Anmal Experimentation

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Chapter 12

Public and Private Funding

Toward the Development

of Alternatives

The most authorit at i ve source for i nformati on on alt ernati ves to t he use of l iv e animal s in research is the NI H i tself .

Eleanor SeilingUnited Action for Animals, Inc.

April 18, 1984

Cutti ng the NIH appropriati on and eli minat ing t his Federal agency w il l be an excell ent place to start t rimming w ast e from the Federal budget.

Helen JonesInternational Society for Animal Rights, Inc.

July 1984

I become very suspicious w hen I see a grant for $5,664 or a grant for $22,000. What can a researcher accomp l i sh w i t h $22,000?

Sen. Alfonse M. D’Amato (R-NY)Senate Hearing

October 2, 1984



C O N T E N T S

Page

Funding Toward Alternatives in Research , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .259Public Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................259Private Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................263

Funding Toward Alternatives infesting . . . . . . . . . . . . . . . . . . . . . .............264Public Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . 264

Private Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... 265Funding Toward Alternatives in Education. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..268

Related Types of Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............269Animal-Facility Improvement Grants . . . . . . . . . . . . . . . . . . . . , . . . . ...........269Researching Animal Health and Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..270

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

Chapter 12 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......271

L i st o f Ta b l es

Table No. P a g e

12-1. Approaches Used in National Science Foundation Research Grants,

Fiscal Year 1983 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................26212-2. Alternative Tests Under Development at the Food and DrugAdministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .266

12-3, Alternative Tests in Use at the Food and Drug Administration. . . . . . . . . . .26612-4. Selected Research Projects Supported by The Johns Hopkins

Center for Alternatives to Animal Testing . . . . . . . . . . . . . . . . . . . . . . . .. ...267

L i s t o f F i g u r e s

Figure No. Page

12-1. Trends in NIH Research Subjects, 1977-82, asPercentage of Research Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....261

12-2. Trends in NIH Research Subjects, 1977-82, as

Percentage of Research Dollars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......26112-3. Funding Levels of National Toxicology Program Activities,Fiscal Year 1985 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................265



C h a p t e r 1 2

Public and Private Funding Toward

the Development of Alternatives

Attempts to find alternatives to using animalsin research, testing, and education are so diversethat it is difficult to cite firm figures on fundinglevels. An investigation of public and private fund-ing practices does make it clear, however, that nosingle policy covers such research and develop-ment (R&D). Much of the work that could lead tothe replacement, reduction, or refinement of ani-mal use is not even considered R&D of alterna-tives by the body that funds it.

Research is seldom targeted toward alternativesas ends in themselves. Few projects are initiated

with this specific goal. Consequently, confining theinquiry to only those cases where developmentof an alternative method is the desired result, suchas programs to find in vitro substitutes for theDraize eye irritancy test, drastically narrows thecategory of funding classified as supporting alter-

natives. In addition, it is especially difficult to ex-amine funding policies related to reductions andrefinements, because these considerations gener-ally enter into the construction of any protocol.

This chapter covers targeted as well as inciden-tal cases of research into alternatives—investiga -tions directed toward the development of alter-natives as well as those pursued for other reasons but that lead to or use alternatives. Also consid-ered are research into laboratory-animal healthand some types of pain research that may increaseknowledge about the mechanisms of pain and im-

prove methods of alleviating distress. Resourcesallocated to upgrading animal facilities are closelyrelated, since inadequate facilities may skew ex-perimental results, thereby requiring that moreanimals be used.

FUNDING TOWARD ALTERNATIVES IN RESEARCH

Developing replacements for the use of animalsin research is far more likely to be incidental thantargeted. Refinements and reductions may be in-cidental developments as well, but they are morelikely to result from conscious efforts on the partof the investigator. Areas in which alternatives,especially replacements, are discovered will often be those in which animals are not used at all. Thistype of development is exemplified by basic re-search in cell biology that resulted in improvedcell culture capabilities, and work in basic physicsthat led to noninvasive imaging techniques. Iden-tifying funding in this area is particularly difficult:Few agencies view these projects as alternativesto animal use or label them as such, even though

the methods may yield techniques and systems thatcould replace animals, reduce the numbers used,or refine the protocols. (Most testing-related re-search has been deliberately excluded from thiscategory.)

In an attempt to obtain a rough indication of ex-penditures on alternatives, OTA examined therange of models in use, identifying the numberof projects and amount of research money in eachsystem area. Of course, not every nonanimal meth-od evolves into an alternative to animal use. Yetresearch in specific techniques, such as biostatis-tics, may have broad or unanticipated applicationsacross many areas of research and testing.

P u b l i c F u n d i n g

Two major granting agencies, the National In-stitutes of Health (NIH) and the National ScienceFoundation (NSF), account for most of the basic

biomedical research sponsored by the Federal Gov-ernment. Neither agency currently funds alterna-tives as a targeted goal. In few cases is the devel-opment of a replacement a major objective of theresearch that produces one. However, considera-

259



260 Alternatives to Animal Use in Research, Testing, and Education

tion of models of all types, and the selection of aresearch model appropriate to the problem un-der investigation, occurs with every grant. Otherscientific and ethical considerations may lead toreductions and refinements within protocols dur-ing the grant review process (see ch. 15).

