Animal Alternatives, Welfare And Ethics

Edited By:

L.F.M. van Zutphen
Faculty of Veterinary Medicine
Utrecht University, Utrecht
The Netherlands

and

M. Balls
European Centre for the Validation
of Alternative Methods (ECVAM)
21020 Ispra (VA)
Italy

Contents

Preface

Sponsors

Introductory Lectures

Opening Address
E. Terpstra
A festival of animasl
W.M.S. Russell
The study of animal welfare: a moral oligation
HRH Prince Laurent

Plenary lectures

The Three R's concept of alternatives to animal experimentation
M. Balls
Ethics, codes, and animal research
A. Brennan
Alternatives to animal experiments: expectations and limitations
S. Garattini
Animal research and pluralist policies: the British and American experience
R. Garner
The use of cell lines genetically engineered for human xenobiotic-metabolizing enzymes
H. Glatt, W. Engst, M. Hagen, H. Hermersdorfer, R. Landsiedel, and U. Pabel
Transgenic technology as an alternative to animal experimentation
J.W. Gordon
Progress in biotechnology and the use of laboratory animals
A.D.M.E. Osterhaus

National/regional developments

National/regional development in alternatives and animal use: an overview
J.D. Strandberg
Developments in alternatives and animal use in Europe
P. de Greeve and W. de Leeuw
Developments in alternatives and animal use in Australia/New Zealand
N.E. Johnston
Development in alternatives and animal use in Japan
Y. Kuroda
Developments in alternatives and animal use in North America
M.L. Stephens

Animal welfare and refinement

The concepts of animal welfare and animal suffering
A.N. Rowan
Intrinsic value and animal welfare
H. Verhoog
Housing requirements: what ethology can tell us
M. Stauffacher
Environmental enrichment: practical applications
V. Baumans
Environmental enrichment for laboratory mice: short- and long-term evaluation
H.A. van de Weerd, V. Baumans, P.L.P. van Loo and L.F.M. van Zutphen
Rat and mice enrichment
K.E. Purves
Welfare by deign: the natural selection of welfare criteria in laboratory rats
J.L. Hurst, C.J. Barnard, and C.D. West
Noise in dog kennels, effects of design and husbandry
R. Hubrecht, G. Sales, a. Peyvandi, S. Milligan, and B. Shield
Biocontainment facilities: implications for animal care and welfare
J. MacArthur Clark
Measuring welfare aspects of transgenic animals
M. van der Meer, V. Baumans, and L.F.M. van Zutphen
A scheme for the recognition and assessment of adverse effecs in animals
D.B. Morton
Avoidance and alleviation of pain and distress
P. Flecknell
An alternative model for testing opioid analgesics and pain research using amphibians
C.W. Stevens
In vitro assays for transient and long-term repopulating hemopoietic stem cells
R.E. Ploemacher, D.A. Breems, A.E.M. Mayen, E.A.W. Blokland, I.M. den Hoed, P.B. van Hennik, N. Kusadasi, A. Prins, and W. Terpstra
The re-use of animals is research: legal, ethical, scientific, and managerial aspects
J.M. Fentener van Vlissingen, P. de Greeve, and H. Verhoog

Point/counterpoint: Transgenic animals
Transgenic animals: an alternative?

Proponent's statement
E. Wolf
Opponent's statement
T. Poole
Comments of the moderator
D.A. Neumann

Workshop: Scientific procedures and humane endpoints

Scientific procedures and practices causing concern
V. Baumans
Humane endpoints: some perspectives from farm animal studies
D.J. Mellor
Humane endpoints in research and testing. Synopsis of the workshop
D.J. Mellor and D.B. Morton

