The third European Workshop of National Platforms on Alternative Methods took place in Brussels on the 9th and 10th of November 2002.
55 participants from 15 different countries attended this workshop in order to discuss chances and ways of introducing and implementing alternative methods into national, European and supra-national guidelines more efficiently as well as to pave the way for the official launching of ecopa as a non-profit organization by approving its statutes. Among the participants were EU and OECD decision-makers as well as representatives from various National Consensus Platforms. In addition to experts from industry, academia, animal welfare and governmental institutions, a number of guests and speakers from DG Research, the OECD-secretariat as well as ministries of several European countries were present.
Throughout the meeting a constructive working spirit among the participants was present which was then also highlighted by the official signing of the statutes and formal founding of ecopa by ten members on Sunday, November 10th, 2002, as a new international not-for-profit, non-governmental organization registered in Belgium.
Mr. J. Tavernier, Belgian Minister for Consumer Protection, Public Health and Environment: Opening of the Workshop
Mr. Tavernier, firstly referred to his predecessor, Mrs. Aelvoet that had expressed her support for ecopaat last year’s workshop, describing ecopa as the independent non-governmental organization that should play the crucial role in the development, promotion and application of alternative methods to the use of experimental animals in research and regulatory testing. As her successor, he joined to support since he was convinced that the only strategy for a real and reasonable chance was an all party-involvement, being industry, animal welfare, academia and governmental institutions, working together in a European context.
Regarding alternatives, he stressed that though some success had been achieved, one was still quite far away from the ultimate goal, namely toxicity testing without the need for experimental animals. He outlined that most experimental animals were not used today in the field of cosmetic testing , but in the protocol testing of chemicals, drugs, crop protection products, etc. for long-term toxicity. Tests including reproductive toxicity, carcinogenicity, systemic toxicity, chronic and subchronic toxicity were still consuming huge numbers of animals. For all these basic regulatory tests, however, there were no relevant replacement, reduction or refinement method proposals available at present.
He then expressed his view that the public and political perception with respect to animal testing was changing quickly. Ethical acceptance of animal testing was decreasing fast, thus increasing the pressure and need to develop alternative methods more vigorously. Yet, he also pointed out that one needed to be realistic. The past had shown that success could only be achieved when there was financial and intellectual input as well as mutual respect between scientists and non-scientists as well as manufacturers and animal welfare representatives.
H. Koeter: Development of Guidelines: Policies and Technical Procedure: Slow Process at OECD?
Approaches by New Testing Strategies vs. Validation
Dr. Koeter explained the policy for the development of OECD Test Guidelines, saying that the development of test guidelines was driven by science and that human health and environmental safety concerns were the first priorities. The development of test guidelines was based on regulatory need for defined data. He also stressed that the process was transparent, that there was no limit to the scientific input from member countries and recognised NGO’s, and that test guidelines were developed on the basis of full consensus.
He referred to a High Level Joint Meeting in 1982, a Council Decision on the Mutual acceptance of Data for the Assessment of Chemicals in 1981 and the OECD Principles of Good Laboratory Practice pointing out that within the regulatory context the welfare of animals was important and would continue to be an important factor influencing the work of the OECD Chemicals Programme.
On average the process of developing a test method as an OECD test guideline would take about 3-4 years. Expert involvement was normally on a voluntary basis. Experts from 30 member countries plus other stakeholders were involved in a process that worked on the basis of consensus. The secretariat’s staff was limited. Posing the question whether the job could be done faster, he argued that it would be possible by using smaller numbers of experts, or it could also be achieved by hiring experts for the job and by not involving stakeholders but only regulatory authorities. Yet, he felt that this would not be acceptable if a sound scientific basis and wide acceptance were the objectives.
He elaborated on the process by giving two examples, e.g. in vitro skin corrosion and percutaneous absorption. Dr. Koeter argued that the lessons learned from these cases were that guidance was needed for the conduct and review of retrospective validation approaches and that the unilateral development of test methods in the EU was a duplication of efforts and a waste of resources both at the EC and in member states. In addition, the unilateral development of Test Methods in the EU could result in severe delays in the development of OECD Test Guidelines.