Nat io n a l In s t i tu t es o f Hea l th

In fiscal year 1985, national expenditures onhealth R&D exceeded $12.8 billion (24). Of this to-tal, industry accounted for the largest portion (39percent), followed by the National Institutes of Health (37 percent), other Federal research, andother funding groups (24). Of health R&D sup-ported by the Federal Government, NIH has fundedapproximately 90 percent in recent years (13).About 60 percent of the research funded by NIH

can be characterized as basic (25). NIH basic re-search has accounted in recent years for about40 percent of all Federal basic research conducted(18).

Until recently, NIH had no concerted programunder which it pursued the development of alter-natives in research, as opposed to any such meth-ods that may occur as byproducts during investi-gations. However, the new Biological Models andMaterials Resources Section within the Divisionof Research Resources may assume this function.

This office was created in February 1985 and

its function was mandated (Public Law 99-158) inNovember 1985 to address the need to explore andsupport the use of nonanimal models in biomedi-cal research, Its missions include developing theuse of cell systems, lower organisms, and nonbio-logical systems (mathematical and computer mod-els) for biomedical research and actually provid-ing biological materials that serve as criticallyimportant resources to the biomedical researchcommunity, such as those just mentioned (28).

The office intends to implement some of the rec-ommendations offered in the recent report of the

National Academy of Sciences’ Committee on Mod-els for Biomedical Research:

As favorable systems are identified, the NIHshould strive to make them readily available

to the research community by providing sup-port to supply organisms for research, main-taining stock centers for mutant strains andfor cell lines, facilitating access to computerprograms for biomedical modeling, maintain-ing databases like those for protein and DNA

sequences, and providing long-term supportfor collections of cloned genes and useful vec-tors or collections of monoclinal antibodies.NIH should consider supporting proposalswhose objective is the development of modelsystems for specific research areas. Indeed,funds might be targeted for the developmentof new model systems that appear to be par-ticularly promising.NIH should encourage interest in nonmam-malian systems through postdoctoral fellow-ships, symposia, and direct support of modeldevelopment (12).

The office today tracks the use of model systemsin research supported by NIH and serves as NIH’sfocal point for the exchange of information withindividuals, organizations, and institutions con-cerning the use of model systems in biomedicalresearch. In addition, the Biological Models andMaterials Resources Section serves as the newhome of four previously existing resources:

T h e Amer ican T y p e Cu l tu re Co l l ec t io n :

Support for this collection of cultured cells,$600,000 in fiscal year 1985, was recentlytransferred from the NIH Director’s office.

The Massachusetts Institute of TechnologyCell Culture Center This facility producesanimal cells in large quantities tailored to spe-cific investigator needs; 85 percent of its usersare NIH grantees. Funding is in the processof being taken over from NSF in fiscal year1985 (NIH contribution: $165,000) and will becomplete in fiscal year 1986.Caeno r h a bd i t i s e l eg a n s Ge ne t i c s Ce n t e r

This resource serves as a repository fornematodal mutants and a clearinghouse forthe mapping of the C. elegans genome. It issupported jointly with the National Instituteof Aging ($15,000 in fiscal year 1985).Na t i ona l D ia be t e s Re s e a r c h I n t e r c ha n ge :

This information resource is supported jointlywith the National Institute of Arthritis, Dia-



Ch. 12—Public and Private Funding Toward the Development of Alternatives 261

betes, and Digestive and Kidney Diseases withfunds ($25,000 in fiscal year 1985) providedthrough the General Clinical Research CentersProgram (28).

An analysis of research systems within variousprojects and subprojects funded by NIH providessome idea of the patterns of subjects and modelsused overall for NIH; it may also indicate nationalpatterns because NIH supports more than one-third of the health-related R&Din the United States(24). Use of both human subjects and mammals(expressed as the percentage of research projectsusing each) was essentially stable from 1977through 1982 (see fig. 12-1). At the same time therewas a slight increase (approximately 5 percent) inthe percentage of research dollars being spent onmammalian systems and a corresponding decreasein the percentage of research dollars spent on re-

search involving human subjects (see fig. 12-2). Thedata in these figures do not indicate, of course,the number of individual animals used; they onlyillustrate the relative percentages of projectsfunded and dollars spent among several types of research subjects.

NIH-supported research uses many models.Three widely used ones are in vitro cells and tis-sues, invertebrates, and mathematical and com-puter 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 NI Pro-grams,” 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 NI Pro-grams,” 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 NIHsupported 378 research projects that used humancells or tissues, for a total commitment of over $32million (27). The projects included studies of cel-lular aging, in vitro studies of immune responseand regulation of antibodies, the cellular basis of disease, and the mechanisms of DNA repair. A fur-ther 381 projects and subprojects used cells andtissues from sources other than humans in thecourse of their investigations. These accounted for

nearly $34 million, directed toward research intomodels for diseases such as herpes, leprosy, andparasitic diseases; hormonal effects on the con-trol and function of differentiated cells; differences between tumors and normal tissues; and other cel-lular and biochemical mechanisms. Invertebratesused in fiscal year 1981 included annelids, aplysia,cephalopods, crustaceans, Drosophila, echino-derms, gastropod, helminths, horseshoe crabs,mollusks, nematodes, platyhelminths, and proto-zoans, accounting for 608 subprojects and over$46 million.