Noninvasive methods

NMR: a noninvasive tool in animal experimentation
A. Heerschap
Telemetric data acquisition of cardiovascular functions in biology and pharmacology
B. Lemmer and K. Witte
Gamma scintigraphy: a tool for reducing dissection and animal numbers in experimentation
A.C. Perkins, M.V. Pimm, and M.D.O. van der Kamp
In vitro evaluation of cancer cell invasiveness by confocal laserscan techniques
T.T. DeVaney, h.A. Tritthart, h. Ahammer, and C. Helige
Atherosclerosis in rabbits: looking beyond arteries
J. Ritskes-Hoitinga, A. Wiersma, and G.W. Meijer

Ethics and animal protection viewpoints

Animal protection movement: finding the balance between action and dialogue
H. Smid
Animal tests and alternatives: an animal protection viewpoint
G. Langley
Transgenic xenotransplantation: utilitarian and deontological caveats
T.B. Mepham and R.E. Crilly
Animal ethics committees and the implementation of the Three R's
R. Yates
Animal test advisory commissions: ethics committees in Germany
F.P. Gruber and R. Kolar

Workshop: Ethics committees

Training members of ethics committees
Tj. de Cock Buning
Ethical evaluation of animal research protocols: how it can be enhanced
F. B. Orlans
Ethics committees: how do they contribute to the Three r's? Synopsis of the workshop
N.E. Johnston and B. Rusche

Workshop: Three R's policies of journals

Editorial policies and animal welfare
D.P.J. Boisvert
Guidelines for reviewing manuscripts on scripts involving live animals. Synopsis of the workshop
M.F.W. Festing and L.F.M. van Zutphen

Education

Continuing educaiton and training (CET) as a tool for dissemination of alternatives
r.P. Maickel, L.A. Terril, and M.A. Suckow
Replacement, reduction, and refinement through education, at the University of Sydney
R. Einstein
Teaching animal welfare: a new postgraduate subject at the University of Adelaide
R.M. Baker
Teaching statistics can save animals
M.F.W. Festing
Alternatives in education: overcoming barriers to acceptance
J.P. Balcombe
Adapting animal alternatives from veterinary medical education to precollege education
R.L. Zasloff and L.A. Hart
Virtual reality: an alternative to animal use?
G.F. Coppa and M.S. Nachbar
Australian alternatives to animals in eduation
W. van Dok
Implementation of laternatives in research protocols: a systematic approach in education
J. Nab
Computer simulations in education
H. van Wilgenburg
The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) as an educational resource
J. Zurlo and A.M. Goldberg

Databases and communication

On-line databases and the World-Wide Web: What is available? What is missing?
T. Allen
How networking benefits the quality of research and animal welfare
K. Boschert
The development of a multimedia database, INVITTOX (in vitro methods for toxicology), and an associated World-Wide Web information service provider
r. Rudowski, D. Sladowski, R. Radomski, and J. Galletly
The ZEBET Databank and Information Service on alternative methods to animal experiments
B. Grune-Wolff, A. Dorendahl, S. Skolik, and H. Spielmann
The NORINA database of audiovisual alternatives
A.J. Smith and K. Smith
The pursuit of better science - a personal view of the search for alternatives
D.C. Anderson