B. Garthoff: Guidelines for Alternatives: Does it require Decades? The Need for Research!
Dr. Garthoff quoted the OECD 1982 High Level Joint Meeting statement that testing in animal could not be eliminated at present, but that every effort should be made to discover and validate alternative testing systems. The sources were drying up with respect to the implementation of alternative methods. He pointed to the experiences gained with the LD50 acute toxicity test alternative, the 3T3 NRU phototoxicity test and the local nymph node assay for sensitising properties as examples to illustrate the current situation. The decades required for the development of Acute Toxicity Testing Guidelines had been a disaster as far as the time required for adoption was concerned. The perception of slowness at OECD was indeed the reality.
Dealing with the issue of regulatory testing, he argued that the earlier new test models were introduced to the scientific community, the „regulated“ community and the regulating authorities, the more rapid implementation would be. There would not always be a need for “validated” tests requiring lots of funds and time. Taking the HET CAM-test and the bovine cornea test as examples he concluded that there were comparable tests serving the purpose to some extent, being used for screening/optimisation rather than the “final” regulatory test. There was circumventious evidence that should be submittable and acceptable to authorities. Action and respective funding was needed in all kinds of research areas, such as photoallergy, subacute toxicity, chronic toxicity and reproductive toxicity. In addition new methodology and technology had to be screened for application in alternatives ( specifically toxicogenomics).
Asking who was responsible for research into alternatives and which governmental institutions were fostering further development, Dr. Garthoff said that there was nobody and none responsible. Then, asking who had made efforts in the past, he stated that different institutions and associations such as the OECD, ECVAM, COLIPA, Zebet, various DGs, animal welfare organisations and countries has made efforts organising conferences, workshops and so on, but nobody really felt responsible to guide all efforts towards the real needs and towards those tests that still are lacking now and that are consuming the highest number of animals e.g. chronic tests, carcinogenicity tests, reprotox tests, etc.
Regarding the EU regulations he saw a European “Disconnect”. He felt that on the one hand, the EU White Paper on Chemicals called for major testing in lab animals but on the other hand, the 6th Framework Program being released at about the same time, initially did not even consider research funding of alternatives. Such funding needed to be ensured by addressing institutions such as the DGs. He saw a need for giving the floor to ideas that did not need „official“ validation and, suggested that ecopa should figure as the European sponsor taking the lead. It would be necessary to initiate joint research projects, in between the national consensus platforms, the stakeholder parties, the institutions and associations and the EU 6th Framework program research fund base. Creating a platform for supra-national activities and promoting research results would thus achieve the impact needed.
M. L. Stephens: View of the Animal Welfare Associations / ICAPO
Dr. Stephens provided background information on the International Council for Animal Protection in the OECD Programs (ICAPO). ICAPO aims at promoting animal protection and the 3Rs within the OECD and the Member States. As part of its related activities ICAPO participated in relevant meetings and working groups, submitted comments on test guidelines, guidance documents and meeting reports as well as lobbying Member States regarding OECD activities.
Outlining the general views of ICAPO, he said that tests should be developed and validated using high scientific standards and that those standards should be the same for in vivo and in vitro methods. In particular, animal-based methods should not be assumed to be automatically relevant to humans. Animal tests should be more rigorously validated than currently. In addition, only adequately validated tests should be considered for adoption as test guidelines and in general, in vitro methods should be given priority over in vivo methods.
Referring to the OECD he stated the system was slow, in part resulting from the bureaucratic, consensus-based structure. A single member could delay or even block an initiative. Yet, he acknowledged that successes occurred and that the system would allow though not foster the implementation of the 3Rs. Bottlenecks along the process are the limited financial and other resources and a problem regarding the political will to make the 3Rs a priority. Concerning the short- and long-term steps to be taken by OECD, ecopa and other organizations, Mr. Stephens stressed the need to foster the 3Rs as a priority among stakeholders. He called for a better funding as well as international co-ordination to reduce and eliminate duplicate testing, to maximise the use of pre-existing data, to combine multiple endpoints into a single test and to thoughtfully assess existing exposure information to gauge the need for further toxicity testing.
