

and Use of Laboratory Animals is the benchmark

AAALAC uses in assessing the adequacy of laboratory facilities, sanitation, veterinary care, animal husbandry, and such basic but important details such as cage size. Approximately 25 percent

of the close to 1,000 institutions with approved

assurances on file with NIH are AAALAC-accredited.

POLICIES OF SCIENTIFIC AND PROFESSIONAL SOCIETIES

A number of scientific societies and professional ture (l). It states, in part: “The AALAS is committed

organizations associated with science and research to the principles of humane care and treatment

have generated policies on the standards of con- of laboratory animals and endorses membership

duct expected of their members in the care or use compliance with established scientific and legal

of animals. Some of these are simple statements standards .“

of support for research use and for humane care The AALAS policy statement also contains some of research animals in accordance with Federal

and State laws and the NIH Guide. For example, of the strong language that has only recently bethe American Association for Laboratory Animal gun to appear in statements of scientific and profesScience (AALAS), an organization that emphasizes sional organizations:

improved animal care and personnel training (13), Many of the factors that affect both animal and

has issued a four-paragraph statement of this na- human life can only be studied in intact animal

38-750 0 - 86 - 12
346 . Alternatives to Animal Use in Research, Testing, and Education

systems by systematically manipulating specific

research variables. Given an incomplete knowledge of biological systems, it is inconceivable that

animal experimentation can be replaced, in the

foreseeable future, by mechanical models or

other incomplete biological systems.

Several organizations have developed more comprehensive policies. These statements of principle have tended to evolve from early concern with

solely humane animal care to a concentration on

the humane care and use of animals.

Ethical standards and policies may be developed

in a variety of ways. Some are prepared by committees or boards composed of members from

different areas of research within a given discipline

(e.g., American psychological Association), from

many countries (e.g., International Association for

the Study of Pain), from several disciplines (e.g.,

Federation of American Societies for Experimental

Biology), from the faculties and communities associated with a university (e.g., University of Southern California), or from within industry (e.g., Smith

Kline &French Laboratories). Guidelines may also

be issued by a professional society as part of the

requirements for publication of research reports

in a society’s journal (e.g., Society for the Study

of Reproduction).

The comprehensive statements of well-established organizations are examined here to provide

insight into both the development and the promulgation of policies affecting large numbers of

research investigators and their experimental subjects. The guidelines of the societies and associations reviewed by OTA share certain common elements, in that they all support or require:

●

Ž

●

●

●

humane care and use of animals in accordance

with relevant laws and the NIH guidelines;

use of minimum numbers of animals of an

appropriate species;

limitations of the time and/or degree of allowable pain or discomfort during chronic experiments;

use of proper types and amounts of analgesics

or anesthesias or of euthanasia to prevent or

terminate excessive pain during acute experiments; and

assurance that all animal experiments are conducted by or under the supervision of qualified personnel.

Beyond these common elements, most policy statements contain principles tailored to the specific

research interests of each organization’s members.

The Animal Care Guidelines of the Animal Behavior

Society, for example, offer instruction on the observation of natural populations (9):

Observation of free-living animals in their natural habitat may involve disruption, particularly

if feeding, trapping, or marking is involved. While

field studies may further scientific knowledge and

advance awareness of human responsibility towards

animal life, the investigator should always weigh

any potential gain in knowledge against the adverse consequences of disruption for the animals

used as subjects and also for other animals in the

ecosystem.

American Psychological Association

The American Psychological Association (APA)

was founded in 1892 to advance the understanding

of basic behavioral principles and to contribute

to the improvement of human health and welfare.

Today, there are approximately 61,700 members

of the APA in research, education, and clinical practice. Policies adopted in 1979, entitled Principles

for the Care and Use of Animals, were designed

to be posted in all facilities and included several

additions to the common elements listed previously. They read, in part (5):

All research conducted by members of the

American Psychological Association or published

in its journals must conform to these Principles.

Investigators are strongly urged to consult with

the Committee on Animal Research and Experimentation at any stage preparatory to or during

a research project for advice about the appropriateness of research procedures or ethical issues

related to experiments involving animals.

Apparent violations of these Principles shall be

reported immediately to the facility supervisor

whose signature appears below.

All persons in each laboratory, classroom, or

applied facility shall indicate by signature and date

. . . that they have read these Principles.

Although the issues of ethics and responsibility

were briefly addressed in the 1979 Principles, the

APA soon felt that a more complete statement was

needed. The principles were extensively revised
Ch. 15—institutional and Self-Regulation of Animal Use ● 347

and issued in 1985 as the Guidelines for Ethical

Conduct in the Care and Use of Animals (6).

The most comprehensive document of its type,

the APA Guidelines is a detailed statement covering all aspects of animal care and use—personnel,

facilities, acquisition of animals, care and housing,

experimental design and procedures, field research, educational use of animals, and disposition and disposal of animals. The importance of

the use of sound ethical judgment is reiterated

throughout, and the new guidelines are to be

signed by a supervisor and an administrative official and posted wherever animals are maintained

or used.

The APA statement is distinguished by both the

number and diversity of its requirements, In addition to supporting the principles previously mentioned, it states that “considerations limited to the

time, convenience, or expense of a procedure do

not justify violations of any of the principles.” When

violations are not resolved at the local level, they

“should be referred to the APA Committee on

Ethics, which is empowered to impose sanctions.”

The possible nature of such sanctions remains

undefined.

The APA Guidelines state: “Psychologists should

ensure that all individuals who use animals under

their supervision receive explicit instruction in experimental methods and in the care, maintenance,

and handling of the species being studied .“ All research should be justifiable, with “a reasonable

expectation” that the research will:

● increase knowledge of the processes underlying the evolution, development, control, or

biological significance of behavior;

. increase understanding of the species under

study in the research; or

● provide results that benefit the health or welfare of humans or other animals.

These contributions “should be of sufficient potential significance as to outweigh any harm or

distress to the animals used.” Moreover, “when

appropriate, animals intended for use in the laboratory should be bred for that purpose.”

The APA stands virtually alone among scientific

societies in offering guidance in the educational

use of animals:

When animals are used solely for educational

rather than research purposes, the consideration

of possible benefits accruing from their use vs.

the cost in terms of animal distress should take

into account the fact that some procedures which

can be justified for research purposes cannot be

justified for educational purposes.

The Guidelines further urge that alternatives to

the use of animals be investigated and that alternatives to euthanasia, such as animal sharing and

return of wild-trapped animals in the field, be considered. Following euthanasia, “no animal shall be

discarded until its death is verified.” Investigators

are invited to seek assistance from the APA on relevant issues, and a list of references on the ethics

of animal research is mentioned as available. The

association supports the formation of institutional

animal care and use committees (including representatives from the local community) to assist in

the resolution of questions within individual institutions, but it recognizes that “laws and regulations

notwithstanding, an animal’s immediate protection

depends upon the scientist’s own conscience.”

American Physiological Society

The minutes of the 1913 meeting of the Council

of the American Physiological Society (APS) contain the first written statement by a U.S. scientific

society in support of the prevention of cruelty to

research animals. Although it did not receive much

attention at that time, the statement later led to

the development of the NIH Guide (33). The present

APS policy statement, revised in 1980 as Guiding

Principles in the Care and Use of Animals (30), is

sent to each member to be signed and posted.

In addition to the principles they have in common with other societies, the APS Guiding Principles require that “animal experiments are to be

undertaken only for the purpose of advancing

knowledge” and that “consideration should be

given to the appropriateness of experimental procedures.”

“Only animals that are lawfully acquired shall

be used, ’’and, when muscle relaxants or paralytics

are employed, ‘(they should not be used alone for

surgical restraint, rout] in conjunction with drugs

known to produce adequate analgesia.” In 1984,

this provision concerning relaxants and paralytic
348 ● Alternatives to Animal Use in Research, Testing, and Education

became the object of a proposed revision, stating

that they:

. . . must only be used after administration of a

general anesthetic, adequate to cause unconsciousness, so that when the muscle relaxant is

given, the animal is already unconscious. The animal must then be kept unconscious until complete

recovery from paralysis occurs. The only exception to this guideline would be in unusual cases

where the use of an anesthetic would defeat the

purpose of experiment and data cannot be obtained by any other humane procedure.

The revision was proposed in 1984 by the APS Animal Care and Experimentation Committee and is

presently under consideration by APS members

for comment on its impact on the design of their

research.

Federation of American Societies

for Experimental Biology

The Federation of American Societies for Experimental Biology (FASEB) is composed of six constituent

societies (APS, the American Society of Biological

Chemists, the American Society for Pharmacology

and Experimental Therapeutics, the American Society of Pathologists, the American Institute of

Nutritionists, and the American Association of Immunologists) and one affiliated society (the American Society for Cell Biology). As such, FASEB represents more than 28,000 research investigators

and clinicians.

The organization adopted a policy on animal experimentation in 1913 that in 1984 it reaffirmed,

while endorsing the APS Guiding Priniciples and

issuing a policy statement on the appropriate use

of animals for scientific experimentation and education (16). The latter document urges ‘(appropriate safeguards to preclude inadvertent use of pet

animals,” supports the “wide application of accreditation procedures for animal experimental facilities)” and resolves “that continuing collection of

appropriate data on the conditions and number

of animals used in scientific research and education is necessary for development of legislative or

administrative remedies in the field. ”

International Association for

the Study of Pain

The International Association for the Study of

Pain publishes the journal Pain, which first appeared in 1975, In its first issue, the journal expressed its ‘(one proper duty; to pursue knowledge

for the alleviation of suffering in man and animals

without any deviation in which we justify the passive observation or intentional production of

suffering” (48). Pain refuses “to publish any reports

where the animal was unable to indicate or arrest

the onset of suffering” (48). In 1980, the association’s Committee for Research and Ethical Issues

published Ethical Standards for Investigations of

Experimental Pain in Animals (15). These urge the

acceptance of “a general attitude in which the animal is regarded not as an object for exploitation,

but as a living individual” and offer a list of guidelines “concerned with the importance of the investigation, the severity and the duration of the pain.”

The statement speaks to the need for justification

and review by colleagues, ethologists, and laypersons. In addition, it:

●

●

●

●

states that “if possible, the investigator should

try the pain stimulus on himself”;

urges careful assessment of the animal’s “deviation from normal behavior” during the experiment;

requires that by escape or avoidance, the animal “be able to control the effects of acute

experimental pain” and be treated for chronic

pain or “allowed to self -administer analgesic

agents or procedures, as long as this will not

interfere with the aim of the investigation”;

and

urges researchers to “choose a species which

is as low as possible in the phylogenic order .“

In 1983, the committee issued Ethical Guidelines

for Investigations of Experimental Pain in Conscious Animals (50), containing two salient revisions from the 1980 document, First, when submitting a manuscript to Pain, authors are “required

to show” that they have followed the ethical guidelines that are published in every issue. Second,
Ch. 15—institutional and Self-Regulation of Animal Use ● 349

“studies of pain in animals paralyzed with a neuromuscular blocking agent should not be performed without a general anesthetic or an appropriate surgical procedure that eliminates sensory

awareness .“

Society for Neuroscience

After more than 2 years of revision, review, and

commentary by members of the Society for Neuroscience (17), an Ad Hoc Committee on Animals in

Research published its Guidelines for the Use of

Animals in Neuroscience Research in 1984 (14).

In addition to the requirements in common with

other societies, these Guidelines place particular

emphasis on good experimental design and state

that “advances in experimental methods, more efficient use of animals, within-subject designs, and

modern statistical techniques all provide possible

ways to minimize the numbers of animals used

in research. ”

The Guidelines show particular concern about

prolonged immobilization or restraint, suggesting

that “reasonable periods of rest and readjustment

should be included in the experimental schedule

unless these would be absolutely inconsistent with

valid scientific objectives ,“ R is noteworthy that

although the policy statement was formulated to

deal with research using warm-blooded vertebrates, it includes a statement concerning invertebrates:

As a general principle. . . ethical issues involved

in the use of any species, whether vertebrate or

invertebrate, are best considered in relation to

the complexity of that species’ nervous system

and its apparent awareness of the environment,

rather than physical appearance or evolutionary

proximity to humans.

In this inclusion of invertebrates into its Guidelines, the Society for Neuroscience is unique among

scientific organizations. This policy likely reflects

an enhanced awareness in neurobiology of the degree of sophistication exhibited by some invertebrate nervous systems.

Society for the Study

of Reproduction

The Society for the Study of Reproduction (SSR)

publishes its Guiding Principles for the Care and

Use of Research Animals in each issue of its journal, Biology of Reproduction, as part of the instructions to authors. Investigators are urged to give

consideration to, among other things, “the use of

in vitro models.”

An investigator wishing to present data at the

annual meeting of the SSR must first make a declaration regarding the use of animals in generating

those data. The researcher is required to attest

with his or her signature (see fig. 15-2) that the

research described in the abstract is in strict accord with the guiding principles for experimental

procedures endorsed by the society. Written affirmations of this nature are becoming increasingly

common among scientific societies; the American

Physiological Society, the Society for Neuroscience,

and the International Association for the Study of

Pain are among the groups with prerequisites of

signed statements of humane treatment of experimental subjects for abstract presentations.

American College of Physicians

In a 1983 position paper entitled Animal Research, the American College of Physicians (ACP)

stated that “scientists and animal welfare advocates

share a belief that safeguards are necessary to ensure humane treatment of animals used in scientific research and testing” and that other issues

needing to be addressed include “development of

alternative testing methods” and “mechanisms to

ensure that. . . treatment, care, and experimental

methods limit animal pain and suffering.”

ACP suggests that appropriate safeguards “may

require the establishment of procedures not unlike human subjects protection review” and “recognizes the importance of standards that promote

the conduct of quality research and ensure the

humane care of healthy animals for research activities” (4).
350 . Alternatives to Animal Use in Research, Testing, and Education

Figure 15-2.– Declaration Required for the Presentation of Data at the

Annual Meeting of the Society for the Study of Reproduction, July 1985

Abstract for

SOCIETY FOR THE

STUDY OF

REPRODUCTIO N

I have read and understand the Society’s Guiding Principles for the Care and Humane

Treatment of Research Animals and affirm that the research described in the above abstract

is in strict accord with these principles.

Presenter’s signature

Telephone No. (Area Code) No.

SOURCE: Society for the Study of Reproduction, Champaign, IL.

American Pharmaceutical

Association

In 1981, the Policy Committee on Scientific Affairs of the American Pharmaceutical Association

offered a number of recommendations on the use

of animals in drug research (36). These included:

provision for adequate regulation, controls,

and enforcement directed toward the procurement, transportation, housing, care, and

treatment of animals;

encouragement of further development of

alternative methods; and

opposition of legislation penalizing properly

controlled and conducted animal research and

testing.

In what stands as one of the most strongly worded

statements of support for the use of alternative

methods from any scientific organization, the policy committee also observed that:

. . . the use of animals for research, testing, control and production purposes is all inherently

quite expensive when compared to other procedures, such as microbiological, chemical, instrumentation and tissue culture. Moreover, both

the speed and accuracy of analytical tests and the

yields of biological production are much superior

when these alternate methods can be employed

in place of animal procedures. As a result, there

has been a continuing shift away from the use

of animals and in favor of alternate procedures

as the latter have been developed and have been

demonstrated to be acceptable substitutes.

American Veterinary Medical

Association

In 1982, the American Veterinary Medical Association (AVMA) approved the AVMA Animal Welfare Guiding Principles (7), which states that

veterinarians must consider certain ethical, philosophical, and moral values relating to the welfare

of animals. Among these considerations are the

encouragement of humane care and proper stewardship, implementation of relevant laws and regulations, support of research to illuminate animal

welfare issues, and identification of individuals

qualified to speak to these issues as a continuing

education resource. In 1983, an AVMA Animal Welfare Positions report recommended the voluntary

establishment of standards of excellence for animal care and use (8). This report includes a number of recommendations on animal welfare issues

outside of research use, such as ownership of exotic animals, declawing of domestic cats, and eartrimming and tail-docking of dogs.

Association of American

Veterinary Medical Colleges

In A Policy on Standards and Procedures Related

to the Use and Care of Animals in Veterinary Medical Education and Research, the Association of
Ch. 15–institutional and Self-Regulation of Animal Use ● 351

American Veterinary Medical Colleges recom- continual monitoring of animal use and policies.

mended use of the NIH Guide and pursuit of It urges that “administrators. . . voluntarily estabAAALAC accreditation by all its member institu- lish standards of excellence for animal care and

tions (1 1). It also supports education in ethical con- use programs rather than relying upon external

siderations, use of alternatives where feasible, and enforcement agencies.”

STATEMENTS OF INSTITUTIONAL POLICY

In addition to scientific and professional societies, several universities have formulated policies

regarding animal use in research and education.

Three such statements are reviewed here for purposes of illustration.

University of Southern California

In 1984, the University of Southern California

published Policies Governing the Use of Live Vertebrate Animals, which contains a “Code of Ethics

for the Use of Animals in Research and Teaching”

adopted by the university’s Animal Ethics Review

Board. The code contains guidelines on avoidance

of unnecessary pain or distress, searching for alternatives for all LD5O studies, prohibition of prolonged physical restraint or deprivation studies,

the use of euthanasia and anesthesia, and consideration of alternatives to animal use. It further

states that “this University shall expect each Investigator to consider alternatives to the use of

animals in research or teaching before presenting a protocol for the use of live animals. The signed

protocol should contain a statement to that effect .“

All protocols must be approved by the Animal

Ethics Review Board. Principles governing the use

of live animals for teaching are similar to those

for research animals (47).

University of Wisconsin

The University of Wisconsin system began requiring in 1981 that all animals used for teaching

and research on all of its campuses be used and

cared for according to the NIH Guide, regardless

of the species or source of funds used to conduct

the teaching or research. The university at that

time took a second extraordinary step and required

the certification of all investigators, technicians,

graduate students, or staff who supervise, use, or

care for animals. On the main campus in Madison, for example, approximately 1)400 persons

have been certified to date through instruction

and examination (49).

Wisconsin Regional Primate

Research Center

In 1982, the Director of the Wisconsin Regional

Primate Research Center (WRPRC) published a Policy Statement on Principles for the Ethical Uses

of Animals at the Wisconsin Regional Primate Research Center (18). This statement deals with the

issues of respect for animals, care, choice of alternatives, use of animals in education, personnel

training, appointment of animal rights advocates

to oversight groups, and the use of good ethical

judgment in evaluating the significance of proposed

research. It is official WRPRC policy that “all animals under its control are recognized as creatures

of great intrinsic value, remarkable complexity,

and inherent dignity. ”

In a section of the Policy dealing with the unique

value of nonhuman animals as models, researchers are charged to make the following choices

when designing experiments:

●

●

●

When the research question can be meaningfully pursued using nonanimal or in vitro

models, the researcher must choose these

alternatives.

When animal experimentation is required, the

researcher must seek the least traumatic techniques feasible, minimize the intensity and duration of any distress, and minimize the number of subjects.

Nonhuman primates shouId be used only in

projects for-which they are the most suitable

animal model.

All research at the WRPRC must have a “reasonable expectation that the experiment will contribute significantly to knowledge that may even-
352 ● Alternatives to Animal Use in Research, Testing, and Education

tually lead to improvements in the health and

welfare of humans or nonhuman animals” and the

expected benefits must “clearly outweigh any pain

and suffering experienced by the. . . animals. ’’Consideration of time or expense alone may never

justify violation of the principles. Sanctions for violation of the Policy include dismissal in accordance

with due process and university regulations.

School of Veterinary Medicine,

Purdue University

Purdue University’s School of Veterinary Medicine drafted a Policy Statement on the Utilization

of Animals in 1985 (38). The statement makes clear

that the school “cannot fulfill its teaching, research,

and service missions without the utilization of animals .“ Purdue’s policy spells out the sources of animals for veterinary medical research and education:

Animals must be legally acquired, and properly

housed, fed, cleaned, and cared for to insure their

comfort and well-being.

The instructional programs require that preventive medicine, curative medicine, and surgery

be practiced in a sequence involving, first, animals owned and maintained by the School and

second, animals owned by the general populace

who seek professional health services.

STATEMENTS OF CORPORATE POLICY

Industrial testing and research laboratories often

have standard operating procedures in writing regarding animal care and use. One of the most comprehensive policy statements on animal welfare

comes from the Research and Development Division of Smith Kline&French Laboratories of Philadelphia, PA. In its Policies and Procedures for the

Conservation and Humane Treatment of Experimental Animals, Smith Kline & French adopted

the following initiatives (29):

● Animal studies of a seemingly unwarranted

nature, but that are required to meet regulations set by external agencies, will be reported

to the Director of Laboratory Animal Science.

SUMMARY AND

In mid-1985, the Public Health Service of the Department of Health and Human Services released

a new policy on humane care and use of laboratory animals for all awardee institutions. The policy requires self-regulation of animal welfare by

all institutions using animals in research and obtaining PHS funds. It is based on a PHS 1979 policy

●

●

●

●

Animal tests required by regulatory authorities in certain countries, but generally not by

others, will be reported to the Director of Laboratory Animal Science,

In vitro test methods developed to replace in

vivo studies are to be documented so that other

areas may consider potential applications.

Mistreatment of animals is a serious violation

of policy and may be grounds for dismissal.

A series of Animal Welfare Achievement

Awards will recognize and encourage a maximum effort toward conserving animals and

developing in vitro techniques.

CONCLUSIONS

and on information obtained during 15 site visits

by NIH to awardee institutions with general assurances on file with NIH. The new policy is more

stringent and structured than the old one. It

revolves around the institutional assurance to NIH

and the institutional animal care and use commit -

tee. To obtain assured status with NIH, an institu-
Ch. 15—institutional and Self-Regulation of Animal Use ● 353

tion must either be AAALAC-accredited or fulfill

the steps outlined in the policy for self-assurance

status.

In 1985, Congress gave the force of Federal law

to some of the provisions of the PHS policy and,

in separate action, mandated the establishment of

institutional animal care and use committees at

all research facilities covered by the Animal Welfare Act as well as at Federal facilities (see ch. 13).

Taken together, the new PHS policy and Federal

statutes bring the overwhelming majority of animal users in the United States under the oversight

of institutional animal care and use committees.

Researchers who use animals, their institutional

colleagues, their peers in science, laboratoryanimal veterinarians, and local community members are today viewed as the appropriate arbiters

of what constitutes acceptable care and use of animals. The PHS policy charges these individuals with

membership on institutional animal care and use

committees at each site where animals are involved

in PHS-funded research. Each IACUC shall have

broad oversight authority of the animal welfare

program at the institution and approve all portions

of research protocols involving animals for proper

animal care and treatment.

The functions of animal care and use committees may include:

●

●

●

●

●

●

●

●

●

ensuring compliance with local, State, and Federal laws and regulations on animal care and

use;

inspecting animal care facilities;

reviewing protocols for animal welfare issues;

assessing the qualifications of investigators;

overseeing student use of animals;

advising on institutional needs, costs of animals, and animal procurement policies;

controlling allocation of animals within the

institution;

serving as a resource on animal welfare issues and as an educator of the university community and the community at large on animal welfare issues; and

acting as a community complaint forum.

The concept of review by committee is not

unique to the use of animals in experimentation.

In fact, institutional review boards and humansubjects committees have overseen research using

humans for a decade or more. Current thinking

about animal care and use committees is modeled

after experience with IRBs.

A voluntary private organization, the American

Association for Accreditation of Laboratory Animal Care, functions as a respected agent of certification of an individual laboratory’s standards

of care. As of April 1985, a total of 483 institutions

using animals had received AAALAC accreditation

after passing an inspection based on the NIH Guide

for the Care and Use of Laboratory Animals.

Several scientific and professional societies,

universities, and corporations have promulgated

statements of policy concerning their members’

and employees’ standards of conduct in the care

and/or use of animals. An organization’s policy

statement usually reflects its characteristic interests. Some policies are brief enough to cover only

one column of a page, while others (e.g., American Psychological Association) take many pages

and go into great detail. These policies generally

require:

● humane care and use of animals,

. use of a minimum number of animals,

● alleviation of pain and suffering, and

. supervision of animal use by qualified personnel.

At least eight of the organizations and institutions whose policies were reviewed by OTA support the concept of animal care and use committees. Twelve of the fifteen organizations reviewed

specifically support or require consideration of

the use of alternatives to animals in research, and

three specify the maximum use of available statistical methodology.

Several statements of policy require signed statements attesting to humane animal care prior to

the publication and/or presentation of papers. only

three policy statements, those of the American Psychological Association, the Wisconsin Regional Primate Research Center, and Smith Kline & French

Laboratories, directly mention any sanctions against

violators of their guidelines. As a rule, there are

neither enforcement provisions accompanying the

stated policies and principles of scientific and

professional societies nor any apparent penalties

for the violation of these policies. For these reasons, the practical significance of certain of these

statements of principle is open to question.
354 Alternatives to Animal Use in Research, Testing, and Education

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Will, J. A., Director, Research Animal Resources

Center, University of Wisconsin, Madison, WI, personal communication, Mar. 12, 1985.

Zimmerman, M., “Ethical Guidelines for Investigations of Experimental Pain unconscious Animals,”

Pain 16:109-110, 1983.
Chapter 16

Regulation of Animal Use

in Selected Foreign Countries

One of the tests of a civilized society is its treatment of animals.

Scientific Procedures on Living Animals, (Command 9521

British Home Office

May 1985

We have come to the conclusion that the status of the dog in Western Sociey is such that

it is desirable to minimize its use in the laboratory. Some SO percent of Canadian households include a dog. These pets are regarded by most owners in an anthropomorphic way

as being full members of the family. Clearly, such people are very receptive to emotional

appeals to ban the use of animals-especially dogs like theirs-for research. Thus, it will

probably be necessary to phase out the significant use of dogs if a major battle over the use

of animals for research is to be avoided.

J.C. Russell and D.C. Secord

University of Alberta, Edrnonton

Perspect. Biol. Med. 28:374-381, 1985

Possibly the most important feature of any legislation on behalf of laboratory animals is

the acknowledgment that the ultimate responsibility for their welfare rests with society and

not with the research community.

Anne Doncaster

Mississauga, Ontario

“Experiments on Animals—Review of

the Scientific Literature, ” June 1982
CONTENTS

Australia . . . . . . . . . .

Canada . . . . . . . . . . . .

Japan . . . . . . . . . . . . .

Western Europe . . . .

Denmark . . . . . . . .

Federal Republic of

Netherlands . . . . . .

Norway . . . . . . . . . .

Sweden . . . . . . . . . .

Switzerland . . . . . .

United Kingdom . .

..,,. ...+

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

Germany

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

Summary and Conclusions ...,

Chapter 16 References. . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . .,..,, . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

List of Tables

Table No,

16-1.

16-2.

16-3.

164.

16-5.

. .

. .

. .

. .

. .

. .

. .

. .

. .

. .

. .

. .

. .

National Laws for the Protection of Animals in

Selected European Countries . . . . . . . . . . . . . . . .

Comparison of the United Kingdom’s Cruelty to

and Proposed Amendments . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

+, ..............,, ,

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

Animals Act of 1876

. . . . . . . . . . . . . . . . . . .

Experiments by Species of Animal, 1977-84, United Kingdom. . . . . . . .

Primary Purpose of Experiments, 1977-84, United Kingdom . . . . . . . . .

Experiments by Type of Registered Facility, 1977-84, United Kingdom

+..

. . .

, . .

. . .

. . .

. . .

. . .

$ . .

. . .

. . .

. . .

. . .

. . .

. , .

Page

359

360

362

363

363

366

367

368

369

371

373

377

377

Page

364

374

375

376

376
Chapter

Regulation of Animal Use

in Selected Foreign Countries

The protections afforded animals vary greatly

among countries, from almost complete disregard

of animal welfare to the many cultural and legal

protections provided in Western Europe and Canada. These protections are currently the subject

of heated debate in many countries, particularly

where animal protection is already significant. In

1985, for example, Switzerland’s voters rejected

a referendum that would have virtually banned

the use of animals for experimental purposes. The

use of the LD5O in safety testing continues to be

given careful scrutiny by Government and scientific organizations in Switzerland (73,76, 77) and

the United Kingdom (4,67,69).

Actions taken in other countries are relevant to

U.S. policies for several reasons. First, steps taken

by trading partners can lead to political and economic pressures to take similar actions. Second,

decreased use of animals abroad, particularly by

multinational corporations, can lead to an increased use in the United States. Finally, the experiences of other countries can serve as instructive models, both for policies and for their effects.

This chapter describes the laws of Australia, Canada, Denmark, the Federal Republic of Germany,

Japan, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom. The most common provisions are prohibitions against painful

experiments without anesthesia unless anesthesia would frustrate the purpose of the experiment;

requirements for licensing or permitting of facilities, investigators, or experiments; limitations on

animal use for education; and requirements for

internal or external review of experiments by

interdisciplinary committees. Two of the more

unusual provisions are the protection of crustaceans (Norway) and of native nonvertebrates (the

Netherlands).

The impact of these laws on the welfare of animals is affected by several factors other than the

substantive requirements of the laws, including

societal attitudes toward animals; training of scientists and technicians, both in techniques and in

ethics; the composition and procedures of reviewing committees; and the vigor of animal welfare

advocates. This chapter discusses the substantive

and procedural aspects of these various laws and,

where information was available, criticisms and

comments on the effectiveness of the systems.

In addition to the array of national laws, there

are international agreements—both in effect and

proposed–that affect animal welfare. Among

these, the Convention on International Trade in

Endangered Species, bans on trade in primates,

the Draft Convention of the Council of Europe,

and the guidelines of the Council for International

Organizations of Medical Sciences, are discussed

in appendix E.

AUSTRALIA

In Australia, as in the United States, animal wel- Of the States, New South Wales has the most

fare is primarily a State concern. Each State has extensive laws. Its Prevention of Cruelty to Aniits own legislation and regulations for animal ex- mals Act, passed in 1901 and amended many times,

perimentation. At the Federal level, a select com- prohibits activities such as inflicting umecessary

mittee of the Australian Senate is in the early stages pain; killing, mutilating, or poisoning; and failing

of an 18-month examination of animal welfare, and to provided proper food, drink, shelter, or exerin 1985 the National Health and Medical Research cise. Experimentation is permitted only in the most

Council revised its Code of Practice for experimen- humane manner available and pain must be altal animals (41a). leviated. The most recent amendments, in 1979,

359
360 Ž Alternatives to Animal Use in Research, Testing, and Education

primarily served to make the act more specific.

Two levels of cruelty were defined and penalties

specified—aggravated cruelty, resulting in death

or severe injury or disease (fined at about $1,400

and/or 1 to 2 years imprisonment), and simple cruelty, resulting in pain or distress (fined at about

$700 and/or 6 months) (2).

In addition to the act’s prohibitions, it requires

that those performing surgery have certain scientific credentials or a license. Recognizing that

credentials alone do not prevent cruelty, the Minister for Local Government has the power to require those performing surgery as licensees to report the details of a procedure (1).

In 1985, the New South Wales Parliament passed

legislation establishing an Animal Research Review

Panel to oversee licensing of research institutions

and animal suppliers. Each institution is required

to establish its own review committee (56). These

requirements make the laws of New South Wales

quite similar in their comprehensiveness and approach to the laws existing in Western Europe.

CANADA

As in the United States and Australia, the Provinces have primary authority over animal use; national action is not taken unless there are interprovincial or national concerns. Although Canada

has no national legislation pertaining specifically

to protecting laboratory animals, it has a comprehensive voluntary national system.

Three Provinces have legislation affecting laboratory animal use: Two deal primarily with

procurement of unclaimed pound animals (8,9,10),

while Ontario has a more comprehensive Animals

for Research Act, amended in 1979 (6) and accompanied by regulations (i’). Many provisions of

the Ontario law parallel the voluntary national

program.

Although Canada is rather proud of its voluntary program, some Canadian animal protectionists

are not satisfied. Vandalism and threats against

an official have occurred at the University of British Columbia in Vancouver, the Clarke Institute

of Psychiatry in Toronto has been firebombed, and

protesters have campaigned against the use of

pound animals at Dalhousie University (55).

Many years ago, scientists at the University of

Alberta went further than their counterparts in

other Provinces in protecting animal welfare. They

employed a research veterinarian who upgraded

their facilities to levels as high as animal hospitals

and clinics, added various precautions against the

use of stolen dogs, and established open communication with the press and the local community.

Another policy, certainly welcomed by dog enthusiasts, has been the gradual replacement of the

dog with the small Yucatan pig for many kinds of

experiments. Some Alberta researchers feel that

animal protectionists have not been active in Alberta because of these initiatives (55).

Canada’s voluntary national program is run by

the Canadian Council on Animal Care (CCAC). The

first step toward the creation of the CCAC was

taken in 1963, when the Canadian Medical Research Council requested the National Research

Council (of Canada) to investigate the procurement

of experimental animals, the facilities for their care,

and control of experiments. This request followed

on the heels of the inauguration of the Canadian

Society for Animal Care (which became the Canadian Association for Laboratory Animal Science,

an organization similar to the American Association for Laboratory Animal Science).

After completing its investigation, the National

Research Council recommended that institutions

voluntarily assess and control animal experimentation through:

●

●

●

animal care committees that would monitor

care and use of experimental animals and ensure compliance with uniform standards;

Provincial advisory boards to deal with procurement matters; and

a national, independent advisory body to establish guiding principles and oversee their application and to advise Provincial governments.
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 361

These recommendations led to the formation of

the CCAC in 1968 as a committee of the Association of Universities and Colleges of Canada (AUCC).

CCAC is independent of governmental and direct

university control and is funded by the Medical

Research Council and the National Research Council. Its 20 members are drawn from various sectors: 8 from national associations of higher education (including the AUCC), 5 from departments

of the Federal Government, 4 from national agencies providing research grants, 2 from the Canadian Federation of Humane Societies, and 1 from

the Pharmaceutical Manufacturers Association of

Canada. The members of the CCAC also participate informally in curriculum committees for institutions that educate animal care attendants and

technicians and, together with the Canadian Association for Laboratory Animal Science, certify laboratory animal personnel at five skill levels (28,

50)51)52).

The CCAC has two executive officers: the Executive Director, responsible for standards and

overall operation; and the Director of the Assessment Program, responsible for compliance with

the voluntary program. They organize the CCAC’s

activities around the Guide to the Care and Use

of Experimental Animals, a two-volume publication much like the Guide for the Care and Use of

Laboratory Anhnals issued by the U.S. National

Institutes of Health (NIH). The CCAC’s Guide, provided at no charge to every researcher using animals, details standards for the care and use of animals in experiments for government, university,

and pharmaceutical research institutions.