Alternatives in toxicology

Toxicity at the cellular level
O.P. Flint
Alternatives: spin-off of good science
B. Ekwall
Closing the gap between cell death and in vitro toxicity testing
F. Zucco
Organ toxicity: the challenges ahead
J.V. Castell, D. Hernandez, A.M. Gomez-Foix, and M.J. Gomez Lechon
In vitro testing of local effects: the challenges ahead
P.A. Botham
In-house strategies for the safety evaluation of cosmetic products: the contribution of alternative methods
F.W. Baker and L.H. Bruner
Use of the in vivo reconstituted human epidermis, EPISKIN, to assess the molecular mechanisms of skin irritation and sensitization
E. Corsini and C.L. Galli
The utility of a two-test in vitro battery to assess the ocular irritancy of drug intermediates
R.D. Curren, J.W. Harbell, H.A. Raabe, R.G. Sussman, and T.A. Kimmel
A strategy for predicting in vitro phototoxicity at the cellular and molecular level
C. Agapakis-Causse
The combined cell/complement assay
D. Sladowski, A. Dabrowski, and M. Balls
US National Toxicology Program strategies for use of alternate test systems
R.S. Chhabra, J.R. Bucher, and W.S. Stokes
Mechanism-based toxicology in cancer risk assessment: biologically based models
M.C. Kohn and G.W. Lucier
Detection nongenotoxic carcinogens: major barriers to replacement of the rodent bioassay?
R.D. Combes
The use of transgenic cell lines in mutagenicity testing
G.J. Horbach, W.A. Kappers, and E.M. de Groene
Aggregate cell cultures for neurotoxicity testing: the importance of cell-cell interactions
F. Monnet-Tschudi, M.-G. Zurich and P. Honegger
Expression of the FP receptor in neuronal cells and the role of prostaglandin F2 as a neuroprotective agent
E. Walum, M. Risling, S. Lake, E. Ahlbom, K. Vikman, and C. Arlinde
Sensitization of the immune system: a challenge for in vitro toxicology
W. Seinen, R. Albers, E. van't Erve, C. de Heer, R. Pieters
The embryonic stem cell test (EST), an in vitro embryotoxicity test using two permanent mouse cell lines: 3T3 fibroblasts and embryonic stem cells
H. Spielmann, I. Pohl, B. Doring, M. Liebsch, and F. Moldenhauer
The effects of hypoxia on embryoid bodies
M. Gassmann
A cell culture model of endotoxic shock
T. Hartung, A. Sauer, and A. Wendel
The detection of pyrogens with a method involving human whole blood
T. Hartung and A. Wendel
The role of apoptosis in organotin-induced thymus atrophy
A. Gennari, M. Potters, M. Bol, A. Penninks, W. Seinen, and R. Pieters
In Vitro methodology for the safety evaluation of transgenic food crops
H.P.J.M. Noteborn, R.C.M. van der Jagt, and I. Rowland
Integrated toxicity testing: putting the pieces back together
J.M. Frazier
Application of in vitro data on toxicity and biokinetics for estimation of systemic toxicity: the ECITTS scheme
B.J. Blaauboer and J. de Jongh
Application of QSAR, expert systems and in vitro mthods
M. Chamberlain
QSARs for the eye irritation potential of neutral organic chemicals
M.D. Barratt
Use of principal component analysis for Draize eye irritation tissue scores
D.P. Lovell
StAR: a knowledge-based computer system for carcinogenic risk assessment
J.J. Langowski, P.N. Judson, M. Patel, and C.A.G. Tonnelier

Point/counterpoint: Benchmarking
Acceptance of the benchmark approach to toxicity testing

Proponent's statement
R.C. Hertzberg
Opponent's statement
D.H. Blakely
Comments of the moderator
R.A. Woutersen

Point/counterpoint: In Vitro toxicology
In Vitro toxicology: a recognized new scientific discipline?

Proponent's statement
C.A. Reinhardt
Opponent's statement
L.L. Smith
Comments of the moderators
O.P. Flint and R.D. Combes

