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EUROPE GOES ALTERNATIVE Animal Testing and Alternative Methods - a Scientific Perspective Coenraad F.M.Hendriksen Netherlands Centre Alternatives to Animal.

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Presentation on theme: "EUROPE GOES ALTERNATIVE Animal Testing and Alternative Methods - a Scientific Perspective Coenraad F.M.Hendriksen Netherlands Centre Alternatives to Animal."— Presentation transcript:

1 EUROPE GOES ALTERNATIVE Animal Testing and Alternative Methods - a Scientific Perspective Coenraad F.M.Hendriksen Netherlands Centre Alternatives to Animal Use (NCA), Utrecht University & Netherlands Vaccine Institute (NVI)

2 Animal Testing and Alternative Methods - a scientific perspective NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Topics of presentation science and alternatives - the way to go! Other reasons for going alternative 3Rs recommendations Conclusion

3 Science and Alternatives - the way to go! phenotype Treatment Incubation time minutes years Until now questions are based on what : - what is the toxicity of a chemical? - what is the potency of a vaccine? - what is the safety of a pharmaceutical? Future: why questions will dominate: - why is a chemical toxic? - why is a batch of vaccine potent? - why is a pharmaceutical not safe? Scientific and regulatory evolution: from what to why (1) NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, (Timo Breit)

4 NCA | The Netherlands Centre Alternatives to Animal Use Paradigm shift in Science and regulatory testing: from what to why (2) What questions ParameterEndpoint (animal model) vaccine potencyprotection after challenge chemical toxicityincrease tumour frequency drug safetyclinical signs Conference Europe Goes Alternative, Brussels, Why questions EndpointModel (e.g.) 3-D configuration antigenphysiochemical DNA or DNA repair change at molecular leveltissue culture interaction at receptor leveltissue culture Science and Alternatives - the way to go!

5 New developments Examples - omics technologies & bioinformatics embryonic stem cells in silico modelling tools improvements in tissue culture techniques systems biology etc. NCA | The Netherlands Centre Alternatives to Animal Use Micro-array analysis: genes Conference Europe Goes Alternative, Brussels, Science and Alternatives - the way to go!

6 NCA | The Netherlands Centre Alternatives to Animal Use Paradigm shift in science and regulatory testing: from what to why (3) Conclusion: Future will give a shift in research and regulatory testing paradigms: non-animal models will increasingly being used to generate answers to the why questions (mechanistic info) while the animal model will be used to verify and confirm data from non-animal studies Conference Europe Goes Alternative, Brussels, Past/ present Future R & D start End of research objective

7 Other reasons for Europe to go alternative Animal use & concerns Moral concerns Economic and pragmatic concerns Scientific concerns (In)validation concerns NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels,

8 Other reasons for Europe to go alternative Animal use & concerns Moral concerns Economic and pragmatic concerns Scientific concerns (In)validation concerns NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, % Societies acceptance of animal use for specific purposes (Aldhous et al. 1999)

9 Other reasons for Europe to go alternative NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Increased legislation and regulation concerning laboratory animal use Revision of Council Directive 86/609/EEC Appendix A of the European Convention Animal use & concerns Moral concerns Economic and pragmatic concerns Scientific concerns (In)validation concerns

10 Other reasons for Europe to go alternative NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Animal use & concerns Moral concerns Economic and pragmatic concerns Scientific concerns (In)validation concerns

11 Europe goes alternative - Future trend in Lab. Animal use? NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, year

12 Europe goes Alternative: the way forward Objective Conference demonstrate that the European Union keeps animal welfare high on the political agenda and remains in the lead for animal protection, show industrys approach to actively promote research in alternative methods, illustrate progress made in the area of alternative methods to animal tests at EU and intermational level, identify further possibilities to improve development, validation and legal acceptance of alternative methods NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels,

13 R eality ealism eaction R Rex Burch Bill Russell R NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Objective: identify further possibilities to improve development, validation and legal acceptance of alternative methods Effective EU policy towards Europe goes Alternative should include the following elements

