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4th ecopa Annual Workshop 2003 – Minutes

The Fourth European Workshop of National Platforms on Alternative Methods took place in Brussels on the 29th and 30th of November 2003.

67 participants from 15 different countries attended this workshop in order to discuss the issue of developing sufficient numbers of alternative methods in face of the EU Chemical White Paper and new Cosmetics Legislation.

Among the participants were EU 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 Enterprise, ECVAM, as well as the European Food Safety Authority were present.

Throughout the entire meeting a constructive working spirit among the participants was present which was then also highlighted by the confirmation of the final ecopa statutes as published in the ‘Moniteur Belge’ and the first ecopa Board elections by eleven members.

Workshop Presentations

Mr. A. Carvalho, DG Enterprise, Head of Unit:
Opening of the Workshop

Mr. Carvalho stressed the need to move from theoretical discussions about policy objectives such as public health versus animal protection to deliverables. This mainly because of the fact that the European Parliament and the Council had taken a clear decision with respect to the new Cosmetics Legislation by setting a framework for action.

With regard to the marketing ban, he informed the participants about the prohibition of marketing any finished cosmetic product tested on animals using a method other than a validated alternative method, together with the prohibition of marketing any cosmetic product containing ingredients or combinations of ingredients which have been tested on animals using a method other than a validated alternative method.

As far as the testing ban is concerned, Mr. Carvalho explains that the performance of any animal test on EU territory on a finished cosmetic product is prohibited, while strict deadlines have been set for the performance of animal testing on (combinations of) ingredients. Before March 2013, validated alternative methods are to be available for repeated-dose toxicity, reproduction toxicity and toxicokinetics testing, while all other animal toxicity tests should be replaced by validated alternative methods before March 2009.

As far as the timetables on this matter are concerned (including the timetables on the phasingout of animal testing), the Commission is charged with their publicationbefore 11 September 2004, i.e. 18 months after the entry into force of the 7th Amendement to Dir. 76/768/EEC.

Mr. Carvalho also explained that there were not only internal but also external challenges to face. Internal challenges were in particularly concerned with scientific development and setting priorities in research. Research efforts would have to be increased in order to produce more alternative methods. With respect to external challenges, the process at the OECD level needed to be accelerated and one should look for a maximum consistency between ECVAM and OECD. In addition, bilateral cooperation is necessary with major players such as ICCVAM in the USA.

Mr. Carvalho also stressed the need for adequate accountability meaning that an efficient monitoring system is necessary to meet the deadlines. Furthermore, an atmosphere of mutual trust between all stakeholders must be promoted in order to cope successfully with the challenges ahead.

Mr Carvalho, on behalf of the Commission services, congratulated the organisers and stressed that this ecopa’s initiative was most welcome as a good example of a pragmatic attitude that contributed to the necessary progress in this subject and to a climate of confidence-building between the interested parties.

B. Garthoff:
Basic Research and Development Work on Alternative Methods: We are falling short of News!

Dr. Garthoff briefly referred to the so-called “EU-Target” initiative that aimed by the year 2000 at reducing by half the number of lab animals used in 1992. This initiative was sacrificed due issues as the EU chemicals policy (REACH), endocrine disruptors etc. He also stressed that the given timetable for alternative methods was a political one that did not reflect good science. It did not take into account what was actually available in the field of alternatives or what could realistically be achieved over the next years. The same irresponsibility with setting dates and deadlines was now also present in the REACH programme.

Several recent statements from EU officials (Busquin, Liikanen) and MEPs (Roth Berendt, Florenz) acknowledged that there were not yet sufficient validated alternative methods available to avoid an extensive use of experimental animals as foreseen by the draft version of the new chemicals legislation. Yet, recognising the potential benefits of alternative methods, these statements also highlighted the conflict between the avoidance of animal tests and the safety of chemicals in question.

Speaking of the REACH document Dr. Garthoff illustrated that about 1/3 of the 1200-pages counting draft dealt with testing, most of it being animal testing, while there was only one small paragraph devoted to alternatives, stating that a scientific objective for the European Union is the development and validation of alternative techniques, and that such methods, as they became available, would have to be considered. Yet, Dr. Garthoff continued, that when posing the question why the REACH would result in more animal testing, it was mentioned in the question and answer sections that animal testing might be necessary in the case existing
information and validated alternative methods were not sufficient.

In order to address this issue seriously there was a considerable need for an intensified development work as well as a constant flow of new methods out of basic research to be further validated. He also stressed that this was currently not the case. Asking the question whether or not it was true that we were falling short of new developments, he argued that superficially seen this was not the case. Yet, thereality was different. A closer look and evaluation of the scientific literature showed that apart from reviews there had been only a total of 22 new alternative methods published over the past 5 years! Not more reviews are needed but action.

Dr. Garthoff added that this was also true in the case of cosmetics giving the example of skin irritation. He explained that skin irritation had once been considered to be an „easy“ area for replacement tests, but the OECD 404 currently in place was actually still an in vivo methodology with some refinement procedures. Promising tests were under study for years but did not make it yet through validation.

Facing these issues and problems, he concluded that a new approach was needed to intensify the knowledge base, enhance basic research, streamline the development process, and touch upon new methodology by approaching other science areas. To ensure the necessary funding for such an approach, he stated that ecopa would claim a major part of the envisaged EU funds for the proposed ERC (European Research Council) that should be in place by 2005 and be funded with a total of up to 2 billion €.

Furthermore, Dr. Garthoff announced the launch of an „ecopaScienceInitiative“ in 2004. The aim would be to reach the top scientists of all research areas that might be relevant to alternative method development, and to organise a workshop with them. Further activities would be to invite young scientists and to initiate exchange by Science Fairs. The goals of this „ecopaScienceInitiative” would thus be to draw the best science to initiate „thinking about and for alternatives“, to improve recognition of science in that area and to get the „alternative method research“ out of the corner of mediocre science. Furthermore, to organize the funding and PR around it, and to hold science fora to foster exchange with other basic research scientists and scientists of NCPs and ECVAM.

Closing his presentation Dr. Garthoff stressed that the activities and goals of the EU Commission programmes and projects such as the REACH programme and the 7th Amendment Cosmetics Directive required strong action in the area of alternative development, especially in the field of basic research. Therefore ecopa requested immediate action in- and outside the EU by funding via the future ERC-Programme, by supporting the “ecopaScienceInitiative”, and assisting ecopa to organize the first Science Fair, respectively Forum on Alternatives in 2004.

Prof. Thomas Hartung:
Running European Prevalidation and Validation-Studies, Pipeline and Future Impact

Prof. Hartung gave a short overview of number of animals used in toxicology and other safety evaluations. He explained that a total of approximately 10 million animals were used in the EU per year out of which only 0.4 per cent were actually used in the field of cosmetics. The industry share was about 12 per cent while 25 per cent of all animals were being used for the testing of vaccines.

Nevertheless, ECVAM was currently challenged primarily with the 7th Amendment Cosmetics Directive and the upcoming REACH legislation. Prof. Hartung then briefly summarized the tasks of ECVAM as being charged with validation, research, running a database and most importantly serving as a communication link for alternative methods. With respect to these tasks he stated that he saw a good and sound base for cooperation with ecopa.

In addition, Prof. Hartung explained that ECVAM had undergone some reorganisation including the set-up of various task forces in order to face the challenge as good as possible. He further illustrated that the reorganisation had involved such key areas as systemic toxicity, local toxicity, sensitisation, carcinogenicity, reproductive toxicity, toxicokinetics, ecotoxicology as well as biologicals. Besides there were also some cross-cutting activities mainly with respect to the SIS databases, QSARs and strategic developments.

Prof. Hartung then gave some practical example in the field of local toxicity to illustrate what was already at hand. He explained that the phototoxicity test and skin corrosion test had made it to the OECD-level in 2002.These two methods had undergone the entire process of prevalidation,validation, formal ECVAM Scientific Advisory statement and finally regulatory acceptance. He emphasized that, though these two methods did not represent tremendously huge numbers of animals, they did represent a proof of principle. They had proven that it was indeed possible to achieve an international agreement on the validity of an alternative method fully replacing an animal experiment. This was a milestone that should always be kept inmind and emphasized, especially since at that time few people had believed in it.

He added that in this field actually also the most promising current activities were situated, especially with respect to skin and eye irritation. Nevertheless, he also pointed out that phototoxicity and skin and eye corrosion only amounted to 6 per cent of all animals being used in 1999. Thus, only 6 per cent of lab animals used in the area of toxicological testing had been replaced by alternative methods so far. It would be necessary to address the issue of acute systemic toxicity testing since 35 per cent of all animals are used in the LD50 test for the classification and labelling of substances.