Mathematical models were used by 8 BIDs, in23 projects and subprojects for nearly $1.2 mil-lion, to analyze renal flow and neural networks,to model biological waves and kinetics, to modelclinical trials, to predict fetal outcomes, and to sup-port mathematical biology. Computer simulations




were supported by 10 BIDs to study a range of research questions including computer analysesof cellular differentiation and homeostatic controlmechanisms, modeling of bladder cancer andstructure-activity relationships in drugs, simula-tions of renal function, imaging reconstruction and

display of biological surfaces, and the modelingof artificial intelligence. These 54 projects ac-counted for close to $6 million in awards.

Nonanimal models, including invertebrates andnonmammalian vertebrates in addition to thosedescribed above, account for approximately 26percent of NIH’s projects and an average of 29 per-cent of the funds in any given year. Mammaliansystems account for slightly more than 43 percentof the projects and about 46 percent of the dollarsspent. Many projects use several systems at once.

National Science FoundationNSF considers project proposals for support in

all fields of science. Among its programs are eightthat have potential to support alternatives-relatedresearch:

Behavioral and Neural Sciences,Biotic Systems and Resources,Information Science and Technology,Mathematical and Computer Sciences,Cellular Biosciences,Molecular Biosciences,Research Instrumentation and Equipment,

andScience and Engineering Education (21).

The National Science Foundation normally doesnot support clinical research either with humans

or animals, the development of animal models forspecific diseases or conditions, or the developmentof drugs or other therapeutic procedures. For themost part, it supports only what can be classifiedas basic research.

The character of research projects and modelsused in investigations funded by NSF varies widely.Table 12-1 indicates the distribution of the ap-proaches proposed in NSF research grants for fis-cal year 1983. In the categories that include livingorganisms, only those projects involving actual ex-perimentation manipulations have been included.Thus the data do not include studies on animals,plants, or micro-organisms that are observationalor descriptive in nature; these might be ecologicstudies, population dynamics, and studies of field

behavior, for instance. However, field studies thatincluded the actual capture of animals, involved

invasive or noninvasive placement of electric track-ing devices, or used physiological sampling wereincluded.

In addition, NSF supports three additionalawards that relate to the use of animals in research,although these projects do not directly use ani-mals, The first is a grant to the Institute of Labora-tory Animal Resources of the National Academyof Sciences for its activities in developing and mak-ing available to the biomedical community scien-tific and technical information on laboratory-ani-mal science resources. The other two, related toresearch on ethical issues surrounding the use of animals, originate in the Ethics and Values inScience and Technology (EVIST) program in NSF’sDirectorate for Biological, Behavioral, and SocialSciences.

Table 12.1.—Approaches Used in National Science Foundation Research Grants, Fiscal Year 1983

Number of Range of award sizesApproach used awards (in thousands) Total expenditure

Whole nonhuman primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 $9-$135 $ 1,875,958Whole nonprimate vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 2-289 32,872,503Culture 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- 100 747,079Mathematical modeling without animal use . . . . . . . . . . . . . . . 9 25- 176 657,000Invertebrates ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 5- 266 18,451,785Micro-organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 7- 250 21,440,070Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 9“ 250 20,288,332

Total ... , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,906 $2-$289 $104,701,251

SOURCE: L mmlnger 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 12-1involve the culture of animal derived components,invertebrate animals, micro-organisms, plants, ormathematical modeling, the intent of NSF-fundedinvestigations 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 sub-sequent development of alternative techniques.

The Biological, Behavioral, and Social SciencesDirectorate houses most of the work related toalternatives. NSF’s total basic research budget isapproximately $1.5 billion in fiscal year 1986, in-cluding approximately $260 million for this divi-sion. If past patterns continue, the bulk of thesefunds will not be spent on animal research buton a much broader group of projects,

S mal l Bu s in ess In n o v a t io n Resea rch

The Small Business Innovation Act (Public Law97-2 19) requires agencies of the Public Health Serv-ice and certain other Federal agencies to reservea specified portion of their R&D budgets for theSmall Business Innovation Research (SBIR) pro-gram. The stated goals of this project are to “stim-ulate technological innovation, use small businessesto meet federal research and development needs,increase private sector commercialization of in-novations derived from federal R&D, and to fos-ter and encourage participation by minority anddisadvantaged persons in technological innovation”

(26). The NIH set-aside for the SBIR program to-tals $18.2 million, NSF retains a similar SBIR set-aside pool equal to 1.25 percent of its budget infiscal year 1986.

Small businesses seeking to commercialize alter-natives can take advantage of these funds for prod-uct research and development. The grants aregenerally in the range of $35,000 to $100,000, de-pending on how quickly commercialization is like-ly to follow the research. For fiscal year 1983, NIH’sSBIR program funded many projects that might

be related to alternatives, such as:

phase I structure activity relationship estima-tion of skin and eye irritation,

an interactive teaching system for medicalstudents,

CAT scanning for carcinogenesis bioassay inrodents,cell growth chambers for chemotherapeuticdrug screening,continuous cell culture for monoclinal antibodies,

a new method to detect immune complexes,synthetic peptides as animal vaccines, bacterial/laser bioassay to detect environmen-tal pollutants,rapid methods to monitor genetic damage inhumans, anddevelopment of mammalian cell culture aneu-ploidy-assay.