14 NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Focus of Commission concerning 3Rs research priorities Reality: numbers and purposes of animal use

15 NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, No. of animals used in EU-MS in 2002 (N total = ): purposes Reality: numbers and purposes of animal use

16 Reality: alternatives and the 3Rs principle R eplacement of animal tests by methods not using animals R eduction: reducing the numbers of animals needed to answer a scientific question R efinement: reducing pain and distress in a particular animal experiment NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Reduction: ….of all modes of progress it is the one most obviously, immediately, and universally advantageous in terms of efficiency. (Russell & Burch, 1959) Refinement: Happy animals make good science. (Trevar Poole) Replacement: Desirable as replacement is, it would be a mistake to put all our humanitarian eggs in this basket alone. (Russell & Burch, 1959)

17 Objective: identify further possibilities to improve development, validation and legal acceptance of alternative methods R eality R ealism R eaction NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels,

18 Realism: Proposed timeframe for full replacement of animal tests NCA | The Netherlands Centre Alternatives to Animal Use Human Health effects Foreseeable time involved for full replacement ______________________________________ acute toxicity> 2014 skin irritation> 2014 skin corrosion< 2004 eye irritation> 2010 skin sensitisation> 2019 skin absorption/penetration> 2006 subacute/subchronic toxicity>> 2014 (not foreseeable) genotoxicity/mutagenicity> 2016 UV-induced effects>> 2019 (not foreseeable) Toxicokinetics and biotransformation>> 2014 (not foreseeable) Carcinogenicity>> 2014 (not foreseeable) Reproductive toxicity>> 2014 (not foreseeable) (SCCNFP, 2004) Conference Europe Goes Alternative, Brussels,

19 Realism: Legislative and Regulatory context Sectorial regulation Regulations to animal testing and multilateral agreements, e.g. Council Directive 86/609/EEC (According to Schiffelers et.al.2005) Council Directive pharmaceu ticals Council Directive vaccines Council Directive pesticides Council Directive chemicals Horizontal legislation NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels, Examples of conflict between sectorial European directives and EU legislation 86/609/EEC: re-testing of biological products entering the European market shellfish toxin testing policies Other concerns Slow progress in Harmonisation and/or mutual acceptance Increased priority for risk minimisation Sectorial regulations and decisions regulate the activities of particular sector. Horizontal legislation interacts with aspects of sectorial regulations

20 Objective: identify further possibilities to improve development, validation and legal acceptance of alternative methods R eality R ealism R eaction NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels,

21 Reaction: obstacles concerning implementation of validated alternatives Council Directive 86/609/EEC on the protection of laboratory animals Art. 7 (2) An experiment shall not be performed if another scientifically satisfactory method of obtaining the results sought, not entailing the use of an animal, is reasonably and practically available Art. 7 (3) In a choice between experiments, those which use the minimum number of animals, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected. Examples: - European Pharmacopoeia monographs for Diphtheria and Tetanus vaccine specify two possibilities for potency testing, substantially differing in the level of suffering from each other - Production of monoclonal antibodies Conference Europe Goes Alternative, Brussels, NCA | The Netherlands Centre Alternatives to Animal Use The difficulty lies not in the new ideas, but in escaping from the old ones (John Maynard Keynes, )

22 Europe goes Alternative: the way forward Objective Conference demonstrate that the European Union keeps animal welfare high on the political agenda and remains in the lead for animal protection, show industrys approach to actively promote research in alternative methods, illustrate progress made in the area of alternative methods to animal tests at EU and international level, identify further possibilities to improve development, validation and legal acceptance of alternative methods NCA | The Netherlands Centre Alternatives to Animal Use Conference Europe Goes Alternative, Brussels,

23 Alternatives developed and validated for regulatory testing in the last decade Conference Europe Goes Alternative, Brussels, NCA | The Netherlands Centre Alternatives to Animal Use Chemicals/biologicals Animal model Alternative model skin corrosivity test tissue culture tests phototoxicity tests cell culture test embryotoxicity tests cell culture test skin sensitization test LLNA test potency testing of tetanus Elisa test and ToBI test potency test erysipelas Elisa test vaccine target animal safety test deletion monoclonal antibody in vitro culture production Chemicals/biologicals Animal model Alternative model