Regarding developments in the field of skin irritation he explained that ECVAM had just completed a contract with ZEBET being the contractor to coordinate a study the validation of three assays for skin irritation. Two of these assays are based on reconstituted human skin and the third on the use of mouse skin explants.

The study design is such that in phase 1, the so-called preliminary phase, confirmation of test protocols and prediction models for 20 coded chemicals in lead laboratories as well as respective training of participating laboratories would take place. The following intermediate analyses would then focus on the performance of the assays and a comparison with in vivo data. In case of satisfactory results, phase 2 would be entered comprising an evaluation of the inter-laboratory reproducibility and predictive ability of the tests in three labs with 60 coded chemicals. In case of non satisfactory results the respective prediction model would be redesigned and supplementary endpoints used.

As far as the timeframe for the completion of the study was concerned, he added that Phase 1 would most likely start in January 2004 to be followed by the intermediate analysis of phase 1 in April 2004 and the start of phase 2 in June 2004. The data analysis of phase 2 would then take place in November 2004 to be followed by the publication as well as submission to ESAC in February 2005.

Returning to the issue of eye irritation, Prof. Hartung said that six validation studies had already been done but none of them had proven that any of these assays could be used as alternative, although they were broadly used as partial replacements as well as for screening purposes. Instead of running new validation studies for these assays he suggested a validation on a weight-of-evidence approach (retrospective validation) that could be undertaken jointly with ICCVAM. To this end, he added that there would be an assistant appointed and a taskforce created at ECVAM while a secondment had already been offered by Procter & Gamble.

Concerning the issue of acute toxicity testing Prof. Hartung referred to an ongoing joint ECVAM-ICCVAM validation study of two in vitro basal cytotoxicity assays that would enable to predict the starting dose to the tiered testing strategy for acute testing. He furthermore gave another example in the area of acute toxicity by referring to the A-Cute-Tox project that he regarded as an extension of the ICCVAM/ECVAM validation and MEIC study approach towards a full replacement test strategy. He explained that this study would be piloting strategies for systemic toxicity.

Prof. Hartung concluded that REACH and the Cosmetics Directive would require new testing strategies based on exposure information, in silico methods (QSARs/SARs), in vitro methods and in vivo data brought together, in an intelligent tiered approach. The clear aim would be to reduce animal tests, speed-up the assessment process and reduce the costs to Industry and Member States.

Finally referring to the ECVAM business plan, he explained that there was a ten year program to meet the expectations from legislation with a focus on bundling of all stakeholder activities, and combining strategic and technical developments. With respect to the FP6 he added that ECVAM would play a proactive role in the field of coaching and management but avoid competing with academia for funding. In addition, ECVAM would be available for support un such areas as coaching of the development of alternatives, not the development itself, (pre-) validation in international collaborative studies, support for regulatory acceptance and international harmonization.

Dr. Herman Koeter:
Other Alternatives in the Making on a Worldwide Basis, Summary of the OECD

As a starting point for his presentation Dr. Koeter referred briefly to the number of lab animals used in the EU, pointing out that only a relatively small number would actually be used for regulatory testing. He illustrated that the safety testing of one pesticide ingredient required approximately 1,100 mammals and that the EU Base set testing required approximately 60-80 mammals, excluding reprotox. Furthermore, one SIDS required approximately 88 mammals (TG 422, 425).

Referring its objectives, Dr. Koeter said that the OECD is devoted to develop alternative methods to animal tests for regulatory hazard assessments; to revise existing animal tests to accommodate animal welfare to the extent possible; and to develop guidance documents on animal welfare issues. The OECD includes animal welfare considerations in all technical discussions of test guidelines and provides justification for the numbers of animals recommended in each new and revised test guideline.

The final goal is to harmonise internationally principles and criteria for validation and regulatory acceptance of alternative test methods and to make an effort to reach international consensus on the need for and the extent of validation of new and revised test guidelines referring to the Revised Draft Guidance Document No.34 of October 2003.

Dr. Koeter then provided an overview of adopted and draft Guidelines that were developed specifically because of animal welfare reasons or included elements instigated by animal welfare concerns, e.g. TG 401, 402, 404, 405, 406, 407, 414, 420, 421, 422, 423 as well as TG 428,429, 430, and 431 as true alternatives to the in vivo methods.

Yet, he concluded that a few thousand mammals saved by the available alternatives was not really a giant number. Despite major pressure to develop more non-animal tests, the number of adopted true alternative tests was only two. There were still major disagreements on validation and subsequent peer review approaches. Besides, he added that formal validation is extremely expensive and that a simple test costs more than €2,000,000.

Dr. Koeter said that he would like to see a gradual shift of focus from the development of alternative tests to cover specific current data requirements to the development of conceptual hazard characterisation approaches in order to achieve better science. This could be accomplished by means of a cross-fertilization of governmental, academic and industry knowledge and expertise including such bodies and organisations as ecopa, ECVAM, scientific societies and national centers. In addition there should be recruitment and education of young scientists as well as an investment in long range projects. In this regard he stressed that there are a number or promising areas and subjects such as humane science and technology, (Q)SAR development and application, exposure characterisation and assessments, probabilistic risk assessmenst; toxicogenomics, transcriptomics, proteomics, and metabonomics.

With respect to (Q)SARs, he also pointed to the problems and limitations of this approach such as the availability of databases, the identification of data quality and variability, the application to complex endpoints; the lack of mechanistic understanding and of transparency concerning data, models and methods. In addition, he was concerned with respect to ownership issues and a lack of support tools to help the user. Dr. Koeter therefore stressed the need for acceptability criteria. He said that in order for QSARs to be acceptable for regulatory use, they should be reliable, relevant and scientifically valid. The acceptability criteria should thus address elements of QSAR prediction uncertainty characterization, QSAR applicability domain description and QSAR validation.

Dr. Koeter explained that “probabilistic” in this regard refers to such risk assessment that would attempt to quantify variability and/or uncertainty in factors that influence risk, and express risk in terms of the probability and magnitude of adverse effects. It includes better defined exposure data as a key element.

Regarding toxicogenomics he illustrated that conceptual frameworks in this field could help to reduce animal testing in the future. In this regard a risk characterization approach would comprise a description of hazard elements/parameters relevant for a comprehensive assessment. Furthermore it would comprise a toolbox filled with a variety of methods for effects and exposure determination (screens, tests, in vitro, in vivo, in silico, microarray, and human), defined interim formal assessment points and an overall final assessment.

Closing his presentation Dr. Koeter gave a brief illustration with respect to the animal welfare activities of the EFSA. The outlook for the years 2004 and 2005 is as such that there would be a new “scientific expert service department” with 10 science units including one science unit that would focus on replacement, refinement and reduction of experimental animals. This unit would be charged with developing conceptual frameworks; predictive tests, humane techniques, applying new assessment approaches (e.g., QSARs, -omics, microarray techniques), providing service and advice to all panels and cooperating with (European) leading groups in the area like ecopa, ECVAM, OECD and national centers.

Dr. Beatrice. Lucaroni:
Does the Set-Up of the EU 6th Framework Program help to address the need for new approaches?

Dr. Lucaroni gave a short overview regarding the set-up of FP6 and outlining the areas in which the development of alternative methods was welcome. She explained that this was primarily the case with respect to the “Priority 1 area” (Life Sciences, Genomics and Biotechnology for health) as well as the anticipating needs as part of “Integrating European Research”. In addition, alternatives development had its place in structuring ERA when dealing with Science and Society.

Providing further details Dr. Lucaroni outlined that the first call in Priority 1 had been closed on the 25th of March 2003. What had been called for in the area of new in vitro tests to replace animal experimentation was an Integrated Project (IP), a Specific Targeted Research Project (STREP) and a series of four Specific Support Actions (SSA).

She then stressed her disappointment that with respect to the SSAs there was only one application received, while in the STREP area there had been 11 applications out of which one was selected for funding. The three IP applications though were still in the selection and evaluation process due to ethical concerns regarding the use of human embryonic stem cells.

Dr. Lucaroni then explained that the second call in the Priority 1 area had been closed on the 13th of November 2003. In the area of new in vitro tests to replace animal experimentation it was called again for an Integrated Project (IP) and two Specific Support Actions (SSA). Once again she had to express her disappointment since there were only four proposals submitted for the SSA.

She then took a more detailed look at the Integrated Project that called for an optimisation of test batteries for human acute toxicity. Dr. Lucaroni explained that research in this IP should focus on the development of scientifically sound, standardised and reliable alternative test methods for toxicokinetics and organ toxicity. The methodology could also include QSARs (quantitative structure-activity relationships) or computer modelling, providing data for an efficient risk assessment strategy. The focus would be on the development of models of neurotoxicity and biotransformation. Attention would also be given to biokinetic studies, prediction models, study of barrier functions (including the Blood Brain Barrier) and in vitro tests for chronic toxicity.