Although not all of these will develop as replace-ments, reductions, or refinements of animal use,some may eventually produce commercially via-

ble alternatives.

P r i v a t e F u n d i n g

Private funding in research, especially basic re-search, is most difficult to evaluate and classifyaccording to its applicability to alternatives. And

because most basic biomedical and behavioral re-search is sponsored by the Federal Government,it is through public sector funding that alterna-tives in research are most likely to develop.

Private foundations and research institutes sup-port biomedical research internally as well as ex-

tramurally. Although some of this research maypertain to alternatives, it is not often the case un-less the mission of the institution is specifically re-lated to animal welfare. Disease-oriented founda-tions conduct research on aspects of a particularsystem or affliction and support a variety of re-search approaches, animal as well as nonanimal.Though some of these initiatives may indeed qual-ify as alternatives, examining this research on aproject-by-project basis is beyond the scope of thisassessment.

In 1985, the Nation’s first professorship in hu-mane ethics and animal welfare was establishedat the University of Pennsylvania School of Veteri-nary Medicine with the an endowment of $1.25million from Marie A. Moore. One goal of the en-dowed professorship will be to investigate alter-



264 Altematives to Animal Use in Research, Testing, and Education

natives to animal experimentation in medical re-search (15).

Several foundations have animal welfare as theirprimary mission or included as a principal goal.Since 1981, the Geraldine R. Dodge Foundation hasdisbursed over $450,000 in grants related to alter-

natives (7). The foundation awards grants in sev-eral 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 cellhybridization laboratory to enhance diagnostic,therapeutic, and disease prevention capabilities.Dodge has also contributed $63,000 to the Centerfor 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 inmany ways the support most easily identified, espe-cially when the alternative is intended to replacea test that currently uses animals. This applied R&D

draws on basic research from other areas, incor-porates it into a testing methodology, and then vali-dates the new test. Developing an alternative re-quires that the alternative system be shown tocorrelate with the effect that is of interest. Nar-row efforts such as these contrast markedly withthe broader goals of basic research, and the de-velopment of alternatives is correspondingly easier.

P u b l i c Fu n d i n g

Public funding of research toward alternatives

in testing stems from the Federal Government’srole as regulator and guardian of safety. Federalagencies conduct toxicological and other tests onmany substances and devices in order to estab-lish effects as well as standards for safety (see ch.7). The greatest impetus for Federal funding of replacements for animal tests would be a strongindication that an alternative could be found thatwould be superior to the comparable conventionalassay with animals. This has not yet occurred interms of technologies that would totally replacethe use of animals, nor is it likely to in the nearfuture, although promising areas like in vitro as-

says may someday replace some whole-animal

tests. It is more likely that short-term in vitro tests,functioning primarily as screens, will reduce thenumber of substances run through the complete

battery of tests with animals (see ch. 8).

T o x i c o l o g i c a l T e s t i n g

The National Toxicology Program (NTP) waschartered in 1978 as a cooperative effort by theDepartment of Health and Human Services (DHHS),involving four principal groups— the National Can-cer Institute (NCI) and the National Institute of Envi-ronmental Health Sciences (NIEHS), both of whichare part of NIH; the National Center for Toxico-logical Research (NCTR) of the Food and Drug Ad-ministration (FDA); and the National Institute forOccupational Safety and Health (NIOSH) of the Cen-ters for Disease Control (CDC). Fiscal year 1985

funding for the NTP totaled $76.7 million, drawnfrom contributions by the DHHS member agen-cies that were negotiated after each agency re-ceived its congressional appropriation. NIEHS pro-vides approximately 86 percent of the program’sresources (8).

The stated goals of the NTP include the expan-sion of toxicological information obtained on chem-icals nominated, selected, and tested; the expan-sion of the number of chemicals to be tested, withinthe constraints of funding; the development, vali-dation, and coordination of tests and protocols to

match regulatory needs; and the communication




of program plans and results to the public (22,23).Figure 12-3 illustrates the relative priorities of theseactivities and their components with reference tospending in fiscal year 1985. Testing activities con-sume by far the largest share of resources. Withineach of the three divisions, efforts are divided into

four major areas: mutagenesis (cellular and genetictoxicology), carcinogenesis, toxicological charac-terization, and fertility and reproduction (repro-ductive and developmental toxicology).

According to the NTP’s “Fiscal Year 1984 AnnualPlan” (22), planning activities are directed towardreducing the number of chemicals that requirechronic testing through the development, valida-tion, and application of more efficient and moresensitive testing systems. It is in this area—estab -lishing new batteries of tests and subsequentlyvalidating them—that the development of alter-

natives is most likely to occur.NIEHS directs between $18 million and $20 mil-

lion toward testing and research related to alter-native test systems, especially short-term indica-tors of intoxication. Approximately 85 percent of this money is channeled through NTP in the formof grants for research and testing, R&D contractsfor testing and development, and in-house re-search. These funds cover the actual testing in addi-tion to methods validation and evaluation of alter-natives. Test systems receiving the bulk of attentioninclude 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

$5.00.61.50.92.0

$54.5

Carcinogenesis ., . . . . . . . . . . 28.4

Toxic characterization. . . . . . . 17.0

Mutagenesis. . . . . . . . . . . . . . . 6.9

Fer t i l i ty and reproduct ion . 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 fourconstituent agencies of NTP), DHHS support forresearch related to toxicology is also found withinthe Alcohol, Drug Abuse, and Mental Health Ad-ministration, CDC, FDA, and NIH. Substantial Fed-eral support for toxicological research and testing

is also provided by the Environmental ProtectionAgency (see ch. 11, table 11-3).