The most important requirement of the Guide

is that a local institutional Animal Care Committee (ACC) be set up. Volume I lists the following

general requirements for a facility’s committee:

●

●

●

It must consist of senior scientific personnel

experienced with laboratory animals. An experienced veterinarian or a biological scientist should be a member of the ACC or retained

as a consultant.

It must be kept informed of all activities involving animals.

It must establish procedures to ensure that

in any experiment likely to result in pain, the

animal is anesthetized or given analgesics except when it would interfere with the experiment.

● It is responsible for all training and qualifications of personnel who care for animals.

● If its members believe required procedures

are not being followed and unnecessary pain

is being experienced, it has the power to stop

the procedure and to destroy the animal humanely if necessary to alleviate distress (11).

In 1983, an addendum to Volume I, The Use of

Animals in Psychology, provided additional guidelines to those engaged in psychological research

(13). Volume II of the Guide, published in 1984,

provides information on selection, acquisition, use,

and care of 22 distinct classes of laboratory animals (14).

In addition to the Guide, CCAC has also published

Ethics of Animal Experimentation, a set of principles for “all those utilizing vertebrates in the conduct of research, teaching, or testing. ’’These stress

the

●

●

●

●

●

●

●

●

●

importance of:

exhausting all alternative methods before animal use is considered;

using the best methods on the smallest number of appropriate animals required to obtain

valid information;

having a reasonable expectation that the study

will contribute significantly to knowledge that

may eventually improve the health or welfare

of humans or animals;

avoiding unnecessary pain and duress, both

in intensity and duration;

humanely destroying animals when severe

pain cannot be alleviated;

seeking humane end points;

withholding food or water on a short-term

basis only;

avoiding physical restraints; and

using anesthetics or analgesics for surgery or

traumatic procedures (burning, freezing, fracturing) (12).

CCAC publications that do not necessarily promote

animal welfare, but that are useful to experimenters, include Canadian Suppliers of Laboratory Animals (a detailed list of suppliers, with species, producers, and locations) and annual editions

of Research Animals in Canada (comprehensive

information, by species, on laboratory-animal resources available to researchers) (15).

Compliance with the various guides and principles and the functioning of the local ACCS are over-
.

362 ● Alternatives to Animal Use in Research, Testing, and Education

seen by assessment panels chosen by the CCAC.

The typical panel consists of three scientists, one

representative appointed by the Canadian Federation of Humane Societies, and the Director of

Assessments, acting ex officio. Panelists are selected, to the extent possible, for the fields of research at the institution to be assessed.

Institutions, contacted in advance, complete a

questionnaire describing the local ACC, the research facilities, the animals used, and the personnel, After the facility has been inspected (for as

long as 4 days in large institutions), the panel discusses its general findings with the ACC and

reports in confidence to the principal official of

the institution. If the panel is dissatisfied, a followup

visit may be scheduled. Major assessments occur

approximately every 2 years; minor ones, or reassessments, occur less frequently (15,23).

Identified problems that are widespread are

solved at the national level. For example, inappropriate use of certain animals as models, poor

surgical or anesthesia techniques, dated equipment, and poor husbandry led the CCAC’s ad hoc

Education Committee to issue the Syllabus of the

Basic Principles of Laboratory Animal Science in

1983 (16). Several Canadian universities have used

the syllabus in short courses in basic laboratoryanimal science, and one university proposed that

such courses be mandatory for graduate students

who may use animals during research (27).

Although there are no penalties in law or regulation for violating CCAC standards, an incentive

for compliance has been provided by the Health

Protection Branch of the Department of National

Health and Welfare since 1975. It includes in its

contracts with private sector institutions a requirement that the CCAC Guide be followed. All governmental departments with contracts involving

animal experimentation have now adopted similar provisions, and a finding of noncompliance is

grounds for terminating a contract (28,51).

Responding to increasing criticism from some

quarters about CCAC's reliance on researchers to

police themselves and to more frequent demands

for Provincial legislation controlling research animal use, Canada’s Minister of State for Science and

Technology requested a review of CCAC’s effectiveness in 1981. A special committee formed to

conduct the review found that the CCAC has had

considerable influence in eliminating those problems that led to its establishment and that it works

effectively to produce further improvements. The

site inspections involving the humane society and

the facility upgrading were found to have resulted

in Canadian animal care facilities now being among

the best in the world (28).

JAPAN

The protections afforded animals in Japan are

like those of Europe in their requirements for

anesthetics and euthanasia, as well as in their

concern, in particular, about dogs and cats. An

interesting facet of the Japanese laws is that they

combine the protection of animals with the responsibility of those possessing animals to protect other

humans from them.

The principal law governing animal control and

treatment in Japan (33) went into effect in 1974.

Its purposes are to prevent cruelty to animals; to

provide for appropriate treatment, taking natural habits into account; to engender a feeling of

love for animals among people, thereby contributing to the development of respect for life and

sentiments of friendship and peace; and to protect humans from any hazards to themselves or

their property that could result from possession

by others of domestic or laboratory animals. The

law establishes a fine of up to $1,400 for violations

of the law or of standards implementing it (32,

33,34).

The law protects all mammals and birds, but it

is apparently intended to apply to other species

as well. It establishes several responsibilities relevant to research:

● Those possessing animals are responsible for

their maintenance, health, safety, and control,

● Where an animal is used for education, experimental research, manufacture of biotics,

or other scientific purposes, the animal is to
Ch. 16–Regulation of Animal Use in Selected Foreign Countries .363

suffer the minimum pain possible within the

limits imposed by these purposes.

If an animal will not recover from a scientific

procedure, the person who used the animal

must immediately dispose of the animal by a

method that causes it the minimum pain

possible.

These responsibilities do not apply to education

and research in livestock husbandry or breeding

or to experiments for the purpose of observing

animal’s roles in an ecosystem (37).

The Prime Minister has issued three standards

in implementing this law: Standards for the Keeping and Custody of Dogs and Cats (1975); Standards Relating to the Keeping and Custody of Animals for Exhibition, etc. (1976); and Standards

Concerning the Raising, Custody, etc. of Animals

in Experimental Use (1980) (37), The first two establish general requirements for adequate food,

water, shelter, exercise, care, safety, and disease

control for animal owners, custodians, and exhibitors. As the title indicates, the first standard applies to dogs and cats; the most recent standard

covers other mammals, birds, and reptiles. Enforcement guidance for local authorities was also

provided in 1980 (37), and a licensing system was

established for facilities conducting experiments

(35).

The law establishes a decentralized system for

general administration and enforcement. Local

authorities at various levels—prefectures, cities,

towns, villages, and wards—pass ordinances and

establish custody and disposition programs. Prefectures, the largest units, can levy fees for custodial

programs and can enlist the aid of animal protection societies. Such programs can also be granted

subsidies by Cabinet Order (38).

An Animal Protection Council created by the Cabinet in 1974 (36) aids the Prime Minister at his request. Though the 15-member Council is advisory,

the Prime Minister must consult with it before

establishing, enlarging, or abolishing standards.

The Council, together with the Government and

the Japanese Science Council, recommended in

1980 that the Government establish guidelines for

animal experimentation (39). The guidelines developed are quite like the NIH’s Guide for the Care

and Use of Laboratory Animals; they cover standards for housing, husbandry, veterinary care, handling during and after experimental procedures,

anesthetics, euthanasia, and disposal (63).

In addition to these several publications on how

to use animals, the Government has also published

detailed information on licensed and regulated facilities, including statistics on experimental-animal

use (75). According to this publication, mice accounted for 78 percent of total animal usage in

1980, while rats accounted for a little less than

17 percent. The total number of animals used has

been declining from a peak in 1970 (13.6 million),

though the use of hamsters, dogs, cats, and primates has increased (30).

WESTERN EUROPE

Throughout Western Europe, animals have legislative protections. The first such protections were

anticruelty laws, many of which were passed in

the late 19th century. Most anticruelty laws had

only limited application to experiments, but in the

last several decades, additional laws were passed

to protect experimental animals, primarily from

pain. This section describes the laws of seven of

the more active countries. Table 16-1 compares

the major provisions of these laws.

Denmark

The philosophy in Denmark, as in other Scandinavian countries, is that animal experiments are

prohibited unless specifically allowed. This belief

was first expressed by statute in 1953 (19). With

amendments in 1977 (18), Denmark gave authority for all experiments involving animals to an Animal Experiment Board at the Ministry of Justice.

This board has seven members who are doctors
Table 16-1.—Natlonal Laws for the Protection of Animals in Selected European Countries

Federal Republic

Provisions Denmark of Germany Netherlands Norway Sweden Switzerland United Kingdom

Species protected. . . . Vertebrates

Distinctions among species Should use lowest

rank; dogs, cats,

rabbits purpose-bred

Alternatives must be used

if availabl e Yes

Anesthetics, analgesics, or

approval required for

painful experiments Except for minor or

transient pain

Educational use s Higher education,

technique

Ban on animal use for more

than one painful experiment. All dogs, cats,

monkeys; most

experiments

License/permit for dealers,

facilities, and investigators .All facilities, head

investigators

Review of experiments ., Most experiments need

approval by national

Board

Administration Centralized,

government/

All animals

Better to use

invertebrates or coldblooded vertebrates

Yes

If pain, suffering, or

injury likely

High school and above

No multiple surgeries

on vertebrates

Dealers, facilities,

investigators

Not needed; proposed

that facility’s animal

welfare officer review

States enforce and

administer (proposed

nongovernment board; that facilities have

licensee is animal welfare

responsible officer)

Animal welfare representation ...3 nominees to Being considered

national Board

Reporting Annual report In-house

recordkeeping

Vertebrates, native Vertebrates,

species crustaceans

Vertebrates better Monkeys, dogs, cats

protected better protected

Vertebrates Yes

If injury or pain likely If pain is possible

(unless Board

approves)

University and Professional training

vocational

Rarely reused because Only one experiment

of pain requirements allowed per animal

Dealers (dogs and cats), Investigators or facilities

facilities licensed

Head of institute Investigator or facility

reviews (licensee) review

Central enforcement Central coordination,

and reporting: some functions

Vertebrates Vertebrates Vertebrates

Should use lowest Should use lowest rank

rank; all purpose-bred

Alternatives promoted

Surgery on mammals

unless committee

approves

Allowed, but restricted

Rarely reused because

of pain requirements

Breeders, facilities

Notification/application;

tiered system

Central coordination

with oversight by

administration by delegated to licensees facility head and

institute committee

Not required, but Not required On all committees;

facility reports are being reconsidered

public

Annual report Annual report Government

recordkeeping

SOURCE Office of Technology Assessment

Yes

Slight pain or anxiety;

if too painful, must

forgo

Not allowed

Only reused if pain

was slight

Breeders, facilities

2 State committees

review

Central coordination,

administered by

States

Members of national

commission

In-house

recordkeeping

Primates, dogs, cats,

equidae preferred; no

stray dogs

Alternatives encouraged

Statute does not specify,

but certificate may

require

Some demonstration; not

for practicing

If anesthetized or

because of pain

requirements

Facilities registered,

investigators licensed

Home Office and

Advisory Committee

Centralized, shared by

Head Office, Advisory

Committee, Royal

Society

Advisory Committee

Annual report
—

Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 365

or veterinarians. Members are nominated by various groups—two by the Medical, Agricultural, and

Veterinarian Scientific Councils; one by the Public Health Authority; one by the Council for Industry; and three by associations for the protection

of animals.

Because there are fewer than 300 experimenters,

most of whom are clustered in a handful of facilities, the Board is able to oversee all experiments.

A permit must be obtained from the Board for most

experiments, and its decisions cannot be appealed.

The only exceptions to the requirement for approval are nutrition studies that will cause conditions similar to what might occur naturally, and

experiments that cause only transient and minor

pain, as in the taking of blood samples or skin biopsies, but even these procedures are subject to

the statute’s other requirements. In a change from

the earlier statute, Government institutes must obtain permits for experiments, although licensing

of individual investigators in certain positions and

of facilities is still automatic. Those having permission to conduct experiments may delegate this authority to others, but they remain responsible for

the experiment.

There are two other important changes in statutory law. First, the use of animals in experiments

is forbidden if alternative methods, such as cell,

tissue, or organ cultures, could achieve the same

results. Second, in the area of education, animals

may only be used in universities and other institutions of higher learning, and then only to train people in experimental techniques. One troublesome

provision, carried over from the 1953 act, is that

animals of the lowest possible “rank” must be used.

One can infer from the special protections given

dogs, cats, and monkeys that these are the highest species, but the statute does not specify how

rank is to be determined. A recent ordinance requires that as of January 1, 1986, all dogs, cats,

and rabbits be purpose-bred. The Animal Experiment Board is also studying the need for the LD5O

test, with decisions expected no earlier than mid1986 (40).

The law requires the use of as few animals as

possible and the prevention and alleviation of pain,

Invasive (surgical) procedures and physically and

chemically induced insults that might cause pain

must be performed under anesthesia. The animal

involved must be killed before recovery unless the

experimenter can assume that pain will not endure or unless the procedures require that the animal be kept alive. If the latter, the animal must

be given pain relievers and special care. If it survives in an abnormal state, any suffering that results must be relieved to the extent possible. The

abnormal condition must be corrected as soon as

possible, or the animal must be destroyed humanely. If dogs, cats, and monkeys are not killed

at the conclusion of experiments, reasons must

be given; the exact details of destruction and disposal must be included (40), This is similar in effect to those statutes requiring that an animal be

used in no more than one painful experiment.

Licensees must keep records and file a detailed

annual report on numbers and species of animals

used; type of euthanasia performed on dogs, cats,

horses, ungulates, and nonhuman primates; and

purposes of experiments. Since 1979, the Board

has required reporting that is unique. Research

institutions must distinguish between the total

numbers used in experiments (Category A), and

those used as controls and sacrificed for harvesting organs or some other purpose only indirectly

related to the performance of an experiment (Category B). Categories are further subdivided to reflect the risk of pain and suffering:

● procedures of short duration performed not

under anesthetic (Category A-l);

● procedures of longer duration, when the animal is not sacrificed while still anesthetized

(Category A-2);

● procedures performed under anesthetic,

when the procedure is of short (Category A3-a) or long (Category A-3-b) duration;

● procedures to produce or test substances performed without anesthetic and not included

in the following two categories (Category A-4);

● procedures involving the induction of pathogens or infection (Category A-5); and

● procedures involving the injection of other

matter (Category A-6).

There has been a steady growth in the number

of licensees in Denmark, from 159 in 1970, to 276

in 1983, some of which is due to broadening scope

of licensing requirements. Animal use has been

fairly steady, but Category A uses have grown.

Mice and rats accounted for 91 percent of all po-
366 ● Alternatives to Animal Use in Research, Testing, and Education

tentially painful experimental animal use in Denmark in 1983. Of those two species, 66 percent

were used for toxicological testing. Nonhuman primates and companion animals (dogs and cats) were

used in less than 0.25 percent of the total experiments. Most dogs and cats were used in longer

term procedures under anesthetic, from which

they recovered. In painful procedures, primates

were used most often in long-term procedures under anesthetic, but 56 percent were used for purposes exempt from the law (40), that is, nutrition

studies or experiments involving only minor or

transient pain.

Federal Republic of Germany

West Germany’s animal protection laws have

been evolving since 1883, at which time anesthetics

were required, if possible; experiments using animals could be done by trained persons only; the

number of animals and amount of distress were

to be minimized; and greater protection was afforded “higher” animals. Amendments in 1933 retained these requirements and added a licensing

requirement for institutions using animals. In the

1972 Animal Protection Act, licenses were also required for individual scientists for each study (19).

The Parliament is considering new legislation

that would create an ethics commission of scientists and animal protectionists that would review

detailed applications for each project involving animals, require that each laboratory appoint an animal welfare officer, and require that the Government identify alternatives and promote their use.

Finally, Parliament is also considering a special tax,

probably 5 to 25 percent of costs, on animal experiments as a means of providing additional incentive to use alternatives (26,29).

Although the law is national, it is administered

by the States (Lander). In enforcing the law, States

can use sanctions ranging from stopping an experiment and seizing the animals or revoking a

permit, to imposing penalties of about $3,800 and

up to 2 years’ imprisonment (24).

The basic goal of the law is that no one shall be

permitted to cause pain, suffering, or injury to animals without acceptable reasons. Other provisions

require that vertebrates not be used when invertebrates would suffice and that warm-blooded vertebrates not be used when cold-blooded ones

would do. Further, experiments should be limited

to the number absolutely necessary.

Those desiring a permit must be affiliated with

a university or otherwise conducting research, and

they must provide detailed information to the permitting authorities in the Lander documenting that:

●

●

●

●

●

the desired results cannot be obtained by more

humane methods;

the experiment is necessary for the prevention, diagnosis, or cure of diseases in humans

or other animals or serves scientific purposes;

the director and deputy director of the experiment are reliable;

the necessary equipment, facilities, supplies,

and personnel are available; and

proper care and medical treatment will be

provided.

Permits may be restricted or revoked if requirements are not met by a specified time or if permit

restrictions or regulations are not complied with.

The permit contains the name of the director of

the experiment and a deputy.

Unlike Denmark and other countries discussed

in this chapter, educational uses are permitted at

the high school level and a permit is not required.

However, such activities must be reported to the

authorities before they take place. Other experiments that do not require permits are those that

fulfill governmental requirements and those used

for diagnostic purposes.

Several restrictions pertain to pain. An animal

should not endure pain, suffering, or harm if avoidable, Experiments on vertebrates may be performed only under anesthetic unless it is incompatible with the purpose of the research or the

pain connected with the operation is less than the

damage inflicted by anesthesia. A painful operation or treatment may be performed on an unanesthetized animal only once unless the purpose

of the experiment cannot otherwise be achieved;

the animal may be used for another experiment

only if the second experiment does not involve pain,

suffering, or harm. After an experiment, certain

species must be presented immediately to a veterinarian, others to the experimenter, and killed painlessly if the animal can live only in great pain.
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 367

Animal experiments may be performed only by

persons with the required professional knowledge

in veterinary medicine, medicine, or biology. Surgery may only be performed by a certified veterinarian.

Detailed standards governing housing, care, and

treatment of live vertebrates in experiments were

published in 1977. The Federal Government has

published a number of monographs and guidances

for the use of the States and regulated facilities

in interpreting the act in a variety of circumstances

(25). In 1983, the German Veterinary Society issued codex experiendi providing advice and suggestions to investigators on the ethical use of experimental animals (26).

There are specific reporting requirements for

regulated experiments. Each experiment for which

permission was required must have a report on

file that describes the purpose of the experiment,

the number and types of animals used, and the

nature and performance of the experiment. The

reports must be signed both by experimenters and

the director and retained for 3 years. ownership

histories must be kept for dogs and cats. Though

no official national statistics are kept, the Ministry of Food, Agriculture, and Forestry estimates

that approximately 7 million animals were used

in experiments in West Germany in 1984 (71).

Netherlands

The Netherlands places a great deal of responsibility for animals’ welfare on the head of the facility in which experiments are conducted. This oversight is coordinated by the Veterinary Chief

Inspectorate of the Ministry of Public Health, who

in 1984 began a major project in cooperation with

five animal welfare organizations to identify potential alternatives to the use of animals in testing

vaccines, serums, and other diagnostic methods.

This report, and other initiatives, are expected to

increase research on alternatives (53).

Like most other West European countries, the

Netherlands has had a general statute that protects animals from cruelty since the late 19th century. It prohibits causing pain, suffering, or injury

to an animal, or withholding proper care without

reasonable cause. It provides criminal penalties

for violations, but it has not been necessary to use

them for animal experiments (21). A law governing trade in livestock confines trade in dogs and

cats to licensed dealers, thus protecting pets (43),

and an ordinance taking effect in 1986 requires

that dogs, cats, and rabbits be purpose-bred (31).

Finally, the Netherlands has a “protection of nature” law, which protects some invertebrate

species—such as Helixpomatia, the Roman snail—

and all native amphibians (42,44).

The Law for Experimental Animals, passed in

1976, established a comprehensive system for regulation of animal experimentation, including the

filing of annual reports by all animal facilities with

the Ministry of public Health (45). The law is based

on general guidelines issued by the International

Committee for Laboratory Animals, and became

the Council of Europe’s model for the Draft Convention on protection of laboratory animals (see

app. E).

The law requires justification for all animal experiments on vertebrates that are likely to be injurious or cause significant pain or other distress.

Experiments must benefit human or animal health

or food, or science, and must be approved by the

head of the institute where they are to be done.

Statistics on registered experiments compiled by

the Dutch Government indicate that from 1978

to 1983 about 20 percent of the experiments were

related to the production of serums, vaccines, and

other biological products; about 30 percent were

related to toxicological and pharmaceutical research; less than 10 percent were related to the

diagnosis of pregnancy or disease; and about 30

percent were related to the solution of a scientific

problem (and the vast majority of these were related to medical research). Less than 2 percent

were for training and education. These statistics

also indicate that about one-third of the experiments were done because of legal requirements,

and less than 10 percent were toxicity tests.

As do many other countries, the Netherlands

does not permit painful experiments on vertebrates

when alternatives are available, and requires

anesthetics for more than negligible pain except

where their use would frustrate the purpose of

the experiment. Where severe and prolonged pain

will likely result from the procedure, the animal

must be humanely killed without recovering from

anesthesia (45). Statistics for 1978-83 indicate that
368 . Alternatives to Animal Use in Research, Testing, and Education

some 20 to 30 percent of experiments do not require anesthetics (though the figure is steadily decreasing); that more than 10 percent of the animals are killed without treatment to obtain organs

or blood; that about 10 percent of the operations

end in euthanasia or slight pain; and that the greatest number of experiments producing significant

pain are those involving pathogens, immunization,

or toxic substances.

The Government entrusts most of the responsibility for administering the law to the head of the

research enterprise to whom licenses are issued.

The director of research need not be an expert,

but he or she is responsible for appointing experts

to ensure that:

●

●

●

●

animal technicians involved in licensed experiments are qualified and accredited up to the

level established by the Ministry;

those engaged in animal experimentation cooperate in matters affecting the welfare of the

subjects;

research workers are qualified to perform assigned tasks; and

the welfare of experimental animals is supervised by a qualified veterinary surgeon or

equivalent professional.

From January 1986, licensed institutions are required to have an institutional ethics committee

composed of persons of several disciplines, including ethics, who oversee all experiments (31).

Licensed institutions must keep records on experiments and care. They are further required to

report research activities, including data on numbers of animals used by type and purpose. The

information is available to the public.

The law also provides for establishment of a central veterinary inspectorate under the Ministry of

Public Health, responsible for:

● registering research facilities, as of 1984 (22);

● periodically inspecting facilities conducting research;

. issuing regulations and guidelines governing

laboratory animal housing; and

● regulating sources (breeders and suppliers)

of laboratory animals.

In addition, the law also authorizes the appointment of an advisory committee of persons skilled

in animal experimentation, laboratory-animal

science, and animal welfare to advise the Ministry. This committee includes two representatives

of animal welfare organizations. The committee

participates in the drafting of regulations and other

aspects of implementing the 1976 law.

The Ministry of Public Health is the central enforcement agency for the 1976 law. It has the power to issue detailed regulations on laboratory-animal treatment and presides over them using teams

of veterinary inspectors who supervise and advise research institutions. The director of the research facility is also expected to enforce standards of care and treatment.

Regulations require that investigators and technicians complete training in laboratory-animal

principles and techniques (22), including a 20-day

course that emphasizes animal well-being and the

social and ethical aspects of animal use (53). A 4-

year program for training animal technicians is

also available.

Data compiled from the 1983 annual reports indicate that there are 71 licensed institutes (containing 387 distinct research departments); 2,118

investigators working directly with animals; 2,541

persons involved in animal care management; and

4,683 students taking classes involving animal experiments.

Indications of the commitment to protecting animals are the use of experimental review committees in 17 percent of the departments surveyed

and the fact that in 19 of 71 establishments, methods had been introduced to replace animals in experiments, reduce the use of animals, or refine

procedures (54). Furthermore, there has been a

steady decline in the use of experimental animals

over the reporting years, from 1.6 million in 1978

to 1.3 million in 1983. Of these, mice account for

about 56 percent and rats, about 26 percent.

Norway

Norway requires more of people in their behavior toward animals than most other countries.

The Welfare of Animals Act, passed in 1974 and

in effect since 1977, even goes as far as requiring

people encountering a domestic animal or tame

reindeer in pain to come to its assistance or to call
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 369

the appropriate authority, and the act forbids the

display of animals other than fish (46,47).

The act applies to vertebrates and crustaceans;

it provides that animals shall be treated well and

that due regard shall be given to their natural instincts and needs so that they are not in danger

of being caused unnecessary suffering. Adequate

care must be provided and many procedures can

only be performed by a veterinarian or other

highly qualified professional. Anesthetics must be

used when there is reason to believe that a procedure may cause considerable suffering unless it

would interfere with the purpose of the experiment, but such an experiment would require special permission from the National Experimental

Animal Board. Experiments must be planned and

carried out to avoid any unnecessary suffering,

sometimes necessitating pilot studies. Destruction

without delay is required where suffering after

recovery will occur. Animals used in painful procedures without anesthetic may not be reused in

further experiments.

The provisions of the act most applicable to research are its prohibitions on the use of live animals for educational purposes, except as a necessary part of professional training. It also requires

permission to carry out biological tests on animals.

The purpose must be to diagnose animal or human disease, test a hypothesis, produce or control a product, or test medicines or other substances for effects. Such tests must not inflict

greater suffering than is strictly necessary to

achieve the purpose, and licensees are permitted

to acquire and use local and general anesthetics

for this purpose. Inspection authority is broad, and

anyone “willfully or negligently” violating the act

or authorized regulations is guilty of a misdemeanor, carrying penalties of a fine or imprisonment up to 6 months for the first offense, and up

to a 1 year for subsequent offenses (47).

The Experimental Animal Board, first appointed

under the statute by the Minister of Agriculture

in 1976, has primary authority. Its five members

issue and administer regulations on obtaining permission for experimentation on protected animals.

In 1985, the regulations were amended to provide that no experiment on a live animal can be

carried out without the written consent of the institute’s or organization’s license holder. Copies

of executed consent forms must be filed with the

Board (20).

Sweden

Sweden’s approach to experimental use of animals has much in common, both in substance and

procedure, with that of the other countries of

Western Europe surveyed here. For example, experiments involving pain or suffering receive

greater scrutiny, anesthesia during painful experiments is generally required, and licenses are issued to facilities in which experiments are conducted. Its more unusual features are the close

working relationships among scientists, technicians, and laypeople (most often animal welfare

advocates) at all levels of review and the complex

system of ethical review, which divides responsibilities among many organizations and committees.

The review procedures, which have evolved over

many years, are being reevaluated by the Government. Matters being reconsidered include the extensive use of Iaypeople (who often disagree with

other reviewers); the use of small subcommittees

(which sometimes disagree with full committees);

and the limited review given to experiments that

cause little or no pain (which leaves their aim unexamined) (57). Sweden’s active animal welfare representatives can be expected to vigorously oppose

any changes that would decrease their input in

the review process or that might reduce the protections provided to animals (17).

The first law pertaining to experimental use of

animals, passed in 1944 (58), prohibited cruel treatment and governed care and transport of classes

of animals. Painful experiments on animals were

generally prohibited and experiments could be performed only in licensed institutions by persons

with established qualifications for conducting such

research (64). Furthermore, anesthetic was required where more than minor pain was produced,

except where its use would frustrate the study’s

purpose (58).

Several ordinances and amendments were published between 1978 and 1982 (59,60,61). They

added both substantive and procedural requirements, Experiments involving pain, suffering, or

anxiety now have to be licensed by the National
370 ● Alternatives to Animal Use in Research, Testing, and Education

Board of Agriculture (unless conducted by the Government). Vertebrates were ranked hierarchically,

ranging from mammals to birds to reptiles to frogs

to fish. The use of warm-blooded vertebrates in

education at or below the secondary level became

subject to approval, regardless of whether pain

or suffering would occur. Animals used in laboratories now must be bred for that purpose, and dogs,

cats, and rabbits must be marked and various

records kept showing their origin. Most responsibility for the conduct of experiments is placed on

individual licensees and heads of licensed institutions.

Several changes were also made in how experiments were to be reviewed. These changes were

based on a voluntary system that began at the

University of Uppsala. A Laboratory Animals

Board, established by the National Medical Research Council in 1965, was called on in 1972 to

help the Council review grant applications. Drawing from the considerable expertise of Karl-Johan

Obrink, a professor of physiology at the University of Uppsala’s medical school, and of Lars Wass,

a representative of the National Board of Universities, guidelines were developed for both the organization and operation of an ethics committee.

In response to the Board’s request for a system

through which the Council Administration could

determine automatically whether a grant application involving the use of animals ought to be referred for ethical review, Obrink and Wass proposed a scale of expected discomfort. Experiments

causing little or no discomfort received little, if any,

review, with other experiments receiving scrutiny

in proportion to the pain they would cause. (This

is not so different from other European systems—

pain normally triggers review, and the reviewers

would most likely take the degree of expected pain

into account.) Other key provisions of the guidelines include:

●

●

●

Members of the committee would be within

easy reach of anyone planning animal work,

even if the committee were large.

The committee would be composed of animal

technicians and laypeople, as well as researchers.

The day-to-day work of the committee would

be performed by ad hoc subcommittees,

formed after submission of an investigator’s

‘ o

●

●

proposal to a member of the parent committee.

Experimentation could begin immediately

upon approval of an experiment by the subcommittee.

To protect an investigator’s privacy, the committee and subcommittees would be voluntary only and would have no legal or administrative authority.

Discussion between investigators and subcommittee members would promote increased

awareness of research ethics.

The prototype committee consisted of 30 individuals, mostly investigators. Meetings were held

frequently and applications were reviewed in full

committee, with investigators present to discuss

experiments and answer questions.

With the election of a new National Government

in 1976, the Minister of Agriculture decided that

the Uppsala system, with minor modifications,

should be introduced throughout the country and

incorporated into the National Board of Agriculture’s regular system of experimental control. It

was in place by 1979.

As the laws have become more comprehensive,

their administration has become more complex.

The National Board of Agriculture has the broadest

range of responsibilities. In addition to its involvement with the ethical committees and the Board

for Laboratory Animals, it oversees government

laboratories that use animals, approves plans for

new facilities for animals, conducts inspections,

oversees breeding and transportation of animals,

provides a variety of forms needed for review and

recordkeeping, and keeps journals of experiments

that have been approved (59,60).

The 1979 laws gave certain enforcement and

administrative functions to the County Public

Health Committee, with consultation and direction with the National Board of Agriculture. Operating somewhat independently of the National

Board of Agriculture is the Swedish Laboratory

Animals Board (referred to as CFN in Sweden). It

has members nominated by Government (including the National Board of Agriculture), universities, the Swedish Medical Research Council, and

the Swedish Natural Science Research Council. The

Board, most recently the subject of a 1982 statute,
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 371

is now charged with promoting cooperation between scientists, technicians, and animal welfare

organizations; planning for long-term improvements in conditions for laboratory animals; promoting the development of alternatives, which it

also funds; reviewing the work of ethical committees; and working toward the efficient use of animals by promoting cooperation among animal

users (58).

The 1982 statute also required the establishment

of six ethical committees, one in each university

region. The requirements were based on the prototype committee developed in Uppsala. These

committees, overseen by the National Board of

Agriculture, advise and consult on individual experiments and report to their County’s Public

Health Committee. They have equal numbers of

scientists, animal technicians, and laypeople.

The Central Veterinary Board of the National

Board of Agriculture solicits nominees for review

committees from each of six Regional Boards of

Higher Education (that consist of university and

political officials) and major animal welfare groups.

Nominees are of three kinds: researchers, technicians, and laypeople. The animal welfare organizations nominate laypeople only. From the nominations submitted, the Board appoints six regional

ethical committees, designating a chair and vice

chair; six regional subcommittees for secret projects; and one special committee for military research. The special military-research group and

the regional subcommittees for secret research

were created to protect national defense interests

and pharmaceutical trade secrets.

Although full committees meet at least twice annually, day-today application review is conducted

by subcommittees, consisting of equal numbers

of researchers, technicians, and laypeople. The

technicians and laypeople are chosen from mandatory rotation lists, to avoid exclusion of any represented interest, and each subcommittee must

have at least three members.

The applicant completes a one-page form, stating the objective of the research project; describing the experiment, with an emphasis on the use

and disposition of the animals and the number of

animals of different species that will be used; and

describing what the investigator plans to do to alleviate and abbreviate suffering. When the subcommittee meets with the applicant, it may suggest improvements in the description of the procedure, modifications to the procedure itself, or

a reduction in the number of animals used. If the

subcommittee agrees to the applicant’s proposal,

it forwards a signed form to the central authority.

If an applicant or a subcommittee member disagrees with the decision of a subcommittee, the

application is referred to the full committee, which

can call a session to review appeals. All subcommittee decisions are discussed by the full committee at its regular meetings. A permit, valid for up

to 3 years, is all that iS needed to begin work. Rereview is required only if an investigator plans to

conduct experiments more severe than those for

which approval was granted.

Precise data on numbers of animals used for various kinds of procedures are not available. Reporting is only done in conjunction with the application process, although certain records must be

submitted and others must be kept.

The time required to obtain a decision varies

from region to region. Two contributing factors

have been identified: difficulty in scheduling meetings, and some applicants’ inability to use simple

language, thus requiring extra time for clarification. To help remedy the lag problem, the 1982

ordinance required a subcommittee to reach a decision within 3 weeks of receipt of the application.

The 1982 ordinance also abolished the requirement that experiments be grouped into the traditional discomfort categories, thus eliminating

needless discussion. Obrink, the architect of the

voluntary review mechanisms, has expressed worry

over the system’s potential, with increasing regulatory emphasis, to become bureaucratized to the

point where it sacrifices the objectives of ethical

review for the sake of control (5,48,49).

Switzerland

Switzerland has probably gone further to protect animals than any other country and recently

came to the brink of going even further. In 1985,

Swiss voters were presented with a constitutional

amendment that read: “The vivisection of vertebrates as well as all cruel animal experimentation

shall be forbidden in Switzerland. ” The proposal
372 ● Alternatives to Animal Use in Research, Testing, and Education

was rejected by a two-to-one margin. This law

would have had a major impact on the three large

pharmaceutical firms with facilities in Switzerland.