24 Alternatives developed and validated for regulatory purposes in the last decade Conference Europe Goes Alternative, Brussels, NCA | The Netherlands Centre Alternatives to Animal Use Chemicals/biologicals Animal model Alternative model skin corrosivity test tissue culture tests phototoxicity tests cell culture test embryotoxicity tests cell culture test skin sensitization test LLNA test potency testing of Elisa test, ToBI test tetanus vaccine monoclonal antibody in vitro production production classical LD50 tests 3 alternative approaches pyrogenicity testing LAL test and in vitro model percutaneous adsorption cell culture test production inactivated in vitro culture polio vaccine (monkeys) abnormal toxicity test test deleted specific tox, diphtheria cell culture test vaccine potency test diphtheria cell culture test vaccine potency testing of diph- single dose testing theria and tetanus vaccine potency test polio vaccine antigen quantification Chemicals/biologicals Animal model Alternative model potency test hepatitis antigen quantification vaccine neurovirulence test PCR & transgenic animals polio vaccine potency test erysipelas Elisa test vaccine potency test various clos- Elisa tests tridial vaccines safety test erysipelas test deleted vaccine potency test leptospirosis antigen quantification vaccine target animal safety test safety testing poultry in vitro methods vaccine abnormal tox.test hormones test deleted safety testing hormones test delted potency test rDNA physico-chemical tests hormones lethal endpoints use of humane endpoints

25 Alternatives developed and validated for regulatory purposes in the last decade (tests developed in Europe are given in blue) Conference Europe Goes Alternative, Brussels, NCA | The Netherlands Centre Alternatives to Animal Use Chemicals/biologicals Animal model Alternative model skin corrosivity test tissue culture tests phototoxicity tests cell culture test embryotoxicity tests cell culture test skin sensitization test LLNA test potency testing of Elisa test, ToBI test tetanus vaccine monoclonal antibody in vitro production production classical LD50 tests 3 alternative approaches pyrogenicity testing LAL test and in vitro model percutaneous adsorption cell culture test production inactivated in vitro culture polio vaccine (monkeys) abnormal toxicity test test deleted specific tox, diphtheria cell culture test vaccine potency test diphtheria cell culture test vaccine potency testing of diph- single dose testing theria and tetanus vaccine potency test polio vaccine antigen quantification Chemicals/biologicals Animal model Alternative model potency test hepatitis antigen quantification vaccine neurovirulence test PCR & transgenic animals polio vaccine potency test erysipelas Elisa test vaccine potency test various clos- Elisa tests tridial vaccines safety test erysipelas test deleted vaccine potency test leptospirosis antigen quantification vaccine target animal safety test safety testing poultry in vitro methods vaccine abnormal tox.test hormones test deleted safety testing hormones test delted potency test rDNA physico-chemical tests hormones lethal endpoints use of humane endpoints

26 Europe goes alternative! Vision without action is daydream ~ Action without vision is nightmare --Japanese proverb Recommendation: an independent advisory board to the Commission to identify critical aspects of animal use, priorities in 3Rs research potential obstacles concerning implementation, and potential conflicts between 86/609/EEC and other Directives

27 Thanks for your attention!!

28

29 Validated non-animal tests Only 9 non animal tests endorsed as scientifically valid by ECVAM: skin corrosivity (Rat TER, CORROSITEX, Episkin, Epiderm), phototoxicity (3T3NRU), embryotoxicity (EST, MM, whole embryo assay), in vitro percutaneous absorption. NCA | The Netherlands Centre Alternatives to Animal Use Annual European Meeting Toxicology Forum, Brussels, if so, why do we still use animals?

30 Ontwikkelingen in het gebruik van proefdieren NCA jubileum symposium, 25 november 2004 (De Boo)


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