F o o d an d Dru g Ad min i s t r a t io n

FDA conducts primarily mission-oriented, ap-plied research. Its interest in alternatives derivesfrom FDA requirements for product testing. Al-though intramural funds are not allocated on aproject-by-project basis, the agency has tried toestimate expenditures on the basis of person-yearsinvolved in the work (4). Assuming a person-yearis $40,000 (salary, overhead, and benefits), in-

tramural research into alternatives to testing withanimals was estimated at 35 person-years, an ex-penditure of roughly $1.2 million. Extramuralwork consists of one project, valued at $87,000,to develop an in vitro model as a primary screento detect active agents against Di ro f i l a r i a immi t i s

larvae (a heartworm found in the dog, wolf, andfox) and microfilariae (the prelarval stage of a para-sitic roundworm). For the most part, these in vitromodels have been developed elsewhere, and theseprojects involve the application to FDA-regulatedproducts. Tables 12-2 and 12-3 list alternative testscurrently under development and in use at the

Food and Drug Administration.

P r i v a t e F u n d i n g

private sector motivation to develop alternativesin testing ranges from scientific concerns througheconomic and political ones. Investors in this sec-tor account for perhaps the most diverse groupof supporters of this type of research.

T rad e an d In d u s t r i a l Gro u p s

The development of alternatives in testing is sup-

ported by trade groups and industry for severalreasons, mostly linked economically to the finan-cial health of the company or industry. Commer-cial concerns find alternative methods generallytake less time and labor and are therefore less ex-pensive to perform than standard animal-based




Table 12=2.—Alternative Tests Under Developmentat the Food and Drug Administration

Tabie 12=3.-Aiternative Tests in Useat the Food and Drug Administration

. Genetic probes for toxigenic strains of Campylobacter je juni

. Genetic probes for invasive Escherichia coli

. In vitro invasiveness test based on siderophore avidityfor iron

Enzymatic and chemical in vitro evaluation of infantformula 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 themechanism by which effects are produced

Porcine kidney explant cultures for screeningpotentially nephrotoxic agents

. In vitro macromolecular biosynthesis as an index ofpotential tissue damage by chemical agents

. In vitro determination of effects of chemical agents ofT- and B-lymphocyte function

Improved procedures for use of unscheduled DNAsynthesis for genotoxic effects

. In vitro use of renal cortex tissue to determinebiochemical 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 andenvironmental pollutants

Liquid and thin-layer chromatographic methods forciguatera and paralytic shellfish toxins

. In vitro immunoassay methods (RIA, ELISA) forassessment 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 andresponsiveness to public concern over animal usealso drive the search for alternatives. As publicrelations tools, nonanimal methods have provedvaluable in reassuring the public that these cor-porations share their concern about animal useand are exploring other systems, while being care-ful not to jeopardize public health and safety.

In 1980, Revlon Research Center, Inc., awardeda 3-year, $750,000 grant to Rockefeller Universityto establish the Rockefeller Laboratory for In Vitro

Toxicology Assay. Revlon’s investment was the firstserious, publicly taken step by industry in thesearch for alternatives. The Revlon award has beenextended into a fifth year and totals more than$1.25 million (5). The laboratory employs fourscientific staff, working on projects including alter-

Genetic probes for heat-labile and heat-stableenterotoxin of Escherichia coli

Genetic probes for invasive strains of Yersinia enterocolitica

Genetic probes for classical 01 cholera toxin

Genetic probes for pathogenic organisms (01 andNon-01 Vibrio cholerae, Vibrio parahemolyticus, Vibrio vulnificus)

In vitro tests for percutaneous absorption of cosmeticingredients

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 ofpotential cardiotoxic agents

Ž High-performance liquid chromatography as a screenfor 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 potencyof biological vaccines

Genetic probes for invasive Shigella In vitro assays for tumor-producing potential (HL 60

differentiation, V-79 metabolic cooperativity, andEpstein-Barr virus activation

. Assays for detection of mycotoxins (massspectrometry, instrumental methods, brine shrimpassay)

SOURCE: A P Borsettl Staff Scientist, Office of Science Coordination, Food andDrug Administration, U.S. Department of Health and Human Services,Rockviile MD, personal communication, 1985.

natives to the Draize eye irritancy test and otheranimal cell culture applications. Prior to the estab-lishment of this facility, there were no laboratoriescommitted to alternatives research.

The Johns Hopkins Center for Alternatives toAnimal Testing has committed $2.1 million to thesearch for alternatives since 1981, funding 30grants for research (19). The Center has both aninformation program (consisting of a regularlypublished newsletter, symposia, and a book series)and a research program (focused on in vitro acuteand 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, in-cluding the Bristol Myers Company, as well as byconsumer and industrial groups and private indi-viduals. CAAT solicits projects from scientists by






Both the Animal Protection Institute and the In-stitute for the Study of Animal Problems have sur-veyed corporations that do animal research andtesting (2,14). Many companies indicated that theywere taking steps to promote alternatives. Sup-port often took the form of membership in a trade

association (e.g., CTFA) that sponsors research intoalternatives. Others indicated that investigationswere being undertaken within their own researchprograms. Responses and levels of commitmentvaried greatly among corporations.