Dr. Lucaroni then referred to the first and second calls in the Priority 8 area, e.g. policy support and anticipating S&T needs, which both had to be republished since only one proposal had been received but was not selected for funding. She informed the participants that in the context of the Commission’s White Paper on a strategy for a future Chemicals’ Policy, the Commission was committed to the promotion of non-animal test methods, through maximising use of non-animal test methods, encouraging development of new non-animal test methods and minimising test programmes. To serve this purpose both calls requested proposals to carry out research on the development of alternative methods for testing chemicals, both at the European Community level and at the level of Member States, and to enhance and share the relevant information that could be obtained from testing.

But she also hinted that there were some mandatory requirements that had to be fulfilled. The results generated should lead to the production of globally accepted test guidelines, statistically valid for formal validation purposes and dissemination of knowledge and competencies that could pave the way for their regulatory acceptance.

Turning to the Action Plan Science and Society, Dr. Lucaroni pointed out that alternatives research had its place specifically in Action 34 that focused on the protection of animals used in scientific research. Though not directly linked to the development and validation of alternatives, there was a minor budget allotted to fund a study related to the ethical review and the implementation of the Three Rs in animal welfare.

Referring to the Council Decision on 30/09/2002 regarding the specific programmes for FP6, she furthermore explained that a number of fields would not be funded such as research activity related to human cloning for reproductive purposes, research intended to modify the genetic heritage of human beings, studies to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including somatic cell nuclear transfer. But she also stressed that the use of banked or isolated human embryonic stem cells in culture was already being funded from the start of FP6.

Closing her presentation she stressed that the development was going the right direction. Funding was ensured for the Three Rs (R&D, training, studies, public and private activities) and collaboration with national programmes, initiatives and activities were another source of funding and inspiration. She also emphasized the importance of networking between scientists, national administrations, industry, NGOs and policy makers. Furthermore, she stated that there was a need to boost external scientific excellence and the validation of test methods and strategies, as well as to support the legislative process. In addition it was also necessary to continue assessing the results generated and to increase the visibility of responsible animal research. Dr. Lucaroni concluded that success would heavily depend on the mobilisation of all actors! Finally, she provided a several internet links as further
information sources:

Project Approaches in the FP6 / ecopa-initiated projects resp. projects with ecopa-participation

Prof. José Castell:
EU Research Initiatives of ecopa

Giving a short overview Prof. Castell explained that on the occasion of the preparations of the sixth framework program (FP6), scientists were asked by the Commission to forward an “Expression of Interest (EoI)”, showing potential research proposals that could be of interest for FP6. Ecopa submitted a total 16 EoI dealing with 3R-alternatives that had been collected in the different ecopa member countries.

He added that at the end of the last ecopa Workshop, held in Brussels October 2002, the initiative was taken to participate in FP6 through several projects. All participants of the Workshop, with an interest to collaborate in these projects, were asked to contact either ecopa’s President Vera Rogiers or him. The plan was to make both a fundamental research project in which several ecopa members could participate, and also to write a more general project for ecopa in order to create some possibilities for the different working groups. The ECVAM and the OECD representatives present at the workshop, Dr. Thomas Hartung and Dr. Herman Koeter, respectively, forwardedthe idea to initiate a big (integrated) project on reproductive toxicology, in which ecopa could play an advising role.

All these initiatives mentioned were worked out and in addition ecopa was asked to be present on the Board of two other integrated projects, namely Edit and Sensa CellTox. Prof. Castell stressed that ecopa was very successful in this regard since three projects were selected! The selected projects were CONAM (a special support action (SSA) with ecopa’s president V. Rogiers as coordinator) and Predictomics (a specific targeted research project (STREP) with ecopa’s Vice-President J. Castell as coordinator and ecopa also being on the Managing Board of this project), and finally Reprotect (an integrated project (IP) with ecopa present on the Board).

Prof. Vera Rogiers:
CONAM

She explained that the CONAM (SSA) project was about consensus networking on alternative methods within Europe. The main objectives were to build a solid network on 3R-alternatives and to exchange information (scientific, societal, and technological) on the development and validation of 3R-alternatives. She then illustrated the main topics to be covered as part of the CONAM-project as being the formation of new NCPs, in particular in non-EU candidate countries, the creation, creation of a newsletter on 3R-alternatives and the expansion of the ecopa website as well as the organisation of workshops and meetings. Further important topics would be to establish links with other FP6 projects on 3Rs, to report on the “-omics” field, and to stimulate international cooperation.

Prof. Rogiers then explained that a strong managerial and organisational back-up of the project was needed and had been regarded a vital competent by the European Commission. To this end, she explained that ecopa was well prepared since there were already four working groups in place. One working group dealt with consensus networking on 3R-alternatives with her as the team leader while the second one worked on the EU White Paper on Chemicals and was headed by Mrs. Karin Gabrielson. The third working group dealt with education and training matters being headed by Dr. Jan van der Valk while the fourth and most recent working group had been established to work on issues in the field of ethics with Prof. Tjard de Cock Buning being the team leader. In addition, the ecopa board would be in charge of the management tasks with three of its members (Prof. Castell, Dr. Garthoff and herself) being responsible for the daily follow-up of the CONAM-project.

Prof. José Castell:
Predictomics

Regarding the Predictomics-project, Prof. Castell explained that it was dealing with the question of short-term in vitro assays for long term toxicity. The project comprised 14 partners from nine countries with a total of six work packages ranging from liver cell model 10 developments to the optimisation of tools and analyses to the identification of toxicity markers. He then stressed that the development of new pharmaceutical compounds would be more efficient if human relevant toxicology information was available early in the selection process.

While acute toxicity could be reasonably detected during the early preclinical stages of drug development, long-term toxicity was more difficult to predict, relying almost exclusively on animal experiments. He added that animal experimentation of this kind was expensive and time consuming, rose ethical issues and did not necessarily represent a toxicological relevance to man. Thus, this project would address the urgent need to develop in vitro based systems which were capable of predicting long term toxicity in humans.

He then summed up the major objectives of this project. The project was aimed at developing advanced cell culture systems which as best possible would represent the human liver and kidney in vivo. This would be achieved using combined strategies namely: co-cultures of resident cell types, targeted cell transformation, stem cell technology and new developments in organotypic cell culture (i.e. perfusion cultures and 3D cultures). It was furthermore intended to identify specific early mechanistic markers of toxin induced cell alterations by using integrated genomic, proteomic and cytomic analysis. In addition the project would strive to establish and prevalidate a screening platform (cell systems together with analysis tools) that was unambiguously predictive of toxin induced chronic renal and hepatic disease. He also pointed out, that this proposal was unique in its mechanistic integration of the three levels of cellular dynamics (genome, proteome and cytome) together with advanced cell culture technology to detect early events of cellular injury. Prof. Castell argued that only with such an integrated approach would in vitro techniques ever be applicable to predicting chronic toxicity in man.

Closing his presentation, he stressed that this project, if successful would contribute to the replacement of animal testing in drug development, increase the speed and decrease the cost of bringing new pharmaceutical compounds to the patient and finally increase our understanding of toxin induced chronic disease development.

Prof. Thomas Hartung (introduction) and Dr. Rita Cortvrindt:
Reprotect

Giving a short introduction, Prof. Hartung explained that Dr. Herman Koeter had brought up the idea to initiate an integrated project on reproductive toxicology. He added that the project was still under evaluation due to ethical concerns regarding the use of human embryonic stem cells. The acronym Reprotect was aiming to combine reproductive toxicology, protection of animals and detection of reproductive toxicants.

The main idea behind it was to break down the reproductive cycle. It was looked at the different elements that were being assessed in a two generation study. Attention was paid not only the in vivo assays but also to the kind of in vitro batteries that could perhaps be used. He stressed that it was realized that there were indeed many in vitro tests that nobody had ever thought of as potentially being useable to replace animal tests although they were widely used in reproductive medicine for instance.

He then explained that an assessment of these results lead to a grouping into four areas of concern, that is pre- and post-natal development, fertility, implantation and a cross-cutting area of some technologies. The idea was to elaborate these findings towards a pre-validation of test and test strategies and combine it with strategic discussions on how to develop a respective conceptual framework.