Another, less restrictive referendum is being readied for Swiss voters, but may be 4 years away from

a vote (74).

The Swiss antivivisection movement has become

particularly active, if not violent in recent years.

Research facilities have been broken into, scientists sued, and untrue or overstated stories publicized (for example, that vaccines had no part in

fighting infectious diseases) (72).

Swiss scientists have not fought controls, and

some have pointed out the benefits to good science—more attention is given to planning and

scientists have greater incentives to keep abreast.

Of course, there are also disadvantages to science—senior scientists must spend time answering simple questions and there can be delays of

4 to 6 weeks for licensing an experiment.

An indication of the importance of animal welfare to the Swiss is the fact that animal protection

is addressed in the Constitution, which recognizes

the necessity for and utility of humane treatment

of animals. Controls on animal experimentation

in Switzerland are found in the Federal Law of

1978 Regarding the Protection of Animals (as

amended by the Ordinance of 1981 Regarding the

Protection of Animals).

In response to antivivisectionist pressures, additional guidelines were developed in 1981 by the

Swiss Academies of Medical Sciences and of

Sciences. These have been adopted by government,

industry, and academia. Under the guidelines, a

permanent committee was set up to review animal experiments, and stringent requirements were

set up for experiments involving severe pain—if

the experiment cannot be modified to reduce pain,

it must be forgone. Under the statute, any experiment that could cause pain to a protected animal

or that would adversely affect its well-being must

be licensed, whether conducted by government

or by private institutions. Even where pain is not

significant, licensing authorities must be satisfied

that the expected benefits of the proposed experiment outweigh the adverse effects on experimental

animals. Furthermore, animals that have suffered

more than minor pain or anxiety may not be reused (62).

Licenses are issued to individual investigators

for each experiment or series of related experiments. Licenses to perform experiments are issued

by the cantons, or Swiss States. Special commissions must determine whether all legal requirements and qualifications are met before a license

is issued. Thus, the commission must verify, in each

instance, whether the proposed experiment:

●

●

●

●

is essential in order to achieve the objective

of the experiment, or whether alternative approaches are possible;

is sound from a methodological point of view;

can be performed with a lower order of species than the one proposed; and

can be modified to reduce the number of anireals to be used.

The conditions under which experimental animals

are to be kept and used are specified in the law,

setting standards for accommodations of differing species, by size and weight, and prescribing

care. Animal caretakers must demonstrate their

competency by passing a Federal examination.

Records of licensed experiments must be kept for

a minimum of 2 years after the experiment ends,

and they must be available for inspection by local

authorities (77).

Most licensed experiments in Switzerland are

conducted by large pharmaceutical companies (74),

with some work done by Government and universities. In addition, a few private institutes do testing and research, The experiments’ purposes fall

into four major categories: research and development (87 percent); production and quality assurance (12 percent); teaching (1 percent); and diagnostics (less than 1 percent).

According to the Swiss Government, the three

pharmaceutical companies used 36 percent fewer

animals in 1983 than in 1976; the decrease between

1981 and 1983 averaged 23 percent for all species, with the largest categorical decreases occurring in the use of mice (26 percent) and rabbits

(25 percent). The authorities believe this indicates

a general trend toward reduced animal use, since

the firms involved account for about two-thirds

of all experimental-animal use; one governmental

representative has said the decline was hastened

by the implementation of the 1981 ordinance (77).
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 373

United Kingdom

The United Kingdom has been a pioneer in the

protection of experimental animals. The Cruelty

to Animals Act, passed in 1876 (68), was the most

protective statute of its kind for many decades.

Although the act has not been amended, the protections afforded animals have continued to expand through administrative actions of the Home

office and by voluntary actions by institutions and

individuals (69).

As in other parts of Western Europe, animal welfare advocates have been actively campaigning for

more protective laws, Unlike many other countries, some of these groups have also made major

scientific contributions to the development of alternatives. The most active of these scientifically, the

Fund for the Replacement of Animals in Medical

Experiments, was recently given over $200,000

by the Government to fund research on alternatives.

Contributing to the debate over how the act

should be changed, the British Veterinary Association, the Committee for the Reform of Animal

Experimentation, and the Fund for the Replacement of Animals in Medical Experiments made recommendations that became the basis for a 1983

White Paper by the Home Office. Several items

in that paper provoked considerable debate, leading to the 1985 White Paper Scientific Procedures

on Live Animals (70). This was presented by the

Home Office to the Parliament in May 1985 and

recommends substantial amendments to the 1876

Act, some of which would codify current practice. The 1876 act (as it is currently practiced) and

the proposed legislation are summarized and compared in table 16-2.

Other acts that bear on these activities include

the Dogs Act of 1906 and the Theft Act of 1968

(as amended by the Criminal Theft Act of 1977),

which address the problem of stolen pets. Experiments regulated by the Cruelty to Animals Act are

excluded specifically from the reaches of the Protection of Animals Act of 1911, the Protection of

Animals (Scotland) Act of 1912, the Protection of

Animals (Anesthetics) Act of 1954 (65), and the

Protection of Animals (Anesthetics) Act of 1964

(66).

A basic philosophy of the act is that experiments

should be permitted if they lead to new knowledge, but the use of animals to develop manual

skills is not permitted. (Demonstrations—another

educational use—are permitted, however, if the

animal is anesthetized and does not recover.) In

permitting the development of new knowledge,

the authorities, as in many other countries, will

not try to predict which experiments will result

in useful knowledge or practical applications.

Control over experiments occurs in three ways:

through the granting of licenses to experimenters,

through the registration of facilities where experiments take place, and through the appointment

of government inspectors. Although responsibility rests with the Home Office, assistance is provided by an Advisory Committee with representation by animal welfare organizations. In addition,

many institutions have established their own informal review procedures (3).

The Secretary of State approves and registers

every place for the performance of experiments

or for the purpose of instruction, imposes conditions on licenses, and revokes licenses for cause.

The Secretary may require reports, appoint inspectors, and require inspections. Most licenses are

issued with one or more certificates. Certificates

may be given for the period and series of experiments the persons signing the certificate may think

expedient. There are six kinds of certificates, based

on species use, pain, and the use of anesthetic,

A practical approach to the assessment of pain,

suggested by a Royal Commission appointed in

1906, is that it would be unreasonable to impose

greater restrictions on the infliction of pain for

the advancement of knowledge than those imposed

by public opinion in the pursuit of sport, in carrying out such operations as castration and spaying,

or in the destruction of rabbits, rats, and other

vermin (41).

The United Kingdom is able to compile detailed,

accurate statistics on animal use through its reporting requirements as well as the through the issuance of licenses and certificates. Each licensee (except those who have no experiments to report for

a given year) must submit an annual report for

as many of each of the following reporting cate-
374 ● Alternatives to Animal Use in Research, Testing, and Education

Table 16-2.—Comparison of the United Kingdom’s Cruelty to Animals Act of 1876 and Proposed Amendments

Provision Current law Proposed amendments

Animals

protected

Permissible

purposes

Licensing

system

Severity

Assessors

Registering

facilities

Fees

Source of

animals

Reuse of

animals

Killing of

animals when

procedure

ends

Use of animals

to attain

manual skill

Use of

alternatives

Use for

education

and training

Advisory

Committee

Codes of

practice

Offenses and

penalties

Records

All living vertebrates; additional

protection for nonhuman primates,

dogs, cats, and equidae

Advance new discovery of

knowledge or lead to longer life,

less suffering

Any person Home Secretary allows:

difficult to alter issued license;

restrictions must be specified

No statutory limit on pain, but may

be limited in certificates; pain may

be severe or enduring, not both

No mechanism to assess integrity or

competence for personal license

Most facilities for experiments are

registered; most breeders and

suppliers are not

None

Only stray dogs protected

(Dog Act)

Only anesthetized animals must be

killed

Only if animal is in severe pain or

was anesthetized

Not permitted unless decerebrated

Encouraged but not required

Only anesthetized animals that

killed before recovery for

university lectures

are

Not required, but has existed since

1912, with lay members since 1979

Voluntary codes are often used

Experimenting without a license; 6

months and $3,000

All licensees keep records of

All living vertebrates, fetuses of mammals, embryonic or larval

young of other species at specified stages, (would also add

authority over breeding of animals with potentially disabling

genetic defects; would allow the Home Secretary to protect

invertebrates; would require justification of all species choices)

Adopts permissible purposes of European Convention (Article

2) (see app. E), encompassing many procedures rather than

experiments (e.g., production of serums, maintaining tumors

or pathogens); Secretary must balance the severity (pain)

against the purpose

Personal license would only allow specified techniques and

species; project license for each experiment, specifying

purpose of work, species, number of animals, techniques;

Secretary must answer to Parliament for balance of severity

and purpose (Secretary must publish guidelines for the

decision criteria)

An animal in severe pain or distress would have to be killed

immediately and painlessly; severity would encompass pain,

distress, suffering, morbidity, and mortality and would be

tailored to each project license; would require licensees to

minimize severity wherever possible; would broaden

inspector’s power to kill humanely

Senior licensee with personal knowledge of applicant and

applicant’s abilities would certify applicant’s competence;

Home Office would continue to issue license

All facilities would be registered; Secretary would have power

to set standards for staffing, care, and accommodation;

facilities would name person responsible for day-to-day care

and outside veterinarian must be called for problems;

breeders and suppliers would register

Registered facilities, based on number of procedures

All animals purpose-bred in registered establishments (except

for farm animals and animals taken from the wild);

recordkeeping on source and disposal

Reuse would require Secretary’s permission, and only if the

animal has returned to normal

Not required to kill animals at the end of a procedure; if

certified fit, surviving wild animals may be returned to the

wild, farm animals to a farm, and certain domestic animals

may be offered to private homes

Secretary would authorize for special, specific skills such as

microsurgery on anesthetized animals

License would not be issued until Secretary was convinced

that alternatives were not suitable and that no further

refinements or reductions could be made

Would be extended to allow other nonrecovery training for

approved professional courses; would permit recovery if

animal suffers only trivial pain or distress under exceptional

circumstances, decerebration would become a licensed

procedure and no longer permitted in schools

Would require Animal Procedures Committee, with lay members

(including animal welfare advocates), doctors, veterinarians,

and biologists; no more than half of the Committee would be

licensees; would advise Secretary on procedures, standards,

trends, licensing, and revisions of the law

Secretary would issue guidelines and codes of practice on

animal husbandry and would give guidance on recognizing

and alleviating stress and pain

Performing, aiding, or abetting performance of a procedure without

authority; providing false information; disclosing information

obtained in confidence; 2 years and an unlimited fine

Same

experiments

SOURCE: Office of Technology Assessment.
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 375

gories as apply. (The number of distinct entry codes ● toxicity tests [6];

for each list subclassification is given in brackets.) ● experiments in response to domestic or for-

●

●

Ž

●

●

anesthetic (none, for part of experiment, or

entire experiment) [3];

types of vertebrates (mammals—rodents, rabbits, primates, carnivores, ungulates, and

others—birds, reptiles, amphibians, and fish)

[16];

neoplasia [4];

infection and immunology [41;

primary purpose (to study body function or

structure, to develop or study the various

products or chemicals, to develop transplant

techniques) [15];

eign legislation [14]; and

● use of particular painful techniques (such as

eye irritation) [141.

These annual reports are compiled in detailed

reports. Several tables from the 1984 report are

included here. Table 16-3 shows the frequency

with which various species are used in the United

Kingdom, table 16-4 shows the primary purpose

of the experiments, and table 16-5 shows the registered institutions performing experiments. These

tables represent only highlights of the considerable data available.

Table 16-3.—Experiments by Species of Animal, 1977=84, United Kingdom

Species of animal (thousands of experimental animals used)

Year Mouse Rat Guinea pig Other rodent Rabbit Primate Cat Dog

1977 . . . . . . . . . 3,234.9 1,073.0 187.7 38.7 191.8 9.0 8.5 14.3

1978 . . . . . . . . . 3,168.5 1,062.6 193.4 39.4 199.2 7.2 7.9 13.7

1979 . . . . . . . . . 2,901.3 994.8 165.7 37.2 187.0 6.4 7.5 12.0

1980 . . . . . . . . . 2,780.7 957.9 188.6 36.4 181.5 5.2 6.8 11.5

1981 . . . . . . . . . 2,616.9 908.6 159.1 35.0 176.0 6.2 8.0 13.5

1982 . . . . . . . . . 2,442.7 932.3 154.7 36.8 165.0 7.3 13.1

1983 . . . . . . . . . 2,070.2 878.4 144.7 36.2 160.0 5.6 7.5 13.9

1984 . . . . . . . . . 1,903.8 888.0 141.7 36.5 156.0 6.0 6.4 14.4

Other Horse, donkey, Other Other Reptile or

carnivore or crossbred ungulate mammal Bird amphibian Fish Total a

1977 . . . . . . . . . 2.2 0.5 31.9 3.0 344.3 7.2 157.5 5,385.6b

1978 . . . . . . . . . 2.7 0.6 36,0 2.6 314.3 6.6 140.6 5,195.4

1979 . . . . . . . . . 2.2 0.6 36.5 2.4 241.4 7.6 117.4 4,719.9

1980 . . . . . . . . . 1.3 0.5 33.4 2.6 211.6 7.8 175.5 4,579.5

1981 . . . . . . . . . 2.3 0.4 35.4 1.8 194.2 8.6 178.9 4,344.8

1982 . . . . . . . . . 1.9 0.5 33.6 2.7 251.8 7.8 165.8 4,221.8

1983 . . . . . . . . . 1.8 0.6 36.4 3.0 132.6 18.2 115.2 3,624.2

1984 . . . . . . . . . 1.7 0.6 33,1 2.7 155.0 8.1 143.2 3,497.3

%olumns do not add up to total due to rounding.

blncludes 81.3 thousand experimental animals that could not be classified.

SOURCE: U.K. Home Office, Secreta~ of State, Statlstks of Experiments on Living Anima/s: Great Britain, 19S4 (London: Her Majesty’s Stationery Office, 1985).
376 . Alternatives to Animal Use in Research, Testing, and Education

Table 16-4.—Primary Purpose of Experiments, 1977-84, United Kingdom

(thousands of experimental animals used)

To select,

develop, or

study the use,

etc., of medical, To select, develop, or study the use, hazards, or safety of

To study normal dental, and

or abnormal veterinary To develop

body structure products and transplant

Year or function appliances techniques

1977 . . . . . 1,266.0 2,932.6 22.5

1978 . . . . . 1,164.8 2,925.7 16.2

1979 . . . . . 1,051.7 2,680.8 25.4

1980 . . . . . 909.3 2,680.1 14.7

1981 . . . . . 1,119.2 2,403.0 14.6

1982 . . . . . 997.0 2,373.0 15.2

1983 . . . . . 875.2 2,039.9 12.6

1984 . . . . . 824.8 1,915.7 15.0

Herbicides or

Plant pesticides, substances Substances Substances

including modifying plant used in used in the

fungicides growth industry household

35.8 20.3 81.6 18.8

50.4 18.8 88.0 14.9

34.1 24.0 75.3 18.5

40.1 17.5 80.4 13.8

30.6 12.9 69.2 14.3

33.0 15.1 66.2 13.9

35.4 17.9 59.1 17.2

46.7 18.1 64.5 12,9

Cosmetics and

toiletries

24.6

28.2

30.5

31.3

24.4

18.9

18.0

17.5

To select, develop, or study the use, hazards, or safety of

Plants or General

Tobacco and animals and environmental To demonstrate Other More than

Food additives its substitutes their toxins pollutants known facts purposes one purpose Total a

1977 . . . . . 39.3 15.2 4.2 60.4 2.7 676.8 83.4 5,385.6 b

1978 . . . . . 42.5 2.7 2.7 70.4 2.6 709.8 57.6 5,195.4

1979 . . . . . 27.7 4.6 3.3 33.6 1.8 600.5 108,1 4,719.9

1960 . . . . . 21.3 1.9 3.3 40.9 1.7 635.9 87.2 4,579.5

1981 . . . . . 20.2 2.3 2.7 45.8 1.9 519.4 64.3 4,344.8

1982 . . . . . 20.1 3.2 5.9 27.3 1.6 562.5 68.9 4,221.8

1983 . . . . . 14.1 2.7 4.8 34,4 1.6 444.9 46.4 3,624,2

1984 . . . . . 12.0 2.2 5.8 31.8 1.1 453.1 76.0 3,497.3

%Iurrms may not add up due to rounding.

blncludes 81.3 thouaand experimental animals that could fiOt be classified.

SOURCE: U.K. Home Office, Secretary of State, Statistics of Experiments on Ming Animals: Great Britain, 1984 (London: Her Majesty’s Stationew Office, 1985).

Table 16-5.-Experiments by Type of Registered Facility, 197744, United Kingdom

1977 1978 1979 1982 1963 1984

Type of registered place a

(thousands of experimental animals used)

Public health Iaboratoriesb 

. . . . 37.8 41.8 120.6 106.7 117.0 106.4 78.4 63.7

Universities (including

medical schools). . . . . . . . . . . 875.5 927.4 975.9 895.3 847.6 813.6 785.9 772.7

Polytechnics . . . . . . . . . . . . . . . . 32.9 46.7 38.4 37.7 34.9 29.5 36.9 29.8

Quasi-autonomous

nongovernmental

organizations. . . . . . . . . . . . . . 316.4 280.6 255.7 274.6 242.8 268.9 239.5 209.3

National health service

hospitals (excluding

medical schools). . . . . . . . . . . 180.5 157.4 147.7 159.4 154.3 144.2 132.2 134.4

Government departments . . . . 323.9 273.5 163.7 169.8 174.0 154.0 101.9 103.2

Nonprofitmaking

organizations, . . . . . . . . . . . . . 858.3 779.5 614.0 546.9 507.0 512.3 396.2 340.3

Commercial concerns . . . . . . . . 2,760.4 2,688.6 2,403.8 2,389.0 2,267.2 2,192.9 1,853.1 1,843.9

Total c . . . . . . . . . . . . . . . . . . . . . . 5,385.6 d5,195.4 4,719.9 4,579.5 4,344.8 4,221.8 3,624.2 3,497.3

aRaor&j on the bssis of the registered pl~e that the licensees regard ss their main place of work at the time the returna were issued. A liCenSee maY have commenced

experiments at more than one registered place during the year.

bThe differences betw~n 1978 and 1979 are partly because some establishments were reclassified from one type of registered place to another.

c~lumns may not add up due to rounding.

dlncludes 813 thousand experimental animals that could not * classified.

SOURCE: U.K. Home Office, Secretaw of State, Statistics of Experiments on Living Animals: Great Britain, 1984 (London: Her Majesty’s Stationery Office, 1985).
Ch. 16—Regulation of Animal Use in Selected Foreign Countries ● 377

SUMMARY AND CONCLUSIONS

Most of the countries examined for this assessment have laws far more protective of experimental animals than those in the United States.

Despite these protections, animal welfare advocates have been applying considerable pressure

for even stronger laws, and many countries,

including Australia, Switzerland, West German}’,

and the United Kingdom, are considering major

changes.

Many of the laws have similar requirements.

Almost all require anesthetics or analgesics for

painful experiments unless these would frustrate

the purpose of the experiment. Switzerland goes

so far as to require that certain experiments be

forgone because they are too painful. Some countries balance the importance of the experiment

and the level of pain it would cause before giving

approval.

Several countries require euthanasia after a painful experiment is finished; some require destruction of an animal even when it is no longer in pain,

rather than allowing it to be reused, Euthanasia

requirements sometimes apply only to certain animals, such as dogs, cats, and monkeys. These species are also preferred in other ways, such as requiring that lower animals be substituted for them

wherever possible.

Many countries encourage the use of alternatives, and Denmark, West Germany, the Netherlands, Norway, and Sweden require that nonanimal alternatives be used if they are available.

Sweden and the United Kingdom have provided

funding for the development of alternatives, and

West Germany is considering doing so. Many countries restrict educational uses of animals to professional or vocational training, and Switzerland prohibits even this.

All West European countries reviewed for this

assessment require that facilities that use experimental animals be licensed. Some also license

dealers, breeders, or experimenters. Many also

require that individual experiments be approved,

some by Government authorities, some by committees. Such committees, except in Sweden and

the United Kingdom, do not require lay representatives, although Switzerland and Denmark have

such representatives on national advisory boards.

The use of ethics committees within the facilities

that use animals is growing; their use is presently

most well developed in Canada and Sweden,

The experiences of these selected countries can

serve as useful models for various protections that

are being considered in the United States. However, in trying to apply them, it is necessary to consider the size of a country, and perhaps more importantly, those cultural considerations that affect

compliance with the laws.

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Appendixes
Appendix A

Testing Guidelines

Testing Guidelines

Testing guidelines are developed for a variety of reasons: to allow results of various test substances or species to be easily compared, to encourage the use of certain protocols so that testing need not be repeated, and

to facilitate the work of those who design and carry

out tests. Many organizations have developed testing

guidelines. Three such compilations have been selected

for discussion.

FDA Guidelines Involving

Whole Animal Testing

To the extent possible, the Food and Drug Administration (FDA) makes its animal testing guidelines consistent throughout the agency and consistent with those

of other agencies and organizations. However, special

uses of products require special testing, and guidance

is available from agency staff to help manufacturers

meet those requirements. In this table, tests that generally can be considered common or standard toxicological tests usually used throughout the agency are

grouped together. Those that are more specific for

evaluation of the safety of certain products are identified with the FDA Center responsible for regulating

that product.

I. Agency-wide

A. General Toxicity

1. Acute oral—rodent, nonrodent

2. Acute dermal—rodent, nonrodent

3. Acute inhalation—rodent

4. Subchronic oral—rodent, nonrodent

5. Chronic oral—rodent, nonrodent

6. Carcinogenicity —rodent

7. Combined chronic/carcinogenicity —rodent

B. Specific Effects

1. Dermal sensitization—guinea pig

2. Dermal irritation—rabbit

3. Eye irritation—rabbit

4. Teratogenicity—rodent, rabbit

5. Reproduction—rodent

6. Absorption, distribution, metabolism,

elimination—rodent, nonrodent

7. Neural-behavioral—rodent, rabbit

H. Center-oriented

A. Human Drugs

1. Subchronic inhalation—rodent, nonrodent

2. Subchronic dermal—rodent, nonrodent

3. Vaginal and rectal administration—rodent,

nonrodent

4. Immunotoxicity—rodent

B. Food Additives/Color Additives

I. Immunotoxicity—rodent

2. Protein quality—rodent

3. Vitamin D assay—rodent

C. Biologics

1. All biologics administered by injection

a. Safety—guinea pigs, mice

b. pyrogenicity–rabbits

2. Vaccines

a. Safety—mice, suckling mice,

chimpanzees, monkeys, guinea pigs,

rabbits

b. Potency–guinea pigs, mice, monkeys

c. Hypersensitivity-guinea pigs

d. Toxicity—mice

3. Antitoxins

a. Potency—guinea pigs, mice

4. Toxins

a. Potency—mice

5. Toxoids

a. Potency—mice

6. Immune globulins

a. Potency—guinea pigs

7. Tuberculin

a. Safety—guinea pigs

b. Potency—mice

D. Devices

1. Corneal metabolism—rabbit

2. Biomaterial implant—rabbit, primate, cat

3. U.S.P. intracutaneous—rabbit

E. Cosmetics

1. Primary skin irritation and corrosivity -

rabbit

2. Phototoxicity—nude mouse, rabbit, guinea

pig

F. New Veterinary Drugs

1.

2.

3.

4,

5.

6.

7.

8.

Safety, efficacy—target species

Drug tolerance—target species

Reproduction studies—target species

Tissue irritation—target species

Combination drug—target species

Drug disposition—target species

Route of administration—target species

Intramammary infusion-dairy cows, goats

383
384 ● Alternatives to Animal Use in Research, Testing, and Education

OECD Guidelines Involving

Whole Animal Testing

The Organization for Economic Cooperation and Development (OECD) guidelines have wide acceptance in

the United States and abroad because of the Mutual

Acceptance of Data Decision (l). Under the terms of

this decision, member countries of OECD must accept

data generated in other countries if done so according

to these guidelines. Animal tests contained in the guidelines are listed below.

1. Effects on Biotic Systems

202 Daphnia, acute immobilization test and reproduction test

203 Fish, acute toxicity test

204 Fish, prolonged toxicity test: 14 day study

205 Avian dietary toxicity test

206 Avian reproduction test

2. Degradation and Accumulation

305A Bioaccumulation:

Test

305B Bioaccumulation:

305C Bioaccumulation:

Bioconcentration

305D Bioaccumulation:

305E Bioaccumulation:

3. Health Effects

Sequential Static Fish

Semi-static Fish Test

Test for the Degree of

in Fish

Static Fish Test

Flow-through Fish Test

Short-Term Toxicology

401 Acute oral toxicity

402 Acute dermal toxicity

403 Acute inhalation toxicity

404 Acute dermal irritation/corrosion

405 Acute eye irritation/corrosion

406 Skin sensitization

407 Repeated dose oral toxicity—rodent: 14/28

day

408 Subchronic oral toxicity–rodent: 90 day

409 Subchronic oral toxicity—nonrodent: 90 day

410 Repeated dose dermal toxicity: 14/28 day

411 Subchronic dermal toxicity: 90 day

412 Repeated dose inhalation toxicity: 14/28 day

413 Subchronic inhalation toxicity: 90 day

414 Teratogenicity

415 One-generation reproduction toxicity study

416 Two-generation reproduction toxicity study

417 Toxicokinetics

418 Acute delayed neurotoxicity of

organophosphorous substances

419 Subchronic delayed neurotoxicity of

organophosphorous substances: 90 day

Long-Term Toxicology

451 Carcinogenicity studies

452 Chronic toxicity studies

453 Combined chronic toxicity/carcinogenicity

studies

Genetic Toxicology

474 Genetic toxicity: micronucleus test

475 In vivo mammalian bone marrow

cytogenetic test—chromosomal analysis

478 Rodent dominant lethal test

Pesticide Assessment Guidelines

Involving Whole-Animal Testing

The Office of Pesticide Programs of the Environmental Protection Agency (EPA) has developed guidelines

for testing required under the Federal Insecticide, Fungicide, and Rodenticide Act. These Pesticide Assessment

Guidelines contain standards for conducting acceptable

tests, guidelines for the evaluation and reporting of data,

guidelines as to when additional testing might be required, and examples of acceptable protocols (2). Similar guidelines have been developed by EPA’s Office of

Toxic Substances (OTS) for testing required under the

Toxic Substances Control Act (3).

Subdivision E: Hazard Evaluation: Wildlife and

Aquatic Organisms

Series 70: General Information and Requirements

Series 71: Avian and Mammalian Testing

71-1 Avian single-dose oral LD5O test

71-2 Avian dietary LC5O test

71-3 Wild mammal toxicity test

71-4 Avian reproduction test

71-5 Simulated and actual field tests for mammals

and birds

Series 72: Aquatic Organism Testing

72-1 Acute toxicity test for freshwater fish

72-2 Acute toxicity test for freshwater aquatic

invertebrates

72-3 Acute toxicity test for estuarine and marine

organisms

72-4 Fish early life-stage and aquatic invertebrate

life-cycle studies

72-5 Life-cycle tests of fish

72-6 Aquatic organism accumulation tests

72-7 Simulated or actual field testing for aquatic

organisms

Subdivision F: Hazard Evaluation: Humans

and Domestic Animals

Series 80: Overview, Definition, and Genera]

Requirements

Series 81: Acute Toxicity and Irritation Studies

81-1 Acute oral toxicity study
App. A—Testing Guidelines ● 385

81-2 Acute dermal toxicity study

81-3 Acute inhalation toxicity study

81-4 Primary eye irritation study

81-5 Primary dermal irritation study

81-6 Dermal sensitization study

81-7 Acute delayed neurotoxicity of

Series

82-1

82-2

82-3

82-4

82-5

Series

83-1

83-2

83-3

83-4

83-5

Series

84-1

84-2

Series

85-1

85-2

organophosphorous substances

82: Subchronic Testing

Subchronic oral toxicity (rodent and

nonrodent): 90 day study

Repeated dose dermal toxicity: 21 day study

Subchronic dermal toxicity: 90 day study

Subchronic inhalation toxicity: 90 day study

Subchronic neurotoxicity: 90 day study

83: Chronic and Long-Term Studies

Chronic toxicity studies

Oncogenicity studies

Teratogenicity study

Reproductive and fertility effects

Combined chronic toxicity/oncogenicity

studies

84: Mutagenicity

Purpose and general recommendations for

mutagenicity testing

Mutagenicity tests (described in very general

terms, with reference to the OTS guidelines)

85: Special Studies

Metabolism study

Domestic animal safety testing

Subdivision G: Product Performance

Series 95: Efficacy of Invertebrate Control Agents

95-1 Genera] considerations

95-8 Livestock, poultry, fur and wool-bearing animal treatments

95-9 Treatments to control pests of humans and

pets

Series 96: Efficacy of Vertebrate Control Agents

96-1

96-2

96-3

96-4

96-5

96-6

96-7

96-8

96-9

General considerations

Fish control agents

Aquatic amphibian control agents

Terrestrial amphibian and reptilian control

agents

Avian toxicants

Avian repellents

Avian frightening agents

Mole toxicants

Bat toxicants and repellents

96-10 Commensal rodenticides

96-11 Rodenticides in orchards

96-12 Rodenticides on farm and rangelands

96-13 Rodent fumigants

96-14 Rodent repellents on tree seeds

96-15 Rodent repellents on cables

96-16 Rodent reproductive inhibitors

96-17 Mammalian predacides

96-18 Domestic dog and cat repellents

96-19 Browsing animal repellents

96-30 Methods and protocols

Subdivision M: Biorational Pesticides

(This subdivision duplicates many of the provisions

of other subdivisions, and is therefore not described

in detail. )

Series 150: Overview, Definitions, and General

Provisions

Series 152: Toxicology Guidelines

Subseries 152A: Toxicology Guidelines

Subseries 152B: Toxicology Guidelines for

Microbial Pest Control Agents

Series 154: Nontarget Organism Hazard Guidelines

Subseries 154A: Nontarget Organism Hazard

Guidelines for Biochemical

Agents

Subseries 154B: Nontarget Organism Hazard

Guidelines for Microbial Agents

Series 157: Experimental Use Permit Guidelines

Subdivision N: Environmental Fate

Series 165: Accumulation Studies

165-4 Laboratory Studies of Pesticide

Accumulation in Fish

165-5 Field Accumulation Studies of Aquatic

Nontarget Organisms

Appendix A References

1. Organization for Economic Cooperation and Development,

Guidelines for Testing of Chemicals, and addenda (Paris:

1981).

2. US. Environmental Protection Agency, Pesticide Assessment Guidelines (Springfield, VA: National Technical Information Service, 1984).

3. U.S. Environmental Protection Agency, Office of Toxic Substances Health and Environmental Effects Test Guidelines

(Washington, DC: update October 1984).
Appendix B

Regulation of Animal Use within

Federal Departments and Agencies

Six Federal departments and four Federal agencies

conduct animal experimentation within Federal facilities, or “intramurally. ” Of those, only the Departments

of Commerce and Transportation, which use few animals, have no specific guidelines. A seventh Federal

department, the Department of Energy (DOE), conducts

no intramural animal experimentation, but has a policy on animal experimentation for its extramural contracted work. The other entities all have some type of

policy for intramural use of animals.

Effective December 1986, each Federal research facility will be required to establish an animal care and

use committee with composition and function as described in the 1985 amendments to the Animal Welfare

Act (see ch. 13). Each Federal committee will report

to the head of the Federal entity conducting the animal

experimentation.

Several generalizations can be drawn about the guidelines of the Federal entities conducting intramural animal experimentation. Most policies on proper animal

care and treatment include:

●

●

●

●

●

●

●

adherence to the Animal Welfare Act and to the

Guide for the Care and Use of Laboratory Animals

of the National Institutes of Health (NIH) (26) as well

as the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals by

Awardee Institutions (see app. C);

an animal care and use committee with at least

three members (the attending veterinarian and two

scientists within the agency);

an attending veterinarian responsible for maintaining the proper animal care standards;

some prior review of protocols and animal species

use, usually accomplished by an animal care and

use committee;

no real mechanism for enforcement of the policy,

with the primary responsibility for maintaining the

proper standards and adhering to agency guidelines lying with the individual investigator;

a minimal number of site inspections and no real

oversight mechanism; and

a policy calling for using as few animals as possible and encouraging the use of alternative methods wherever feasible.

Some agency policies are noteworthy for additional

provisions intended to promote high standards of animal care and use:

• NIH requires all animal research committees to include one member sensitive to bioethical issues and

●

●

●

●

not employed in the same NIH bureau, institute,

or division. This person must be a Federal Government employee and so may or may not be a layperson. These committees have explicit responsibilities and a detailed administrative structure in

which to carry out duties.

The Ames Research Center of the National Aeronautics and Space Administration (NASA) has demonstrated the successful participation of lay committee members in the consideration of animal

welfare issues: 40 percent of the committee are

laypeople, a format set up at NASA’s instigation.

Since 1971, the Veterans’ Administration (VA) has

required that all facilities using animals seek and obtain accreditation by the American Association for

Accreditation of Laboratory Animal Care (AAALAC).

The VA has a contract with AAALAC covering all

its research facilities, thus prohibiting failure of

accreditation of any constituent facility solely for

financial reasons. The Department of Energy also

requires the facilities of its extramural contractors

to be AAALAC-accredited.

The Department of Defense (DOD) has a policy and

committee distinct from its general animal policy

to ensure proper care and use of nonhuman primates.

The policies at the Food and Drug Administration

(FDA) and the Department of the Interior give a

great deal of flexibility to the research centers to

allow specific policies tailored to the needs and demands of each animal facility. Although this may

have many advantages, it may make the maintenance and monitoring of a standard of care throughout the agency difficult.

Department of Agriculture

Regulation of animal use in research within the U.S.

Department of Agriculture (USDA) involves adherence

to the Animal Welfare Act and to the NIH Guide (26).

Much of the animal research performed by USDA involves farm animals, which are largely excluded from

these policies. The system of compliance involves periodic checking of intramural research facilities. For extramural research, no enforcement occurs; hence the

system is largely voluntary and self-regulating (15).

Department of Defense

The general policy on animal use in all Department

of Defense programs is contained in DOD Directive No.