D. Esdaile: View of an Industrial Toxicologist
Dr. Esdaile gave examples of the 3Rs and the OECD process stating that change with respect to alternative methods was a slow process in the OECD. Regarding the perspectives on national, supra-national and guidelines in human safety testing, he stressed that it would be necessary to rethink and redefine the substances and exposure scenarios that should be regulated to ensure an acceptable level of human safety. It would be necessary to think about the possible effective methods for testing each type of substance for each intended use and the exposure routes. Finally, one should contemplate what national and international regulatory structure would be best suited to provide an acceptable level of human safety, and how the testing requirements could be satisfied with a minimum of animal suffering.
Regarding the process and its problems, he pointed to the difficulties encountered in trying to remove an OECD test guideline, the administrative “requirements” for documentation and the resistance to change. One reason why change could be difficult to achieve was the fear that alternative methods might be inferior and thus lead to a reduction of standards. Money and support were two essential points. He stated that up to date most progress had been achieved and funded by industry but that additional support from other sources was needed if the process was to be speeded up. National differences due to experts working apart would often design different potential testing strategies.
He concluded that the system worked but slowly, calling for an international commitment to the 3Rs with the selection of experts taking this aim into account. He suggested that information of actual human risks, quality of regulatory data and SAR (Structure Activity Relationship) would help to direct policy. The international harmonisation of requirements should be given a higher priority and OECD manpower (expert scientists) be strengthened.
H. Spielmann: View of a Governmental Institution for Implementation of Alternatives
Prof. Spielmann explained that article 7.2 and 23 of the EU Directive 86/609/EEC formed the basis for developing alternative methods. Meanwhile a number of centres for alternatives to animal testing had been founded in various European countries. Regarding Zebet (in Germany), he explained that its mission was to establish and maintain a database and information service on alternatives at the national and international level. It was further charged with developing alternatives according to the 3Rs-principle of Russell and Burch, with funding of research on alternatives, and the co-ordination of validation studies. Zebet was also co-operating with national and international funding agencies and validation centres as well as providing a forum for information on alternatives to animal testing.
Concerning Zebet’s involvement, he referred to the in vitro skin corrosion tests and the 3T3 NRU in vitro phototoxicity test as examples. Having illustrated both cases in more detail, he concluded that Zebet’s activities had shown how governmental centres could play an active role in promoting and implementing alternatives. For the latter he argued that it was important to be in close contact with regulator colleagues. In addition, for implementing alternatives at the EU and OECD levels, it would be important to provide funding for test development and the validation of alternatives. One would also need to have a tissue culture laboratory to participate in international validation studies and the knowledge on how to manage prevalidation and validation studies. If support with experts and funding was provided it could speed up the implementation of alternatives internationally.
J. Küllmer: Out of the View of the Authority Governing the National Co-ordinator (NC)
Dr. Küllmer outlined that key elements of the OECD test guidelines program were the mutual acceptance of data, a wide applicability for all chemicals, the consideration of animal welfare issues, an expert network via national coordinators and a strict standard procedure for the elaboration of test guidelines. He argued that the OECD system was slow due to a number of factors such as the limited resources of the OECD-secretariat, the national coordinators and other stakeholders. The review processes and the consensus building were very time consuming while the validation processes were in addition to this also expensive. The aim of general applicability required an additional extension of review and validation processes.
Sharing the workload would help to increase the capacity and speed of the current Test Guidelines Program (TGP). The OECD secretariat should be enabled to focus its resources on final consensus seeking for well-advanced projects. He also expressed the need for promoting TGP efficiency by such means as a short, rather formalised project description on Standard Project Submission Forms to be submitted to the secretariat.
To improve the overall efficiency, he proposed that lead parties should establish small ad hoc expert groups that would strive for well advanced proposals, prepared to reach consensus on NC and Joint Meeting level. Regarding the issue of general applicability, he added that it should also be possible to have test guidelines focussing on specific applications.
With respect to Germany’s 3R-contribution to the current Test Guidelines Program, he explained that Germany had actively contributed to the deletion of TG 401 by the development of an alternative test method, e.g. the acute-toxic-class method (ATC) for oral acute toxicity. He added that Germany was currently involved in the development of ATC for dermal and inhalative acute toxicity as well as an alternative for the acute fish test (fish embryo test).