Concerning the project’s structure he added that there was an advisory board in place on which ecopa would also be present. The day-to-day scientific management would be handled by ECVAM while the coordination had to be given up for legal reasons since ECVAM was not allowed to take up such financial obligations. The proposed budget was 16 million Euros. In addition he felt that this consortium of 35 partners was nicely balanced with respect to affiliations to stakeholders (academia, industry, animal welfare and government) as well as the involvement of SMEs and big companies.

The real problem at the moment was the issue of using human embryonic stem cells. Yet, he was convinced that the ongoing evaluations would end with a positive decision since the stem cell lines to be used in this project would have already been established more than five years ago. He then gave the floor to Dr. Rita Cortvrindt who would report on a very special aspect of the Reprotect-project.

Dr. Cortvrindt stressed that she would only give one example of the many tests that would be available in the Reprotect-project. She explained that a mouse follicle culture system had been developed to study the ovarian physiology in vitro. Briefly, with this new system, one was able to grow follicles in vitro to the Graafian follicle and to end up with mature oocytes. Since this culture system contained all cell types that would even differentiate as one would expect from an in vivo model, it was contemplated if it could also serve as a model to test toxicity, especially in the field of in vivo fertility testing. In this regard she stressed that the current in vivo fertility testing was not only time consuming and cumbersome but it was also costly and involved animal suffering.

She continued that in order to have an idea of the reproducibility of this system, all tests over a period of 1 year of her research group were collected and mean percentages of different parameters were scored. The yield of our follicle bioassay was very good. The percentage of follicles surviving the culture was 96%. Also antrum formation and mucification of the cumulus-oocyte complex after LH-stimulus (so ovulation) were high.

Furthermore she explained that a group of drugs, the benzodiazepines, were tested in her research group. There were two binding sites for benzodiazepines: the central benzodiazepine receptor which was located in the CNS and the peripheral benzodiazepine receptor located in the outer mitochondrial membrane of peripheral tissues, especially steroidogenic tissues, like the ovary. The pharmacologically action of the benzodiazepines was supposed to work through binding of the drug to the CBR in the CNS. Binding of benzodiazepines to the PBR could also stimulate the steroid biosynthesis and could influence the mitochondrial functions in peripheral tissues like the ovary. Few experimental data was available concerning the effect of benzodiazepines on reproduction. She added that mostly in vivo exposure studies would be done during the gestation period, and that these results were contradictory. The specific ovarian toxicity had not been evaluated yet. That’s why she wanted to study the effect of benzodiazepines on folliculogenesis and oogenesis in an in vitro mouse follicle bioassay system.

Several experiments were carried out to study the direct action of Diazepam (DZ) on the nuclear maturation phase, and to examine the effect of DZ on the oocyte growth and folliculogenesis. In a third group, a full exposure was performed, that is follicles were exposed to DZ not only during oocyte growth but also during the final nuclear maturation phase, after the ovulation stimulus. Apart from the effects caused by DZ-exposure, the study also looked into the effects of Flumazenil (FL) and Chlorodiazepam (CD).

Taking together the nuclear maturation stage and the analysis of spindle and chromosome organization, Dr. Cortvrindt stated that apart from a delay in first meiosis, one had also found more spindle aberrations and chromosome dislocations in DZ-exposed groups. She added that DZ-exposure from day 12 to day 13 did not affect the oocyte quality, while DZ- exposure during 12 or 13 days affected the oocyte quality significantly. She further explained that Flumazenil, the specific central receptor binding benzodiazepine, did not disturb the follicle growth, even with a concentration of 15 µg/ml, while diazepam and chlorodiazepam on the other hand gave very similar results with a significant decrease in survival in a dosedependent way. 15 µg/ml for example appeared very toxic to the follicles for both benzodiazepine exposures.

Closing her presentation, Dr. Cortvrindt stated that this mouse follicle bioassay system was a promising model and she expressed her hope that it could be brought to the stage of (pre-) validation as a viable in vitro tool for female reproductive testing.

Dr. David Cowell:
SensaCellTox

Dr. Cowell started out by shortly referring to the respective FP6 call in the Thematic Priority Area 1 (Life Sciences, genomics and biotechnology for health). Reading the call he felt that the call’s objectives were taken out of the Expression of Interest (EoI) for the SensaCellToxproject that had been submitted earlier. He thus thought that the Commission had clearly understood and welcomed the conceptual idea behind this project especially with respect to the implications for toxicological and pharmacological testing.

He then gave some background information with respect to the reasoning that lead to the formulation of this proposal. Dr. Cowell said that cellular toxicity screening was important in a number of commercial areas such as the pharmaceutical and chemical as well as agrochemicalindustries. In addition there was the issue of industrial affluents and wastes. He stressed that all areas had to deal with very similar problems regarding their respective toxicity tests like speed; multiple cell types; multi-organism and large numbers. It was therefore discussed if it was possible to come up with a kind of platform technology that would allow taking cell lines in suspension or some form of construct and monitoring what was happening to those cells. In this regard, he added that multi-well plates could be used with either a single sensor per well or a multi-sensor array per well approach that would provide plenty of data.

He explained that the objectives were thus to develop new in vitro model systems based on freshly isolated, fully characterised cells with longevity in culture that would maintain in vivo characteristics using genomics and proteomics and by applying new knowledge in tissue engineering and materials technology. In addition, proteomics and metabolomics would be used to identify new markers of cell toxicity. Furthermore, current and developing sensing technologies would be applied to monitor changes non-invasively in real-time. He also said that one was going to integrate the in vitro model systems with the sensing technologies by the design and fabrication of instrumentation and software that would form the basis of generic technology implementation in the pharmaceutical, chemical and environmental industries. One would also make an effort to obtain pre-validation data on the selected sustainable cell models, markers and instrumentation for housekeeping and toxicity.

Referring to the project’s structure he explained that it consisted of three phases. The first 18-months phase was the applied research phase with 23 projects and 19 sub-projects. Yet, he pointed out that the people involved were clearly told that they would have to come up with an endpoint that was applicable to the future development or they would certainly not be able to enter the second phase. The second phase was about the development of instrumentation and application. Then the third phase had dealt with such topics as pre-validation and demonstration, transfer to other systems, sustainable cell supply, and sensor supply.

Dr. Cowell explained that the Commission decided not to fund the project arguing that it had failed a number of criteria. It was said that it had failed on the cost and size criteria since the project was too large. Furthermore it was stated that the proposal included the environment which was not relevant to this call. In addition there would have been an overlap of expertise and the entire project would have been too difficult to manage and relevant expertise on validation missing.

Asked by Dr. Garthoff what parts of this project he would like to save and find funding for from sources other than the Commission, Dr. Cowell replied that he regarded the longevity of cells the most crucial topic to focus on in the future.

Dr. Cecilia Clemedson:
EDIT

Providing some brief background information, Dr. Clemedson explained that the EDIT-programme was actually a continuation of the MEIC (Multicenter Evaluation of In vitro Cytotoxicity tests) study that was done between 1989 and 1999. The aims of the MEIC study had been to evaluate the relevance of in vitro tests for predicting human oral acute systemic toxicity and to recommend combinations (batteries, models) of in vitro tests as replacement for animal toxicity tests. She stressed that the MEIC study had confirmed the high relevance of using human cell line tests, which determined basal cytotoxicity for estimating human acute toxicity. However, it was also concluded that at least two types of tests ought to be added to the MEIC in vitro test battery that is toxicity tests on important mechanisms of human toxicity (models for target organ toxicity) and tests on key kinetic events. This lead to the initiation of EDIT (Evaluation-guided Development of In vitro Test batteries).

She then explained that the EDIT programme had several goals. The short-term goal was to develop and pre-validate an optimal in vitro test battery (5-10 tests) which could replace acute animal toxicity tests (i.e. the modified LD50 tests). The medium-term goal was to establish a model where in vitro toxicity and non-animal data would be used in hazard/risk assessment of chemicals. Finally, the long-term goal was to present a battery of in vitro tests predicting human subchronic/chronic toxicity.

Dr. Clemedson added that 20 reference chemicals were to be used in this study. Furthermore the sub-programmes of EDIT would have included data collection (SP1) and in vitro models for predicting distribution (SP2), biotransformation and elimination (SP3), absorption and bioavailability (SP4)and target organ toxicity, that is neurotoxicity and other target-organ toxicity(SP5). Furthermore, it would have also included in vitro models for DNA damage(SP6) and long-term toxicity (SP9) as well as modelling of human lethal and toxic blood concentrations (SP7), and toxic doses (SP8).

She then provided a number of examples with respect to the various sub-programmes and the partners and tasks involved. Dr. Clemedson illustrated that Dr. Annalaura Stammati (I) and Prof. Per Artursson (S) would specialise on in vitro models for predicting absorption and bioavailability (SP4) using the Caco-2 model and computer-based models. Regarding the field of biotransformation and elimination (SP3), Dr. Maria José Gómez-Lechón (Spain) for example would focus on comparing IC50 from metabolic competent cells (human hepatocytes) and non-metabolising cells (cell line).