386
App. B—Regulation of Animal Use Within Federal Departments and Agencies ● 387

3216.1, issued by the Deputy Secretary of Defense in

1982. This statement sets policy on the humane treatment and appropriate care of animals used in research

and the responsibilities of different DOD personnel to

carry out the directive. In general, it follows the Animal Welfare Act and the NIH Guide, along with attempting to incorporate alternatives to animal use in the form

of replacement, reduction, and refinement. Other, special policies treat the general use of nonhuman primates

and prohibit the use of dogs, cats, and nonhuman primates for developing nuclear weapons. The directive

also requires that all proposals or designs for animal

experiments undergo appropriate animal welfare review to confirm: “I) the need to perform the experiment or demonstration; 2) the adequacy of the design

of the experiment or demonstration; and 3) compliance

with established policy on the use of animals” (20).

Army Regulation 70-18 (a Joint Service regulation)

implements the directive’s policies uniformly for all

DOD components. The authority for enforcing this regulation is conferred to the Secretary of the Army, who

is required to develop and issue, in consultation with

the other DOD components, regulations implementing

the directive. Army Regulation 70-18 states that all DOD

facilities using animals should seek AAALAC accreditation. Also, it sets up a long chain of responsibilities

for establishing and policing animal welfare policies.

The regulation states that the Under Secretary of Defense for Research and Engineering will:” 1) issue policies and procedural guidance under DOD directive

3216.1, 2) allocate nonhuman primate resources, and

3) designate a veterinarian as the DOD representative

to IRAC [Interagency Research Animal Committee]” (21).

The Surgeon General of each DOD component involved

in animal research must supervise animal use and implement this regulation in each component, establish

a joint working group to identify and conserve nonhuman primate resources, and establish and provide

representatives to a joint technical working group that

periodically reviews the care and use of animals in DOD

programs. Finally, the local commander of a facility

must ensure that:

all programs involving animals conform to the

guidelines cited in Army Regulation 70-18;

local animal care and use, procurement, and transportation policies and procedures comply with the

regulation;

animals used or intended to be used will experience no unnecessary pain, suffering, or stress, and

their use will meet valid DOD requirements;

alternatives to animal species will be used if they

produce scientifically satisfactory results; and

dogs, cats, or nonhuman primates are not used in

research conducted to develop nuclear, biological,

or chemical weapons (21).

Thus, the powers and responsibilities for carrying out

DOD animal welfare policies are decentralized. DOD

does not do any inspections of its facilities. The facilities are required to submit annual reports to USDA

under the regulations implementing the Animal Welfare Act.

The Army regulation builds the institutional review

structure around the local animal care committee. Local commanders must form a committee to oversee the

care and use of animals in their facilities. The committtee must have at least three members, including at least

one person not involved in the proposed project and

one veterinarian. The committee reviews: 1) all aspects

of animal care to ensure that established policies, standards, and regulations are complied with; and 2) all

research protocols and proposals for proper animal welfare policies and good animal experimentation standards. Sufficient information to do this animal care and

treatment review must be presented with all research

proposals. In addition, proposals that involve experimentation on nonhuman primates are reviewed separately by the proper DOD component office (21).

As with other departments in the Federal Government, DOD contracts with outside investigators for

some of its research. The DOD extramural animal research policy requires that the same standards outlined

in Army Regulation 70-18 be followed by contractors

in order to receive DOD funds. Assurance is obtained

by written statements from the recipient animal care

committee or other responsible official. An assurance

is also required that the proposal or protocol has been

reviewed and approved by the local animal care and

use committee or by the attending veterinarian (21).

Enforcement of these policies for extramural research

is more difficult than the intramural policy, since investigators and administrators are not directly responsible to the military line of command.

In addition to DOD-wide policies issued by the Office

of the Secretary, a recommendation is pending in the

Army Medical Research and Development Command

that an Advisory Committee on Animal Welfare be appointed, including non-DOD representatives, to meet

periodically about concerns related to the use of animals for research and training purposes (7).

In 1983, the Air Force commissioned an outside review panel to study animal use in its Aerospace Medical Division. The panel looked at Brooks Air Force Base

(San Antonio, TX) and Wright -Patterson Air Force Base

(Dayton, OH), which together account for 95 percent

of the service’s animal use. The panel found the current policy in place to be satisfactory and was (17):

... impressed with the thoroughness and genuine concern of all those involved to ensure that appropriate

measures are taken to effect proper care and use of

animals. Furthermore, there was a clear emphasis on

selection of alternatives to animal use where feasible.

Excellent progress was shown in the use of simulation

models for a variety of radiation and toxicological

studies.
388 ● Alternatives to Animal Use in Research, Testing, and Education

The panel did note that the system of care and treatment policies was too informal and based on the current personnel; it was unconvinced the system would

remain in place if staff were transferred. The Aerospace Medical Division of the Air Force drafted a Supplement to Army Regulation 70-18 to implement some

of the review panel’s recommendations. The most substantial change deals with the animal care and use committee membership (21):

The local commander will appoint at least one lay

person from the local community who has no direct

Department of Defense connections to serve as a member of the Committee. This lay member should not be

a veterinarian or research scientist who works with

animals; however, a background in sciences would be

helpful. The Committee may have permanent or ad hoc

membership. Its specific purpose is to review all protocols, experimental designs, or lesson plans that involve the use of animals and assure compliance with

[DOD policy].

The Air Force Supplement to Army Regulation 70-18

also requires that each organization using animals submit not just the Annual Report of Research Facility of

USDA’s Animal and Plant Health Inspection Service

(APHIS), but also an Annual Animal Use Report, listing

all species used, the inventory at the beginning of the

year, additions and losses to the facility, the ending inventory, the utilization of the animals, the different experimental situations, and the projected use of animals

for the next fiscal year (18).

Department of Energy

The Department of Energy has no intramural research facilities and so contracts for all its research.

The division involved with animals is the Office of

Health and Environmental Research (OHER); programs

involving research with animals represented less than

15 percent of OHER’s total research budget for fiscal

year 1985 (5), Proposals for OHER-funded research are

subjected to outside peer review for scientific merit. An

OHER research committee from the Office’s four divisions has final approval before funding a research

proposal.

The OHER policy for animal use by its extramural

contractors places the prime responsibility for the maintenance of animal facilities and for animal care on the

contractor. OHER contract research facilities are bound

by law to comply with the Animal Welfare Act and its

regulatory policies, and OHER personnel maintain close

liaison to assure such compliance. In addition, the IRAC

principles are part of the OHER policy statement, along

with the requirement to maintain AAALAC accreditation (5),

To enforce these policies, one OHER staff member

has responsibility for monitoring animal research programs for compliance. This staff member must maintain contact with the research facilities to assure accreditation and to affirm, at least yearly, that it is being

maintained. Site visits with at least one noncontract

veterinarian who is an expert in laboratory-animal care

may be conducted to evaluate the care and treatment

of experimental animals (5,6).

Department of Health and

Human Services

Food and Drug Administration

The Food and Drug Administration has recently

played a major role in attempting to address animal

welfare issues. In 1983, the agency took two steps in

this direction by sponsoring an acute studies workshop

and by establishing an Agency Steering Committee on

Animal Welfare Issues.

The workshop helped clarify FDA’s position on its

need for toxicity data, especially from the LD50 test.

The points emerging from the workshop were that:

FDA had no regulations mandating use of the LD5O

test;

the requirement by Federal agencies for LD5O data

from regulated parties was much less than perceived by the public;

government and industry agreed that there are better determinants of acute toxicity than the LD5O

test and that they supported developing valid alternatives to the use of animals for testing chemicals;

U.S. Government agencies are cooperating with

other countries through organizations like the

Organization for Economic Cooperation and Development; and

improvements in the way animals are used for tox -

icity testing can and should be made administratively rather than through legislation (1,22).

The steering committee, which in part grew out of

the acute studies workshop, found several FDA references to the LD5O that could be misinterpreted as requirements to perform the test, and one involving three

antitumor antibiotics where the requirement still existed (in contrast to the workshop findings). Its 1984

report states that, in all these instances (except for the

antitumor antibiotics), regulations and guidelines are

being rewritten to resolve any misunderstandings.

They will then reflect the position of FDA that “the use

of this test should be avoided except for those rare situations where no alternative exists. ” In the case of the

antitumor antibiotics, FDA is considering eliminating

the requirement (23).

Addressing five specific considerations, all part of its

investigation of agency testing guidelines and practices
App. B—Regulation of Animal Use Within Federal Departments and Agencies ● 389

to answer questions raised at the acute studies workshop, the steering committee concluded that:

●

●

●

●

●

FDA practices and procedures are designed to obtain the maximum amount of data from the minimum number of animals;

despite general references to the use of LD5O tests,

FDA has no requirements for LD5O data obtained

by using the classical, statistically precise test, except for batch release toxicity tests of three antitumor antibiotics;

there are many alternative tests being studied and

developed throughout FDA;

practices and procedures for assuring humane

care and treatment of animals are agency-wide;

and

FDA has a number of regular channels of communication to industry, consumers, and the private

sector in general and efforts to improve communication channels will continue (23).

The steering committee recommended workshops

on acute toxicity studies throughout the agency, on the

use of in vitro alternatives by various centers, and on

agency and PHS practices and procedures for the care

and handling of animals. The recommendations also

called for the establishment of an agency-wide animal

welfare committee (23). FDA is now setting up two inhouse workshops to address the first two topics (l).

Furthermore, it has established a Research Animal

Council to see that the recommendations of the report

are carried out, to consider animal research issues at

FDA in a broad context, and to serve as an oversight

committee for individual FDA centers. FDA’s Research

Animal Council began meeting quarterly in 1984 and

will report to the Commissioner; its membership includes one representative from each of the centers

within FDA (3).

FDA policies on humane animal care and treatment

require compliance with the Animal Welfare Act as well

as with other standards for humane care and use of

animals. The steering committee report found that all

centers have acceptable procedures, but that they varied in specific details. The centers conduct different

amounts of research and testing; some have more formal procedures than others and stronger veterinary

staff capabilities. Accreditation by AAALAC is sought

on a voluntary basis, and two of FDA animal facilities,

the National Center for Toxicological Research (NCTR)

and the Center for Drugs and Biologics of the Office

of Biologics Research and Review, are fully accredited

(23).

The policies and procedures in place at the National

Center for Toxicological Research (Jefferson, AR) are

a good example of FDA system for addressing animal

welfare issues, since NCTR is the primary animal research facility within FDA (24):

The policy of NCTR management is to use laboratory animals under practical and reasonable conditions

of humane treatment, in carefully planned experiments

with in vitro methodologies balanced against minimally

required test species numbers in in vivo bioassays, and

via procedures set forth in national standards and

guidelines.

The Director of NCTR has primary responsibility for

assuring compliance with the policy but delegates some

aspects of that control. The duties of the Senior Scientists in NCTR’s Office of Research include technical overview of animal use, strain selection, genetic quality control, state-of -the-art reviews, and recommendations for

adopting new concepts in animal care and control. The

Director of the Division of Animal Husbandry is responsible for breeding-colony operations, animal production and laboratory-animal care in NCTR’s various holding areas, and quarantine procedures (25). The animal

care committee has adopted an “Animal Use Form for

Experimental Protocols” and requires every investigator using animals to provide the committee with detailed

information for evaluation (23). Finally, the Director

has set up ad hoc committees of in-house personnel

to evaluate specific areas of animal care, such as change

in feed for the facility (1,24).

The FDA policy on extramural research requires adherence by awardee institutions to the PHS policy and

procedures (23):

This includes (1) having in place a program of animal

care which meets federal and Department standards,

(2) providing, through AAALAC accreditation or defined self-assessment procedures, assurance of institutional conformance, and (3) maintaining an animal

research committee to provide oversight of the institution’s animal program, facilities and associated

activities.

National Institutes of Health

NIH has a specific animal care and use program for

intramural research and for research within NIHcontrolled space (25). The NIH policy requires individual investigators to adhere to the NIH Guide. In addition, each bureau, institute, or division (BID) is encouraged to pursue accreditation of its animal facilities by

either AAALAC or any other NIH-approved accrediting

body (at present AAALAC is the sole body) and to report its accreditation status each year to the Deputy

Director, who ensures compliance with the policy by

each BID.

The NIH policy delegates responsibility to five different authorities, including two types of committees. The
390 . Alternatives to Animal Use in Research, Testing, and Education

first is the local BID Animal Research Committee (ARC).

This committee must have at least five Federal Government employees; the BID Scientific Director is responsible for annual appointments of the chairperson and

members and for carrying out the committee’s recommendations. Included among the five ARC members

must be the attending veterinarian on the BID staff,

a tenured investigator representing laboratories and

divisions that use animals, and “a person who is sensitive to bioethical issues, does not possess an advanced

degree in one of the life sciences, and is an employee

from outside that BID” (26).

The NIH policy gives the BID ARCS many specific

responsibilities beyond the general duties of many such

committees. As with other local animal care committees, each ARC is required to make recommendations

on animal care matters to its Scientific Director and

to review proposals and protocols for humane standards of animal care. It is also supposed to advise individuals on the BID’s policies and oversee their implementation within the facility, The major specific duties

of the ARC are:

●

●

●

●

●

to hold quarterly meetings at which a majority of

the ARC members are present;

to maintain a file of all minutes, memorandums,

waivers, and project review documents;

to perform site visits of each facility within the BID

at least annually to assess compliance, and to submit written reports on these inspections to the

Scientific Director;

to develop a plan for attaining accreditation of the

animal facilities or for pursuing accreditation

standards; and

to prepare an annual report for the NIH Deputy

Director for Intramural Research addressing problems and accomplishments related to attaining accreditation.

Individual investigators are responsible for submitting appropriate information needed for ARC review

of a proposal, advising the ARC chairperson of any significant deviations from procedures described in the

most recent project review, and ensuring that all personnel working directly with animals have been trained

in the proper care and use of that species. Thus, the

system puts much of the burden for proper animal care

during an experiment on each investigator.

The second authority set up by the NIH intramural

policy was the NIH Animal Research Committee

(NIHARC). Committee members are appointed annually by the Deputy Director for Intramural Research

and must include a veterinarian, the chairperson from

each BID ARC, and a nonaffiliated member. NIHARC

holds quarterly meetings, advises the Deputy Director

on animal care and use at NIH, discusses issues referred

from the BID ARCS, develops and coordinates training

programs for NIH employees on animal care and use,

and prepares NIH’s Annual Report of Research Facility

for USDA.

Department of the Interior

The Department of the Interior does more than 95

percent of its research in-house. All research and development facilities must comply with both the Animal Welfare Act and with the Department Research

and Development Policy Procedures Handbook (27),

which calls for an approved animal welfare plan. The

National Wildlife Health Laboratory (NWHL) must provide assistance upon request in the development, implementation, and maintenance of each program. Due

to the diversity of the research programs and the

uniqueness of the species involved, each facility is allowed to develop an animal welfare plan peculiar to

its own needs as long as it is approved by NWHL.

Each division plan must discuss:

●

●

●

●

●

●

●

persons responsible for compliance;

reporting and recordkeeping procedures for animals used;

all components of the Animal Welfare Act and the

Department animal health and husbandry standards that cannot be complied with, due either to

the general design of anticipated studies or the

unique natural requirements of the species involved;

quarantine procedures for exotic species;

personnel health monitoring and disease prevention programs;

a schedule for periodic onsite evaluations by the

NWHL Veterinary Medical Officer; and

procedures for handling carcasses following unexpected mortalities (27).

The NWHL Veterinary Medical Officer oversees enforcement of these policies.

Consumer Product Safety

Commission

The Consumer product Safety Commission (CPSC),

as part of its mission to enforce the labeling requirements of the Federal Hazardous Substances Act (FHSA)

(see ch. 7), conducts its own oral acute toxicity studies

to determine the toxic potential of regulated substances.

If the demand for testing exceeds the capacity of the

CPSC’s Health Sciences Laboratory Division, the agency

contracts with FDA’s NCTR (13).
App. B—Regulation of Animal Use Within Federal Departments and Agencies ● 391

In addition to requiring its own personnel, contracting agencies, and regulated parties to observe the requirements of the Animal Welfare Act and the NIH

Guide in performing required safety tests on animals,

CPSC has published an Animal Testing Policy, “which

is intended to reduce the number of animals tested to

determine hazards associated with household products

and to reduce any pain that might be associated with

such testing” (49 FR 22522). The policy states that CPSC

itself and manufacturers of substances covered by the

FHSA “should wherever possible utilize existing alternatives to conducting animal testing [including] prior

human experience, literature sources which record

prior animal testing or limited human tests, and expert

opinion. ”

Citing the provision in FHSA regulations that gives

preference to studies based on humans over those with

animals, the policy states that CPSC “resorts to animal

testing only when the other information sources have

been exhausted. ” It also states that:

●

●

●

“limit” tests for acute toxicity studies, rather than

the “classic” LD5O, are performed when necessary,

requiring fewer animals;

eye irritancy testing is not performed if the test

substance is a known skin irritant; and

agency-required Draize (eye irritation) tests are

modified to eliminate the need for restraining test

rabbits, allowing them full mobility and access to

food and water (49 FR 22522).

Environmental Protection Agency

The guidelines and policies that the Environmental

Protection Agency (EPA) follows governing humane

treatment and appropriate veterinary care for laboratory animals involve AAALAC accreditation for its two

major laboratories, adherence to the NIH Guide, and

adherence to the Animal Welfare Act. In addition, EPA

has an intra-agency committee that oversees animal research issues. There is no separate policy for extramural

research; NIH Guide principles and requisites are enforced in such cases by a signed statement from the

investigator that the proper animal care is being observed (16).

The EPA facility at Research Triangle Park, NC, has

an animal care committee that oversees and carries out

an institutional review of animal care and welfare issues. The committee is composed of representatives

of the different research divisions within that facility

along with the attending veterinarian. Its 8 to 10 members, who meet approximately once a month and keep

records of their proceedings, are responsible for animal care issues only, and do not conduct scientific reviews of research proposals, Scientific review is done

separately before proposals reach the committee. The

overall responsibilities for the committee are to:

● oversee the functioning of the animal care facility,

● plan improvements for the facility and carry them

out ,

• set policy for humane treatment of animals,

● set policy for sharing facility resources,

● address any day-to-day animal care problems

brought to its attention, and

● review proposals for appropriate animal use and

care (2).

In addition, the committee can recommend experimental changes to improve animal care and treatment

and has the authority to interrupt or terminate an experiment if it finds any instances of inhumane treatment or inappropriate care of the animals, a step that

has been taken at least once since the committee was

established (2).

The committee does not monitor experiments while

in progress or handle the day-to-day activities of the

animal care facility. These powers are delegated to the

attending veterinarian (who is under contract with EPA

to work at the facility 3 days a week) and a staff of approximately 20 (2).

National Aeronautics and Space

Administration

The overall National Aeronautics and Space Administration policy on animal research is based on the Animal Welfare Act, the NIH Guide, and the IRAC principles. All NASA facilities, all users of NASA facilities,

aircraft, or spacecraft, and all NASA contractors using

animals are subject to this policy. The overriding philosophy of the policy is based on three principles:

●

●

●

Animals will be used only to answer valid questions that improve the health, welfare, or general

medical and scientific knowledge of humans.

Experimental animals must not be subject to avoidable discomfort or distress.

Experiments requiring the use of invasive procedures without benefit of anesthetic agents demand

strong justification and attention to possible alternatives (12).

Although the NASA policy exists today as only a proposed NASA Management Instruction (NMI), it is already

being implemented. For example, the NMI establishes

an Animal Care and Use Committee (ACUC) in each

facility with animals (12); the committee includes a

research veterinarian, a biomedical scientist, a nonscientist, and a person not affiliated with NASA. It is

responsible for overseeing the animal care facility,

establishing specific guidelines, reviewing proposals,

and making recommendations for approval or dis-
392 Alternatives to Animal Use in Research, Testing, and Education

approval of funding (9). The committee must ask the

following questions for each experiment (12):

● Will the minimum possible number of animals be

used?

● Is the use of animals necessary in this experiment?

● Are provisions for care of these animals adequate?

Different compliance with these policies is needed

for intramural versus extramural research. For NASA

facilities, ACUC reports are required to be sent to the

Director of the Life Sciences Division at NASA headquarters reviewing facility procedures. AAALAC accreditation is required for all NASA installations. Currently

all facilities are moving toward AAALAC accreditation

but have not yet obtained it (12). For extramural research, the institution must submit a written assurance

that its animal care policies are equivalent to the NASA

policy. (AAALAC accreditation is one way of showing

compliance. ) Noncompliance will result in termination

of the research by the ACUC and possibly sanctions

after review by the Director of the Life Sciences Division (19).

The Ames Research Center (Moffett Field, CA), NASA’s

primary center for nonhuman research, illustrates the

implementation of NASA policy. The Ames Research

Center has established the Animal Users Guide for

Ames-sponsored laboratory experiments using animals.

This guide sets up two entities to ensure that all legal

requirements are met: The animal care facility is responsible for housing and maintaining the animals properly, and the animal care and use committee must monitor all animal care and experimentation progress at

the center. In addition, the guide states (28):

EVERY RESEARCH SCIENTIST AND ALL RESEARCH

PERSONNEL, CONTRACTORS, AND GRANTEES ARE

RESPONSIBLE FOR OBSERVING THE LEGAL REQUIREMENTS CONCERNING LABORATORY ANIMALS.

The Ames committee reports to the center’s Director of Life Sciences and is responsible for:

● reviewing the use of animals in proposed and ongoing experiments;

● reviewing all animal experimentation performed

by contractors or grantees;

● serving as an advisory committee on all questions

of animal care and use, and as a forum for resolving differences that may occur; and

● reviewing animal-related inventions and devices

(28).

At present, the Ames committee has 10 members—4

non-NASA, non-life-sciences laypersons; 1 veterinarian;

1 scientist-veterinarian; 1 engineer; 2 scientists; and 1

science manager. In addition, 2 veterinarians accredited in Laboratory Animal Medicine are advisors. The

lay members include an attorney, a professor of religion (ethics), the chairman of the Department of Education at a local college, and the public relations director

of the Santa Clara Valley Humane Society. This is one

of the few such committees in the country with a 40

percent lay membership. According to the Acting Director of Life Sciences at Ames Research Center, “the

out -of -house members have contributed materially to

the [committee].” Two of the lay members head subcommittees that are reviewing and updating the Animal Users Guide and committee charter and developing an animal user’s orientation program (14).

National Science Foundation

A summary of the animal care requirements of the

National Science Foundation (NSF) is found in Section

713 of the NSF Grant Policy Manual (30) and included

in the NSF document “Grant General Conditions, ” that

is sent to each grantee when an award is made. Any

grantee performing research on warm-blooded animals

must comply with the Animal Welfare Act and its regulations and follow the NIH Guide. NSF has no formal

inspection system to check on compliance with these

policies, as that is judged to be the responsibility of

USDA/APHIS (8). The result is a voluntary adherence

system by NSF grantees,

Beginning in 1986, NSF imposed two new requirements on grant applicants and grantees who perform

research on vertebrate animals:

● Each proposal must be reviewed by an institutional

animal care and use committee.

● Each proposal must be accompanied by a statement

from the grantee that assures the grantee’s compliance with the PHS policy.

Grant proposals submitted to NSF thus face three separate reviews-one by the grantee’s institutional committee, one by outside reviewers, and one by NSF staff.

Although these are primarily scientific in nature,

reviewers are asked to comment on animal welfare issues. If a proposal involves the use of animals, sufficient information must be provided to allow evaluation of the appropriateness of experimental protocols

with respect to the choice of species, the number of

animals to be used, and any necessary exposure of animals to discomfort, pain, or injury (29). With this information, the reviewers are asked to (29):

. . . comment if you have any concerns regarding the

violation of animal welfare laws or guidelines, the exposure of animals to unnecessary pain or mistreatment,

or the use of excessive numbers of animals. If the species being used is not the one most appropriate, or if

alternative or adjunct methods could be used to eliminate or reduce the need for animal experimentation,

please comment.

Veterans’ Administration

The Veterans’ Administration is unique in its policies

governing humane treatment and appropriate veteri-
— .

App. B—Regulation of Animal Use Within Federal Departments and Agencies Ž 393

nary care for laboratory animals because it has required

all its facilities using animals to seek and obtain AAALAC

accreditation (see ch. 15). This policy was originated

in 1971, and 81 out of 174 VA facilities (as of Apr. 1,

198.5) had some level of AAALAC accreditation. Not all

VA constituents apply for accreditation, since some do

not engage in animal research. In fact, the VA has a

contract with AAALAC covering all its research facilities that prohibits failure of accreditation of any constituent facility solely for financial reasons (10).

In addition to requiring adherence to the PHS policy,

the VA has a lengthy research review process with a

strong committee structure. At the local research facility, each research and development committee has

a subcommittee for animal studies that oversees all such

research. The membership varies, though it includes

at least one member of the research and development

committee, a Veterinary Medical Officer (VA employee),

and two to four investigators who are involved in

studies using animals. Thus, there are no laypersons

or persons not affiliated with the research facility on

the subcommittee. Except for the veterinarian, who

serves indefinitely, members serve 3-year terms (31).

The subcommittee has three primary functions:

●

●

●

to approve the use or uses made of animal subjects in all research studies as they relate to animal

welfare laws, regulations, and policies;

to review all animal studies for need, adequacy,

and availability of essential animal research facility support; for the appropriateness, quality, and

availability of the animal models; for the humaneness and appropriateness of procedures and conditions surrounding animal subjects before and

throughout the study; and

to evaluate, at least annually, the animal research

facility and recommend appropriate actions to correct deficiencies noted (11).

Proposals are reviewed again at a regional VA office

by two committees, first for veterinary medical review

(appropriate use and care of animals) and then for scientific merit (10). The animal welfare review is done by

a Veterinary Medical Panel of specialists chosen for

their experience, knowledge, and research in laboratory-animal science and medicine. This panel attempts

“to assure that proposals include sound, acceptable animal medicine and husbandry practices in animal research facilities that are operated in conformance with

all pertinent animal welfare laws, regulations, and policies” (11). Specifically, the panel conducts reviews:

● to ascertain the description of the animal model;

● to ascertain the biological and medical definition

of the animal model;

• to ascertain the environmental and experimentalanimal-related factors;

● to determine if there is evidence of adequate experience with the proposed technology of manipulations, monitoring, or measuring;

● to determine if use of intact animals is required

or if animal parts could be obtained from or shared

with other investigators who have scientifically

compatible studies;

● to determine if painful procedures are involved

and whether these can be avoided or if their control has been satisfactorily planned; and

● to relate the budget of the experiment to the animal costs and to the animal maintenance needs (11).

In 1984, the VA required that all research proposals

have an appendix with a detailed discussion of animal

protocols, the number of animals to be used, and why

the specific choice of organism was made. This appendix is signed by three people from the local facility–

the researcher, the animal committee chairperson, and

the research and development chairperson—to guarantee that the procedures are carried out.

The enforcement of the VA’s animal research policies rests with the committee structure and is overseen by the Chief Veterinary Medical Officer for the

VA, whose duties include making sure all Federal and

State animal research laws are observed and that the

individual facilities have the funds to continue to remain AAALAC-accredited. In addition, the VA began

in fiscal year 1984 strict enforcement of the completion of the Annual Reports of Animal Research Facilities for APHIS by every VA facility, whether the facility used animals in research the preceding year or not

(lo).

At the local VA facilities, the attending veterinarian

has authority for veterinary medical matters. This person must monitor the housing, general treatment, and

care of the experimental animals while the experiment

is in progress as often as needed. If inhumane treatment or inappropriate care is found, the veterinarian

and animal subcommittee do not have the authority

to interrupt or terminate an experiment. The subcommittee would make a recommendation to the research

and development committee and to the Associate Chief

of Staff for Research and Development, who may make

a decision or a recommendation to the Director (4). This

means there is some enforcement of the proper animal care standards at each local VA facility on a day-today basis.

Appendix B References

1. Borsetti, A., Staff Scientist, Office of Science Coordination, Food and Drug Administration, U.S. Department of

Health and Human Services, Rockvil]e, MD, personal communications, October and November 1984 and March

1985.

2. Chernoff, N,, U.S. Environmental Protection Agency, Research Triangle Park, NC, personal communication, 1984.
394 ● Alternatives to Animal Use in Research, Testing, and Education

3. Crawford, L., Director, Bureau of Veterinary Medicine,

Food and Drug Administration, US. Department of Health

and Human Services, Rockville, MD, personal communication, November 1984.

4. Ditzler, J., Chief Medical Director, Department of Medicine and Surgery, Veterans’ Administration, Washington,

DC, persona] communication, Jan. 17, 1985.

5. Edington, C., Associate Director, Office of Health and Environmental Research, Office of Energy Research, U.S. Department of Energy, Washington, DC, personal communication, Nov. 16, 1984.

6. Edington, C., Procedures for Selection of Animal Research

Projects for Funding Through OHER/DOE (Washington,

DC: Department of Energy, Jan. 24, 1985).

7. Kainz, R,, Office of the Commander, U.S. Army Medical

Research and Development Command, Ft. Detrick, MD,

personal communication, September 1984.

8. Kingsbury, D,, Assistant Director, National Science Foundation, Washington, DC, personal communication, Nov.

2, 1984.

9. Lewis, C. S., “NASA’s Use of Animals in Research,” prepared for the Life Sciences Division, National Aeronautics and Space Administration, Washington, DC, Sept. 28,

1983.

10. Middleton, C., Chief Veterinary Medical Officer, Veterans’

Administration, Washington, DC, personal communication, Oct.3, 1984.

11, Moreland, A., “Animal Research Protocol Review Within

the Veterans’ Administration,” mimeo, Gainesville, FL,

1984.

12. Nicogossian, A., Director, Life Sciences Division, National

Aeronautics and Space Administration, Washington, DC,

personal communication, Oct. 19, 1984.

13. Porter, W., Health Sciences Laboratory Division, Consumer Product Safety Commission, Washington, DC, personal communication, Nov. 19, 1984.

14. Sharp, J., Acting Director of Life Sciences, Ames Research

Center, National Aeronautics and Space Administration,

letter to A. Nicogossian, Director, Life Sciences Division,

NASA, on Animal Care and Use Committee, Moffett Field,

CA, Sept. 12, 1984.

15. Stewart, W., Senior Veterinarian, Animal and Plant Health

Inspection Service, U.S. Department of Agriculture,

Hyattsville, MD, personal communication, November

1984.

16. Ulvedal, F., Acting Director, Water and Toxic Substances

Health Effects Research Division, U.S. Environmental Protection Agency, Washington, DC, personal communications, September and October 1984.

17. US. Department of Defense, Air Force, Aerospace Medical Division Animal [Jse Review Panel Meetings (Washington, DC: May 1984).

18. U.S. Department of Defense, Air Force, Aerospace Medical Division, ‘(Animals in DOD Research and Training AMD

Supplement 1“ (draft), Brooks Air Force Base, TX, 1985.

19, U.S. Department of Defense, Assistant Secretary of Defense for Health Affairs, Memorandum to the Secretaries

of the Uniformed Services, President of the Uniformed

Services University of the Health Sciences, and Directors

of Defense Agencies (Washington, DC: Jan. 4, 1984).

20. U.S. Department of Defense, The Use of Animals in DOD

Programs, DOD Instruction 3216.1 (Washington, DC: Feb.

1, 1982).

21. U.S. Department of Defense, The Use of Animals m DOD

Programs, Army Regulation 70-18 (Washington, DC: June

1, 1984).

22. U.S. Department of Health and Human Services, Food and

Drug Administration, Office of Science Coordination, Final Report of Acute Studies Workshop (Washington, DC:

Nov. 9, 1983).

23. U.S. Department of Health and Human Services, Food and

Drug Administration, Final Report to the Commissioner,

FDA Agency Steering Committee on Animal Welfare Zssues (Rockville, MD: Aug. 15, 1984).

24. U.S. Department of Health and Human Services, Food and

Drug Administration, National Center for Toxicological

Research, iWTR Quality Assurance Program (Jefferson,

AR: May 1983).

25. U.S. Department of Health and Human Services, Public

Health Service, National Institutes of Health, Animal Care

and Use in the Intramural Program, NIH Policy 3040-2

(Bethesda, MD: Dec. 30, 1983).

26, U.S. Department of Health and Human Services, Public

Health Service, National Institutes of Health, Guide for

the Care and Use of Laboratory Animals, NIH Pub. No.

85-23 (Bethesda, MD: National Institutes of Health, 1985).

27. U.S. Department of the Interior, Research and Development PolicyRocedures Handbook (Washington, DC: July

26, 1984).

28. US. National Aeronautics and Space Administration, Ames

Research Center, Animal Users Guide AHB 7180-1 (Mof -

fett Field, CA: June 1982).

29. U.S. National Science Foundation, Office of the Assistant

Director for Biological, Behavioral, and Social Sciences,

ATSFADDBS circular NO. 1.3 (Washington, DC: June 15,

1982).

30. US. National Science Foundation,lWFG rant Policy A4an -

ual, Section 713 (Washington, DC: Apr. 15, 1984).

31. U.S. Veterans’ Administration, Department of Medicine

and Surgery, Research and Development in Medicine General (Washington, DC: Apr. 27, 1982).
Appendix C

Public Health Service Policy on

Humane Care and Use of Laboratory

Animals by Awardee Institutions

The following is reprinted from U.S. Department of

Health and Human Services, Public Health Service, National Institutes of Health, “Laboratory Animal Welfare, ” NIH Guide for Grants and Contracts 14(8), June

2.5, 1985.

Introduction

It is the policy of the Public Health Service (PHS) to

require institutions to establish and maintain proper

measures to ensure the appropriate care and use of

all animals involved in research, research training and

biological testing activities (hereinafter referred to as

activities) supported by the PHS. The PHS endorses

the “U.S. Government Principles for the Utilization and

Care of Vertebrate Animals Used in Testing, Research

and Training” developed by the Interagency Research

Animal Committee (IRAC). This policy is intended to

implement and supplement those Principles.

Applicability

This policy is applicable to all PHS-approved activities

involving animals, whether the activities are performed

at an awardee institution or any other institution and

conducted in the United States, the Commonwealth

of Puerto Rico, or any territory or possession of the

United States. Institutions in foreign countries receiving PHS support for activities involving animals shall

comply with this policy, or provide evidence to the

PHS that acceptable standards for humane care and

use of the animals in PHS-supported activities will be

met, No PHS support for an activity involving animals

will be provided to an individual unless that individual is affiliated with or sponsored by an institution

which can and does assume responsibility for compliance with this policy for PHS-supported activities, or

unless the individual makes other arrangements with

the PHS. This policy does not affect applicable state

or local laws or regulations which impose more stringent standards for the care and use of laboratory animals. All institutions are required to comply, as applicable, with the Animal Welfare Act, and other Federal

statutes and regulations relating to animals.