Alternatives in pharmacology

Efficacy testing in drug development: the in vitro approach
B. Garthoff
Drug discovery through focus on human biology
R.A. Coleman and G.S. Baxter
Replacement of animals in drug screening through biotechnology
A.M.L. van Delft, F.A. Dijcks, A. Garritsen, and N.J. Stam
Establishment of cell lines carrying human genes: applications in pharmacology and toxicity testing
T. Kamataki, M. Sawada, and H. Hashimoto
Microtitration fluorimetric assays on living cells: new tools for screening in cell pharmacotoxicology
P. Rat, R. Osseni, M.O. Christen, M. Thevenin, J.-M. Warnet, and M. Adolphe
Mammalian in vitro systems: predictive value in drug metabolism
A.R. Boobis
Potentials and limitations of in vitro biotransformation systems in preclinical drug development
A.E.M. Vickers
Cytochrome P-450 induction and expression of early response genes followed by DNA synthesis in cultured liver slices
M. Gokhale, J. Zurlo, T. Bunton, S. Yang, A. Diehl, and J. Yager
A simple method for the cryopreservation of liver slices from man and other species
R. de Kanter, P. Olinga, H.J. Koster, M. de Jager, M.J.H. Slooff, D.K.F. Meijer, and G.M.M. Groothius
New drug delivery systems: validation of transdermal in vitro models
P. Daddona and L. Holladay
In Vitro models for the carrier-mediated intestinal absorption of drugs
A. Tsuji
The in vitro blood-brain barrier: the assessment of drug transport to the brain
M.-P. Dehouck, L. Fenart, B. Dehouck, and R. Ceccheli
Drug transport across blood-brain barriers: in vitro vs. in vivo models
A.G. de Boer, P.J. Gaillard, E.C.M. de Lange, M. Danhof, H.E. de Vries, J. Kuiper, and D.D. Breimer
Investigations of radical scavgengers by using an in vitro model of blood-brain barrier
K. Mertsch, R.F. Haseloff, and I.E. Blasig
Test-system for radioreceptor-binding assays using a lyophilized membrane preparation of the rat brain
V. Malygin, O. Serebryakova, S. Evdokimenko, and G. Makhaeva
Drug metabolism in newborn rat choroid plexus from lateral, third, and fourth ventricle
N. Strazielle and J.-F. Ghersi-Egea
"Loss of function" strategies in vitro: ß1 integrin-deficient embryonic stem cell-derived cardiogenesis, myogenesis, and neurogenesis
A.M. Wobus, J. Rohwedel, and R. Fassler
The pharmacological effect of ß-blockers can be evaluated by using a chick embryo tachycardia model
T. Sugiyama, H. Miyazaki, K. Saito, and H. Shimada
Drugs protecting the arterial wall: in vitro and in vivo studies
M. Soma, A. Corsini, and R. Paoletti

Alternatives in the testing of medical devices

In vitro testing for medical devices
S.J. Northrup and R. Dabbah
Biocompatibility of carbon composites: comparison of in vitro and in vivo observations
M. Lewandowska-Szumiel, J. Komender, D. Kudelska, and M. Mazur
In vitro cytotoxicity of stomatological materials: comparison of different approaches
M. Cervinka, V. Puza, Z. Cervinkova, and M. Hroch
A method for in vitro stimulation of experimental infections due to prostheses
L. Selan, C. Passariello, S. Schippa, M.A. Condemi, and M.C. Thaller

Alternatives in testing antibodies and blood products

Novel developments in vaccine production technologies
E. Griffiths
Three R's approaches in the quality control of blood products
E.J. Ruitenberg, F. Korse, and W. Bleeker
Production of monoclonal antibodies: in vivo vs. in vitro methods
M. Goodall
Egg yolk antibody: state of the art and advantageous use in the life sciences
R. Schade, P. Henklein, and A. Hlinak
Chicken IgY: efficacy of alternative adjuvants compared to FCA
C. Schwarzkopf and B. Thiele
The use of adjuvants in the production of polyclonal antisera to protein antigens
D.E.S. Stewart-Tull
A model for testing the efficacy of immunization procedures by early cytokine production in mice
M. Leenaars, L. Nagelkerken, C. Hendriksen, and E. Claasen
Reducing the use of animals by abolishment of the safety test as a rountine batch control test on veterinary vaccines
J.J.W. Zeegers, W.F. de Vries, and R. Remie
Detection of avian infectious bronchitis virus in poultry vaccines by the polymerase chain reaction
E. Falcone, E. D'Amore, L. Di Trani, S. Puzelli, and M. Tollis
Transgenic mice and a molecular assay as alternatives to the monkey neurovirulence test of oral poliovirus vaccine
I. Levenbook, E. Dragunsky, K. Chumakov, R. Taffs, Y. Chernokhvostova, T. Nomura, K. Hioki, D. Gardner, J. Cogan, and D. Asher
An in vitro alternative for in-process testing of clostridial antigens
K. Hamel, M. Callus, and A. van de Moer
The passive haemagglutination assay as a secondary method for assessing the tetanus antibody response of guinea pigs in the potency assay for adsorbed diptheria tetanus and combined vaccines: comparison of in vitro and in vitro methods
Y.P. Shinde and S.S. Jadhav
In vitro assays for estimating the activity of therapeutic preparations of botulinum toxin
D. Sesardic, P.H. Corran, K. McLellan, I.M. Feavers, and T.A.N. Ekong
An alternative bioassay for botulinum neurotoxin type A based on its endopeptidase activity
T. Ekong, C. Gee, J. Blasi, and D. Sesardic
European Pharmacopoeia quality control of hormonal products
J. van Noordwijk