G. Bengtsson: Governmental View, State’s Involvement: Sweden
Concerning the Government’s position on chemicals testing, a bill had been passed in 2000 calling for a non-toxic environment. This goal encompassed a number of points regarding animal welfare. The government called for vigorous efforts to develop alternative test methods and to look initially for in vitro screening measures. It also decided on a phase-out policy for substances based on their intrinsic properties with respect to persistency and bio-accumulation, requiring little animal testing.
A government investigation had concluded with respect to the role of animal testing that studies on whole animals would be necessary for final risk assessment, if the actual level of production of a substance was to be maintained or raised. Yet it was also stated that there was no need for certain animal tests such as carcinogenicity and reproduction toxicity tests at lower production volumes. Sweden would continue to stimulate high-quality research that might lead to a reduction or elimination of animal testing. Another research initiative, the so-called “new strategies for chemicals management” was aiming at bringing regulators and researchers together to influence respective EU legislation. One aspect of this project was an investigation into the possibility of applying precautionary defaults. He added that the program was also taking into consideration the decision making to determine the uncertainties and subjectivities involved in this process.
With respect to Sweden and the OECD guidelines, he stated that his country was participating actively in the OECD process by also supplying personnel temporarily. He personally regarded the process as an effective one promoting global acceptance and giving high priority to alternatives since there were large numbers of test guidelines currently being prepared. Finally he described a tiered structure, including screening and precaution as well as the existing OECD system, as the best opportunities for speeding up the process.
B. Lucaroni: The Scientific View: Alternatives to be Introduced
Follow-up on the Commission Stakeholders Meeting of 9-10 July in Brussels and 6th Framework Program
With respect to alternatives in the EU, Dr. Lucaroni illustrated that the Commission, particularly DG Research, was in a partnership with other interested parties such as governments, industry, animal welfare organisations and other stakeholders. Speaking of changing attitudes with respect to animal welfare issues she then referred to the Amsterdam Treaty as a major milestone, stating that the Commission’s policies tended to further the objective of improving protection and respect for the welfare of animals as sentient beings. This was also true with respect to the handling of animal experimentation in EU research programs.
She then explained that funding of alternatives had already been incorporated in FP5 under policy aspects, food, nutrition and health, control of infectious diseases, the “cell factory” and environment and health. There were 43 projects with a total funding of approximately 65 million €. In addition, a stakeholders-oriented conference had been co-organised by DG RTD and DG JRC in July 2002 bringing together the concerned parties, e.g. MEPs (Members of European Parliament), scientists, policy makers, industry, patients, NGOs and regulators. At scientific sessions and round tables the impact on, and the contribution of R&D to the New Chemicals Policy, transgenic animals, cosmetics and the overall dialogues had been discussed. The outcome of this meeting was recognition of the strategic importance of the area and the view that regulatory acceptance should be accelerated and awareness be increased.
Speaking of FP6, Dr. Lucaroni outlined that alternatives research would be welcome in a number of areas such as Action 34 (protect animals used in scientific research) of the Action Plan Science and Society or the area of advanced genomics and its applications for health as part of “Integrating ERA”. Referring to the EU Chemicals Policy she further stressed that there was also a possibility of funding research on alternatives in this area. Dr. Lucaroni concluded by quoting Commissioner Busquin that the Commission was committed to fostering the 3Rs, also by its own research funding, but there was need for a joint effort between scientists, national administrations, industry, NGOs and policy makers.
P. Vanparys: Small Scale Pre-Validation Studies in Industry: The Way Forward
Proposal for the Reduction of Animal Use in Routine in vivo Micronucleus Testing
Dr. Vanparys gave a presentation on the subject of small-scale pre-validation studies in industry. He explained that at his company (J&JPRD) testing of all final compounds and intermediates was done with the in vitro bovine eye irritation test. But when in 1998 the problem of mad cow disease arose, the company had to look for an alternative model. The in vitro human cornea (BCOP) model appeared to be a suitable alternative for the bovine eye irritation test.
The respective pre-validation process comprised three phases. Phase I was marked by the selection of compounds to be tested, a protocol refinement, preliminary experiments, the identification of possible end-points and a protocol revision. Then in Phase II, reference compounds were tested in two phases (A & B), end-points implemented, and the protocol was revised. In addition, a proposal for a prediction model had been made and was currently being discussed. In the first two phases, the preliminary results were quite promising but some adjustments were necessary before entering the third phase. Phase III thus comprised the testing of 20 coded compounds, the finalization of the prediction model and the protocol, and the submission of data to ECVAM (ICCVAM). The current timelines were that the experimental phase would start in January or February of 2003 while the data analysis would take place in March or April of next year.