A.

B.

c.

D.

E.

F.

G.

H.

Definitions

Animal

Any live, vertebrate animal used or intended for

use in research, research training, experimentation or biological testing or for related purposes.

Animal Facility

Any and all buildings, rooms, areas, enclosures,

or vehicles, including satellite facilities, used for

animal confinement, transport, maintenance, breeding or experiments inclusive of surgical manipulation. A satellite facility is any containment outside

of a core facility or centrally designated or managed area in which animals are housed for more

than 24 hours.

Animal Welfare Act

Public Law 89-544, 1966, as amended, (P.L. 91-

579 and P.L. 94-279) 7 U.S.C. 2131 et seq. Implementing regulations are published in the Code of

Federal Regulations (CFR), Title 9, Subchapter A,

Parts 1, 2, 3 and 4, and are administered by the

U.S. Department of Agriculture.

Animal Welfare Assurance or Assurance

The documentation from an awardee or a prospective awardee institution assuring institutional

compliance with this policy.

Guide

Guide for the Care and Use of Laboratory Animals, DHEW, NIH Pub. No, 78-23, 1978 edition or

succeeding revised editions.

Institution

Any public or private organization, business, or

agency (including components of Federal, state and

local governments).

Institutional Official

An individual who has the authority to sign the

institution’s Assurance, making a commitment on

behalf of the institution that the requirements of

this policy will be met.

Public Health Service

The Public Health Service includes the Alcohol,

Drug Abuse, and Mental Health Administration, the

Centers for Disease Control, the Food and Drug

Administration, the Health Resources and Services

Administration, and the National Institutes of

Health.

395
396 . Alternatives to Animal use in Research, Testing, and Education

I. Quorum

A majority of the members of the Institutional

Animal Care and Use Committee.

Implementation by Awardee

Institutions

A. Animal Welfare Assurance

No activity involving animals will be supported

by the PHS until the institution conducting the activity has provided a written Assurance acceptable

to the PHS, setting forth compliance with this policy for PHS-supported activities. Assurances shall

be submitted to the Office for Protection from Research Risks (OPRR), Office of the Director, National Institutes of Health, 9000 Rockville Pike,

Building 31, Room 4B09, Bethesda, Maryland 20205.

The Assurance shall be typed on the institution’s

letterhead and signed by an institutional official.

OPRR will provide the applicant institution with

necessary instructions and an example of an acceptable Assurance. All Assurances submitted to

the PHS in accordance with this policy will be

evaluated by OPRR to determine the adequacy of

the institution’s proposed program for the care and

use of animals in PHS-supported activities. On the

basis of this evaluation OPRR may approve or disapprove the Assurance, or negotiate an approvable Assurance with the institution. Approval of an

Assurance will be for a specified period of time (no

longer than five years) after which time the institution must submit a new Assurance to OPRR.

OPRR may limit the period during which any particular approved Assurance shall remain effective

or otherwise condition, restrict, or withdraw approval. Without an applicable PHS approved Assurance no PHS-supported activity involving animals

at the institution will be permitted to continue.

1. Institutional Program for Animal

Care and Use

The Assurance shall fully describe the institution’s program for the care and use of animals

in PHS-supported activities. The PHS requires institutions to use the Guide for the Care and Use

of Laboratory Animals (Guide) as a basis for developing and implementing an institutional program for activities involving animals. The program description must include the following:

a, a list of every branch and major component

of the institution, as well as a list of every

branch and major component of any other institution which is to be included under the Assurance;

b. the lines of authority and responsibility for administering the program and ensuring compliance with this policy;

c. the qualifications, authority and responsibility of the veterinarian(s) who will participate

in the program;

d. the membership list of the Institutional Animal Care and Use Committee (IACUC) established in accordance with the requirements set forth in IV.A.3.;

e. the procedures which the IACUC will follow

to fulfill the requirements set forth in IV. B.;

f. the health program for personnel who work

in laboratory animal facilities or have frequent

contact with animals;

g. the gross square footage of each animal facility (including satellite facilities), the species

housed therein and the average daily inventory, by species, of animals in each facility;

and

h. any other pertinent information requested by

OPRR.

2. Institutional Status

Each institution must assure that its program

and facilities are in one of the following categories:

• Category l—Accredited by the American Association for the Accreditation of Laboratory

Animal Care (AAALAC). All of the institution’s

programs and facilities (including satellite facilities) for activities involving animals have

been evaluated and accredited by AAALAC,

or other accrediting body recognized by PHS.2

● Category 2—Evaluated by the Institution. All

of the institution’s programs and facilities (including satellite facilities) for activities involving animals have been evaluated by the IACUC

and will be reevaluated by the IACUC at least

once each year. The IACUC shall use the Guide

for the Care and Use of Laboratory Animals

as a basis for evaluating the institution’s program and facilities. A report of the IACUC

evaluation shall be submitted to the institutional official and updated on an annual basis.3 The initial report shall be submitted to

IThe name Institutional Animal Care and Use Committee ([ AC UC) M used

in this policv is intended as a generic term for a committee whose function

is to ensure that the care and use of animals in PHS-supported activities is

appropriate and humane in accordance with this policy. Howe\,er, each in.

stitution may identify the committee by whatever name it chooses. Membership and responsibilities of the IACLJC are set forth in IL’.A,3 and It’ B.

‘As of the issuance date of this policy the only accrediting body recognized

by PHS is the American Association for Accreditation of Laboratory)’ .Animal

Care (AAA1.AC).

3

The IACUC may, at its discretion, determine the best means of conducting an evaluation of the institution’s programs and facilities. The IACUC may

invite ad hoc consultants to conduct or assist in conducting the evaluation.

However, the 1.4CL1C remains responsible for the evaluation and report.
App. C—Public Health Service Policy on Humane Care and Use of Laboratory Animals by Awardee Institutions ● 397

OPRR with the Assurance. Annual reports of

the IACUC evaluation shall be maintained by

the institution and made available to OPRR

upon request. The report must contain a

description of the nature and extent of the institution’s adherence to the Guide and this policy.4 The report must identify specifically any

departures from provisions of the Guide and

this policy, and state the reasons for each

departure, If program or facility deficiencies

are noted, the report must contain a reasonable and specific plan and schedule for correcting each deficiency. The report must distinguish significant deficiencies from minor

deficiencies. A significant deficiency is one

which, in the judgment of the IACUC and the

institutional official, is or may be a threat to

the health or safety of the animals. Failure of

the IACUC to conduct an annual evaluation

and submit the required report to the institutional official may result in PHS withdrawal

of its approval of the Assurance.

3. Institutional Animal Care and Use Committee

(IACUC)

a. Each institution shall appoint an Institutional

Animal Care and Use Committee (IACUC),

qualified through the experience and expertise of its members to oversee the institution’s

animal program, facilities and procedures.

b. The Assurance must include the names, position titles and credentials of the IACUC chairperson and the members. The committee shall

consist of not less than five members, and shall

include at least:

(1) one Doctor of Veterinary Medicine, with

training or experience in laboratory animal

science and medicine, who has direct or

delegated program responsibility for activities involving animals at the institution;

(2) one practicing scientist experienced in research involving animals;

(3) One member whose primary concerns are

in a nonscientific area (for example, ethicist, lawyer, member of the clergy); and

(4) one individual who is not affiliated with the

institution in any way other than as a member of the IACUC, and is not a member of

the immediate family of a person who is affiliated with the institution.

c. An individual who meets the requirements of

more than one of the categories detailed in

—.————

41f some of the institution’s facilities are accredited b}r AAAI,AC or other

accrediting body recognized by PHS, the report should” identify those facilities and need not contain any further information about e~,aluation of those

facilities

IV. A.3.b. (1)-(4) may fulfill more than one requirement, However, no committee may consist of less than five members,

B. Functions of the Institutional Animal Care and Use

Committee

As an agent of the institution the IACUC shall,

with respect to PHS-supported activities:

1. review at least annually the institution’s program

for humane care and use of animals;

2. inspect at least annually all of the institution’s

animal facilities, including satellite facilities;

3. review concerns involving the care and use of

animals at the institution;

4. make recommendations to the institutional official regarding any aspect of the institution’s animal program, facilities or personnel training;

5. review and approve, require modifications in (to

6

7.

secure approval) or withhold approval of those

sections of PHS applications or proposals related

to the care and use of animals as specified in

IV.C.;

review and approve, require modifications in (to

secure approval), or withhold approval of proposed significant changes regarding the use of

animals in ongoing activities; and

be authorized to suspend an activity involving

animals in accord with specifications set forth

in IV.C.5.

C. Review of PHS Applications and Proposals

I. In order to approve applications and proposals

or proposed significant changes in ongoing activities, the IACUC shall conduct a review of those

sections related to the care and use of animals

and determine that the proposed activities are

in accord with this policy. In making this determination, the IACUC shall confirm that the activity will be conducted in accord with the Animal

Welfare Act insofar as it applies to the activity,

and that the activity is consistent with the Guide

unless acceptable justification for a departure is

presented. Further, the IACUC shall determine

that the activity conforms with the institution’s

Assurance and meets the following requirements:

a. Procedures with animals will avoid or minimize discomfort, distress and pain to the animals, consistent with sound research design.

b. Procedures that may cause more than momentary or slight pain or distress to the animals

will be performed with appropriate sedation,

analgesia, or anesthesia, unless the procedure

is justified for scientific reasons in writing by

the investigator.

c. Animals that would otherwise experience severe or chronic pain or distress that cannot

be relieved will be painlessly sacrificed at the
398 ● Alternatives to Animal Use in Research, Testing, and Education

end of the procedure or, if appropriate, during the procedure.

d. The living conditions of animals will be appropriate for their species and contribute to their

health and comfort. The housing, feeding and

nonmedical care of the animals will be directed by a veterinarian or other scientist

trained and experienced in the proper care,

handling and use of the species being maintained or studied.

e. Medical care for animals will be available and

provided as necessary by a qualified veterinarian.

f. Personnel conducting procedures on the species being maintained or studied will be appropriately qualified and trained in those procedures.

g. Methods of euthanasia used will be consistent

with the recommendations of the American

Veterinary Medical Association (AVMA) Panel

on Euthanasia,s unless a deviation is justified

for scientific reasons in writing by the investigator.

2. Prior to the review, each IACUC member shall

be provided with a list of applications and proposals to be reviewed, Those sections of applications and proposals that relate to the care and

use of animals shall be available to all IACUC

members, and any member of the IACUC may

upon request obtain full committee review of

those sections, If full committee review is not requested, at least one member of the IACUC, designated by the chairperson and qualified to conduct the review, shall review those sections and

have the authority to approve, require modifications in (to secure approval) or request full

committee review of those sections. If full committee review is requested, approval of those sections may be granted only after review at a convened meeting of a quorum of the IACUC and

with the approval vote of a majority of the quorum present. No member may participate in the

IACUC review or approval of an application or

proposal in which the member has a conflicting

interest (e.g., is personally involved in the

project), except to provide information requested

by the IACUC; nor may a member who has a

conflicting interest contribute to the constitution

of a quorum.

3. The IACUC may invite consultants to assist in the

review of complex issues. Consultants may not

‘Journal of the American Veterinary Medical Association (JAVMA), 1978,

Vol. 173, No. 1, pp. 59-72, or succeeding revised editions.

approve or withhold approval of an application

or proposal or vote with the IACUC.

4. The IACUC shall notify investigators and the institution in writing of its decision to approve or

withhold approval of those sections of applications or proposals related to the care and use

of animals, or of modifications required to secure IACUC approval. If the IACUC decides to

withhold approval of an application or proposal,

it shall include in its written notification a statement of the reasons for its decision and give the

investigator an opportunity to respond in person or in writing.

5. The IACUC shall conduct continuing review of

applications and proposals covered by this policy at appropriate intervals as determined by the

IACUC, but not less than once every three years.

6. The IACUC may suspend an activity that it previously approved if it determines that the activity is not being conducted in accordance with

applicable provisions of the Animal Welfare Act,

the Guide, the institution’s Assurance, or

IV. C.l.a.-g. The IACUC may suspend an activity

only after review of the matter at a convened

meeting of a quorum of the IACUC and with the

suspension vote of a majority of the quorum

present.

7. If the IACUC suspends an activity involving animals, the institutional official in consultation with

the IACUC shall review the reasons for suspension, take appropriate corrective action and report that action with a full explanation to OPRR.

8. Applications and proposals that have been approved by the IACUC maybe subject to further

appropriate review and approval by officials of

the institution. However, those officials may not

approve those sections of an application or proposal related to the care and use of animals if

they have not been approved by the IACUC.

D. Information Required in Applications and Proposals Submitted to PHS

1. All Institutions

Applications and proposals submitted to PHS

that involve the care and use of animals shall

contain the following information:

a. identification of the species and approximate

number of animals to be used;

b. rationale for involving animals, and for the

appropriateness of the species and numbers

to be used;

c. a complete description of the proposed use of

the animals;

d. assurance that discomfort and injury to animals will be limited to that which is unavoid-
App. C—Public Health Service Policy on Humane Care and Use of Laboratory Animals by Awardee Institutions . 399

able in the conduct of scientifically valuable

research, and that analgesic, anesthetic, and

tranquilizing drugs will be used where indicated and appropriate to minimize discomfort

and pain to animals; and

e. a description of any euthanasia method to he

used.

2. Institutions That Have an Approved Assurance

Applications or proposals covered by this policy from institutions which have an approved Assurance on file with OPRR shall include verification of approval by the IACUC of those sections

related to the care and use of animals, With the

authorization of PHS, such verification may be

filed at a time not to exceed 60 days after submission of applications or proposals.6

If verification of IACUC approval is submitted

subsequent to the submission of the application

or proposal, the verification shall state the

modifications, if any, required by the IACUC.

The verification shall be signed by an individual

authorized by the institution, but need not be

signed b-y the institutional official who signed the

Assurance.

3. Institutions That Do Not Have an Approved Assurance

Applications and proposals involving animals

from institutions that do not have an approved

Assurance on file with OPRR shall contain a declaration that the institution will establish an IACUC and submit an Assurance upon request by

OPRR. After OPRR has requested the Assurance,

the institution shall establish an IACUC as required by IV.A.3. and the IACUC shall review

those sections of the application or proposal as

required by IV.c. The institution shall then submit to OPRR the Assurance and verification of

IACUC approval. The verification shall state the

modifications, if any, required by the IACUC.

The verification shall be signed by an individual

authorized by the institution, but need not be

signed by the institutional official who signed the

Assurance.

E. Recordkeeping

1. The awardee institution shall maintain:

a. an Assurance approved by the PHS;

b. minutes of IACUC meetings, including records

of attendance, activities of the committee, and

committee deliberations;

6(lnt Il further notwe PHS hereh\, authorizes all institutions with approked

Assuraores to file \ ~r]ftration of 1,4(;{ 1(’ appro~ al either along with the ap.

plicatwn or proposal or within f-XI da}s of submission of the application or

proposal From time to time P}iS w ill rem aluate this hl,]nket authorization

An}’ deriwn to withdra}~ this authorization will take place on]? after ample

Opporfllnlt}’ IS pr”ol ided for romment by the Put)]ic

c.

d,

e.

records of applications, proposals and proposed significant changes in the care and use

of animals and whether IACUC approval was

given or withheld;

records of any IACUC reports and recommendations as forwarded to the institutional official; and

records of accrediting body determinations.

2. All records shall be maintained for at least three

years; records that relate directly to applications,

proposals, and proposed significant changes in

ongoing activities reviewed and approved by the

IACUC shall be maintained for the duration of

the activity and for an additional three years after the completion of the activity. All records

shall be accessible for inspection and copying by

authorized OPRR or other PHS representatives

at reasonable times and in a reasonable manner.

F. Reporting Requirements

1. On or before each anniversary of approval of its

Assurance, the institution shall report in writing to OPRR:

a. any change in the institution’s program or facilities which would place the institution in a

different category than specified in its Assurance (see IV.A.2.);

b. any change in the description of the institution’s program for animal care and use as required by IV. A.l.a.-h.;

c. any changes in IACUC membership; and

d. if the institution’s program and facilities are

in Category 2 (see IV.A.2.), verification that the

IACUC has conducted an annual evaluation of

the institution’s program and facilities and submitted the evaluation to the institutional

official.

2. Institutions that have no changes to report as

specified in IV.F. 1.a.-c. shall submit a letter to

OPRR stating that there are no changes.

3. Institutions shall provide OPRR promptly with

a full explanation of the circumstances and actions taken with respect to:

a. any serious or continuing noncompliance with

this policy;

b. any serious deviation from the provisions of

the Guide; or

c. any suspension of an activity by the IACUC.

Implementation by PHS

A. Responsibilities of OPRR

OPRR is responsible for the general administration and coordination of this policy and will:

I. request and negotiate, approve or disapprove,
.

400 ● Alternatives to Animal Use in Research, Testing, and Education

and, as necessary, withdraw approval of Assurances;

2. distribute to executive secretaries of initial review and technical evaluation groups, and to PHS

awarding units, lists of institutions that have an

approved Assurance;

3. advise awarding units and awardee institutions

concerning the implementation of this policy;

4. evaluate allegations of noncompliance with this

policy;

5. have the authority to review and approve or disapprove waivers to this policy (see V.D.); and

6. conduct site visits to selected institutions.

B. Responsibilities of PHS Awarding Units

PHS awarding units may not make an award for

an activity involving animals unless the institution

submitting the application or proposal is on the list

of institutions that have an approved Assurance on

file with OPRR, and the institution has provided

verification of approval by the IACUC of those sections of the application or proposal related to the

care and use of animals in PHS-supported activities. If an institution is not listed, the awarding unit

will ask OPRR to negotiate an Assurance with the

institution before an award is made. No award shall

be made until the Assurance has been submitted

by the institution, approved by OPRR, and the institution has provided verification of approval by

the IACUC of those sections of the application or

proposal related to the care and use of animals in

PHS-supported activities.

C. Conduct of Special Reviews/Site Visits

Each awardee institution is subject to review at

anytime by PHS staff and advisors, which may include a site visit, in order to assess the adequacy

of the institution’s compliance with this policy.

D. Waiver

Institutions may request a waiver of a provision

or provisions of this policy by submitting a request

to OPRR. No waiver will be granted unless sufficient justification is provided and the waiver is approved in writing by OPRR.
Appendix

Laboratory-Animal Facilities Fully

Accredited by the American Association

for Accreditation of Laboratory Animal Care

As of April 1, 1985, there were 483 facilities listed

as fully accredited by the American Association for

Accreditation of Laboratory Animal Care (AAALAC)

(New Lenox, IL). Institutions are categorized as universities, medical schools, combined facilities for health

sciences, veterinary schools, dental schools, colleges

of pharmacy, colleges of biological science, colleges of

arts, colleges of engineering, Veterans’ Administration

medical centers, pharmaceutical manufacturers, government laboratories, commercial laboratories, hospitals, nonprofit research laboratories, or laboratory

animal breeders. The following list of AAALAC-accredited facilities numbers 538, as some institutions are

listed in more than one category. (Facilities receiving

accreditation since April 1, 1985, are not listed.)

Universities

(Programs serving an entire campus)

Alabama:

University of Alabama, University

University of Alabama at Birmingham and the

Veterans’ Administration Medical Center,

Birmingham

Arkansas:

University of Arkansas at Little Rock, Little

Rock

California:

University of California-Davis, Davis

University of California-San Diego, San Diego

University of California at Los Angeles, Los

Angeles

University of Southern California, Los Angeles

Georgia:

Medical College of Georgia, Augusta

Illinois:

University of Illinois at the Medical Center and

the Veterans’ Administration Medical Center,

Chicago

Kansas:

University of Kansas-Lawrence, Lawrence

Massachusetts:

Massachusetts Institute of Technology,

Cambridge

Michigan:

University of Michigan, Ann Arbor, Dearborn,

and Flint

Wayne State University, Detroit

Missouri:

University of Missouri-Kansas City, Kansas City

Montana:

University of Montana, Missoula

Nebraska:

University of Nebraska at Omaha, Omaha

New York:

St. John’s University, Jamaica

State University of New York at Buffalo, Buffalo

Rockefeller University, New York

North Carolina:

Duke University, Durham

Oklahoma:

Oral Roberts University, Tulsa

Rhode Island:

Brown University, Providence

South Carolina:

University of South Carolina, Columbia

Tennessee:

Oak Ridge Associated Universities, Oak Ridge

Vanderbilt University, Nashville

Utah:

University of Utah, Salt Lake City

Virginia:

Virginia Commonwealth University, Richmond

University of Virginia, Charlottesville

Washington:

University of Washington, Seattle

Universities (Programs serving

only a portion of a campus)

California:

Divisions of Animal Resources, University of

California, Berkeley

Georgia:

Yerkes Regional Primate Research Center,

Emory University, Atlanta

Ohio:

Laboratory Animal Center, The Ohio State

University, Columbus

401
402 Alternatives to Animal Use in Research, Testing, and Education

Medical Schools

Arizona:,

Arizona Medical Center, University of Arizona,

Tucson

Arkansas:

Medical Center, University of Arkansas, Little

Rock

California:

California College of Medicine, University of

California, Irvine

School of Medicine, University of California at

Los Angeles, Los Angeles

School of Medicine, University of California at

San Diego, San Diego

Charles R. Drew Postgraduate Medical School,

Los Angeles

School of Medicine, Loma Linda University,

Loma Linda

Colorado:

Medical School, University of Colorado, Denver

Connecticut:

School of Medicine, University of Connecticut

Health Center, Farmington

School of Medicine, Yale University, New Haven

District of Columbia:

School of Medicine, Georgetown University

College of Medicine, Howard University

Florida:

College of Medicine, University of Florida,

Gainesville

Medical Center, University of South Florida,

Tampa

Illinois:

Chicago College of Osteopathic Medicine,

Chicago

The Chicago Medical School/University of Health

Services, North Chicago

College of Medicine-Rockford, University of

Illinois, Rockford

Stritch School of Medicine, Loyola University,

Maywood

School of Medicine, Southern Illinois University,

Springfield

Iowa:

College of Osteopathic Medicine and Surgery,

Des Moines

Kentucky:

Medical Center, University of Kentucky,

Lexington

School of Medicine, University of Louisville,

Louisville

Louisiana:

School of Medicine, Tulane University, New

Orleans

Delta Regional Primate Research Center, Tulane

University, Covington

Maryland:

School of Medicine, University of Maryland at

Baltimore, Baltimore

School of Medicine, Uniformed Services

University of the Health Sciences, Bethesda

Massachusetts:

Medical School, Harvard University, Boston

Medical Center, University of Massachusetts,

Worcester

School of Medicine, Tufts-New England Medical

Center, Boston

Michigan:

Medical Center, University of Michigan, Ann

Arbor

Medical School, Wayne State University, Detroit

Minnesota:

School of Medicine, University of MinnesotaDuluth, Duluth

Medical School, University of Minnesota,

Minneapolis

Missouri:

The University of Health Sciences, Kansas City

Kirksville College of Osteopathic Medicine,

Kirksville

School of Medicine, University of Missouri,

Columbia

Nebraska:

College of Medicine, University of Nebraska,

Omaha

New Hampshire:

Dartmouth Medical School, Hanover

New Jersey:

Medical School, College of Medicine and

Dentistry of New Jersey, Newark

New Mexico:

School of Medicine, University of New Mexico,

Albuquerque

New York:

Albany Medical College of Union University,

Albany

Albert Einstein College of Medicine, Bronx

College of Physicians and Surgeons, Columbia

University, New York

Medical College, Cornell University, New York

Mount Sinai Medical Center, New York

Downstate Medical Center, State University of

New York, Brooklyn
App. D—Laboratory-Animal Facilities Fully Accredited by AAALAC . 403

School of Medicine, University of Rochester,

Rochester

North Carolina:

School of Medicine, University of North

Carolina, Chapel Hill

Bowman Gray School of Medicine, Wake Forest

College, Winston-Salem

Ohio:

Medical College of Ohio, Toledo

College of Medicine, University of Cincinnati,

Cincinnati

College of Medicine, Northeastern Ohio

Universities, Rootstown

Department of Animal Laboratories, Hospitals,

and College of Medicine, The Ohio State

University, Columbia

Oregon:

Oregon Health Sciences University, Portland

Pennsylvania:

School of Medicine, Hahnemann University,

Philadelphia

Milton S. Hershey Medical Center, Pennsylvania

State University, Hershey

Jefferson Medical College, Thomas Jefferson

University, Philadelphia

School of Medicine, University of Pittsburgh,

Pittsburgh

Puerto Rico:

Medical Sciences Campus, University of Puerto

Rico, San Juan

South Carolina:

School of Medicine, University of South

Carolina, Columbia

Tennessee:

Meharry Medical College, Nashville

Texas:

Texas College of Osteopathic Medicine, North

Texas State University, Ft. Worth

Medical School, University of Texas at Houston,

Houston

Utah:

College of Medicine, University of Utah, Salt

Lake City

Vermont:

College of Medicine, University of Vermont,

Burlington

Virginia:

Medical College of Virginia, Virginia

Commonwealth University, Richmond

Medical Center, University of Virginia,

Charlottesville

Eastern Virginia Medical School, Norfolk

Washington:

School of Medicine, University of Washington,

Seattle

Wisconsin:

Medical College of Wisconsin, Milwaukee

Medical School, University of Wisconsin,

Madison

Combined Facilities for Health Sciences

Connecticut:

University of Connecticut Health Center,

Farmington

District of Columbia:

Georgetown University Medical Center

School of Medicine and Health Sciences, George

Washington University

Florida:

University of Florida, J. Hillis Miller Health

Center and the Veterans’ Administration

Medical Center, Gainesville

Illinois:

Life Sciences Vivarium, Southern Illinois

University, Carbondale

Indiana:

Lobund Laboratory, University of Notre Dame,

Notre Dame

Kansas:

University of Kansas-Lawrence, Lawrence

Louisiana:

Medical Center, Louisiana State University, New

Orleans

Maryland:

Johns Hopkins Medical Institutions, Baltimore

Massachusetts:

Boston University School of Medicine and

Graduate School of Dentistry, Boston

Harvard University Medical School, Dental

School, School of Public Health, Animal

Research Center, and the New England

Regional Primate Research Center, Southboro

Tufts-New England Medical Center, Boston

Minnesota:

Health Sciences, University of Minnesota,

Minneapolis

Missouri:

John M. Dalton Research Center, Graduate

School, University of Missouri, Columbia

New Jersey:

College of Medicine and Dentistry of New

Jersey, Newark

New York:

Health Sciences Center, State University of New

York at Stony Brook, Stony Brook

School of Medicine and Dentistry, University of

Rochester, Rochester

North Carolina:

School of Medicine and School of Dentistry,

University of North Carolina, Chapel Hill
—

404 . Altematives to Animal Use in Research, Testing, and Education

Oklahoma:

University of Oklahoma Health Sciences Center

at Oklahoma City, Oklahoma City

Texas:

University of Texas Health Science Center, San

Antonio

Virginia:

School of Basic Sciences, Virginia

Commonwealth University, Richmond

West Virginia:

West Virginia University Medical Center,

Morgantown

Wisconsin:

University of Wisconsin, Madison

Graduate School, University of Wisconsin,

Madison

Veterinary Schools

California:

School of Veterinary Medicine, University of

California-Davis, Davis

Florida:

College of Veterinary Medicine, University of

Florida, Gainesville

Louisiana:

School of Veterinary Medicine, Louisiana State

University, Baton Rouge

Massachusetts:

School of Veterinary Medicine, Tufts-New

England Medical Center, Boston

New York:

New York State College of Veterinary Medicine,

Cornell University, Ithaca

Tennessee:

College of Veterinary Medicine, University of

Tennessee, Knoxville

Wisconsin:

School of Veterinary Medicine, University of

Wisconsin, Madison

Dental Schools

California:

School of Dentistry, University of California at

Los Angeles, Los Angeles

Connecticut:

Dental School, University of Connecticut Health

Center, Farmington

District of Columbia:

School of Dentistry, Georgetown University

Florida:

College of Dentistry, University of Florida,

Gainesville

Illinois:

Dental School, University of Illinois at the

Medical Center, Chicago

School of Dentistry,

Maywood

Indiana:

School of Dentistry,

Indianapolis

Maryland:

School of Dentistry,

Baltimore

Massachusetts:

School of Dentistry,

Loyola University,

Indiana University,

University of Maryland,

Harvard University, Boston

School of Dental Medicine, Tufts-New England

Medical Center, Boston

Michigan:

School of Dentistry, University of Michigan,

Ann Arbor

Minnesota:

School of Dentistry, University of Minnesota,

Minneapolis

New Jersey:

School of Dentistry, Fairleigh Dickinson

University, Hackensack

Dental School, College of Medicine and

Dentistry of New Jersey, Newark

New York:

School of Dentistry, University of Rochester,

Rochester

North Carolina:

School of Dentistry, University of North

Carolina, Chapel Hill

Ohio:

College of Dentistry, The Ohio State University,

Columbus

Oregon:

School of Dentistry, Oregon Health Sciences

University, Portland

Washington:

School of Dentistry, University of Washington,

Seattle

Colleges of pharmacy

Florida:

College of Pharmacy, University of Florida,

Gainesville

Indiana:

School of Pharmacy and Pharmaceutical

Sciences, Purdue University, Lafayette

Kansas:

School of Pharmacy, University of KansasLawrence, Lawrence
—

App. D—Laboratory-Animal Facilities Fully Accredited by AAALAC 405

Massachusetts:

Massachusetts College of Pharmacy and Allied

Health Sciences, Boston

Michigan:

College of Pharmacy, University of Michigan,

Ann Arbor

Minnesota:

College of pharmacy, University of Minnesota,

Minneapolis

Nebraska:

School of Pharmacy,

Omaha

New Mexico:

College of Pharmacy,

Albuquerque

Ohio:

College of Pharmacy,

Columbus

South Carolina:

College of Pharmacy,

Carolina, Columbia

Virginia:

University of Nebraska,

University of New Mexico,

The Ohio State University,

University of South

School of Pharmacy, Virginia Commonwealth

University, Richmond

Washington:

School of Pharmacy, University of Washington,

Seattle

College of Pharmacy, Washington State

University, Pullman

Wisconsin:

School of Pharmacy, University of Wisconsin,

Madison

Colleges of Biological Science

California:

College of Biological Sciences and Scripps

Oceanography, University of California-San

Diego, San Diego

Pomona College, Claremont

South Carolina:

College of Humanities and Social Sciences,

University of South Carolina, Columbia

College of Science and Mathematics, University

of South Carolina, Columbia

Utah:

College of Science, University of Utah, Salt Lake

City

College of Social and Behavioral Science,

University of Utah, Salt Lake City

Washington:

College of Biological and Laboratory Animal

Resource Center, Washington State

University, Pullman

Colleges of Arts

Alabama:

College of Arts and Sciences, University of

Alabama, University

Tennessee:

College of Liberal Arts, University of Tennessee,

Knoxville

Virginia:

School of Arts and Sciences, Virginia

Commonwealth University, Richmond

College of Arts and Science,

Virginia, Charlottesville

Washington:

College of Arts and Science,

Washington, Seattle

College of Arts, Washington

Pullman

College of Engineering

New York:

University of

University of

State University,

Biomedical Engineering Laboratory, Rensselaer

Polytechnic Institute, Troy

Veterans’ Administration Medical

Centers

Alabama:

Birmingham

Arizona:

Tucson

Phoenix

Arkansas:

Little Rock

North Little Rock

California:

Fresno

Loma Linda

Long Beach

Martinez

San Diego

San Francisco

Sepulveda

West Los Angeles

Colorado:

Denver

Connecticut:

West Haven

Delaware:

Wilmington

District of Columbia:

Washington

Florida:

Gainesville
406. Alternatives to Animal Use in Research, Testing, and Education

Tampa

Miami

Lake City

Bay Pines

Georgia:

Decatur

Augusta

Illinois:

Chicago (2)

North Chicago

Hines

Indiana:

Indianapolis

Iowa:

Iowa City

Des Moines

Kentucky:

Lexington

Louisiana:

New Orleans

Shreveport

Maryland:

Perry Point

Baltimore

Massachusetts:

Bedford

Boston

Brockton

West Roxbury

Michigan:

Allen Park

Ann Arbor

Minnesota:

Minneapolis

Mississippi:

Jackson

Missouri:

Kansas City

Columbia

St. Louis

Nebraska:

Omaha

New Mexico:

Albuquerque

New Jersey:

East Orange

New York:

Albany

Brooklyn

Buffalo

Castle Point

New York

Northport

Syracuse

North Carolina:

Asheville

Durham

Ohio:

Cleveland

Cincinnati

Dayton

Oklahoma:

Oklahoma City

Oregon:

Portland

Pennsylvania:

Coatesville

Philadelphia

Puerto Rico:

San Juan

South Carolina:

Charleston

Tennessee:

Memphis

Nashville

Texas:

Dallas

Houston

San Antonio

Utah:

Salt Lake City

Virginia:

Richmond

Washington:

Seattle

Tacoma

West Virginia:

Huntington

Wisconsin:

Madison

Wood

Vermont:

White River Junction

pharmaceutical Manufacturers

California:

Hyland Division, Travenol Laboratories,

Glendale

Quidel, La Jolla

Connecticut:

Boehringer Ingelheim Ltd., Ridgefield

Miles Laboratories, Inc., West Haven

Medical Research Laboratory, Charles Pfizer &

Co., Inc., Groton

Delaware:

Stuart Pharmaceuticals, Division of ICI

Americas, Inc., Wilmington
App. D—Laboratory-Animal Facilities Fully Accredited by AAALAC ● 407

Illinois:

Abbott Laboratories, North Chicago

American Critical Care, American Hospital

Supply Corporation, McGaw Park

Division of Biological Research, G.D. Searle &

Co., Chicago

Travenol Laboratories, Inc., Morton Grove

Indiana:

Bristol-Myers Company, Evansville

Eli Lilly and Company, Indianapolis and

Greenfield

Miles Laboratories, Inc., Elkhart

Michigan:

The Upjohn Company, Kalamazoo

Warner-Lambert/Parke-Davis, Ann Arbor and

Detroit

Minnesota:

Riker/3M, St. Paul

Missouri:

Mallinckrodt, Inc., St. Louis

Marion Laboratories, Inc., Kansas City

Mississippi:

Travenol Laboratories, Inc., Cleveland

New Jersey:

Berlex Laboratories, Inc., Cedar Knolls

Biological Research Division, Bristol-Myers

Products, Inc., Hillside

Pharmaceuticals Division, Ciba-Geigy, Inc.,

Summit

Hoechst-Roussel Pharmaceuticals, Inc.,

Somerville

Ethicon Research Foundation, Somerville

Hoffman-La Roche, Inc., Nutley

Johnson & Johnson Baby Products Company,

Skillman

Johnson & Johnson Research Foundation, New

Brunswick

Merck Institute for Therapeutic Research,

Merck Sharp & Dohme Research

Laboratories, Rahway

Merck Sharp & Dohme Research Laboratories,

Branchburg Farm, Somerville

Ortho Pharmaceutical Corporation, Raritan

Sandoz Inc., East Hanover

Biological Research Division, Schering Corp.,

Bloomfield

Toxicology and Pathology Division, Schering

Corp., Lafayette

Squibb Institute for Medical Research, E.R.