Regarding the modelling of human lethal and toxic blood concentrations (SP7), Prof. Michael Sjöström (S) would use PLS-modelling. Data on distribution (SP2), biotransformation (SP3), and target organ toxicity (SP5) would be used to model toxic and lethal blood concentrations, together with the in vitro toxicity data from the original MEIC battery. She added that the in vitro estimated human toxic and lethal blood concentrations would then be compared with human toxicity and lethal data compiled in the MEMO programme. As part of the modelling of human lethal and toxic oral doses (SP8), Dr. Bas Blaauboer (NL) would use physiologically based biokinetic (PB-BK) models to model human lethal and toxic oral doses. The models would include data on distribution, tissue-blood distribution, biotransformation, absorption, target organ toxicity and data from the original MEIC test battery. Furthermore, the estimated doses will be compared with the human data obtained from the literature.

Closing her presentation Dr. Clemedson reported that EDIT had failed to get funded by the Commission in the first call. She felt that the main reason was that it was too small with only 16 partners involved. She added that most parts of it were now resubmitted with the second call as the A-Cute-Tox Integrated Project with the objective to optimise test batteries for human acute toxicity. Yet, not all parts of the Edit-programme could be included in this new proposal, so that even if it was successful there would still be a need for additional resources to fun the parts that had to be left out.

Session “blue horizon”: Other Novel Research Approaches to Alternative Test Development

Prof. Nicola Loprieno:
Genotoxicity testing in vitro. The Future for oxidative hair dyes
Strategies for In Vitro Testing of Cosmetic Ingredients for their potential Mutagenicity-GenoToxicity

Prof. Loprieno started out by quoting to the SCCNFP’s “Notes of Guidance” of October 2003, stating that in the risk assessment of substances employed in the cosmetic products it was necessary to address the potential effect of mutagenecity. He then referred to the Directive 2003/15/EC of the European Parliament and of the Council of 27 February 2003 amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products, and recited that given the special risks that substances classified as carcinogenic, mutagenic or toxic for reproduction, category 1, 2 and 3, pursuant to Directive 67/548/EEC may entail for human health, their use in cosmetic products should be prohibited. He added that a substance classified in category 3 could be used in cosmetics if the substance had been evaluated by the SCCNFP and found acceptable for use in cosmetic products.

From this starting point, Prof. Loprieno briefly explained mutagenicity and genotoxicity as defined in the Technical Guidance Document on Risk Assessment, provided by the European Chemical Bureau. He said that mutagenicity referred to the induction of permanent transmissible changes in the amount or structure of the genetic material of cells or organisms. These changes could involve a single gene or gene segment, a block of genes or whole chromosomes. Effects on whole chromosomes could be structural and/or numerical. Regarding genotoxicity, he said that was a broader term and referred to potentially harmful effects on genetic material which were not necessarily associated with mutagenicity. He then stressed that there was currently no single validated test method could provide information on all the genetic end-points and so it would be necessary to test each chemical in several assays to get full information on its genotoxic potential.

Continuing he explained that the three basic elementary endpoints for evaluating mutagenic potential were gene mutations, structural chromosome aberrations and numerical chromosome aberrations thereby also forming the basis for constructing a test battery. He then provided information on four tests that were proposed by the SCCNFP for the in vitro testing of cosmetic ingredients for their potential mutagenicity and genotoxicity. This proposal would still have to be discussed in the upcoming months but the tests at hand were the Bacterial Reverse Mutation Test, the In Vitro Mammalian Cell Gene Mutation Test, the In Vitro Mammalian Chromosome Aberration test and the In Vitro Mammalian Micronucleus Test.

But with respect to in vivo studies he also noted that the SCCNFP had stated in its draft proposal of November 2003, that there were several reasons why mutagenicity testing beyond the base level could be required. For instance, if some concern arose from positive results of in vitro tests, further testing could be justified. Besides, it was stated that the selection of the in vivo assays could not be defined a priori and would depend on the positive results observed in the in vitro assays. He added that the British Committee on Mutagenicity was concern that combinations of assays for gene mutation in bacteria and for chromosomal aberrations (plus aneuploidy) in mammalian cells might not detect a small proportion of agents with the potential for in vitro mutagenicity. Thus a third assay, comprising an additional gene mutation assay in mammalian cells, should be used, except for compounds for which there was little or no human exposure. The SSCNFP also agreed that for some classes of compounds with specific structural alerts, it was established that specific protocol modifications/additional tests would be necessary for optimum detection of genotoxicity.

With respect to UV-absorbing cosmetic ingredients, he explained that for the detection of photo- clastogenicity/ mutagenicity, several well-established assays had been adopted to a combined treatment of chemicals with UV-VIS light including bacterial and yeast mutation assays, tests for detecting clastogenicity, tests for detecting gene mutations in mammalian cells and tests for detecting aneugenicity in mammalian cells in vitro. Yet, the SSCNFP Stated that since up-to-date there was no genotoxic photochemical known to be exclusively positive for gene mutations and the recognized photochemical reaction mechanisms were strongly clastogenic, it was suggested that a test for photochemical clastogenicity (chromosomal aberration or micronucleus in vitro tests should have absolute priority).

Regarding hair dyes’ ingredients and formulation, Prof. Loprieno stressed that for risk assessment the following information had to be submitted such as data on genotoxicity and all available data on carcinogenicity. According to the intended use, the dyes/dye precursors had to be tested alone and/or in combination with other substances to simulate conditions of use. He stressed that safety assurance and with it, health protection of consumers could only be applied to those hair dyes and complexes which had been subjected to the above-mentioned assessment

Then Prof. Loprieno gave a broad overview regarding the various types of dyes. He explained that some would be absorbed by the gastrointestinal tract, by the respiratory system and through the skin while several hair dyes were secondary dialkanolamine suspected to undergo nitrosation. Some aromatic amines had two major pathways of metabolic activation implicated in genotoxicity that is formation of N-Hydroxy-N-Acetylaramines that undergo NHydroxy-N-Acetylation and N-Hydroxylation as well as formation of N-Hydroxylamines. He explained that the two pathways would lead to the formation of different types of DNA adducts. He further said that aromatic amines would not interact with DNA directly, but through the formation of DNA adducts following their metabolism.

Prof. Loprieno then illustrated that the SCCNFP had recommended a 3-level strategy for testing hair dye ingredients and reaction products for their potential mutagenicity, genotoxicity and carcinogenicity. Testing assays in vitro (Stage 1), six tests would be available, the Bacterial Reverse Mutation Test (OECD 471); the In Vitro Mammalian Chromosome Aberration Test (OECD 473); the In Vitro Mammalian Cell Gene Mutation Test (OECD 476); the In Vitro Mammalian Micronucleus Test (UK-EEMS); the DNA Damage and Repair/Unscheduled Synthesis in Mammalian Cells in vitro (OECD 482); and the In Vitro Syrian Hamster Embryo (SHE) Cell Transformation Assay (OECD TG495). Testing assays in vivo (Stage 2), the recommendation stated that the aim of the in vivo assays would be to ascertain whether a genotoxic/mutagenic effect shown in vitro could also occur in somatic cells under in vivo conditions. The selection of the in vivo assays cannot be defined a priori and depends on the positive results observed in the in vitro assays. It was further stated that in the case of a positive result in vitro, the in vivo test should use the same end point and the tissue, if possibly.

Testing of Hair Dyes Reaction Products (Stage 3), the recommendation stated that during the application of a permanent hair dye, it was possible to evaluate the kinetics of the disappearance of the basic ingredients and of the appearance of the reaction products. It further recommended isolation and identification of the reaction products and their submission to a tiered genotoxicity testing according to their bioavailability and relevance. In the case of a relevant systemic exposure, an animal model should be developed in order to evaluate the genotoxicity, mutagenicity and carcinogenicity potential of the reaction products in an in vivo situation.

Closing his presentation Prof. Loprieno concluded that mutagenicity and genotoxicityin vitro test methods had established and harmonized protocols as a result of scientificconfrontation based on extended practice of testing chemicals of different structure. In addition,mutagenicity and enotoxicity in vitro test methods were validated against in vivo somatic cells test methods and against long-term animal carcinogenicity studies. Their predictive values ranged between 60 and 100 per cent.

Dr. Odile de Silva:
Cosmetics Industry

Beginning her presentation, Dr. de Silva highlighted that for industry it was of paramount importance to ensure that the cosmetic products brought on the market were safe, i.e. they must not cause any adverse health effects in consumers when used under normal andforeseeable conditions. In addition, she stressed that nobody should compromise consumer safety. To this end she added that an appropriate risk assessment approach was required.