Animal Welfare Groups

Groups such as the American Fund for Alterna -tives to Animal Research (AFAAR), the AmericanAnti-Vivisection Society, the New England Anti-Vivisection Society, the Animal Welfare Founda-tion of Canada, the Lord Dowding Fund in GreatBritain, the Millennium Guild, and the Muriel Low-rie Memorial Fund have supported research in theUnited States aimed at replacing animals in test-ing protocols. These grants range in size from afew thousand to several hundred thousand dollars.

AFAAR, for example, has provided some $130,000in grants between 1977, when it was founded, and1985 (l). Included among these are a grant of $25,905 to develop a test system to determine thenutritive value of protein in foodstuffs, using Tet-

rahymena (ciliate protozoans) in place of wean-ling mammals. This test enables food producersto provide correct diet supplements or therapeutic

diets. In addition, a grant of $45,000 was awardedto develop a replacement for the Draize eye ir-ritancy test using the chorioallantoic membraneof the chick embryo. Additional funding for thisproject has been supplied by other animal welfaregroups (a total of $148,500 from the Lord Dowd-ing Fund, the American Anti-Vivisection Society,the Muriel Lowrie Memorial Fund, and the Ani-mal Welfare Foundation of Canada) and by the Col-

gate-Palmolive Company. In 1985, AFAAR joinedthree other animal welfare groups in awardingan additional $133,987 to develop procedures fortoxicology testing using monolayer cell culturesin gradients of oxygen tension and temperature (l).

The Millennium Guild has offered $500,000 to

encourage the development and implementationof testing methods that will replace or significantlyreduce the use of animals (11). There is a break-through award of $250)000 for nonanimal replace-ments for the Draize eye, the Draize skin, or theLD5O tests for any scientist or team of scientistswho develops a cost-effective test or battery of teststhat can be validated and accepted by a U.S. regu-latory agency. An equal sum is available to pro-mote innovation and to reward the rapid reduc-tion of widely used animal tests, These incentiveawards have been granted in areas such as usesof liver culture, quantitative structure activity rela-tionships, cell culture bioassays, and the use of pro-tozoans as indicators of eye irritancy.

Foundations and Research Institutes

Foundations and research institutes often de-vote in-house and other private funds to researchinto alternate testing methodologies and systems.Battelle Columbus Laboratories (Columbus, OH),for example, is pursuing the development of manyalternatives. Its efforts fall into two major divisions,mammalian and nonmammalian systems. The ba-sic areas of system development include cell and

organ culture, in vitro teratology, and neurotoxi-city. A figure of $500,000 has been conservativelyestimated as the investment in this area. The fund-ing comes primarily from private sources and in-cludes both internal and external funds. Some of the projects now under way are cell culture initi-atives, including microphage work, and teratolo-gy research using rat embryo and frog embryocultures (16),

FUNDING TOWARD ALTERNATIVES IN EDUCATION

Funding of research toward alternatives in edu- education. Alternatives in education also often orig-cation, especially within the public sector, stems inate as research simulations, and then move backmore from a renewed emphasis on science and into the classroom. Exceptions to this are projectsmath education and on computers than from sub- undertaken for the express purpose of develop-stantial concerns with methods of animal use in ing replacements for animals in the classroom, or




programs developed in order to cultivate attitudesconducive to the further development and imple-mentation of alternatives (see ch. 9). Some of theseother initiatives, such as those funded by groupsinterested in issues pertaining to animal use, havedeveloped from concerns related to humane edu-

cation.The Health Professions Educational Assistance

Amendments of 1985 (Public Law 99-129) author-ized the Secretary of the Department of Healthand Human Services to make grants to veterinaryschools for work related to alternatives. Thesegrants can support the development of curriculafor:

Ž training in the care of animals used in re-search,

the treatment of animals while being used inresearch, and

the development of alternatives to the use of animals in research.

Since 1981 the Geraldine R. Dodge Foundationhas given over $240,000 toward education-relatedalternatives programs including:

$25,000 to the Biological Sciences CurriculumStudy to support the development of materialsat the high school level relating to animal wel-fare as a legitimate consideration in biology;

more than $50,000 to the National Associa-tion for the Advancement of Humane Educa-tion to support the development of People and

Animals, an interdisciplinary humane educa-tion guide for preschool through sixth-gradeteachers;

$50,000 to the American Society for the Pre-vention of Cruelty to Animals to broaden andstrengthen its humane education component,particularly through four 15-minute humaneeducation television programs for elementary-school children developed in cooperation withthe New York City Board of Education; and$30,000 toward the development at CornellUniversity of Resusci-Dog, a canine cardio-pul-monary resuscitation mannequin (see ch. 9);this is the first of a series of simulators, in-cluding one that will demonstrate irregulari-ties in heartbeat rhythm (7).

The American Fund for Alternatives to AnimalResearch supports a series of intensive trainingsessions on in vitro toxicology for students plan-ning a biomedical career to promote the develop-ment of scientists who are well trained in the usesand limitations of replacement techniques. This$39,000 grant supports courses that cover the the-ory and practice of cell and tissue culture, in vitromutagenesis, transformation, and cytotoxicity (20).