Dr. Vanparys also presented a proposal for the reduction of animal use in routine in vivo micronucleus testing. In the OECD and ICH guidelines for genotoxicity testing positive controls are needed for in vitro and in vivo testing. Therefore he saw a problem with the requirement for in vivo testing since he did not see the need for positive control groups in in vivo genotoxicity testing. Positive controls were neither needed for chronic toxicity nor for carcinogenicity. So – if the reason was good science – then it would also have to be included within the other toxicological disciplines.
In 1995, the ICH (International Conference on Harmonisation) had detailed that it was important for a micronucleus test to prove target exposure, being more relevant than the response of positive control animals. An evaluation of available data by the IWGTP Micronucleus Assay Expert Panel led to the decision that, where a laboratory was experienced in routine micronucleus testing, it would not be necessary to run a concurrent positive control group. The omission of the positive control group would reduce animal use in micronucleus testing by 10 per cent. Yet, since the IWGTP meeting in 1999 no progress had been made on the omission of positive control groups.
He suggested that ecopa should step in to facilitate the exchange of scientific information among industry on the use of positive controls for in vivo testing, like the necessity of positive controls in every in vivo micronucleus test. Finally, ecopa should take into consideration the view of the IWGTP Micronucleus Assay Expert Panel and make proposals to the OECD to reduce the use of positive control animals in genotoxicity testing.
Speeding up Implementation of Alternative Methods in OECD and other Worldwide Guidelines: Ideas for a speedy process
During the following podium discussion, moderated by Dr. O. de Silva, the discussants Dr. Koeter, Mrs. Heinen, Prof. Hartung. Prof. Spielmann, Dr. Taalman and Mrs. Gabrielson addressed questions regarding the development of OECD guidelines and ways to accelerate the process. Various speakers stressed that the OECD system was slow due to a number of reasons but that progress had been made over the years. Many people felt negative about this progress which had proven against considerable scepticism that validation worked. It was questioned whether colleagues in the US and Japan were as committed to develop alternatives as their European counterparts.
The discussants agreed that there was no easy answer to the question of speeding up the process. But as a significant starting point it was stressed that as far as the OECD was concerned there were currently no alternatives in the pipeline. The need for more research and the appropriate funding and co-ordination was also highlighted by various speakers. The participants stressed that there was now the need to validate tier testing strategies and that guidance was needed for such validation studies .Besides replacement there is also a need for reduction and refinement . QSARs and biostatistics were identified as priorities. There was agreement that it would be crucial to ensure that the OECD was enabled with sufficient in-house resources to tackle the issues, thereby not only meaning money but also qualified experts that would understand the tasks and problems at hand. This could be an area for the national consensus platforms to look into and take the lead.
Preparatory Session on the Founding of ecopa: Statutes, Proposals of Working Group and Assessing Lawyers
This session was marked by a final discussion and vote on the statutes. First a short overview was given regarding the two versions of the statutes (Version A & B) as well as the comments received from the lawyers and several national consensus platforms, i.e. Italy, Czech Republic, Switzerland, The Netherlands and Spain.
There were a number of major and minor issues. Regarding the major ones, it was outlined that though no comments had been received with respect to Version A, the delegates would be asked to vote whether they wanted to go ahead with Version A or Version B as the final version of the statutes. This decision would also be relevant with respect to the overall organisational structure (Art. 9) and the composition of the Board (Art. 10). In addition there was a number of minor changes regarding thepower of the General Assembly (Art.11), the role of Treasurer (Art. 14), the duration of service on the Board (Art. 14), the decision making at the meetings of the Board (Art.16), the responsibilities of the Board (Art. 17), the Delegations (art. 18), the appointment of the General Secretary (Art. 20), the financial operations (Art. 22) and the auditing (Art. 24). In addition, there were changes proposed pertaining to Articles 5 and 6 of the Internal Regulations.