She explained that in 1992 COLIPA was already concerned that a marketing ban actually meant a halt to innovation with respect to new ingredients and new uses unless it would be possible to develop novel approaches for product safety assessment that did not compromise consumer safety and did not involve any new animal testing. To serve this purpose, the COLIPA Steering Committee for Alternatives to Animal Testing (SCAAT) became a focal point for the cosmetics industry’s efforts in the EU to develop alternative approaches for over 10 years. She explained that a number of collaborative projects had been undertaken with academia, other industry sectors and government laboratories, to develop and validate in vitro methods in 5 areas of great importance for the overall safety assessment of cosmetic products that is phototoxicity, skin penetration, eye irritation, as well as skin sensitisation and skin irritation.

With respect to the human health endpoints for which testing may need to be conducted to assess the safety of chemicals, Dr. de Siva illustrated that there were four for which in vitro alternatives had been validated or were considered to be valid, that is skin corrosion, skin absorption, phototoxicity, photomutagenicity.

In addition, she added that in vitro screens for embryotoxicity had been validated which would be a partial replacement for teratogenicity testing (i.e. result in the need to use fewer animals), and that there were reduction and refinement alternatives (i.e. still requiring animal testing, but using fewer animals and/or less harmful procedures) for eye irritation, skin sensitisation, acute (oral) toxicity.

Regarding the current SCAAT R&D programme (2001-2004, she explained that it was directed towards identifying novel cellular and molecular endpoints for incorporation into new and improved alternative methods for eye irritation, skin sensitisation and skin irritation. It was the intention that these alternative methods would be developed and evaluated to the stage that they were ready for prevalidation.

Concerning the issue of eye irritation Dr. de Silva explained that it was necessary to identify endpoints related to the dynamics of injury and recovery and to develop prediction models for prevalidation of new or improved alternative methods. Furthermore, it there was a need for a quantitative response predictive of ocular irritation potential in humans. To this end, she gave examples of two projects addressing this issue. She illustrated that one project was being carried out at the University of Aachen in Germany while the second one was done at Bristol University in Great Britain. She said that the Aachen-project would identify whether patterns of changes in physiological functions and mediators of injury released from the cornea predict the potential of a chemical to damage the eye while the Bristol-project would identify endpoints related to the magnitude of injury and quality of repair in human conjunctival and corneal constructs built sequentially (epithelium, stroma, and endothelium). In addition, she highlighted that another two new projects were to be funded that would focus on the application of genomics to current corneal models being evaluated in Aachen and Bristol projects.

Addressing the issue of skin sensitisation, Dr. de Silva explained that there were currently two projects that focused on dendritic cells. One aimed at optimising dendritic cell lines for detecting allergens using existing endpoints (e.g. CD86, MHC class II, aquaporin 3). The other investigated genomic changes consequent to exposure to allergens as a means to identify novel markers. She added that an additional four projects would be funded, as approaches were needed as part of an integrated testing strategy for predicting skin sensitisation, that is toxicodynamic modelling to predict bioavailability (skin metabolism of allergens in vitro), assessment of peptide binding of chemicals, assessment of peptide reactivity of chemicals, exploration of mechanisms of intracellular signalling in dendritic cells. In addition, the current project on skin irritation was focused on 3D human skin models – gene and protein expression associated with exposure to irritants. Furthermore, she remarked that a new project was to be funded on the proteomics approach.

Concerning other endpoints and R & D needs she told the audience that SCAAT’s current focus was on eye irritation, skin sensitisation, skin irritation (phototoxicity, skin penetration) but that it had also acknowledged the need to develop alternative approaches that cover all toxicological endpoints. SCAAT’s intention was to establish Task Forces on UV-induced toxicity and genotoxicity, and to evaluate testing strategies. But she also stressed that there were big gaps with no significant alternatives R&D activities in some areas of greatest challenge for safety assessment that is repeat-dose systemic toxicity including such aspects as general effects, mutagenicity and carcinogenicity, etc.

Closing her presentation Dr. de Silva argued that in seeking to ban animal testing as a means to assess the safety of cosmetic products, the 7th Amendment would challenges the current paradigm that underpins all toxicological risk assessment. She contemplated that on could either view this as a threat, or as an opportunity to progress the science of toxicology and to develop new, better and more consistent approaches to risk assessment that would actually improve our ability to ensure that products were safe for consumers. Moreover, she concluded that the cosmetics industry had to take a leading role in certain areas and to work in a partnership with other stakeholders for the remaining areas as industry could not cover alone all the field of toxicology, to respond in a positive way to the challenges set by the 7th Amendment in relation to developing alternative approaches to animal testing for assessing safety. Nevertheless the stressed vigorously that the safety of products would always be the most important concern. Any new alternative, non-animal approach for safety assessment would have to be validated, showing unequivocally to provide at least an equivalent level of consumer protection to that afforded today based on animal testing.

Dr. Joan-Albert Vericat:
IVTIP and National Platforms

Starting his talk, Dr. Vericat informed the participants that IVTIP was an informal forum of European companies with an active interest in in vitro testing to be used in regulatory and safety testing or to be used in the compound discovery and development process. He added that IVTIP was also supportive of applying, where possible, the principle of the 3 Rs. In addition he said that the members represented companies in the chemical, cosmetics and pharmaceutical sector and that its success depended heavily on the scientists involved.

Regarding the main objectives, he explained that IVTIP intended to optimise the industrial value of EU funded research projects, to encourage the further development, validation and regulatory acceptance of tests based on this research, to advise European bodies (European Commission, European Parliament) on industrial requirements for current and future research projects in in vitro testing.

Concerning the various activities he pointed out that IVTIP was very interested in the optimisation of the industrial value of EU funded research projects giving the example of Project QLK3-1999-30005, a European Technology Transfer Initiative that was financed under FP5. Dr. Vericat explained that the objective was the evaluation of 5 FP4 projects from the technology transfer point of view, that is immortalised cell lines for testing skin irritancy (PL960036), establishment of immortal differentiated cell lines for testing (PL960052), human reconstructed epidermis for immunopharmacotoxicology (PL960086), germ cell cultures and markers for reproductive pharmacotoxicology (PL960183), and in vitro models for drug allergenicity and IgE synthesis (PL960246).

With respect to this project he added that industries were very interested in the results obtained from in vitro adventures saying that 38 industries out of 190 had responded to a questionnaire. He remarked that industries needed tests that were validated or near validation but none of the projects had resulted in tests ready or near to validation. In general, he criticized that no deep analysis of the potential technological transfer of deliverables, different of those stated in the project, was performed.

He continued by saying that IVTIP was also very interested in the development, validation and regulatory acceptance of in vitro models for safety assessment highlighting that IVTIP was actively involved in research proposals in FP6. He numerated the various projects such as Sensacell with IVTIP being a member of the Steering Committee, Reprotec with IVTIP scouting for technologies and interested industries and A-Cute-Tox with IVTIP being involved in the organisation of pilot trials for evaluating the feasibility of an amended testing strategy.

Reaching the end of his talk, Dr. Vericat added that as part of its activities, IVTIP was also advising European bodies such as the European Commission and European Parliament, and supporting communication in the field through position papers, for example on the industrial need for research (1997) or the role of an industrial platform in the area of in vitro testing (2001). He stressed that there was also great interest in continuing and deepening the contacts and cooperation with ecopa as well as its members, that is the National Consensus Platforms in the various countries.

Prof. Peter Maier:
Academia

Prof. Maier commenced by explaining that he would not present a new test but rather wanted to share his experience as a scientific adviser of a 3R-Research Foundation in Switzerland. Considering the foundation and interface between active researchers that apply for money, he thought that this academic environment was very peculiar. He said that a new idea was usually the driving force for a researcher to contact the foundation. Generally speaking these scientists were individuals not connected to any interest groups, societies or international parties. Quite often they would not care about already existing assays or be aware of ongoing international validation studies. Since they were usually young scientists they would also not belong to the established circles of researchers, regulators and so on. At universities, though, there was often also a lack of understanding and know-how to judge the value of applying for funding in the field of alternative methods.

Turning to the situation in Switzerland Prof. Maier explained that 87 per cent of all animals were being used for drug development and research while REACH would only affect 13 per cent of the animals used. Accordingly the foundation received approximately 20 to 25 proposals per year including 3 to 4 that would be connected to replacement in the field of toxicity testing. Yet, due to the foundation’s size it could only give funding to 3 to 4 projects. He then explained that before taking a decision on funding the foundation would also pose the question whether a given proposal was fit to be accepted abroad by ECVAM and so on. He added, that this was indeed a quite complex task. According to him the main problem regarding the decision making was a lack of standards that would enable the evaluators to ask the applicant to measure his new method against certain established standards and to give a report on what was new and better. He felt that coordination, standardisation and shared know-how were very important in this respect.