Squibb & Sons, Inc., Princeton and New

Brunswick

Wallace Laboratories, Carter Wallace, Inc.,

Cranbury

New York:

American Cyanamid Company, Lederle

Laboratories, Pearl River

Bristol-Myers Company, Buffalo

Norwich-Eaton Pharmaceuticals, Norwich

Pennwalt Corporation, Rochester

Revlon Health Care Group, Tuckahoe

North Carolina:

Becton Dickinson and Company Research

Center, Research Triangle Park and Durham

Wellcome Research Laboratories, BurroughsWellcome, Co., Research Triangle Park

Ohio:

Merrell Research Center, Merrell Dow

Pharmaceuticals, Cincinnati

Pennsylvania:

McNeil Pharmaceutical, Inc., Spring House

Merck Institute for Therapeutic Research,

Merck Sharp & Dohme Research

Laboratories, West Point

Veterinary Services and Veterinary Pathology,

Merck Sharp & Dohme, West Point

William H. Rorer, Inc., Fort Washington

Research and Development DivisonPharmaceuticals, Smith Kline & French

Laboratories, Philadelphia

Wyeth Laboratories, Radnor

Virginia:

A.H. Robins Research Laboratories, A.H. Robins,

Co., Richmond

France:

Searle Recherche et Developpement, G.D. Searle

and Company, Valbonne

Government Laboratories

Alabama:

U.S Army Aeromedical Research Laboratory,

Fort Rucker

Arizona:

National Center for Toxicological Research,

Jefferson

California:

Health Protection Systems/Laboratory Services

Program, California Department of Health,

Berkeley

Letterman Army Institute of Research, Animal

Resources Division, Presidio of San Francisco,

San Francisco

Colorado:

Fitzsimons Army Medical Center, Aurora

Connecticut:

Naval Submarine Medical Research Laboratory,

Naval Submarine Medical Center, Groton
408 . Altematives to Animal Use in Research, Testing, and Education

District of Columbia:

Armed Forces Institute of Pathology,

Washington

Florida:

Naval Aerospace Medical Research Laboratory,

Naval Aerospace Medical Institute, Pensacola

John F. Kennedy Space Center, John F.

Kennedy Space Center

Georgia:

Centers for Disease Control, Atlanta

Hawaii:

Tripler Army Medical Center, Honolulu

Illinois:

Argonne National Laboratory, Argonne

Naval Dental Research Institute, Great Lakes

Naval Base, Great Lakes

Iowa:

National Animal Disease Center, U.S.

Department of Agriculture, Ames

Louisiana:

Naval Biodynamics Laboratory, New Orleans

Maryland:

Bureau of Biologics, Food and Drug

Administration, Bethesda

Frederick Cancer Research Facility, National

Cancer Institute, Frederick

Medical Laboratory Veterinary, Medicine

Service, Department of Pathology, Ft. Meade

Gerontology Research Center, National Institute

on Aging, National Institutes of Health,

Baltimore

Veterinary Resources Branch, National Institutes

of Health, Bethesda

U.S. Army Environmental Hygiene Agency,

Edgewood

U.S. Army Medical Research Institute of

Chemical Defense, Aberdeen Proving Ground

U.S. Army Medical Research Institute of

Infectious Diseases, Fort Detrick, Frederick

Massachusetts:

Human Nutrition Research Center at Tufts

University, Boston

U.S. Army Research Institute of Environmental

Medicine, Natick

Mississippi:

USAF Medical Center Keesler, Keesler Air Force

Base

Montana:

National Institute of Allergy and Infectious

Disease, National Institutes of Health,

Hamilton

New Mexico:

Los Alamos National Laboratory, University of

California, Los Alamos

New York:

Brookhaven National Laboratory, Upton

Food and Drug Research Laboratories, Inc.,

Waverly

North Carolina:

National Institute of Environmental Health

Sciences, National Institutes of Health,

Research Triangle Park

United States Environmental Protection Agency,

Research Triangle Park

Ohio:

National Institute for Occupational Safety and

Health, Cincinnati

United States Environmental Protection Agency,

Cincinnati

USAF 6570th Aerospace Medical Research

Laboratories, Wright-Patterson AFB

Oklahoma:

Civil Aeromedical Institute, FAA Aeronautical

Center, Oklahoma City

Oregon:

Oregon Regional Primate Research Center,

Beaverton

Pennsylvania:

Naval Air Development Center, Warminster

Tennessee:

Oak Ridge National Laboratory, Biology Division,

Oak Ridge

Texas:

William Beaumont Army Medical Center (U.S.

Army), El Paso

Brooke Army Medical Center, Department of

Pathology and Laboratory Services, Fort Sam

Houston

Texas Research Institute of Mental Sciences,

Houston

USAF School of Aerospace Medicine, Brooks

AFB

Washington:

Madigan Army Medical Center, Tacoma

Commercial Laboratories

Arizona:

Armour Research Center, Armour-Dial

Company, Scottsdale

Arkansas:

INTOX Laboratories, Inc., Little Rock

California:

American Pharmaseal Laboratories, Irwindale

Bio-Devices Laboratories, Inc., Orange

Chevron Environmental Health Center,

Richmond
App. D—Laboratory-Animal Facilities Fully Accredited by AAALAC ● 409

Edwards Laboratories, Santa Ana

McGaw Laboratories, Irvine

Science Applications, Inc., La Jolla

North American Science Associates of

California, Irvine

Shell Development Company, Modesto

Stauffer Chemical Company, Mountain View

Connecticut:

United States Surgical Corporation, Norwalk

Stauffer Chemical Company, Farmington

Delaware:

Haskell Laboratory for Toxicology and

Industrial Medicine, Newark

Florida:

Life Sciences, Inc., St. Petersburg

Sherwood Medical Laboratories, Inc., DeLand

Georgia:

American McGaw, Milledgeville

Illinois:

American Biogenics Corporation, Decatur

Kendall Company Health Research Center,

Barrington

Quaker Oats Company, Barrington

Kansas:

Mobay Chemical Corporation, Stilwell

BAVET Division of hliles Laboratories, Inc.,

Shawnee Missions

Maryland:

BioCon, Inc., Rockville

Biotech Research Laboratories, Inc., Rockville

Borriston Laboratories, Inc., Temple Hills

Gillette Capital Corporation, Rockville

Laboratory Animal Services, Inc., Rockville

Litton Bionetics, Inc., Bethesda

Microbiological Associates, Bethesda

Tegeris Laboratories, Inc., Laurel

Massachusetts:

Arthur D. Little, Inc., Cambridge

Bioassay Systems Corporation, Woburn

Biotek, Inc., Woburn

EG & G Mason Research Institute, Inc.,

Worcester

SISA Laboratories Inc., Cambridge

Michigan:

Toxicology Research Laboratory, The Dow

Chemical Company, Midland

Dow Corning Corporation, Midland

General Motors Research Laboratories, Warren

International Research and Development

Corporation, Mattawan

Toxicity Research Laboratories, Ltd., Muskegon

Minnesota:

Medtronic, Inc., Coon Rapids

Missouri:

Environmental Health Laboratory, Monsanto

Company, St. Louis

New Jersey:

Biodynamics, Inc., East Millstone

Colgate Palmolive Research Center, Piscataway

Cyanamid Foundation for Agricultural

Development, Princeton

Exxon Biomedical Sciences, Inc., East Millstone

FMC Corporation Toxicology Laboratory,

Somerville

FMC Corporation, Princeton

Lever Brothers Company, Edgewater

Mobil Oil Corporation, Princeton

Revlon Research Center, Inc., Edison

New York:

Eastman Kodak Company, Rochester

Ohio:

Ben Venue Laboratories, Inc., Bedford

Hill Top Research, Inc., Miamiville

North American Science Associates, Inc.,

Northwood

Procter and Gamble Company, Cincinnati

Toilet Goods Division, Procter and Gamble

Company, Cincinnati

Springborn Institute for Bioresearch, Inc.,

Spencerville

WIL Research Laboratories, Inc., Ashland

Pennsylvania:

Biosearch, Inc. Philadelphia

M.B. Research Laboratories, Inc., Spinnertown

Pharmakon Research International, Inc.,

Waverly

Rohm and Haas Company, Spring House

Texas:

Alcon Laboratories, Fort Worth

Health and Environmental Sciences, Dow

Chemical, U. S. A., Lake Jackson

STILLMEADOW, Inc., Houston

Virginia:

Flow Laboratories, Inc., McLean

Hazelton Laboratories America, Inc., Vienna

Meloy Laboratories, Inc., Springfield

Washington:

Genetics Systems Corp., Seattle

Hollister-Stier, Division of Miles Laboratories,

Inc., Spokane

Oncogen, Seattle

Wisconsin:

Hazelton Laboratories America, Inc., Madison

Canada:

Bio-Research Laboratories, Ltd., Senneville,

Quebec

38-750 0 - 86 - 14
410 . Alternatives to Animal Use in Research, Testing, and Education

Hospitals

Arizona:

Barrow Neurological Institute, St. Joseph’s

Hospital and Medical Center, Phoenix

California:

Children’s Hospital of San Francisco, San

Francisco

Sutter Hospitals Medical Research Foundation,

Sutter Community Hospitals, Sacramento

Colorado:

Denver General Hospital, Denver

National Jewish Hospital, Denver

District of Columbia:

Research Foundation of the Washington

Hospital Center

Research Foundation of Children’s Hospital,

Children’s Hospital

Florida:

Mount Sinai Medical Center, Miami Beach

Illinois:

Evanston Hospital Association, Evanston

Michael Reese Hospital and Medical Center,

Chicago

Louisiana:

Southern Baptist Hospital, New Orleans

U.S. Public Health Service Hospital, Carville

Maryland:

Maryland Psychiatric Research Center,

Catonsville

Massachusetts:

Beth Israel Hospital, Boston

New England Deaconess Hospital, Boston

St. Vincent Healthcare System, Inc., Worcester

New England Medical Center Hospitals, TuftsNew England Medical Center, Boston

Michigan:

Henry Ford Hospital, Detroit

Sinai Hospital of Detroit, Detroit

Wayne County General Hospital, Westland

Minnesota:

Saint Paul-Ramsey Medical Center, St. Paul

New Jersey:

Newark Beth Israel Medical Center, Newark

New York:

Beth Israel Medical Center, New York

Hospital for Special Surgery, New York

Montefiore Hospital and Medical Center, Bronx

Nassau Hospital, Mineola

Nassau County Medical Center, East Meadow

St. Luke’s-Roosevelt Institute for Health

Sciences, New York

St. Vincent’s Hospital and Medical Center of NY,

New York

Ohio:

Akron City Hospital, Akron

Children’s Hospital Research Foundation,

Children’s Hospital, Columbus

Children’s Hospital Research Foundation,

Children’s Hospital Medical Center, Cincinnati

Cleveland Research Institute, Cleveland

Pennsylvania:

Albert Einstein Medical Center, Northern

Division, Philadelphia

Graduate Hospital, Philadelphia

Lehigh Valley Hospital Center, Allentown

Skin and Cancer Hospital of Philadelphia,

Philadelphia

Joseph Stokes, Jr. Research Institute of the

Children’s Hospital of Philadelphia

Rhode Island:

Miriam Hospital, Providence

Tennessee:

St. Jude Children’s Research Hospital, Memphis

University of Tennessee Memorial Hospital and

Research Center, Knoxville

Texas:

Scott and White Memorial Hospital, Temple

Nonprofit Research Laboratories

California:

Cedar-Sinai Medical Research Institute, Los

Angeles

Huntington Institute of Applied Medical

Research, Pasadena

Lawrence Berkeley Laboratory, Berkeley

Palo Alto Medical Research Foundation, Palo

Alto

Research and Education Institute, Inc., HarborUCLA Medical Center, Torrance

SRI International, Menlo Park

Whittier Institute for Diabetes and

Endocrinology, La Jolla

Connecticut:

John B. Pierce Foundation Laboratory, New

Haven

Florida:

Miami Heart Institute, Miami Beach

Illinois:

American Dental Association Research Institute,

Chicago

Life Sciences Division, IIT Research Institute,

Chicago

Kansas:

Menninger Foundation, Topeka
App. D—Laboratory-Animal Facilities Fully Accredited by AAALAC . 411

Louisiana:

Division of Research, Alton Ochsner Medical

Foundation, New Orleans

USL New Iberia Research Center, New Iberia

Maine:

Jackson Laboratory, Bar Harbor

Maryland:

American Type Culture Collection, Rockville

Massachusetts:

Worcester Foundation for Experimental Biology,

Inc., Shrewsbury

Center for Blood Research, Inc., Boston

Dana-Farber Cancer Institute, Boston

Forsyth Dental Center, Boston

Eunice Kennedy Shriver Center for Mental

Retardation, Waltham

Michigan:

Michigan Cancer Foundation, Detroit

Missouri:

Midwest Research Institute, Kansas City

Nebraska:

Eppley Institute for Research in Cancer, Omaha

New Mexico:

Lovelace Biomedical and Environmental

Research Institute, Inc., Albuquerque

iNew Jersey:

Institute for Medical Research, Camden

New York:

American Health Foundation, Naylor Dana

Institute for Disease Prevention, Valhalla

Cold Spring Harbor Laboratory, Cold Spring

Harbor

Memorial Sloan-Kettering Cancer Center, New

York

New York Blood Center, New York

Trudeau Institute, Inc., Saranac Lake

North Carolina:

Chemical Industry Institute for Toxicology,

Research Triangle Park

Research Triangle Institute, Research Triangle

Park

Ohio:

Battelle Memorial Institute, Columbus

Cleveland Clinic Foundation, Cleveland

Oklahoma:

Oklahoma Medical Research Foundation,

Oklahoma City

Pennsylvania:

Bushy Run Research Center, Export

Federated Medical Resources, Honey Brook

Institute for Cancer Research, Philadelphia

Texas:

Southwest Foundation for Research and

Education, San Antonio

Southwest Research Institute, San Antonio

University of Texas Cancer Center, Houston

Veterinary Resources Division, Science Park,

The University of Texas Cancer Center,

Bastrop

Utah:

University of Utah Research Institute, Salt Lake

City

Washington:

Battelle, Pacific Northwest Laboratories,

Richland

Bob Hope International Heart Research

Institute, Seattle

Fred Hutchinson Cancer Research Center,

Seattle

Pacific Northwest Research Foundation, Seattle

Virginia Mason Research Center, Seattle

Laboratory-Animal Breeders

Indiana:

Engle Laboratory Animals, Inc., Farmersburg

Harlan Sprague Dawley, Inc., Indianapolis

Laboratory Supply Company, Indianapolis

Maryland:

M.A. Bioproducts, Inc., Walkersville

Massachusetts:

Charles River Breeding Laboratories, Inc.,

Wilmington

Michigan:

Charles River-Portage, Portage

New Jersey:

Carom Research Institute, Inc., Wayne

Charles River Lakeview, Newfield

H.A.R.E. Rabbits for Research, Marland

Breeding Farms, Hewitt

New York:

Carworth Division, The Charles River Breeding

Laboratories Inc., Kingston

Charles River Research Primates Corporation,

Port Washington

Taconic Farms, Inc., Germantown

Tennessee:

Cumberland View Farms, Clinton

Virginia:

Hazelton Research Primates, Reston

Hazelton Research Animals, Inc., Vienna

Canada:

Charles River Canada Incorporated, St.

Constant, Quebec
Appendix E

International Agreements

Governing Animal Use

Convention on International Trade

in Endangered Species

In 1973, the Convention on International Trade in

Endangered Species of Fauna and Flora (CITES) was

signed by 61 nations. It has since been ratified by a

total of 81 separate nations and has been enforced in

the United States since 1977 (10,11).

In addition to protecting animals from extinction,

the Convention specifies in seven different places that

the Management Authority must be “satisfied that any

living specimen will be so transported and cared for

as to minimize the risk of injury, damage to health or

cruel treatment. ” CITES is administered on an international basis by the International Union for the Conservation of Nature and Natural Resources headquartered in Gland, Switzerland. Endangered plants and

animals are listed in three Appendixes to the Convention, according to level of endangerment. For purposes

of monitoring, all primates have been included in Appendix 11 (“Threatened”) except chimpanzees, which

are classified as “Endangered. ” Under CITES provisions, the effect of the Appendix 11 classification has

been to require export permits for all listed primates.

The U.S. agency responsible for administration of

CITES provisions is the Research Division of the Fish

and Wildlife Service, Department of the Interior, which

has additional responsibilities regarding international

trade in endangered or threatened species under Section 7 of the Endangered Species Act of 1973. (For a

brief discussion of how this act affects experimentation in the United States, see ch. 13.) Current CITES

Appendixes listings, by species of wildlife and family

of plants, can be found in part 23 of title 50 of the

Code of Federal Regulations; lists of endangered and

threatened wildlife species and plant families affected

by the Endangered Species Act are found in part 17.

The Convention’s importance to research is twofold.

First, it has limited trade in nonhuman primates and

a few other species favored at one time or another

in experiments (1). Second, continued review of the

Convention by signatories has served as a forum for

discussion of protection of laboratory animals. CITES

signatories meet periodically in conferences, convened

under CITES provisions, to discuss the required classification of species according to the terms of the Convention. Under regulations promulgated by the Fish

and Wildlife Service (50 CFR 23.31-,39), members of

the public must be given notice of the U.S. negotiating position at CITES conferences and an opportunity

to provide information and comments on the proposed

agenda, including at least one public meeting. Humane

groups have used these meetings to raise the issue of

humane treatment of laboratory-animal species in relation to the Convention’s articles (12). Recently, for

example, CITES delegates were petitioned to ratify

proposed interpretations of the Convention to reach

that very question. The petition was ruled outside the

terms of the Convention (9).

Bans on Exporting Primates

From time to time, nations with indigenous populations of nonhuman primates that have been in demand

for various types of traditional research have considered or implemented prohibitions on their export, either to protect dwindling populations or because of

high mortality rates suffered in transit. India ordered

such a ban in 1955, for the latter reason. Because rhesus monkeys were in demand for testing polio vaccines

at the time, India agreed to reopen trade with the

United States on condition that the Surgeon General

sign a certificate of need for each order of monkeys,

with assurances that they be used humanely and only

for medical research and vaccine production. The ban

was reimposed by the Indian Government when it was

revealed that military experiments, specifically prohibited under the agreement, were being done with

some of the monkeys. Other countries have considered similar bans or have imposed ceilings on exports.

Bans were enacted in Malaysia and Bolivia in 1984, and

a U.S. dealer was ousted from Bangladesh in 1979 for

selling Rhesus monkeys for military research (5). Some

commentators have been critical of U.S. estimates of

need for nonhuman primates in research, finding them

overstated, and have faulted the research community

for attempts to circumvent export bans (13).

Draft Convention of the

Council of Europe

The Council of Europe, headquartered in Strasbourg, France, and with 21 member countries, was

organized in 1949 to work for greater European unity,

412
App. E—international Agreements Governing Animal Use “ 413

to improve the conditions of life and develop humane

values in Europe, and to uphold the principles of parliamentary democracy (6).

Historically, the Council has been concerned about

the treatment of animals. It has drafted Conventions

on the protection of animals in international transport

(1968), on those kept for farming purposes (1976), on

slaughter (1979), and on conservation of European

wildlife and natural habitats (1979). In 1971, the Council adopted Recommendation 621, which contained

three relevant proposals:

●

●

●

Establish a-documentation and information center on alternatives to animal use in testing and experimentation.

Establish tissue banks for research.

Establishment of an Ad Hoc Committee of Experts

to study the problems rising out of the abuse of

live animals for experimental industrial purposes,

The Committee was given the task of drafting international legislation setting out the conditions

under which, and the scientific grounds on which,

experiments on live animals may be authorized

(15).

The Ad Hoc Committee of Experts for the Protection of Animals began its work on the Draft Convention in 1978. In 1983, the committee presented a Draft

Convention, guidelines for care and treatment, and a

guidance note on data collection to the Council of Ministers plenary sessions and seven working party meetings under three successive chairmen. The committee was composed of experts from member countries.

Observers from the United States and Europe, including representatives from several nongovernmental

organizations (World Society for the Protection of Animals, Federation of Veterinarians of the European Economic Community, European Federation of Pharmaceutical Industries’ Associations, and the International

Council for Laboratory Animal Science) were admitted

to the committee’s meetings (2,14).

The form of the Draft Convention follows an earlier

one on the treatment of farm animals. Its preamble,

restating the general objective of European unity in

the context of protection of experimental animals,

balances the need of “man in his quest for knowledge,

health and safety . . . to use animals where there is a

reasonable expectation that the result will be to extend knowledge or be to the overall benefit of man

or animal, just as he uses them for food, clothing and

as beasts of burden” against the “moral obligation to

respect all animals and to exercise due consideration

for their capacity for suffering and memory.” As stated

in the preamble, the general objective of the Convention is ‘(to limit wherever practicable the use of animals for experimental and other scientific purposes,

in particular by seeking alternative methods to replace

the use of animals” (2).

Prospects for final ratification of the Draft Convention remain unclear. Twice in 1983 the Council’s assembly failed to achieve the required two-thirds vote

on the committee’s report to urge the Committee of

Ministers to adopt it as soon as possible. Reported

accounts stated that some delegates did not believe

the Convention goes far enough in controlling animal

experimentation. The assembly, however, rejected

amendments that would have outlawed the use of experimental animals (8).

The Convention itself is

are summarized below.

General Principles

divided into 10 parts, which

Article 1 applies the Convention “to any animal being used or intended for use in any experimental or

other scientific procedure where that procedure may

cause pain, suffering, distress, or lasting harm. It does

not apply to any nonexperimental agricultural or clinical veterinary practice. ” “Animal” means, “unless

otherwise qualified . . . any live non-human vertebrate,

including free-living larval and/or reproducing larval

forms, but excluding other foetal or embryonic forms. ”

‘(Procedure” is defined to include:

. . . any experimental or other scientific use of an animal which may cause it pain, suffering, distress or lasting harm, including any course of action intended to,

or liable to, result in the birth of an animal in any such

condition, but excluding the least painful methods accepted in modern practice (i.e., “humane” methods) of

killing or marking an animal; a procedure starts when

the animal is first prepared for use and ends when no

further observations are to be made for that procedure;

the elimination of pain, suffering, distress or lasting

harm by the successful use of anesthesia or analgesia

or other methods does not place the use of an animal

outside the scope of this definition.

Article 2 provides that a defined procedure can be

performed on an animal for only one or more of the

following purposes, subject to other restrictions contained in the Convention:

the avoidance or prevention of disease, ill health

or other abnormality, or their effects, in humans,

vertebrate or invertebrate animals, or plants,

including the production and the quality, efficacy,

and safety testing of drugs, substances, or products;

the diagnosis or treatment of disease, ill health or

other abnormality, or their effects, in humans,

vertebrate or invertebrate animals, or plants;

the assessment, detection, regulation or modification of physiological conditions in humans, vertebrate and invertebrate animals, or plants;

38-750 0 - 86 - 15
414 . Alternatives to Animal Use in Research, Testing, and Education

● the prolongation or saving of life of humans, vertebrate or invertebrate animals or plants;

● the protection of the environment;

Ž the production and quality control of foodstuffs;

● the breeding of vertebrate or invertebrate animals;

. scientific research;

● education and training; or

● forensic inquiries.

Article 3 requires all member nations “to take all necessary steps to give effect to [its] provisions . . . and

to ensure an effective system of control and supervision” within 5 years of the Convention’s approval for

ratification.

Article 4 stipulates that ratification by a member

country does not bar it from adopting stricter measures to control experimental animal use.

General Care and Accommodation

Article 5 requires any animal to be used in a procedure to be provided with “accommodation, an environment, at least a minimum freedom of movement,

food, water, and care all appropriate to its health and

well-being. Any restriction on the extent to which an

animal can satisfy its physiological and ethnological

needs shall be limited as far as practicable.” Environmental conditions must be checked daily and as

needed to prevent avoidable suffering.

Conduct of Procedure

Article 6 requires that procedures not be performed

where “another scientifically satisfactory method, not

entailing the use of an animal, is reasonably and practicably available,” and asks member nations to “encourage, if possible, scientific research into the development

of methods which could provide the same information as that obtained in procedures.”

Article 7 requires careful consideration of choice of

species in procedures and that choices be explained,

where required, to the responsible authority. Procedures should use the minimum number of animals,

cause the least pain, suffering, distress, or lasting harm

consistent with providing satisfactory results.

Article 8 requires all procedures to be performed

under general or local anesthetic or by other methods designed to eliminate to the extent practicable

pain, suffering, distress, or lasting harm unless the

methods are judged to be more distressing than the

procedure or are incompatible with the aim of the procedure.

Article 9 requires specific authorization of the authority where an animal may experience severe pain

that is likely to endure. Authorization must be refused

if the authority judges that the procedure is not of ex -

ceptional importance for meeting the essential needs

of humans or animals, including the solution of scientific problems.

Article 10 declares that an animal under procedure

remains subject to the provisions of article 5, except

where those provisions are incompatible with the object of the procedure.

Article 11 provides for a decision at the end of procedures whether the animal shall be kept alive or killed

by a humane method, subject to the condition that it

shall not be kept alive if, even though it has been restored to normal health in all other respects, it is likely

to remain in lasting pain or distress. Such decisions

must be made by a veterinarian or a person responsible for the procedure. If an animal is not to be kept

alive it should be killed by a humane method as soon

as possible. Finally, the article provides that no animal be used in more than one painful procedure unless the second procedure is one in which the animal

is subject throughout to general anesthesia, from

which it is not allowed to recover, or the further procedure will involve minor interventions only.

Article 12 permits experimental animals to be set

free as part of the procedure provided that the maximum practicable care has been taken to safeguard the

animal’s well-being. Procedures that involve setting the

animal free are not permitted solely for educational

or training purposes.

Authorization

Article 13 provides that procedures authorized by

article 2 may be performed only by authorized persons or persons under their direct responsibility, or

if the project is authorized by the legislation of a member country. Only persons deemed competent by the

responsible authority may be so authorized.

Breeding or Supplying Establishments

The four articles contained in this part establish

principles for breeders and suppliers of experimental

animals, who would be required to:

●

●

●

●

register and comply with article 5 (article 14);

specify a competent person in charge with authority to administer or arrange for suitable care (article 15);

keep detailed records on breeding, shipment, and

transfer, to be maintained at least 3 years from

the date of last entry (article 16); and

mark humanely for identification dogs and cats

and maintain complete records to promote their

identification (article 17).
App. E—International Agreements Governing Animal Use ● 415

User Establishments

Under the provisions of the seven articles in this

part, users (i.e., experimental facilities) would be required to:

register with national authorities and comply with

article 5 (article 18);

provide equipment and facilities appropriate for

species used and to ensure that the procedures

are performed as effectively as practicable with

the minimum number of animals and the minimum degree of pain, suffering, distress, or lasting harm (article 19);

identify persons administratively responsible for

care and equipment, provide sufficiently trained

staff, and make adequate arrangements for veterinary advice and treatment (article 20);

use only animals supplied by registered breeders

or suppliers, subject to national exceptions (article 21);

use only mice, rats, guinea pigs, golden hamsters,

rabbits, dogs, cats, or quail originating in or acquired directly from registered breeding establishments, subject to national exemptions (member

countries would add species to the list, particularly primates, as soon as there is a reasonable

prospect of a sufficient supply of purpose-bred

animals; straying domestic animals cannot be used

and exemptions are not permitted) (article 22);

conduct procedures outside their establishments

only where authorized by the national authority

(article 23); and

keep records adequate to meet the requirements

of article 27 and, in addition, to show the number and species of all animals acquired, from

whom acquired, and date of arrival, and to make

such records available for inspections by the responsible authority (article 24).

Education and Training

Article 25 specifies that professional and training

procedures must be approved by responsible authorities before being used and must be carried out by or

under the supervision of a qualified person. Procedures are not permitted at or below the secondary

level except when it is specifically directed to preparing for a career involving treatment or care of animals and the procedures entail no severe or enduring

pain or suffering. Only the minimum measures absolutely necessary for the purpose are permitted, and

only if their objective cannot be achieved by audiovisual or any other suitable methods. Article 26 requires that persons who carry out, take part in, or take

care of animals used for procedures, including supervisors, must have adequate education and training.

Statistical Information

Article 27 requires each agreeing nation to collect

and make public, where lawful, statistical information

on animals in experimentation, including:

● numbers and kinds of animals used;

. numbers of animals, by categories, used in procedures directly concerned with medicine and in

teaching and learning;

. numbers of animals, by categories, used in procedures for the protection of humans and their

environment; and

● numbers of animals, by categories, used in procedures required by legislation.

Article 28 specifies that, subject to its own secrecy

laws, each nation must submit information annually

in the form set out in Appendix B to the Secretary General of the Council, who is required to publish it. Each

nation is invited to send the name and address of the

corresponding authority, to be included in the Secretary General’s compilation of statistics.

Recognition of International

Procedures

Article 29 binds agreeing nations to share information on results of procedures and to provide mutual

assistance in order to avoid unnecessary repetition of

procedures for the purposes of satisfying national legislation on health and safety.

Final Provisions

Articles 30 through 36 specify the manner and conditions under which the Convention will become ratified and effective (i.e., 6 months after four member

states express their consent to be bound and, for any

ratifying or acceding state after that, 6 months after

written ratification or accession), and reserve a member state’s right to reservation, partial application, or

denunciation (2).

Appendix A of the Draft Convention

Appendix A, Guidelines on Accommodation and Care

of Animals, contains detailed specifications for physical facilities, holding-room environments and environmental control, and care. Though the specifications

are comprehensive, article 5 does refer to them as

“suggested” (3).

Appendix B of the Draft Convention

Appendix B consists of Statistical Tables and Guidance Notes for Their Completion in Fulfillment of the

Requirements in Articles 27 and 28 of the Draft European Convention for the Protection of Vertebrate Ani-
416 . Alternatives to Animal Use in Research, Testing, and Education

reals Used for Experimental and Other Scientific Purposes. The appendix would require submission by

agreeing nations of experimental-animal data, reported to the Secretary General for each calendar year

under the general classifications established by the

referenced articles. The method of data collection is

left to each member nation (4).

Guidelines of the Council for

International Organizations of

Medical Sciences

Through the World Health Organization (WHO),

headquartered in Geneva, Switzerland, more than 150

nations exchange information and share resources for

laboratory-animal science training, technical information, consultative support, and other activities.

In 1985, in the culmination of a 3-year effort initiated in 1982, the Council for International Organizations of Medical Sciences (CIOMS), an international

nongovernmental organization representative of many

branches of medicine and cognate disciplines that was

established under the auspices of WHO and UNESCO

in 1949, issued International Guiding Principles for Biomedical Research Involving Animals (7).

Modeled after the Tokyo revision of the Declaration

of Helsinki by the World Medical Association in 1975

and CIOMS’s Proposed International Guidelines for

Biomedical Research Involving Human Subjects, issued

in 1982, the CIOMS International Guiding Principles

are intended to provide a conceptual and ethical framework for whatever regulatory measure each country

chooses to adopt with respect to animal use (7).

The International Guiding Principles enumerate 11

basic principles, as follows (7):

1.

II.

111,

IV,

The advancement of biological knowledge and

the development of improved means for the protection of the health and well-being both of man

and of animals require recourse to experimentation on intact live animals of a wide variety of

species.

Methods such as mathematical models, computer

simulation and in vitro biological systems should

be used wherever appropriate.

Animal experiments should be undertaken only

after due consideration of their relevance for human or animal health and the advancement of

biological knowledge.

The animals selected for an experiment should

be of an appropriate species and quality, and the

minimum number required, to obtain scientifically valid results.

V. Investigators and other personnel should never

fail to treat animals as sentient, and should reVI.

VII.

VIII.

IX.

x.

XI<

gard their proper care and use and the avoidance

or minimization of discomfort, distress, or pain

as ethical imperatives.

Investigators should assume that procedures that

would cause pain in human beings cause pain in

other vertebrate species although more needs to

be known about the perception of pain in

animals.

Procedures with animals that may cause more

than momentary or minimal pain or distress should

be performed with appropriate sedation, analgesia, or anesthesia in accordance with accepted

veterinary practice. Surgical or other painful procedures should not be performed on unanesthe -

tized animals paralysed by chemical agents.

Where waivers are required in relation to the

provisions of article VII, the decisions should not

rest solely with the investigators directly concerned but should be made, with due regard to

the provisions of articles IV, V, and VI, by a suitably constituted review body. Such waivers should

not be made solely for the purposes of teaching

or demonstration.

At the end of, or when appropriate during, an

experiment, animals that would otherwise suffer severe or chronic pain, distress, discomfort,

or disablement that cannot be relieved should be

painlessly killed.

The best possible living conditions should be

maintained for animals kept for biomedical purposes. Normally the care of animals should be

under the supervision of veterinarians having experience in laboratory animal science. In any

case, veterinary care should be available as required.

It is the responsibility of the director of an institute or department using animals to ensure

that investigators and personnel have appropriate qualifications or experience for conducting

procedures on animals. Adequate opportunities

shall be provided for in-service training, including the proper and humane concern for the animals under their care.