After having explained all proposals and proceeding towards a vote on every recommended change, the delegates were asked to clearly identify themselves for the record. The delegates participating in the vote were: Walter Pfaller (Austria), Joseph-Paul Beaufays (Belgium), Riitta Salmi (Finland), Dagmar Jírová (Czech Republic), Bernward Garthoff (Germany), Annalaura Stammati (Italy), Wim de Leeuw (The Netherlands), José V. Castell (Spain), Peter Maier (Switzerland), Jane Smith (United Kingdom).
After the voting, the final statutes were to be printed out and presented to the delegates the next day for signing in order to formally express their approval and acceptance as part of the requirements by Belgian laws.
Acceptance of the ecopa Statutes, Board Elections
The delegates of national consensus platforms as indicated above signed the statutes.
Regarding further steps, the signed statutes will be submitted to the Belgian authorities for publication in the “Moniteur Belge”. This process was expected to take about three to four months until February-March 2003. Afterwards, Board elections could be held. To this end, the delegates received one nomination form per National Consensus Platform for discussion and agreement on candidates for the various Board positions at their local platforms. This form must be sent to the Secretariat as soon as the call for final nomination and voting will officially be made, which will likely happen end February 2003.
It was agreed unanimously that the initial working group would serve as an Interim Board until the Board was officially elected in spring 2003. Proposed and nominated were the following functions and incumbents: Vera Rogiers (President), José Castell (Vice President), Bernward Garthoff (Treasurer) and Peter Maier, Karin Gabrielson, Kai Pelkonen, Arthur van Iersel (Delegates). In addition, Lee Bansil (Press Officer) and Thomas Dantes (Secretary General) took up adjunct functions to the Board.
The ten delegates voted unanimously to accept the offer of the Belgian platform to locate the registered seat of ecopa at the premises of the Belgian Platform in Brussels.
Splitting-up of participants in two groups to work on proposals for ecopa initiatives with guidance by Prof. Spielmann and Prof. Pfaller
Prof. Spielmann and Prof. Pfaller presented the results of their groups with striking similarities. Taking up the various suggestions that were elaborated in both groups, the participants decided on the following actions to be taken up by the various ecopa working groups as well as national consensus platforms.
In addition to the existing three working groups a fourth one was initiated to work on the issue of ethics. Tjard de Cock Buning, Eugenio Vilanova, Véronique Delpire, Joseph-Paul Beaufays and Jane Smith volunteered to be part of this new working group on ethics.
Concerning the working group on education up to now, Adrian Smith and Jan van der Valk. Jan van der Valk pointed out that more input and more volunteers were needed (Eugenio Vilanova expressed his interest in also joining this Working Group). Regarding the participation in working groups in general it was stressed that participation was not limited to the national platform representatives but open to all members of national consensus platforms willing to take part.
It was agreed that the initial working group (Interim Board) would check the options in order to make a realistic proposal for the participation of ecopa in the 6th Framework Program. It would also check for which funding/ type of project ecopa should apply (integrated project, network of excellence, etc.). This should be done within the next three months. In addition this working group would collect information on how ecopa could have representative to apply as expert/evaluator to FP6. Finally, the working group would prepare a press release regarding the foundation of ecopa for distribution to journals, national ministries and other relevant authorities. This working group would update the ecopa website by creating a members’ area that would only be accessible via a login with a password, and folders for the national consensus platforms to put in information. These folders would be open to all platforms/members but not to the general public, e.g. to be placed in the members’area.
Regarding the tasks to be handled by all national consensus platforms it was decided to collect a list of relevant government officials as well as other national authorities and groups/associations that should receive the press release regarding the foundation of ecopa. These lists would then be forwarded to the Interim Board. Furthermore, the respective national authorities would be informed of the founding of ecopa. The platforms would also collect and send a list of names of 3-R-experts willing and qualified (minimum of doctoral level) to serve for evaluation of FP6 proposals at the EU level to Vera Rogiers. In addition, they would inform their experts of FP5 that they needed to reapply for participation in FP6 and that they had to request a transfer of their data from the FP5 to the FP6 database.
Furthermore, they would ask their members to discuss the Expression of Interest (EoI) in the program booklet of the ecopa workshop and if relevant to come forward with proposals of themes and names of scientists. Finally all national consensus platforms would prepare a short summary on the activities of their platforms to be incorporated in the ecopa website in a separate member area protected by a password. (http://ecopa.vub.ac.be)