RELATED TYPES OF FUNDING

Three additional categories of funds maybe con-sidered in conjunction with efforts to develop alter-natives. These types of projects are more likelyto contribute to reductions and refinements thanto replacements. Grants to improve animal facili-ties, research in animal health, and research intopain can have broad implications for research, test-ing, and education.

A n i m a l -F a c i l i t y I m p r ov em en t G r a n t s

Research support through grants to improve fa-cilities for housing animals is not specifically de-signed to promote the development of alternatives,

but it may assume that role nonetheless. The qual-ity of animal care provided directly affects thehealth of experimental animals. Those maintainedwithin a more controlled environment are less like-ly to exhibit variations stemming from exposure

within that environment, And if they are kept un-der conditions better suited to their individualneeds, they are less likely to exhibit symptoms of stress. These negative effects, all resulting fromthe intrusion of external stimuli, may skew the re-sults of an experiment. Less reliable results mayin turn demand that more animals be used for eachprotocol, perhaps a needless addition under bet-ter conditions.

To address this problem, the Division of ResearchResources within NIH is offering grants for thedevelopment and improvement of animal facilitiesso that institutions can comply with the AnimalWelfare Act and with DHHS policies on the careand treatment of animals. Eligibility is open to anynonprofit institutions engaged in research sup-ported by NIH. Two programs currently exist. Thefirst, an ongoing program, has funded from two tofour proposals each year for the past several years.




Funds for alterations and renovations are limitedto $100,000, although requests for funds for equip-ment may push the total above this amount.

The second program draws from a one-time poolof $5 million. Support for new construction is not

available, and funding for alterations and renova-tions is limited to $500,000 for each award, Recip-ient institutions are required to match these fundsdollar for dollar. As in the ongoing program, fundsmay be requested for equipment in addition to thisamount. More than 100 applications have been re-ceived; of these, only 12 requested the maximumfunds for renovations and alterations. Many, how-ever, exceeded $700,000 in their total request. Theapplications averaged in the $300,000 to $400,000range. Some 12 to 15 projects are likely to befunded, and grants will probably range from $65,000to $75 0 ,000 (9 ).

It is important to note that at least two othersources of funding for improvement of animal fa-cilities are available to NIH grantees. First, an in-stitution’s maintenance of facilities is an allowa-

ble indirect cost of research. Second, the NationalCancer Institute is allowed to make awards for fa-cilities renovation (6).

Groups other than NIH are also devoting re-sources to improvements in animal facilities. In-dustry laboratories, contract laboratories, anduniversities are mustering both internal and ex-ternal funds to improve their facilities. For com-

mercial groups, a longer term economic advan-tage is recognized in these efforts. Contract testinglabs, in particular, have special incentives to main-tain the highest laboratory standards in order toattract clients.

Resea r c h i n A n i ma l H e a l t h a n d Pa i n

Funding devoted to research in animal healthcan function in an analogous fashion to efforts toimprove animal care facilities. It creates the scien-tific base on which improvements in facilities and

practices may be based, The larger the knowledge base on animal research grows, the more exactand focused research using animals can becomeand, ultimately, the smaller the number of animalsincluded in individual protocols.

Parallel with this, research into the mechanismsof pain and pain perception can contribute knowl-edge that allows researchers to alleviate pain inexperimental protocols. This can include researchon the detection of pain and distress, for example,that would allow an investigator to detect thesephenomena with greater sensitivity. Advances inanalgesics and anesthetics may produce less dis-tortion in some protocols and allow animals a great-er degree of comfort.

As an example, Humane Information Services,Inc., awarded $184,000 in research grants during1984 to support eight agricultural research projectsdirected toward the alleviation of animal suffer-ing. Included were studies on the behavioral ef-fects of several types of housing for pigs andchickens, studies of electronic immobilization, andprojects aimed at reducing the stress of weaningand pre-slaughter handling. Similar efforts could

be undertaken in testing and research to maximize

the information obtained from protocols whileminimizing pain and suffering for the subjects.

SUMMARY AND CONCLUSIONS

Measuring the funding of alternatives is inex- The development of alternatives, especially re-act at best. Funding of replacements is easiest to placements, is likely to be the result of multidisci-measure, while the data are poor for reductions plinary efforts, executed over relatively long pe-and refinements. The easiest type of research to riods of time. The results of research can berecognize 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 tech-ciated with technique development—for example, nologies developed by physicists that are now usedthe effort to replace whole-animal testing assays in the biomedical sciences.with in vitro tests, as with the Draize eye irritancytest.



—

Ch. 12—Public and Private Funding Toward the Development of Alternatives . 271

Three types of grants can augment the develop-ment of alternatives. Funding to improve animalfacilities can result in healthier, less stressed ani-mals and can free research from the confoundingvariables bred by a less well defined or inferiorenvironment. Grants to investigate improvements

in animal health in general can have the same ef-fect. And research into the mechanisms govern-ing pain may spare animals some measure of suf-fering when the techniques are incorporated intoother protocols.

The development of alternatives in research isfunded largely by incidental means through thesupport of basic biomedical research by the Na-tional Institutes of Health and the National ScienceFoundation plus a few targeted efforts that aresupported privately. In a climate of finite researchresources, research and development of alterna-

tives to animal use take their place in the competi-

tion among research priorities. A noteworthy ef-fort by NIH was the creation of the BiologicalModels and Materials Resources Section within theDivision of Research Resources. With funding, thisoffice may serve as a focal point for the exchangeof both nonvertebrate biological materials and in-

formation about the use of model systems in bio-medical research.