Workshop: Polyclonal and monoclonal antiobodies

Production of polyclonal and monoclonal antibodies in The Netherlands
W.A. de Leeuw and P. de Greeve
Alternatives to Freund's adjuvant
W. Nicklas
A European guideline for antibody production: prospects, progress, and problems
D.W. Straughan
Polyclonal and monoclonal antbodies: synopsis of the workshop
C.F.M. Hendriksen and E. Claassen

Validation/acceptance of alternatives

Validation revisited
A.M. Goldberg, J. Zurlo, and L.D. Epstein
The ECVAM approach to validation
J.H. Fentem and M. Balls
The validation of alternative methods for toxicity testing
L.H. Bruner, G.J. Carr, M. Chamberlain, and R.D. Curren
The prevalidation of in vitro tests
J.A. Southee, R.D. Curren, H. Spielmann, M. Liebsch, J.H. Fentem, and M. Balls
The efforts of the cosmetic industry in developing and validating alternatives to animal testing in the period 1993-1996
F.A. Fairweather
A comparative study of in vitro percutaneous absorption tests
D. Howes
Comparative studies on cultured human skin models for irritation testing
M.K. Robinson, M.A. Perkins, and R. Osborne
A validation study of in vitro photoirritation tests in a joint EU/COLIPA project: preliminary report
H. Spielmann, M. Balls, G. Pechovitch, J. Dupuis, O. De Silva, W.J.W. Pape, and H.G. Holzhutter
A validation study in Japan on five different cytotoxicity assays
T. Ohno (and 98 co-authors)
Interlaboratory validation of alternative methods to the eye irritation test for the safety evaluation of cosmetic ingredients: an overview of the plan and the results
Y. Ohno, T. Kaneko, T. Inoue, T. Morikawa, A. Yoshida, A. Fujii, M. Masuda, T. Ohno, M. Hayashi, J. Momma, J. Akiyama, H. Itagaki, K. Ohkoshi, H. Okumura, H. Kakishima, Y. Kasai, A. Kurishita, H. Kojima, K. Saijo, K. Sakamoto, S. Sugiura, M. Sunouchi, K. Takano, H. Tatsumi, N. Tani, K. Chiba, T. Nakamura, K. Matsukawa, and C. Matsushige
Acceptance of acute toxicity alternatives: the challenges ahead
R. Fielder
The worldwide acceptance of validated alternative tests
H.B.W.M. Koeter
Barriers to regulatory acceptance
A.M. O'Connor
The path to regulatory acceptance of in vitro methods is paved with the strictest scientific standards
J.W. Harbell, J.A. Southee, and R.D. Curren
The significance of the Sixth Amendment to the EU Cosmetics Directive for the development, validation, and acceptance of replacement alternative tests
M. Balls and J.H. Fentem
The harmonization of classification and labelling systems
A. Smith

Workshop: The validation and acceptance of alternatives

Criteria for the validation and acceptance of toxicological test methods
W.S. Stokes
The validation process
B.J. Blaauboer
Principles of testing strategies and testing schemes for skin and eye irritation and phototoxicity testing
P.A. Botham
The harmonization of criteria for validation and regulatory acceptance of alternative toxicological tests. A synopsis of the follow-up to the OECD Workshop.
W.S. Stokes and H. Ono

Index of Authors

Subject Index