Additional special provisions accompany the basic

principles. These deal with sources of supply of animal subjects; transport conditions; housing, including

space allocation, hygienic standards, and protection

against vermin; environmental conditions, including

temperature, humidity, lighting, and social interaction;

nutrition appropriate to the species; provision of

veterinary care; and the keeping of records (7).

The CIOMS statement also urges that the development and use of alternatives be actively encouraged.

Specifically mentioned are nonbiological methods—

such as the study of structure-activity relationships or
App. E—International Agreements Governing Animal Use ● 417

computer modeling—and biological methods, including the use of micro-organisms, in vitro preparations,

and sometimes animal embryos (7).

Organization for Economic

Cooperation and Development

The Organization for Economic Cooperation and Development (OECD) is a group of nations whose membership accounts for two-thirds of the world’s chemical production, including the United States, Canada,

Japan, and most of the countries of Western Europe.

It also embraces six organizations that have a major

role in international efforts to regulate chemicals (6).

In 1979-80, an international group of experts convened under the OECD’s Special Program on the Control of Chemicals drafted and recommended for the

Council’s approval OECD Principles of Good Laboratory Practice. The Council approved the document in

1981 (OECD, Guidelines for Testing of Chemicals,

C(81)30 (Final), Annex 2).

Though the main purpose for adopting the Princi-

@es was to promote international harmonization of

chemical-testing practices and thereby help safeguard

the integrity of test results required under health and

environmental safety laws, the document is patterned

very much after good laboratory practice regulations

adopted in 1978 by the U.S. Food and Drug Administration (see ch. 13). Following the Principles’ general

command would certainly have an impact on use of

test animals, but they do not contain the same detailed

language on animal care, management, and housing

that domestic regulations do, nor are any sanctions

to be levied for failure to observe them.

Appendix E References

1. Caufield, C., “Animal Treaty is No Protection,” iVevv ScienIisl 1417:43, 1984.

2. Council of Europe, Ad Hoc Committee of Experts for the

Protection of Animals, Final Activity Report, Addendum

I: Draft European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes and Draft Explanatory Report (Strasbourg,

France: May 18, 1983).

3. Council of Europe, Ad Hoc Committee of Experts for

the Protection of Animals, Final Activity Report, Addendum 11: Draft European Convention for the Protection

of Vertebrate AnimaJs Used for Experimental and Other

Scientific Purposes, Appendix A-Guidelines on Accommodation and Cam of Am”mals (Article 5 of the Draft Convention) (Strasbourg, France: May 18, 1983).

4. Councii of Europe, Ad Hoc Committee of Experts for the

5!

6,

7.

8.

9.

10.

11.

12.

13.

Protection of Animals, Final Activity Report, Addendum

III: Draft European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, Appendix E—Statistical Tables and Guidance Notes for Their Completion in Fulfillment of the

Requirements in Articles 27 and 28 of the Draft Convention (Strasbourg, France: May 18, 1983).

Gravitz, M., ‘

(

Primates Get Top Priority,” The Animals

Agenda 5(5):4-5, 1984.

Held, J., “Animals in Research: An International Overview,” Cal. Vet. 1:93-95, 1983.

Howard-Jones, N., “A CIOMS Ethical Code for Animal Experimentation,” WHO Chronicle 39:51-56, 1985.

Japan Science Council, On the Adoption of Guidelines

for Anima] Experimentation, 80th General ,Meeting, Nov.

5, 1980.

Lazarowitz, A., Management Authority, Division of Research, Fish and Wildlife Service, U.S. Department of the

Interior, Washington, DC, personal communication, August 1984.

Leavitt, E. (cd,), Animals and Their Legal Rights (Washington, DC: Animal Welfare Institute, third cd., 1978),

Appendix.

Nay, A., et a]., Animal Welfare Laws in Foreign Countries (Washington, DC: Library of Congress, 1976).

Humane Society News, “Update: The Good With the Bad,”

28:24, 1983.

Rowan, A, N., Of Mice, Models, & Men: A Critical Evaluation of Animal Research (Albany, NY: State University

of New York Press, 1984).

14. Vallier, G., “European Concepts on the Use of Laboratory Animals in Relationship With Animal Welfare Problems,” Dev. Bio/. Stand. 45:189-195, 1980.

15. Weiderkehr, M., “The Council of Europe’s Conventions,”

Council of Europe Forum, March 1982, p. 7.
For this assessment, OTA commissioned 10 reports

on various topics concerning alternatives to animal use

in research, testing, and education. The manuscripts

of these contract reports are available in three volumes

from the National Technical Information Service, 5285

Port Royal Road, Springfield, VA, 22161.

Volume I: Overview

“Survey and Estimates of Laboratory Animal Use in the

United States, ” Kurt Enslein, Health Designs, Inc.,

Rochester, NY.

‘(Ethical Considerations,” Arthur H. Flemming, Department of Philosophy, The University of Chicago, Chicago, IL.

“Scope of ‘Alternatives’: Overview of the State of the

Art, ” Roland M. Nardone and Lucille Ouellette, Department of Biology, Catholic University, Washing

ton, DC.

“Overview of Computer Use in Research, Testing, and

Education,” Paul N. Craig, Shady side, MD.

Volume II: Research

“Alternatives to Animal Use in Biomedical Research,”

Eileen M. Cline, Springfield, VA.

“Alternatives to the Use of Animals in Behavioral Research)” Gordon G. Gallup, Jr., Department of Psychology, State University of New York at Albany, Albany, NY.

“Alternatives to Animal Use in Veterinary Medicine,”

Bennie I. Osburn and faculty, School of Veterinary

Medicine, University of California, Davis, CA.

Volume 111: Testing and Economics

“Animal Testing for Safety and Effectiveness,” Thomas

D. Sabourin, Betsy D. Carlton, Robin T. Faulk, and

L. Barry Goss, Environmental and Health Sciences

Division, Battelle Columbus Laboratories, Columbus,

OH.

“Animal Testing and Alternatives,” Meyer, Failer, and

Weisman, P, C., Washington, DC.

“Economic and Policy Considerations,” Henry R. Hertzfeld and Thomas D. Myers, Washington, DC.

418
Appendix G

Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report, the

contractors who provided material for this assessment, and the many individuals and organizations that supplied information for the study. In addition, OTA acknowledges the following individuals for their review of

drafts of this report:

Robert F. Acker

National Foundation for Infectious Diseases

James Aftosmis

E.I. du Pent de Nemours and Co., Inc.

Donald G. Ahearn

Georgia State University

Gwynn C. Akin

Syntex Corporation

Robert L. Alkire

Society of Toxicologic Pathologists

Douglas L. Archer

Food and Drug Administration

John L. Bartholomew

U.S. Army

Michael Balls

Fund for the Replacement of Animals in

Medical Experiments

Edward M. Barrows

Georgetown University

George W. Beran

Iowa State University

Richard N. Bergman

University of Southern California

Emmanuel M. Bernstein

Psychologists for the Ethical Treatment of Animals

Keith A. Booman

Soap and Detergent Association

Arnold P. Borsetti

Food and Drug Administration

Joseph F. Borzelleca

Medical College of Virginia

Richard C. Bostwick

Merck and Company, Inc.

Richard P. Bradbury

Food and Drug Administration

John E. Burris

National Research Council

Jack L. Carter

Biological Sciences Curriculum Study

Charles B. Cleveland

Pharmaceutical Manufacturers Association

Eileen M. Cline

Springfield, VA

Thomas G. Coleman

University of Mississippi School of Medicine

Frances K. Conley

Stanford University Medical School

Charles E. Cover

E.I. du Pent de Nemours and Co., Inc.

Geraldine V. Cox

Chemical Manufacturers Association

Paul N. Craig

Shady Side, MD

Arthur L. Craigmill

University of California, Davis

Lester M. Crawford

Food and Drug Administration

Lloyd E. Davis

The University of Illinois

Mary Dawson

University of Strathclyde

Charles DeLisi

National Cancer Institute

Kennerly H. Digges

National Highway Traffic Safety Administration

Rebecca Dresser

Baylor College of Medicine

Ronald Dubner

National Institute for Dental Research

Sarah Wells Duffy

U.S. House of Representatives

James L. Dwyer

Millipore Corporation

419
420 ● Alternatives to Animal Use in Research, Testing, and Education

David M. Ferguson

ICI Americas, Inc.

Kenneth D. Fisher

Federation of American Societies for

Experimental Biology

Michael Allen Fox

Queen’s University

Gordon G. Gallup, Jr.

State University of New York at Albany

Roger W. Galvin

Animal Legal Defense Fund of Washington, DC

William I. Gay

National Institutes of Health

Michael A. Giannelli

The Fund for Animals, Inc.

Robert P. Giovacchini

The Gillette Company

Dawn G. Goodman

American College of Veterinary Pathology

L. Barry Goss

Battelle—Columbus Laboratories

Sidney Green

Food and Drug Administration

Lowe]] M. Greenbaum

Medical College of Georgia

Earl W. Grogan

National Research Council

Francis J. Haddy

Uniformed Services University for the

Health Sciences

Richard E. W. Halliwell

University of Florida School of Medicine

Harlyn O. Halvorson

Brandeis University

Thomas E. Harem

Stanford University Medical School

F. Gene Hampton

National Science Teachers Association

David G. Hattan

Food and Drug Administration

George A. Hedge

West Virginia University Medical Center

Lee A. Heilman

American Association for the Accreditation of

Laboratory Animal Care

Joe R. Held

Pan American Zoonoses Center

John R. Herbold

Department of Defense

Henry R. Hertzfeld

Washington, DC

Karen M. Hiiemae

The University of Illinois at Chicago

Larry Horton

Stanford University

Peter J. Hyde

International League for Animal Rights

Robert Kainz

Walkersville, MD

Gerald S. Kanter

Albany Medical College

Donald Kennedy

Stanford University

Keith F. Killam, Jr.

University of California, Davis

Robert W. Krauss

Federation of American Societies for

Experimental Biology

Sienna LaRene

Michigan Humane Society

C. Max Lang

The Pennsylvania State University

Thomas W. Langfitt

The University of Pennsylvania

Victor G. Laties

University of Rochester School of Medicine

and Dentistry

Chung Lee

Northwestern University Medical School

Joel L. Mattsson

Dow Chemical U.S.A.

Charles R. McCarthy

National Institutes of Health
App. G—Acknowledgments ● 421

Basil E. McKenzie

Ortho Pharmaceutical Corporation

Donald E. McMillan

University of Arkansas for Medical Sciences

Donald R. Meyer

The Ohio State University

Joel A. Michael

Rush-Presbyterian-St, Luke's Medical Center

Robert J. Moolenaar

American Industrial Health Council

John A. Moore

Environmental Protection Agency

Ray E. Moseley

University of Arkansas for Medical Sciences

Thomas H. Moss

Case Western Reserve University

Laila A. Moustafa

World Health Organization

Arnauld E. Nicogossian

National Aeronautics and Space Administration

Sharon J. Northup

Travenol Laboratories, Inc.

Mike G. Norton

British Embassy

Karl Johan Obrink

Uppsala Biomedicinska Centrum

F. Barbara Orlans

Scientists Center for Animal Welfare

Bennie I. Osburn

University of California, Davis

Robert E. Osterberg

Food and Drug Administration

Alex Pacheco

People for the Ethical Treatment of Animals

Douglas L. Park

Food and Drug Administration

Paul C. Rambaut

National Aeronautics and Space Administration

B. Randall, IV

Congressional Research Service

Walter C. Randall

Loyola University Medical Center

Tom Regan

North Carolina State University

Conrad B. Richter

National Institute of Environmental Health Sciences

Carol F. Rodgers

U.S. House of Representatives

Bernard E. Rollin

Colorado State University

Walter G. Rosen

National Research Council

Carl F. Rothe

Indiana University School of Medicine

Harry C. Rowsell

University of Ottawa

H. Rozemond

Staatstoezicht op de Volksgezondheid

Thomas D. Sabourin

Battelle—Columbus Laboratories

Jonathan D. Sackner

Philadelphia, PA

William M. Samuels

American Physiological Society

Robert A. Scala

Exxon Corporation

Trevor H. Scott

World Society for the Protection of Animals

Fred R. Shank

Food and Drug Administration

Kenneth J. Shapiro

Psychologists for the Ethical Treatment of

John F. Sherman

Association of American Medical Colleges

Charles E. Short

Animals

New York State College of Veterinary Medicine

Lee R. Shun

University of California, Davis

Robert S. Shurtleff

Springfield, MA

Evan B. Siegel

The Proprietary Association

Sidney Siegel

National Library of Medicine
422 Alternativws to Animal Use in Research, Testing, and Education

Richard C. Simmonds

Uniformed Services University

Sciences

Peter Singer

Monash University

Cheryl L. Sisk

Michigan State University

Kendric C. Smith

of the Health

Stanford University Medical School

Judy A. Spitzer

Louisiana State University Medical Center

Dennis M. Stark

The Rockefeller University

Donald G. Stein

Clark University

Marshall Steinberg

Society of Toxicology

Christine Stevens

Society for Animal Protective Legislation

Irving 1. A. Tabachnick

Schering Corporation

Dennis J. Taylor

Rhodes and Taylor

J. W. Thiessen

Department of Energy

Robert Thomas

U.S. Department of Energy

Ethel Thurston

American Fund for Alternatives to Animal Research

Charles S. Tidball

George Washington University Medical Center

Richard J. Traystman

The Johns Hopkins Hospital

Bruce L. Umminger

National Science Foundation

James Vorosmarti, Jr.

Department of Defense

William J. Waddell

University of Louisville School of Medicine

James R. Walker

The University of Texas Medical Branch

at Galveston

John S. Wassom

Oak Ridge National Laboratory

William L. West

Howard University College of Medicine

James A. Will

University of Wisconsin Research Animal

Resources Center

James Willett

National Institutes of Health

Robert P. Williams

Baylor College of Medicine

Steven M. Wise

Attorneys for Animal Rights (Boston), Inc.

Earl H. Wood

Mayo Foundation and Mayo Medical School

Constantine J. Zervos

Food and Drug Administration
Appendix H

Glossary of Acronyms and Terms

Glossary of Acronyms

AAALAC —American Association for Accreditation

of Laboratory Animal Care

AALAS —American Association for Laboratory

Animal Science

AAMC —Association of American Medical

Colleges

AAVMC –Association of American Veterinary

Medical Colleges

ACC –Animal Care Committee (Canada)

ACP —American College of Physicians

ACUC —Animal Care and Use Committee

ADAMHA–Alcohol, Drug Abuse, and Mental

Health Administration (PHS, DHHS)

AFAAR —American Fund for Alternatives to

Animal Research

ALD —Approximate Lethal Dose

ALDF –Animal Legal Defense Fund

AMD —Aerospace Medical Division (U.S. Air

Force)

APA —American Psychological Association

APHIS —Animal’ and Plant Health Inspection

Service (USDA)

APS –American Physiological Society

ARC —Animal Research Committee

ASPCA —American Society for the Prevention of

Cruelty to Animals

AUCC —Association of Universities and Colleges

of Canada

AVMA —American Veterinary Medical

Association

BID –bureau, institute, or division (NIH)

BIOSIS —Biosciences Information Service

CAAT -Center for Alternatives to Animal

Testing (The Johns Hopkins University)

CALAS -Canadian Association for Laboratory

Animal Science

CBO -Congressional Budget Office (U.S.

Congress)

CCAC —Canadian Council on Animal Care

CDC --Centers for Disease Control (PHS,

DHHS)

CERCLA —Comprehensive Environment Response,

Compensation, and Liability Act

CFHS —Canadian Federation of Humane

Societies

CFR -Code of Federal Regulations

CIIT --Chemical Industry Institute of

Toxicology

CIOMS

CITES

CPSC

CTFA

CT&T

DHEW

DHHS

DOD

DOE

DOT

EPA

EWST

FAA

FASEB

FDA

FIFRA

FOA

FOIA

FR

FRAME

FTC

GAO

GLP

IACUC

ILAR

IRAC

IRB

ISEF

LADB

LC5O

LD5O

LSRO

MRI

NAL

--Council of International Organizations

of Medical Sciences

--Convention on International Trade in

Endangered Species

—U.S. Consumer Product Safety

Commission

—Cosmetic, Toiletry, and Fragrance

Association

-Chemical Times and Trends

—U.S. Department of Health, Education,

and Welfare (see DHHS)

—U.S. Department of Health and Human

Services

—U.S. Department of Defense

—U.S. Department of Energy

—U.S. Department of Transportation

—U.S. Environmental Protection Agency

—Ethics and Values in Science and

Technology (NSF program)

—U.S. Federal Aviation Administration

—Federation of American Societies for

Experimental Biology

–Food and Drug Administration (PHS,

DHHS)

—Federal Insecticide, Fungicide, and

Rodenticide Act

—Friends of Animals, Inc.

—Freedom of Information Act

—Federal Register

—Fund for Replacement of Animals in

Medical Experiments

—U.S. Federal Trade Commission

-General Accounting Office (U.S.

Congress)

—Good Laboratory Practices

—Institutional Animal Care and Use

Committee

—Institute for Laboratory Animal

Resources (NRC)

—Interagency Research Animal

Committee

—Institutional Review Board

–International Science and Engineering

Fair

—Laboratory Animal Data Bank

—median lethal concentration

—median lethal dose

–Life Sciences Research Office (FASEB)

—magnetic resonance imaging

—National Agricultural Library

423
424 ● Alternatives to Animal Use in Research, Testing, and Education

NAS

NASA

NBS

NCI

NCTR

NIDA

NIEHS

NIH

NIHARC

NIMH

NIOSH

NLM

NRC

NSF

NTIS

NTP

NWHL

OECD

OHER

ONR

OPRR

OSHA

OSTP

OTA

OTS

PHS

PMA

PRI

QSAR

RCRA

R&D

RRF

RTECS

—National Academy of Sciences

—National Aeronautics and Space

Administration

—National Bureau of Standards

(Department of Commerce)

–National Cancer Institute (NIH)

—National Center for Toxicological

Research (FDA)

—National Institute on Drug Abuse

(ADAMHA)

–National Institute of Environmental

Health Sciences (NIH)

–National Institutes of Health (PHS,

DHHS)

—National Institutes of Health Animal

Research Committee

–National Institute of Mental Health

(ADAMHA)

—National Institute for Occupational

Safety and Health (CDC)

–National Library of Medicine (NIH)

—National Research Council

—National Science Foundation

—National Technical Information Service

(Department of Commerce)

–National Toxicology Program (NIEHS)

—National Wildlife Health Laboratory

—Organization for Economic Cooperation

and Development

-Office of Health and Environmental

Research (DOE)

–Office of Naval Research (Navy)

—Office for Protection from Research

Risks (NIH)

-Occupational Safety and Health

Administration (U.S. Department of

Labor)

-Office of Science and Technology

Policy (Executive Office of the

President)

-Office of Technology Assessment (U.S.

Congress)

–Office of Toxic Substances (EPA)

–U.S. Public Health Service (DHHS)

—Pharmaceutical Manufacturers’

Association

—Primate Research Institute (University

of New Mexico)

-quantitative structure-activity

relationships

–Resource Conservation and Recovery

Act

—research and development

–Registered Research Facility

—Registry of Toxic Effects of Chemical

Substances (NIOSH)

SBIR –Small Business Innovation Research

(program)

SPCA –Society for the Prevention of Cruelty to

Animals

SSR —Society for the Study of Reproduction

TDB –Toxicology Data Bank (NLM)

TSCA —Toxic Substances Control Act

UNEP —United Nations Environment Program

UNESCO —United Nations Educational, Scientific,

and Cultural Organization

USDA —U.S. Department of Agriculture

VA —U.S. Veterans’ Administration

WHO —World Health Organization

WRPRC —Wisconsin Regional Primate

Center

Glossary of Terms

Research

Acute Toxicity Test: Tests that are used to detect the

toxic effects of single or multiple exposures to a substance occurring within 24 hours. These are frequently the first tests performed to determine the

toxic characteristics of a given substance. One of the

most common acute toxicity tests is the LD5O test.

Alternatives to Animal Use: For purposes of this

assessment, OTA has chosen to define ‘(alternatives”

as encompassing any subjects, protocols, or technologies that replace the use of laboratory animals altogether; reduce the number of animals required;

or refine existing procedures or techniques so as to

minimize the level of stress endured by the animal.

These technologies involve the continued, but modified, use of animals; use of living systems; use of chemical and physical systems; and use of computers.

American Association for Accreditation of Laboratory Animal Care (AAALAC): A voluntary private

organization that, by April 1985, provided accreditation for 483 institutions. AAALAC accreditation is

based on the provisions of the NIH Guide for the Care

and Use of Laboratory Animals, and is recognized

by the PHS.

Ames Test: The most commonly used test for mutagenicity, it tests “reverse mutation” by exposing an already mutated strain of micro-organism to potential

mutagens. If the mutation is reversed the microorganisms regain their ability to produce the amino

acid histidine and will proliferate in a histidinedeficient culture medium. However, when used alone

the Ames test does not seem to be as predictive of

human carcinogenicity as are animal tests.

Analgesic: An agent that relieves pain without causing loss of consciousness.

Anesthetic: An agent that causes loss of the sensation

of pain, usually without loss of consciousness. Anesthetics may be classified as topical, local, or general.
App. H—Glossary of Acronyms and Terms 425

Animal: For purposes of this assessment, animal is defined as any nonhuman member of five classes of

vertebrates: mammals, birds, reptiles, amphibians,

and fish. Within this group, two kinds of animals can

be distinguished, warm-blooded animals (mammals

and birds) and cold-blooded animals (reptiles, amphibians, and fish). Under this definition, invertebrates are not considered to be animals.

Animal Care and Use Committee (ACUC): An institutional committee that oversees housing and routine

care of animals. The committee may also review

research proposals. The committee’s membership

generally includes the institution’s attending veterinarian, a representative of the institution’s administration, users of research animals, and one or more

nonscientist and lay members.

Animal and Plant Health Inspection Service

(APHIS): A branch of USDA that, among other duties,

is charged with the enforcement of the Animal Welfare Act. Enforcement of the act is directed through

four regional offices and is carried out by 286 APHIS

Veterinary Medical Officers (inspectors) who spend

about 6 percent of their time inspecting over 1,200

research facilities (many of which have multiple sites).

Animal Use The use of animals for research purposes.

Three aspects of animal use are dealt with in this

assessment: in behavioral and biomedical research;

in testing products for toxicity; and in the education

of students at all levels. This assessment does not

cover animal use for food and fiber; animal use to

obtain biological products; or animal use for sport,

entertainment, or companionship.

Animal Welfare Act: This act, passed in 1966 and

amended in 1970, 1976, and 1985, was originally an

endeavor to stop traffic in stolen animals that were

being shipped across State lines and sold to research

laboratories. Amendments to the act have expanded

its scope to include housing, feeding, transportation,

and other aspects of animal care. However, the act

bars regulation of the conduct of research and testing by USDA. Animals covered by the act, as currently enforced, are dogs, cats, hamsters, rabbits,

guinea pigs, nonhuman primates, and marine mammals. The Animal Welfare Act is enforced by APHIS.

Animal Welfare Enforcement Report: Annual report submitted to Congress by APHIS, based on data

collected from the Annual Report of Research Facility forms.

Animal Welfare Groups: There are a number of

groups concerned with animal rights and animal

welfare-e. g., the ASPCA, FOA, and AFAAR. These

groups cover a broad spectrum of ethical concerns

about animal use, they may question the objectives

as well as the means of research, but they generally

find common ground in the principle of humane

treatment of animals.

Annual Report of Research Facility: This is required

under the regulations stemming from the Animal

Welfare Act. Research facilities must submit these

annual reports, detailing animal use, to APHIS for

evaluation. (Elementary and secondary schools are

exempt, as are facilities using exempt species.) APHIS

presents data collected from these reports to Congress in its annual Animal Welfare Enforcement

Report.

Anticruelty Statutes: Laws passed by States that prohibit active cruelty, and in some cases passive cruelty (neglect), to animals. Some of these laws acknowledge the potential application of anticruelty statutes

to research animals, but most of them exempt “scientific experiments” entirely. Twenty States and the

District of Columbia regulate research to some extent. Twenty-one States have some provisions in their

codes requiring the teaching of “kindness” to or the

“value” of animals, and a few place restrictions on

animal experimentation in secondary schools.

Behavioral Research: Research into the movements

and sensations by which living things interact with

their environment, with the purpose of better understanding human behavior. A further goal of behavioral research is the better understanding of animal

species of economic or intrinsic interest to humans.

Behavioral research differs from biomedical research

in that it is difficult to study behavioral phenomena

in isolation; therefore continued, but modified, use of

animals holds most promise for this area of research.

Biological Model A surrogate or substitute for a process or organ of interest to an investigator. Animals

or alternatives can serve as biological models.

Biological Testing: The repetitive use of a standard

biological test situation or protocol employing different chemicals or different test parameters. Such test

protocols are more stereotyped than those used in

research, and may be more amenable to the institution of a computerized data retrieval system.

Biomedical Research: A branch of research devoted

to the understanding of life processes and the application of this knowledge to serve humans. A major

user of animals, biomedical research affects human

health and the health care industry. It is instrumental in the development of medical products such as

drugs and medical devices, and in the development

of services such as surgical and diagnostic techniques.

Biomedical research covers abroad spectrum of disciplines, such as anatomy, biochemistry, biology,

endocrinology, genetics, immunology, nutrition, oncology, and toxicology.

Carcinogen: An agent or process that significantly in-
426 Ž Alternatives to Animal Use in Research, Testing, and Education

creases the incidence of abnormal, invasive, or uncontrolled cell growth in a population. Carcinogens

fall into three classes: chemicals, viruses, and ionizing radiation. A variety of screening assays have been

developed to detect chemical carcinogens, including

the Salmonella-mediated mutagenesis assay (Ames

test), the sister chromatid exchange assay, and traditional laboratory animal toxicity tests.

Cell Culture: Growth in the laboratory of cells isolated

from multicellular organisms. Each culture is usually

of one type. Cell culture may provide a promising

alternative to animal experimentation, for example

in the testing of mutagenicity, and may also become

a useful adjunct in repeated dose toxicity testing.

Center for Alternatives to Animal Testing (CAAT):

Established by the Johns Hopkins University in 1981

to search for alternatives to animal use, CAAT puts

out publications and supports intramural and extramural research. The Center is sponsored by the CTFA

and corporate donors as well as consumer and industrial groups.

Chick Embryo Chorioallantoic Membrane Assay:

A test used to determine the irritancy of a substance.

A test sample is placed on the chorioallantoic membrane formed on top of a chick embryo. The membrane is then evaluated for response to the test substance and the embryo is discarded. This test may

be a promising alternative to the Draize Test.

Chronic Toxicity Test: Repeated dose toxicity test

with exposure to a test substance lasting at least 1

year, or the lifetime of the test species.

Comprehensive Environment Response, Compensation, and Liability Act (CERCLA): Known

as “Superfund,” CERCLA authorizes the Federal Government to cleanup or otherwise respond to the release of hazardous wastes or other pollutants that

endanger public welfare.

Crossover Test: A useful laboratory or clinical method

whereby an animal serves as its own control by first

receiving a drug or a placebo and then receiving the

reverse. This kind of test has potential applications

in anesthesiology, endocrinology, radiology, and various other fields.

Computer Simulation: The use of specially devised

computer programs to simulate cells, tissues, fluids,

organs, and organ systems for research purposes; to

develop mathematical models and algorithms for use

in toxicity testing; and to simulate experiments traditionally done with animals, for educational purposes.

Data Sources: Can provide an alternative to animal

testing by disseminating information generated from

prior use of animals. The TDB and RTECS are two

such sources, as was the LADB.

Descriptive Toxicology A branch of toxicology dealing with phenomena above the molecular level. Descriptive toxicology relies heavily on the techniques

of pathology, statistics, and pharmacology to demonstrate the relationship between cause and effect—

e.g., that certain substances cause liver cancer in certain species within a certain time. It is most often

used in regulatory schemes requiring testing.

Distress: Usually the product of pain, anxiety, or fear.

However, distress can also occur in the absence of

pain. For example, an animal struggling in a restraint

device may be free from pain, but maybe in distress.

Distress can be eased with tranquilizers.

Draize Eye Irritancy Test: A test that involves placing a single dose of a test substance into one eye of

four to six rabbits (the other eye remains untreated)

and observing its irritating effects. A promising alternative to this test is the chick embryo chorioallantoic membrane assay.

Education: The aspect of education dealt within this

assessment is the use of animals and alternatives in

the teaching of life sciences to secondary school students, university students, health professionals and

preprofessionals, and research scientists.

Federal Environmental Acts: A number of these

have been passed to protect human health and the

environment from the adverse effects of toxic substances, and to regulate the release of such substances into the environment. Among these acts are

FIFRA, TSCA, the Clean Air Act, the Clean Water Act,

RCRA, CERCLA, and the Consumer Product Safety

Act, Animal testing provides much of the data needed

for the enforcement of these acts.

Federal Government Use of Animals for Research

Six Cabinet departments and four Federal agencies

conduct intramural research and testing involving

animals. They are: USDA, Department of Commerce,

DHHS, DOD, Department of the Interior, DOT, CPSC,

EPA, NASA, and the VA.

Federal Insecticide, Fungicide, and Rodenticide

Act (FIFRA): Designed to protect the human environment from the adverse effects of pesticides and

their use, FIFRA regulates various aspects of pesticide use by means of registration, labeling, and the

setting of maximum residue levels. It also established

procedures for safe application, storage, and disposal

of pesticides.

Good Laboratory Practices (GLP): Rules adopted by

FDA in 1978 requiring that all regulated parties conducting nonclinical laboratory studies keep records

and permit audits of such studies. The GLP rules

also contain specific provisions for animal housing,

feeding, and care, In 1983, EPA issued similar GLP
App. H—Glossary of Acronyms and Terms ● 427

rules for its toxic substances and pesticides research

programs.

Guidelines for Animal Care and Use: Various organizations outside the Federal Government have

adopted their own guidelines-e.g., the APA’s Guidelines for Ethical Conduct in the Care and Use of Animals, which is the most comprehensive and has been

endorsed by FASEB; the APS’s Guiding Principles in

the Care and Use of Animals; and the AVMA’s Animal Welfare Guiding Principles. For Federal guidelines, see Interagency Research Animal Committee,

NIH Guide for the Care and Use of Laboratory Animals, and PHS Policy.

Hepatotoxicity: The quality of exerting a destructive

or poisonous effect upon the liver.

Homology The correspondence among organisms of

structures and functions derived from a common

evolutionary origin (e g., a common gene structure).

Immunoscintigraphy The use of external radioimaging techniques to locate tumors and to identify certain noncancerous diseases.

Institute for Laboratory Animal Resources (ILAR):

A component of the National Research Council, ILAR

performs periodic surveys on the use of laboratory

animals.

Interagency Research Animal Committee (IRAC):

This committee was formed by 14 Federal entities

in recognition of a need for an interagency body

knowledgeable about the welfare of research animals. IRAC meets regularly to discuss research needs

and has written principles for the Utilization and Care

of Vertebrate Animals Used in Testing, Research and

Training. These Principles, which incorporate nine

injunctions on animal welfare, are intended to serve

as a model for Federal agencies in developing policies on animal use.

Invertebrate Any nonplant organism without a spinal

column-e. g., worms, insects, and crustaceans. Invertebrates account for 90 percent of the Earth’s nonplant species. For the purposes of this assessment,

invertebrates are not considered to be animals.

In vitro: Literally, in glass; pertaining to a biological

process or reaction taking place in an artificial environment, usually a laboratory. Human and animal

cells, tissues, and organs can be cultured in vitro.

In vitro testing may hold some promising alternatives to animal testing-e.g., in testing for eye irritation and mutagenicity.

In vivo: Literally, in the living; pertaining to a biological process or reaction taking place in a living cell

or organism.

Laboratory Animal Data Bank (LADB): Founded by

NCI and NLM in the late 1970s, the LADB was supposed to provide a computer-based registry of research and testing data. However, the data were

limited and consequently LADB had few users. It was

terminated in 1981 because of lack of funding. It exists today only as an archival reference,

LC50:An acute toxicity test used to screen substances

for their relative toxicity. LC50 is calculated to be the

lethal concentration for half of the animals exposed

to a test substance. Exposure may be by breathing

vapor or immersion in liquid (e.g., fish in water).

LD50: An acute toxicity test used to screen substances

for their relative toxicity. LD50 is calculated to be the

lethal dose for half of the animals exposed to a test

substance. Exposure is often by ingestion.

Mechanistic Toxicology An approach to testing that

focuses on the chemical processes by which a toxic

effect occurs. Mechanistic toxicology testing relies

heavily on physiology, biochemistry, and analytical

chemistry techniques to monitor these processes.

Micro-organism: A minute microscopic or submicroscopic living organism, such as bacteria, viruses, and

protozoa.

Mutagen: An agent that induces chemical changes in

genetic material. Chemicals, viruses, and ionizing

radiation can be mutagenic. Most carcinogens are

mutagens, therefore many screening tests to detect

carcinogens are designed to detect the mutagenic

potential of the compound. Some mutagens are not

direct-acting, requiring metabolic activation in the

body before they exert their mutagenic potential.

National Toxicology Program (NTP): NTP was chartered in 1978 as a cooperative effort by DHHS. Participants in NTP are NIH (through its agencies NCI

and NIEHS), FDA (through NCTR), and CDC (through

NIOSH). The stated goals of NTP include the expansion of toxicological information; expansion of numhers of chemicals to be tested; the validation, development, and coordination of tests to meet regulatory

needs; and the communication of programs, plans,

and results to the public.

Neurotoxicity: The quality of exerting a destructive

or poisonous effect on nerve tissue.

NIH Guide for the Care and Use of Laboratory Animals: Revised in 1985, the Guide lays out detailed

standards for animal care, maintenance, and housing. Its provisions apply to all research supported

by NIH, and it is used by most animal research facilities, both within and outside the Federal Government. AAALAC and PHS also use it when assessing

research facilities for accreditation.

Nonliving Systems: Inanimate chemical or physical

systems used in testing.

Oncology: The study of tumors.
428 ● Alternatives to Animal Use in Research, Testing, and Education

Organ Culture: The attempt to isolate and maintain

animal or human organs in in-vitro culture. Longterm culture of whole organs is not generally feasible, but they can be sustained in cultures for short

periods (hours or days).

Pain: Discomfort resulting from injury or disease. Pain

can also be psychosomatic, the product of emotional

stress. Pain can be induced by mechanical, thermal,

electrical, or chemical stimuli, and it can be relieved

by analgesics or anesthetics.