Regarding the 3R-relevance, he emphasized that a proposal would not be funded if the methods would only mean the replacement of an already existing in vitro test. Yet, if the new approach or method was better than the existing one and had 3R-relevance then it could also be funded by the foundation.

Prof. Maier then said that there were additional problems that needed to be addressed. He said that it was very difficult that once the results of a new method were available to actually test this new approach together with ongoing validation studies. He stressed that he did not see so far how one could introduce such a new developed test in ongoing studies in order to speed up the complementation of tests.

Furthermore, there was also a problem with using new technologies. He wondered how they could be compared with ongoing studies if the new systems produced a completely different output. In addition, he saw another problem at universities with respect to the follow-up work on (pre-)validation studies. The personnel at universities usually did not have permanent positions and thus fluctuated relatively often. Many scientists shied away from the paperwork involved and so on. Thus, one would have to pose the question of who could possibly do the job of prevalidation and validation.

Finally he outlined another problem saying that the young scientists often applied for a single test but did not incorporate any other methods. Quite often there were interesting tests but taken alone they would not succeed. Unfortunately many applicants did not address this issue but he was convinced that such a combination would be a very interesting approach and help to replace animal testing.

Closing his presentation he made the case for developing better methods and systems to judge ideas and to choose the most promising proposals as well as to make life easier for scientists by finding ways to incorporate them into ongoing studies without being part of the established test groups.

Dr. Bart de Wever:
Current Status of industrial (pre-)validation initiatives for in vitro skin and eye irritation testing using 3D human epidermal and corneal tissue models

Dr. de Wever started by giving a short introduction with respect to the company and its history as well as current status. He pointed out that by 2003 SkinEthic Laboratories had become the largest supplier of human tissue models worldwide with a semi-automatic human tissue production having a current capacity of 5.000 tissue units per week. The company was furthermore aiming at fully robotising the production that would increase the output to 25.000 tissue units per week. In addition he emphasized that the tissue functionality and ultrastructure was close to human in vivo. Even more importantly was that these tissues were highly reproducible and also the way chemicals would react with them.

He then continued that the company had developed a number of human tissue models over the past ten years such as oral epithelium, gingival epithelium, epidermis or corneal epithelium. He explained that industry usually needed these tissues to predict the human response in topical toxicity. In the case of skin they would use the epidermal model to predict irritation, phototoxicity, corrosively and aspects of sensitization. In terms of eye irritation they would use the corneal epithelial model to predict irritation and recovery. The reason for using these human tissue models was that they were more reliable, reproducible and faster.

Dr. de Wever then illustrated that the next question arising was how to get from internal adoption in pre-screening to regulatory acceptance. The obvious was to proceed was to work with ECVAM but based on previous experience it was quickly understood that this body had a very tight agenda and that the process was a relatively slow. It was thus decided to run own industrial prevalidation projects following the ECVAM guidelines.

Concerning the current (pre)validation projects he said that there was one on in vitro skin irritation and another one on in vitro eye irritation. He explained that the prevalidation of in vitro skin irritation testing of topical formulations and actives was a multi center study involving Novartis Pharma, Pfizer and others. The study would comprise 40 chemicals and was likely to start in spring of 2004 and be completed by the end of 2005. A second project that SkinEthic Laboratories had initiated was a ‘Catch-up’ validation on in vitro skin corrosivity testing. He added that this study was also a multi-center study involving ZEBET, Safepharm and BASF. The in vitro protocol to be used was based on Epiderm and Episkin protocols and was recently evaluated at ZEBET. This study would comprise 12 OECD chemicals and was scheduled to start before the end of 2003 in order to be finished by February 2005.

He then briefly mentioned a third project which was only a proof of principle. It dealt with the assessment of skin irritants versus sensitizers. He said that the initial phase of the project comprised 8 test chemicals (5 sensitizers and 3 irritants) with an in vitro protocol based on a Multiple Endpoint Analysis to be followed by testing of 25 additional chemicals in 2004.

Coming to the end of his presentation he provided further information on a study that focused on the prevalidation of in vitro eye irritation testing of chemicals. Also designed as a multicenterstudy it involved J&J, Novartis and Pfizer. 20 chemicals were being tested with an in vitro protocol based on10, 20, 30, 60 min. topical application as well as a multiple endpoint analysis based on tissue viability and histology. The study was started in 2002 and finished in 2003. Dr. de Wever stressed that the outcome of this prevalidation study was very positive with respect to the reliability of the model as well as the relevance of the data obtained.

Dr. De Wever pointed out however that the quality of the in vivo animal data is critical in the successfull validation of alternative methods: three of the 20 test compounds which were classified as irritant by the corneal in vitro model and as non-irritant when based on the ECETOC data, were identified as in vivo eyes irritants when other sources of in vivo data were consulted [e.g. Hazard Substances Data bank (TOXNET®)]. Consequently, the relevance of the model markedly increases which results in an enhanced predictive power to discriminate between irritant and non-irritant chemicals. A detailed discussion of this approach will be reported in Van Goethem et al.

Prof. Erik Dybing:
Alternative Non-Animal Testing and Risk Assessment CSTEE Joint Working Group on Alternative Non-Animal Testing

Prof. Dybing started out with a brief overview regarding the elements in the risk assessment of chemicals. He explained that hazard identification meant to define the toxic potential of a given chemical while hazard characterisation dealt with the relationship between the dose of the chemical and its toxicity. Furthermore he said that exposure assessment focused on the different types of the exposures to the chemical while risk characterisation dealt with the probabilities and consequences of toxic effects in the exposed population.

Speaking of the elements in hazard characterisation, he explained that it involved the establishment of a dose-response relationship for critical effects, an identification of the most sensitive species and strain as well as an identification of potential species differences (qualitatively and quantitatively). In addition, hazard characterisation required a characterisation of the mode of action/mechanism for critical effects as well as an extrapolation from high to low dose and from experimental animals to humans.

Concerning the use of non-animal test systems in hazard characterisation he stressed that nonanimaltest systems would aid in the identification of the most sensitive species and strain and that non-animal test systems are good models for studying qualitative and quantitative species differences in toxicity. He stated that non-animal test systems were excellent models for characterisation of the mode of action/mechanism for critical effects, but emphasized that findings needed to be validated in vivo. In addition, he said that non-animal test systems would aid in the extrapolation from high to low dose and from experimental systems to humans.

With respect to non-animal test systems in risk characterisation Prof. Dybing stressed that risk characterisation is an essential process for ensuring a high level of safety from chemical exposures to man and the environment. Thus, he argued that it was crucial to identify a dosedependentstarting point by selecting a critical data set and determining a dose-response for the critical effect. He added that for non-genotoxic agents threshold surrogates (NOAEL, BMD) would be identified as the starting point from long-term animal experiments that is structural and functional chronic toxicity as well as reproductive toxicity. For genotoxic agents dose indicators would be identified as the starting point from carcino-genicity studies Very complex physiological and pathological interactions are involved in chronic toxicity, reproductive toxicity and carcinogenicity. Thus, he emphasized that an identification of the dose-dependent starting points for risk characterisation was not possible without the use of animal test systems.

Closing his presentation Prof. Dybing concluded that the CSTEE strongly supported the policy of using research animals in a responsible manner and encouraged research designed to reduce, refine or replace the need for laboratory animals. He further emphasized that research involving laboratory animals was necessary to ensure and enhance human and animal health and protection of the environment. In the absence of human data, research with experimental animals was the most reliable means of detecting important toxic properties of chemical substances and for estimating risks to human and environmental health.

Moderator: Tom J. Feijtel
Round table: “Funding vs. Politics” – Are we on the right track to “REACH the station” of Cosmetic Guideline and EU Chemical Policy without animal testing?

Discussants: Dr. Julia Fentem, Prof. Kay Brune, Dr. Annalaura Stammati, Dr. Roman Kolar, Dr. Odile de Silva, Dr. Martin Kayser, Prof. Thomas Hartung, Mrs. Karin Gabrielson and Dr. Arthur van Iersel

Starting the discussion Dr. Feijtel posed the question what they regarded as the most significant point regarding the issue of funding versus politics. Dr. van Iersel stated that funding was actually the most important point to be discussed since the amount of money for developing alternatives was quite limited partly due to political decisions but partly also to priorities being defined in industry. As a coordinator of the Dutch programme on alternative testing, he had learned that the requests were usually surpassing the available funds by a ratio of ten to one. Dr. de Silva speaking on behalf of Colipa said that the cosmetics industry was now facing very clear and tight deadlines. Since the amount of work was astounding it would be necessary to focus on channelling funds to projects with clear coordination and without redundancy so that the money is used in an efficient and productive way.