In testing, a solid organizational structure forR&D of alternatives is in place, best illustrated bythe National Toxicology Program and the Food andDrug Administration in the public sector and bythe Rockefeller Laboratory for In Vitro Toxicol-ogy Assay and The Johns Hopkins Center for Alter-natives to Animal Testing in the private sector. Anystrong indication that an alternative test methodwould be superior to a comparable conventionalanimal assay is likely to attract funding readily.

CHAPTER 12 R E F E R E N C E S

1. American Fund for Alternatives to Animal Re-search, “Presentation of Grant Awardsby AFAARat the Center for Advanced Training in Cell and Mo-lecular Biology, Washington DC, June 1985.

2. Animal Protection Institute, “The Product TestingUpdate: Who’s Using Animals and Who’s Not, ” re-sponse to “A Day That Counts” program, Sacramen-to, CA, January 1985.

3. Balls, M,, Chairman of Trustees, Fund for theReplacement of Animals in Medical Experiments,Nottingham, UK, personal communication, Mar. 4,1985.

4. Borsetti, A. P., Staff Scientist, Office of Science Co-ordination, Food and Drug Administration, US. De-partment of Health and Human Services, Rockville,MD, personal communication, 1985.

5. Brauer, E. W., Vice-President, Revlon Research Cen-ter, Inc., Edison, NJ, personal communication, Jan-uary 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 Toxi-cology Program, Research Triangle Park, NC, per-sonal communication, July 1985.Holman, J., Director, Laboratory Animal SciencesProgram, Division of Research Resources, NationalInstitutes of Health, Public Health Service, U.S. De-partment of Health and Human Services, personalcommunication, July 1985.

10 ,

11,

12.

13.

14.

15.

16.

17.

18.

McKinney, P., Administrative Officer, Toxicolog-vResearch and Testing Program, National Instituteof Environmental Health Sciences, Research Tri-angle Park, NC, personal communication, July 1985.Millenium Guild, “Half Million Dollar Rewards toGet Rid of Lab Animal Suffering,” press release, NewYork, Apr. 13, 1982. ational Research Council, M odels for Biomedical Research: A N ew Perspecti ve (Washington, DC: Na-

tional Academy Press, 1985).National Science Board, Science Zndica t ors 1982

(Washington, DC: National Science Foundation,1983).Nethery, L. B., and McArdle, J. E., Animals in Prod-

uct D evelopment and Safet y Testi ng: A Surv ey

(Washington, DC: The Institute for the Study of Ani-mal Problems, Humane Society of the United States,1985).Resovsky, E. M., Director of Development, Univer-sity of Pennsylvania School of Veterinary Medicine,Philadelphia, PA, personal communication, Oct. ,

1985.

Sabourin, T.D., Battelle Columbus Laboratories, Co-lumbus, OH, personal communication, February1985.Shadduck, J. A., “Alternative Testing Methods: AProposal for the Development of Alternatives toOcular rrit ncy Tests,” Grants and Contracts Of-fice, University of Illinois at Champaign-Urbana, ov 24, 1982.Shapley, W., “Special Analyses, ’’AAAS Report X: e



272 . Alternatives to nim l Use in Research, Testing, and Education

search and D evelopment, Fiscal Year 1986 (Wash-ington, DC: American Association for the Advance-ment of Science, 1985).

19. The Johns Hopki ns Center for A l ternati ves to An i

mal Testi ng, “New Grants Support Research to Sim-ulate Human Exposure” 3 3 :6, 1985.

20. Thurston, E., Director, American Fund for Alter-natives to Animal Research, New York, personalcommunication, Apr. 25, 1985.

21. Umminger, B. L., Deputy Director, Division of Cel-lular Biosciences, National Science Foundation,Washington, DC, personal communication, Febru-ary 1985.

22. U Department of Health and Human Services DHHS , National Toxicology Program, “NationalToxicology 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 toToxicology,” NTP-84-024 (Research Triangle Park,NC: DHHS, February 1984).

24. U.S. Department of Health and Human Services

DHHS , Public Health Service, National Institutesof Health, N IH Data Book (Bethesda, MD: DHHS,1985).

25. U.S. Department of Health and Human Services DHHS , Public Health Service, National Institutesof Health, “NIH Federal Funds Data Submitted toNSF,” 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 Solicit ati on of t he pub l i c Healt h Serv ice for t he Smal l Business I nnovati on Research Grant Appli cat ions PHS Pub.No. 86-1 (Bethesda, MD: DHHS, 1985).

27. Willett, J.D., “Biological Systems Used as ResearchModels in NIH Programs,” Animal Resources Pro-gram, Division of Research Resources, National In-stitutes of Health, Public Health Service (Bethesda,MD: DHHS, Sept. 24, 1984).

28. Willett, J.D., Project Officer, Biological Models andMaterials Resources Section, Animal Resources Pro-gram, Division of Research Resources, National In-stitutes of Health, Public Health Service, U.S. De-partment of Health and Human Services, Bethesda,MD, personal communication, July 1985.

Documents

Anmal Experimentation