Pharmacokinetic Studies: A branch of toxicity testing that provides information about the mechanics

of absorption.

PHS Policy on Humane Care and Use of Laboratory Animals by Awardee Institutions: Revised

in 1985, the Policy applies to PHS-supported activities involving animals (including those of NIH). It relies on the NIH Guide for the Care and Use of Laboratory Animals, and uses institutional committees

for the assessment of programs and maintenance of

records.

Pound Release Laws: State laws that provide for the

seizure, holding, and humane disposal of stray and

unwanted animals, Most States permit the release

of unowned animals to research institutions that have

met specified conditions. These laws have been

closely scrutinized. In the past 10 years and nine States

have passed laws prohibiting the release of stray animals to research institutions. The most far-reaching

of these laws takes effect in Massachusetts in 1986.

Also referred to as “pound seizure laws.”

Protocol: The plan of a scientific experiment or treatment.

Reduction Considered an alternative to animals when

fewer animals are used in research and education

through changed practices, sharing of animals, or

better design of experimental protocols.

Refinement: An alternative to animal use by better

use and modification of existing procedures so that

animals are subject to less pain and distress. Examples of such refinements are the administration of

anesthetics and tranquilizers, humane destruction,

and the use of noninvasive imaging techniques.

Registry of Toxic Effects of Chemical Substances

(RTECS): An annually published compendium, extracted from the literature, of known toxic and

biological effect of chemical substances. RTECS is

published by NIOSH under the provisions of the Occupational Safety and Health Act of 1970.

Repeated-Dose Toxicity Test: Repeated or prolonged

exposure to measure the cumulative effects of exposure to a test substance. These tests involve chronic,

subchronic, or short-term exposure to a test substance.

Replacement: An alternative to animal use, replacing methods using animals with those that do not.

Examples include the use of a placenta instead of a

whole animal for microsurgical training, the use of

cell cultures instead of mice and rats, the use of nonliving systems, and the use of computer programs.

Research: The development of new knowledge and

technologies, often with unpredictable but potentially significant results. Uncertainty, missteps, and

serendipity are inherent in the research process. Research is distinguished from testing by the ways in

which animals are used, and the identity of the investigators. There are more research procedures

than there are tests, and researchers are more likely

to develop their own procedures.

Research Facility Under the Animal Welfare Act, any

individual, institution, organization, or postsecond -

ary school that uses or intends to use live animals

in research, tests, or experiments. Facilities that receive no Federal support for experimental work and

that either purchase animals only within their own

State or that maintain their own breeding colonies

are not considered research facilities under the act,

however.

Resource Conservation and Recovery Act (RCRA):

This act was passed to protect public health and the

environment through the regulation of the management and handling of hazardous waste and through

the control of solid waste disposal.

Resusci-Dog: A plastic mannequin linked to a computer. The Resusci-Dog can simulate an arterial pulse

and pressure can be applied to its ribcage for cardiac

massage or cardiopulmonary resuscitation.

Sequential Design Test: The comparison of treatment

groups at set stages of experimentation. Further experimentation at higher doses is undertaken only if

there is no significant difference between the two

groups. This kind of test has potential application

in anesthesiology, endocrinology, nutrition, and

other fields.

Serial Sacrifice: The sequential killing of animals to

examine the occurrence and progress of induced

effects.

Short-Term Toxicity Test: Repeated dose toxicity test

that involves exposure to a test substance over a period of 2 to 4 weeks.

Speciesism: A term used by some animal rights activists, referring to the denial of animal rights as a moral

breach analogous to racism or sexism.

State Environmental Acts: Legislation passed by

States to regulate pesticides, air quality, water, and

waste products. These laws are often the simple

adoption or recodification of existing Federal laws.

Subchronic Toxicity Test: Repeated dose toxicity test
App. H—Glossary of Acronyms and Terms ● 4 2 9

of intermediate duration, with exposure to a test substance for 3 to 6 months.

Testing: Standardized procedures that have been demonstrated to predict certain health effects in humans

and animals. Testing involves the frequent repetition of well-defined procedures with measurement

of standardized biological endpoints. A given test may

be used to test many different substances and may

use many animals. Testing is used to establish the

efficacy, safety, and toxicity of substances and procedures.

Tissue Culture: The maintenance in vitro of isolated

pieces of a living organism. The various cell types

are still arranged as they were in the original organism and their differential functions are intact,

Toxic Substances Control Act (TSCA): This act authorizes EPA to regulate substances that present an

unreasonable risk of injury to health or to the environment. The act also requires the reporting or development of data to assess the risks posed by a given

substance.

Toxicity Testing: The testing of substances for toxicity in order to establish conditions for their safe use.

There are now more than 50,000 chemicals on the

market and 500 to 1,000 new ones are introduced

each year. The Federal agencies with the largest role

in toxicity testing are FDA, EPA, CPSC, and OSHA.

Toxicology Data Bank (TDB): Made public by the

NLM in 1978, the TDB provides toxicity information

on more than 4,000 chemicals and substances. TDB

information is based on conventional published

sources.

Tranquilizer: An agent that quiets, calms, and reduces

anxiety and tension, with some alteration of the level

of consciousness.

T-test: An estimate of the difference between the mean

values of one parameter of two treatments. This can

be a powerful measure when the number of comparisons is small, but the potential for error increases

as the number of parameters grows.

Veterinary Medicine: The maintenance and improvement of the health and well-being of animals, particularly the 30 to 40 different species of animals of

‘economic, ecological, and environmental importance.

Veterinary medicine is closely allied with veterinary .

research.

Veterinary Research: A branch of biomedical research devoted to the understanding of the life processes of animals and the application of this knowledge to serve animals as well as humans.
Index
Index

AAALAC, 16, 49

accreditation, process of, 344-345, 401-411

animal use and, 335-337

AAVMC and, 351

Federal agencies and, 386, 387, 388, 389, 392,

393

GLPs and, 293

AALAS, 208, 344, 345-346

AAMC, 204-206

AAVMC, 207, 350-351

ACC, 361-362

ACP, 349

ACUC, 14, 15-16, 292, 386, 391-392

ADAMHA, 45, 92, 295, 337

AFAAR, 210, 268, 269

Agriculture, Department of (U.S.). See USDA

Alabama, 288, 307, 319

Alaska, 288, 307, 308, 319

Alberta, University of, 360

Alcohol, Drug Abuse, and Mental Health Administration. See ADAMHA

American Association for Accreditation of Laboratory Animal Care. See AAALAC

American Association for Laboratory Animal

Science. See AALAS

American College of Physicians. See ACP

American Fund for Alternatives to Animal

Research. See AFAAR

American Physiological Society. See APS

American Psychological Association. See APA

American Society for the Prevention of Cruelty to

Animals. See ASPCA

American Veterinary Medical Association. See

AVMA

Ames test, 186, 187-188, 250

Animal Care Committee. See ACC

Animal Care and Use Committee. See ACUC

Animal and Plant Health Inspection Service. See

APHIS

Animal Research Committee. See ARC

Animal rights

“consistency argument” and, 77-78

“interest theory” and, 76-77

legal action and, 314-316

“speciesism” and, 5, 79

“will theory” and, 76

Animal use

and data accumulations, 5, 43-49, 58-65

economics of, 12, 29, 99, 115, 116, 123, 128, 151,

155, 206, 209-210, 213, 243-253

in education, 3, 199-214, 321-322

ethics of, 6, 71-82, 200, 202

in Federal Government, 14-15, 43-49

guidelines for, 13, 14, 15-16, 31, 33, 152,

157-167, 176, 200-202, 291, 293-296, 335-352,

361, 383-393, 395-400

humane treatment and, 6, 78-79

IACUCs and, 340-344

international agreements governing, 412-417

limitations of OTA study on, 50-52

modified, 7-8, 113, 114-118, 126-132, 175-176,

208-209

and pain, 103-105

patterns of, 43-66

in pharmacokinetics, 153

philosophical traditions of, 74-75

as a policy issue, 26-29, 31-32

product liability and, 157

public concern about, 3, 149, 157, 175, 181, 266,

293-294, 323-324, 339

regulation of, 13-18, 46, 157-167, 201-202, 203,

275-298, 305-322, 335-352, 359-375, 386-393

regulatory practices and, 12, 157-167, 175,

181-182, 188-189, 248, 278, 280, 283-289,

291-292, 297-298

religious traditions of, 71-74

in research, 3, 89-108

restricted necessity and, 80-81

in science fairs, 200-202

in testing, 3, 149-168

trends in, 5, 16-17, 57-65, 157

in the United Kingdom, 203-204

utilitarian principle of, 6, 79-81, 82

Animal use, alternatives to

computer systems as, 7-8, 11-12, 124-126,

136-138, 228-238

economics of, 12, 189, 249-250, 265-266

in education, 10-11, 208-214

funding for, 13, 213-214, 259-270

Health Research Extension Act of 1985 and,

291-292 ‘

IACUCs and, 341

living systems as, 4, 7-8, 118-123, 133-136, 175,

177-179, 183, 184-186, 189-190, 209-210

nonliving systems as, 7-8, 124, 136, 180-181,

210-214

organ culture as, 119-120

OTA’s definition of, 39

as a policy issue, 18-23

reduction as, 4, 10-11, 39, 114-116, 126-128

refinement or replacement as, 4, 10-11, 39

in research, 6-8, 113-138

trends in, 188-190

See also Reduction; Refinement; Replacement

Animal Welfare Act of 1966. See Laboratory

Animal Welfare Act

433
434 . Alternatives to Animal Use in Research, Testing, and Education

Animals

benefits to, of research, 102

classifications of, 37-38

definitions of, 4, 37-38, 306

estimates of numbers and, 5, 43, 206, 207

importation of, 56

moral status of, 71-82

sharing of, in research, 114-115, 128

students’ attitudes toward, 200

Anticruelty laws, 305-314, 318

APA, 346-347

APHIS, 14, 32-33

administration of the Animal Welfare Act by,

283-289, 291, 293

animal use data and, 5, 29, 30, 31, 50, 53, 54,

57, 58-65, 295-297

criticisms of, 297

Federal Government and, 43-44, 46-49, 293, 388,

393

GLPs and, 293

NSF and, 392

U.S. Surgical Corporation inspections by, 324,

325

Approximate lethal dose (ALD), 182

APS, 347-348

ARC, 390

Aristotle, 74

Arizona, 288, 307, 309, 319, 320

Arkansas, 158, 288, 307, 319

ASPCA, 269, 309

Association of American Medical Colleges. See

AAMC

Association of American Veterinary Medical Colleges. See AAVMC

Association of Universities and Colleges of Canada,

361

Augustine, Saint, 73

Australia, 17, 324, 359-360

AVMA, 207, 344-345, 350

Barth, Karl, 74

Biosciences Information Service (BIOSIS), 224, 231,

238

Bristol Myers Company, 13, 266

British Columbia, University of, 360

Brown, Alex & Sons, 56

Bureau of Standards, U.S. Department of Commerce. See National Bureau of Standards

(NBS)

CAAT, 13

animal use alternatives and, 189

funding for alternatives by, 266-267

private funding of, 264

California, 288, 289, 307

pound release laws in, 319, 320

regulations in, 166, 167, 316-317, 321

RRFs in, 287

California, University of Southern, 346, 351

Calvin, John, 74

Canada, 17, 176, 201-202, 268, 359, 360-362

Canadian Council on Animal Care. See CCAC

Canadian Federation of Humane Societies. See

CFHS

Catholic University, 210

CCAC, 360-362

CDC, 295

animal use by, 9,45

economics of testing and, 251

funding for NTP by, 264-265

guidelines of, 337

regulatory activities by, 158, 165

Cell culture, 118

as alternative, 4, 121-122, 133, 175, 177-179, 183,

184-186, 189-190

and polio vaccine, 91

training in use of, 210

See also In vitro techniques; Living systems

Center for Alternatives to Animal Testing. See

CAAT

Centers for Disease Control, See CDC

CERCLA, 163-164

CFHS, 361

Chemical Industry Institute of Toxicology. See CIIT

Chemical Times and Trends (CT&T), 287

CIIT

computer-based registries and, 238

and data sharing, 176, 252

literature prepared for, 219

Clarke Institute of Psychiatry, 360

Colgate-Palmolive Company, 268

Colorado, 166, 286, 288, 307, 312-313, 316, 319,

320

Colorado State University, 320, 342

Commerce, Department of (U.S.), 44, 277, 297, 386

Comprehensive Environmental Response, Compensation, and Liability Act. See CERCLA

Computer systems

as animal alternative, 7-8, 11-12, 124-126,

136-138, 180-181, 182-183, 185, 211-214,

228-238

FRAME and, 189

NIH funding for, 261-262

policy issues and, 22

in research, 13

Congressional Budget Office (CBO), 280

Connecticut, 288, 307, 315, 316-317, 318, 319,

323-328

Consistency argument, 77-78

Consumer Product Safety Commission. See CPSC
Index ● 4 3 5

Cornell University, 213, 264, 269

Cosmetic, Toiletry, and Fragrance Association

(CTFA), 13, 266, 268

Council of International Organizations of Medical

Science (CIOMS), 295, 416-417

CPSC

animal use by, 9, 46

regulations in, 157-158, 164, 390-391

and research funding, 23

Culpability, 306, 308, 313

Dalhousie University, 360

Data accumulation, 151, 223-228

animal use and, 5, 8, 49-65, 180-181, 188-189

epidemiologic, 155, 187

by Federal agencies, 43-49, 161-163, 165, 166

patent claims and, 247-248

as a policy issue, 29-31, 43

species choice and, 98

by States, 165-166

Data analysis, 152, 222

of Ames tests, 187

animal use and, 52-65

of computer simulations, 138

economy of animal use and, 245-246

GLPs and, 293

reduction in animal use by, 126-128, 175, 177,

181

Databases, 11-12, 219-228

computer simulation and, 125-126

EPA use of, 163-164

epidemiologic, 124

and information sharing, 224-238

and micro-organism tests, 186

reduction of animal use and, 176, 181

Data sharing, 10, 11-12, 23-26, 220, 221-228

by APHIS, 295-297

computer systems and, 228-238

by FDA, 295-297

LADB and, 233-238

by NIH, 295-297

on-line, 229, 231-238

proprietary interests and, 176, 252-253

Delaware, 288, 307, 319

Denmark, 18, 359, 363-366

Department of Health, Education, and Welfare,

U.S. (DHEW), 277, 279

Department of Health and Human Services, U.S.

(DHHS), 14, 33, 269, 295

animal use by, 45, 49

animal use guidelines of, 339

animal use regulation by, 388-390

databases and, 163-164

funding by, 157, 264-265

LADB and, 235

Descartes, Rene, 74-75

District of Columbia, 15, 276, 288, 290, 307, 316,

319, 336

DNA technology, 91, 121, 123, 125, 185-186, 188,

261

DOD

and animal use, 15, 44-45, 49

animal use regulations in, 16, 26, 158, 386-388

Dodge Foundation, Geraldine R., 13, 264, 269

DOE, 45,” 162, 388

DOT

animal use by, 9, 45

animal use regulation and, 158, 164, 297, 386

Dow-Corning, 131

Draize eye irritancy test, 8

alternatives to, 183-184, 259, 266

CPSC modification of, 391

funding for alternatives to, 13, 268

methodology of, 154

and policy options, 21

restrictions on, 27-28

trends in use of, 157

Drug Enforcement Agency, U. S., 324

Duke University, 125

Economics

alternatives to animal use and, 13, 189

of animal use, 12, 13, 89, 115, 116, 123, 128,

151, 181, 206, 209, 243-253, 265-266

of the Animal Welfare Act, 278, 279, 281, 287

data sources and, 220, 221, 223

of GLPs, 294

of IACUCS) 342

of LADB, 235

pound release laws and, 319

proprietary interests and, 252-253

regulations and, 251

of research, 245-248, 250-251

and species choice, 99

of testing, 155, 157, 184, 248-251, 252-253

Education

alternatives to animal use in, 10-11, 208-214

animal use in, 30, 199-214

animal use regulation in, 321-322

computer simulations in, 211-214

funding of, 268-269

overlap with research, 202

Environmental Protection Agency. See EPA

EPA

animal use by, 9, 46

and data accumulation, 163-164, 221, 229

funding for toxicological research by, 23, 265

GLPs and, 292-294

and the LD5O test, 19

literature prepared for, 219
. . —— — —

436 c Alternatives to Animal Use in Research, Testing, and Education

protocol restriction and, 28

and regulation of animal use, 13, 15, 157,

161-164

and testing economics, 251

testing guidelines and, 152, 248, 384-385

Epidemiology

database use in, 124

protocol as alternative to animal use, 163, 181

Ethics

of animal use, 6, 71-82, 200, 202

and economics, 247

of embryo use in research, 133

of invertebrate use, 134

Ethics and Values in Science and Technology

(EVIST), 262

FAA, 277

FDA, 292-295

animal use by, 9, 45

animal use regulation in, 386, 388-389

baldness prevention and, 92

CPSC contracts with, 390

and data collection, 31, 47-49

and data sharing, 176, 295-297

economics of, 251

funding by, 13, 23, 264-265

GLPs and, 292-293

guidelines for)

< 337, 383

hepatitis B vaccine and, 91

and the LD5O test, 19

literature prepared for, 219

product liability testing requirements by, 167

protocol restriction and, 28

regulation of animal use by, 13, 14

regulatory activities by, 157, 158-160, 165

testing guidelines and, 152, 383

and toxicological testing, 150-151

Federation of American Societies for Experimental

Biology (FASEB), 235-236, 238, 346, 348

Florida, 286, 288

anticruelty laws in, 307, 308, 314

pesticide program in, 166

pound release laws in, 319, 320

regulation of animal use in, 321-322

RRFs in, 287

FOIA

and data sharing, 24-25, 223

GLPs and, 293

regulation of animal use and, 297

unpublished information and, 221-222

USDA and, 290

Food and Drug Administration, U.S. See FDA

FRAME, 153-154, 189-190, 267

France, 220

Francis, Saint, 74

Friends of Animals, Inc. v. U.S. Surgical Corporation, 315, 316, 323-328

Freedom of Information Act. See FOIA

FTC, 9, 158, 165

Fund for Replacement of Animals in Medical Experiments. See FRAME

GAO

APHIS and, 286

military research and, 293

USDA and, 289-290

Genetics. See DNA technology; RNA replication

Georgia, 288, 307, 308, 319

Germany, Federal Republic of, 359, 366-367

Good Laboratory Practices (GLPs), 292-294

Guide for the Care and Use of Laboratory Animals

(NIH). See NIH, guidelines by

Guidelines, for animal use, 13, 14, 16, 31, 33, 152,

157-167, 176, 200-202, 291, 293-296, 335-352,

361, 383-393, 395-400, 412-417

Harrison, R. G., 120

Harvard University, 115

Hatch, Orrin G., 3

Hawaii, 288, 307, 309, 318, 319

Health Professions Education Assistance Amendments of 1985, 13, 269, 291

Health Research Extension Act of 1985, 14, 281,

291-292

Humane treatment, principle of, 6, 78-79

Hume, David, 74-75

IACUC, 15, 337-344

Idaho, 288, 307, 309, 319

ILAR, 5

and data collection, 31, 50, 53-55, 56, 57, 58-59,

202-203

and LADB, 233-234, 236

NSF funding of, 262

Illinois, 288, 307, 319

regulations in, 314, 316-317, 321

RRFs in, 287

Illinois, University of, 267

India, 56

Indiana, 288, 307, 308, 319

Industry

data sharing and, 219, 221-222

economics and, 252-253

research funding by, 13, 22

Information centers, 220

Information, unpublished, 219-220, 221-222,

224-228

Insects, 186-187
Index ● 4 3 7

Institute for

ILAR

Institutional

IACUC

Institutional

Interagency

Laboratory Animal Resources. See

Animal Care and Use Committee. See

Review Board. See IRB

Research Animal Committee. See IRAC

Interest theory, 76-77

Interior, Department of the (U.S.), 45, 49, 285,

386, 390

International Science and Engineering Fair OSEF),

201

Invertebrates

as animal alternative, 122-123, 133-135, 177, 179,

209

ethical use of, 134

in toxicity tests, 185

In vitro techniques, 157

as animal alternative, 10, 118-122, 124, 126, 150,

177-179, 182-183, 185, 186, 188, 210

delays in implementing, 189

economics of, 250

funding of, 261, 265

mathematical model of, 267

for patents, 248

and policy options, 22

See also Cell culture; Living systems; Organ culture; Tissue culture

In vivo techniques, 120, 157, 184, 186

in education, 210

in research, 117, 124, 188

Iowa, 288, 289, 307, 316-317, 319

IRAC, 16, 295

DOD and, 387

DOE and, 388

guidelines of, 337-339

NASA and, 391

IRBs, 340, 342

Japan, 150

animal use regulation in, 359, 362-363

data sharing by, 223

Johns Hopkins University, The, 13, 23, 57, 264

Kansas, 288, 289, 307, 309, 316-317, 319, 321

Kant, Emmanuel, 76, 81

Kentucky, 288, 307, 319

Laboratory Animal Data Bank (LADB), 11-12, 176,

229, 233-238

Laboratory Animal Welfare Act, 13-14, 16, 46, 49,

275, 276-291, 295

amending of, 16, 26, 32-34

1970 amendments to, 278-279, 281-283

1976 amendments to, 279-283

1985 amendments to, 12, 14, 16, 280-281, 386

animal rights and, 315, 316

and APHIS, 29-30, 31, 283-290, 291-294

CPSC and, 391

criticisms of, 297-298

and data collection, 5

economics of, 278, 279, 281, 287

and Federal agencies, 31, 44, 269, 289-290,

387-392

litigation and, 290-291

research facilities and, 276-277, 278-279, 281-287

State duplication of, 317

Taub case and, 310-312

Labor, Department of (U.S.), 164

LC50 test, 166-167

LD50 test, 8, 80-81

alternatives to, 268, 351

in chemical testing, 151

cost of, 250

CPSC and, 164, 391

data uses, 166-167

in Denmark, 365

FDA and, 388-389

FRAME and, 153

methodology of, 153

modification of, 19, 21, 175, 181-183, 189-190

restrictions on, 28

in science fairs, 201

in Switzerland, 359

trends in use of, 157

Life Sciences Research Office, 235

Limit test

as alternative to LD5O test, 182

CPSC and, 391

methodology of, 153

Litigation, 167-168, 175, 247, 253, 290-291, 323-328

Living systems, 7-8, 118-123, 126, 133-136, 177-179,

209-210

See also Cell culture; In vitro techniques; Organ

culture; Tissue culture

Louisiana, 288, 307, 319

Louisiana State University, 56

Maine, 288, 307, 308, 318, 319

Maryland, 288, 293, 307, 308, 310-312, 319

Maryland, University of, 57

Maryland v. Taub, 310-312, 313, 335

Massachusetts, 15, 287, 288, 307, 313, 316-318,

319, 321-322

Massachusetts Institute of Technology, 260

Mean lethal dose test. See LD50 test

Michigan, 287, 288, 307, 314, 316-317, 319, 320

Microorganisms, 123, 177, 179, 186

Microsurgery, 204, 205, 210

Midgeley, Mary, 78

Minnesota, 288, 307, 316, 319
.

438 . Alternatives to Animal Use in Research, Testing, and Education

Mississippi, 288, 307, 319

Missouri, 288, 289, 307, 319

Montana, 288, 307, 319

Moore, Marie A., 263

Moral theory, 71-82

Nace, George, 56

NASA

animal use by, 46, 115

animal use regulations of, 16, 386, 391-392

species substitution by, 116

use of micro-organisms by, 123

National Agricultural Library (NAL), 12, 21, 24,

238, 281

National Bureau of Standards (NBS), 222, 238

National Cancer Institute. See NCI

National Center for Toxicological Research. See

NCTR

National Institute of Environmental Health

Sciences. See NIEHS

National Institutes of Health. See NIH

National Institute for Occupational Safety and

Health. See NIOSH

National Library of Medicine. See NLM

National Science Foundation. See NSF

National Technical Information Service (NTIS), 24,

235

National Toxicology Program. See NTP

National Wildlife Health Laboratory, 390

NCI

data accumulation and, 11, so

epidemiologic studies and, 181

estimations of animal use by, 57-58

funding by, 23, 233, 235, 264-265, 270

guidelines and, 152

historical data and, 176

NCTR

AAALAC and, 389

animal use and, 158

data accumulation by, 47-49

FDA contracts with, 390

funding of NTP by, 264-265

and policy options, 21

Nebraska, 288, 307, 319

Netherlands, 359, 367-368

Nevada, 288, 307, 319

New Hampshire, 288, 307, 318, 319

New Jersey, 287, 288, 307, 316, 318, 319, 322, 325,

327, 328

New York, 286, 288, 289

enforcement of anticruelty laws in, 307, 309, 314

Friends of Animals in, 324

hazardous waste regulations in, 166

on-line databases in, 231

pound release laws in, 319, 320

regulation of animal use in, 316-317, 321-322

RRFs in, 287

New York State College of Veterinary Medicine, 4

NIEHS, 157, 264-265

NIH, 13, 15, 295

animal use by, 45, 57-58

animal use regulation in, 15-16, 386, 389-390

animal use survey and, 202-203

and Animal Welfare Act’s enforcement, 33

data accumulation and, 31, 50, 295-297

economics of testing and, 251

funding by, 13, 22-23, 46, 259-265, 269-270

guidelines by, 15-16, 335-337, 345-346, 351, 391,

392

Health Research Extension Act of 1985 and,

291-292

IRAC and, 295

literature prepared for, 219

and policy options, 19, 21

regulation of research by, 317

review of IACUCs by, 341

and Taub case, 310

NIH Guide for the Care and Use of Laboratory

Animals. See NIH, guidelines by

NIOSH

animal use by, 45, 164-166

funding by, 23, 264-265

RTECS and, 229-231, 237

NLM

databases of, 11-12, 229

data sharing by, 24, 26, 223, 281

and LADB, 233-235, 237-238

RTECS and, 231

Nonliving systems, 7-8, 124, 136, 180-181, 210-214

North Carolina, 288, 307, 316-317, 319

North Carolina State University, 57

North Dakota, 288, 307, 319

Norway, 359, 368-369

Nozick, Robert, 71

NSF

animal use by, 46

animal use regulation in, 392

funding by, 13, 22, 259, 262-263

NTP

animal use and, 158

computer-based registries and, 238

and data sharing, 24

funding by, 13, 264-265

funding of, 157

and policy options, 21

and test batteries, 250

unpublished data and, 224

Occupational Safety and Health Administration.

See OSHA
Index . 4 3 9

OECD

data sharing and, 223

FDA and, 388

and policy options, 22

testing guidelines use by, 152, 156, 384, 417

unpublished information and, 228

Ohio, 268, 288

on-line databases in, 231, 233, 235

regulations in, 307, 316-317, 319

RRFs in, 287

Oklahoma, 288, 307, 316-317, 319

Oregon, 166, 288, 307, 319

Organ culture, 119-120, 133, 177, 179

See also In vitro techniques; Living systems

Organization for Economic Cooperation and Development. See OECD

OSHA, 9, 157, 162, 166

Pain

Animal Welfare Act and, 279

definition of, 4-5

funding for relief of, 270

in research animals, 103-105, 117-118, 130-132,

176, 209

Patents, 247-248

Paul, Saint, 73

Pennsylvania

regulations in, 307, 308, 310, 316-317, 318, 319,

321

RRFs in, 287, 288 .

Pennsylvania, University of, 263

Pharmaceutical Manufacturers’ Association. See

PMA

Pharmacokinetics, 153, 157, 185, 190

PHS, 13, 15, 26

and data collection, 31

economics of animal use and, 244

guidelines by, 295, 335-339, 340-341, 395-400

Health Research Extension Act of 1985 and, 281,

291

recognition of AAALAC by, 345

VA and, 393

PHS Policy on Humane Care and Use of Laboratory Animals. See PHS, guidelines by

Plants, as animal alternatives, 123, 133, 135-136

PMA

AAALAC and, 344

computer-based registries and, 238

and data sharing, 176

Policy issues

and animal use alternatives, 18-34

data accumulation and, 43

options for, 18-34

Policy on Humane Care and Use of Laboratory

Animals by Awardee Institutions (PHS). See

PHS, guidelines by

Pound release laws, 318-320

Primates, 5, 49, 52, 89-93, 132, 151, 243, 291, 294,

351, 412

Primate Research Institute, 114

Product liability

and animal use, 157, 167-168, 189

and economics, 249

testing and, 175

Protocols

for animal use, 105-108

computer systems and, 138, 228-230

and data quality, 221, 222, 228-230

EPA and, 161, 163

experimental, 149, 156

FDA and, 158-159

IACUCs and, 342

for pain relief, 117-118, 130-132, 176

and product liability, 168

for replacing animals, 8-10, 107, 114-116,

126-128

Public Health Service. See PHS

Purdue University, 352

Quantitative structure-activity relationships (QSAR),

180

Quintana, Pierre, 327, 328

Reduction

of animal use, 4, 10, 11, 39, 114-116, 126-128,

175-179, 186-187, 188-190, 209

computer systems and, 228

data analysis and, 126-128

definition of, 4

funding for, 263-264, 268, 269-270

LD5O test and, 182

protocols and, 8-10

see also Refinement; Replacement

Refinement

of animal use, 4, 10, 11, 39, 182, 183, 188-190,

209

definition of, 4

funding for, 263-264, 270

limit test as, 182

Regan, Tom, 77, 81-82

Registered Research Facilities (RRFs), 287, 288, 291

Registry of Toxic Effects of Chemical Substances.

See RTECS

Regulations

animal rights and, 315-316

of animal use, 13-18, 46, 157-167, 201-202, 203,

275-298, 305-322, 335-352, 359-375, 386-393

criticisms of, 297-298

economics and, 251, 252-253

Federal preemption of State, 33-34, 311-313

funding for alternatives and, 264

of nonanimal organisms, 179
440 . Alternatives to Animal Use in Research, Testing, and Education

product liability and, 167-168

unpublished data and, 221-222

Regulatory practices

Animal Welfare Act and, 278, 279, 280, 283-290

APHIS and, 286-289

effect on animal use of, 12, 157-167

Health Research Extension Act of 1985 and,

291-292

modifications of animal use laws and, 297-298

patents and, 248

testing methods and, 150, 157-167, 175, 181-182,

188-189

Replacement

of animals in testing, 4, 10-11, 39, 128-130,

179-181, 182-183, 185-190, 209-214

definition of, 4

funding of, 259-269

plants as, 135-136

in research protocols, 107

Resusci-Dog as a, 4, 213, 269

vertebrates as, 133-135

Research

alternatives to animal use in, 6-8, 13, 113-138

animal use in, 3, 89-108

Animal Welfare Act and, 276-291

anticruelty laws’ applicability to, 310-314

benefits to animals from, 102

economics of, 245-248, 250-251

and education, 202

funding of, 22-23, 259-264, 269

Health Research Extension Act of 1985 and,

291-292

IACUCs and, 340-344

pain reduction in animals used in, 117-118,

130-132

pound release laws and, 318-320

species choice in, 94-99, 103

and testing, 149

Restricted necessity, 80-81

Resusci-Dog, 213, 269

Revlon Inc., 265-266

Rhode Island, 288, 307, 316-317, 318, 319

Rickaby, Joseph, 73

RNA replication, 122, 125

Rockefeller University, 13, 23, 189, 265-266, 267

Rowan, Andrew N., 56, 57

RTECS, 229-231, 237

Saunders & Co., W.B., 55

Schweitzer, Albert, 74

Science, 117

Science fairs, 200-202

Singer, Peter, 76-77, 79

Small Business Innovation Research Program, 263

Smith, Kline & French Laboratories, 346, 352

Snell, Inc., Foster D., 55-56

Society for the Study of Reproduction (SSR), 349

South Carolina, 288, 307, 319

South Dakota, 288, 307, 316, 319

“Speciesism,” 6, 79

Superfund, See CERCLA

Sweden, 359, 369-371

Switzerland

economics of test ban in, 251

information center in, 220

regulations in, 28, 369, 371-372

Taub, Edward, 310, 312

Tennessee, 220, 288, 307, 316, 319, 321

Testing

animal use in, 3, 8-10, 149-168, 175-190

data accumulation and, 8

economics of, 248-251, 252-253

funding for alternatives to animals in, 264-268

Government’s role in, 157-167

methods of, 150-157

overlap with research, 149

standardized methods in, 152, 156

Texas, 286, 288, 289, 307, 319

constitutionality of anticruelty laws in, 309

hazardous waste regulations in, 166

RRFs in, 287

Thomas Aquinas, Saint, 73, 81

Tissue culture, 120-122, 133, 210

See also In vitro techniques; Living systems

Toxicology Data Bank, 229

Treasury, Department of (U.S.), 277

T-test, 115, 135

Tufts University, 57

United Kingdom, 268

animal use regulation in, 17, 18, 203-204, 359,

373-375

and data collection, 29

licensing animal users in, 28

United Nations Environment Program, 224

Unrestricted necessity, 81

USDA, 5, 33, 46, 53

animal use by, 9, 44

animal use regulation and, 386, 387, 388, 392

and the Animal Welfare Act, 14, 44, 276-281,

283-289, 291, 293-295, 298

and Federal agency use, 43, 289-290

FOIA and, 290

GLPs and, 293

pound release laws and, 318
/ndex ● 4 4 7

regulatory activities by, 158, 159, 165

Taub case and, 310, 312

U.S. Surgical Corporation and, 324, 325

See also APHIS

U.S. Surgical Corporation, 315, 316, 323-328

Utah, 288, 307, 316, 319, 321

Utilitarian principle, 6, 79-81, 82

Varana, Rudolph, 327

Vermont, 288, 307, 318, 319

Veterans’ Administration

animal use by, 46, 49

policy of, 16

regulation in, 386, 392-393

Virginia, 288, 307

constitutionality of anticruelty laws in, 309

regulations in, 306, 314, 316, 319

Virginia, University of, 114

Washington (State), 288, 307, 319

West Virginia, 288, 307, 319

Will theory, 76

Winkler v. Colorado, 312-313

Wisconsin, 288, 307

hazardous waste regulations in, 166

pound release laws in, 319, 320

regulations in, 321

Wisconsin Regional Primate Research Center

(WRPRC), 351-532

Wisconsin, University of, 57, 351

World Health Organization (WHO), 176, 219

Wyoming, 288, 307, 319, 321

Zoonoses, 94