Mr. Kolar regarded coordination of the various existing funding activities, both national and international, as the most crucial point in this context. Furthermore, he stressed the importance of quality control of ongoing funded projects. Past experience had shown that some partners in various projects failed to deliver the work they had taken upon them since they lacked motivation. Projects therefore needed to be constantly monitored to be able to draw appropriate consequences. Dr. Kolar regarded coordination as the most crucial point in this context. Furthermore, he stressed the importance of motivation and quality control. Past experience had shown that some partners in various projects failed to deliver since they were not as dedicated as they should have been. Prof. Brune representing a private foundation stressed the need to be precise in allotting funds. In addition, a private institution could further basic research and help to raise awareness among young scientists as well as provide add on funding. Mrs. Gabrielson agreed and also highlighted the great importance of funding and coordination stressing that one was on the right track in this respect. Yet, there was a need to attract and motivate more young scientists.

Prof. Hartung felt that a strategic discussion was the most important activity at the current stage. He thought that the significance of conceptual frameworks to solve the problems in the various fields had been underestimated for quite some time. He added that it would only be possible to attract more young scientists if they regarded it as a success and thus a challenging field to be part of. But to serve this purpose, first clear conceptual frameworks had to be formulated and respective successes had to be achieved. Dr. Stammati speaking of behalf of the Italian Platform emphasized with respect to funding that scientists needed to learn on how to apply for funding to make better use of the funding that was available with the EU and other institutions. Yet, she also stressed that in general the amount of funding available was insufficient pointing out that in Italy for instance there had been serious cuts regarding the funding of alternative methods development.

Prof. Brune pleaded that all animal protection societies should actively involve themselves in research by contributing to research projects for the development of alternative methods. He pointed out that within Europe at least 5 million inhabitants are members of animal protection societies. If each would contribute 1€ to research, projects selected by representatives of the societies could be funded amounting to about 5 million €. Moreover such action would attract senior people to donate to active research geared towards implementing the 3R concept.

According to Dr. Kayser it was of outmost importance to bring all stakeholders together in order to change the way risk assessment was done. This, of course, required that all data would be taken into account including in vito data. But at the end it would also take politics since any change in risk assessment needed to be acceptable not only to scientists but also to politicians, regulators and society in general. Dr. Fentem stressed that there was a huge amount of work to be done and she felt that the challenge was less in the sense of what to do but how to do it, especially in the light of the given deadlines. She felt that a clear structure and programme was needed in which everyone would focus on his or her strength to avoid unnecessary duplication of work and so on. In addition, she thought it necessary to get more people involved at all levels that are academia, youngsters, and other people in companies to give a few examples.

Dr. Feijtel then asked Prof. Hartung how validation could be accelerated. Prof. Hartung replied that progress had already been made with respect to speeding up validation giving the example of a major validation study that was finalised within three years. Yet, he doubted that it would be possible to be much quicker following the traditional concepts of validation. Nevertheless, he hoped that the future would see a greater use of evidence data since it was not always necessary to start from scratch. Using this data more systematically could help to save time. In addition, he stressed that he was actually very concerned with the regulatory implementation that followed validation. He made the case for contacting and involving regulators much earlier in the process to define the actual needs before starting a validation study. Thus, the upcoming validated method would already be recognised by the regulator but even more important it would also deliver what was really needed. He believed that this approach would save much of the time that was currently needed.

Day 2

Ecopa Annual Meeting: Presentation of the New National Platforms
Mrs. Karin Gabrielson, Swedish Platform for Alternatives

Mrs. Gabrielson said that the new Swedish Platform was established in February 2003 and registered as organisation in Sweden in spring. The platform consisted of members from the four parties with an interest in animal experiments and alternatives: animal protection, government authorities, industry and academia. She furthermore said that an interim board, consisting of representatives from all four parties was elected, with Karin Gabrielson (Animal Welfare) as chair, Cecilia Clemedson (Academia/Animal Welfare) as treasurer and secretary, Krister Martin (Industry, AstraZenenca), Roland Grafström (Academia, KI) and Staffan Jakobsson (government authority, CFN). In addition, three working groups were formed on education, chemicals and to follow the construction of the new Animal Welfare authority.

The purpose of the platform was to form a basis for co-operation and discussions for issues regarding 3R’s alternatives. It would also serve as a distributor of information on the 3Rs between the parties and others, such as students, politicians and the general public. The platform would also be used to discuss and agree on strategies on how the 3R’s alternatives could be used to reduce the use of animals in experiments and to minimize suffering of the animals used.

For next year the platform would focus on setting up a system to disseminate information. It was thus being contemplated to set up a website or to publish a newsletter. The platform would further focus on establishing good links with the new animal welfare authority to be set up in Sweden that was also supposed to take over funding for alternatives.

Dr. Annalaura Stammati:
Italian Platform on Alternative Methods

Dr. Stammati informed the members that the Italian platform was officially established as a non-profit organisation in May 2003. She added that all four parties were participating in the platform. In addition there was an observer from the Ministry of Health. In May 2003 there were a total of 14 founding members with 3 from government institutions, 4 from industry, 5 from academia and 2 from animal welfare organisations. In the meantime there were 29 new 25 members with 3 from government institutions, 8 from industry, 5 from academia and 13 from animal welfare organisations.

Furthermore, she explained that a directive committee of 8 persons was elected comprising two persons from each party that is A. Stammati and E. Testai (government institutions), M. Zanotti Russo and F. Fassio (industry), M. Dacasto and F. Zucco (academia) and G. Felicetti and M. Gualano (animal welfare organisations). Among them a president would be elected at the upcoming first meeting of the directive committee in December of 2003. At this meeting there would also be decisions taken regarding the future programme and so on.

The official presentation of the new platform took place in Rome on the 19th of November 2003 as part of a scientific day titled “Alternative Methods to Animal Testing, Science, Ethics and Communication”. This initiative was hosted by the Ministry of Health while the platform had organised speeches of four platform members, one form each party, presenting their point of view. In addition there were four invited guest speakers that are Beatrice Lucaroni, Thomas Hartung, José Castell and Flavia Zucco.

Dr. Dagmar Jírová:
Czech Consensus Platform for Alternatives – CZecopa

Dr. Jírová reported that the activities between 2002 and early 2003 had focused on the registration and establishment of CZecopa as a not-for profit organisation. During this period the statutes were produced, a general assembly was convened and representatives elected. In addition a working plan with respective priorities was elaborated. She added that a website and logo were also under construction.

Regarding the support of legislative actions, Dr. Jírová said that CZecopa had given support with respect to the update of the Animal Protection Act 246/1992 Coll., and demanded improvements regarding the implementation of alternatives and the registration of alternative methods. Furthermore, CZecopa was heavily involved in the exact transposition of wording for the 7th Amendment of the Cosmetic Directive.

Concerning the promotion of education and information, she explained that CZecopa was focused on broad public information at the initiative of animal welfare organizations. Leaflets and brochures on alternative methods were prepared, books translated and a number of public meetings held. Regarding alternatives at schools and universities, she reported that practical demonstrations of in vitro methods were introduced at the Medical Faculty of Charles University in Hradec Králové and EuroNICHE had become a part of regular education at the 3rd Medical Faculty of Charles University in Prague. Furthermore, demonstrations of photodynamic reactions in cell cultures took place at the Medical Faculty of Palacký University in Olomouc while a broader participation of students in veterinary practice instead of animal experiments was being promoted at the Veterinary and Pharmaceutical University in Brno.

Concerning the scientific development and implementation of methods, Dr. Jírová explained that it involved mainly laboratories at the National Institute of Public Health in Prague where cytotoxicity and phototoxicity tests in vitro were performed and the 3D human skin models were introduced: At the Department of Physiology (Czech Academy of Sciences Prague) they had performed photodynamic effects in cell culture and used alternative multimedia in courses for students.

Furthermore, members of CZecopa participated in workshops and symposiums giving scientific presentations such as the conferences on Alternatives 2002 (Prague) and Alternatives 2003 (Poland). Finally, with respect to industry Dr. Jírová added that results were being presented to facilitate the introduction of alternatives to practice of testing laboratories such as the routine testing of medical devices, cosmetics, items of common use, chemicals (BIOTEST, ITC, NIPH). Besides there were presentations of alternative methods results at regular industry meetings and workshops of PROKOS and CSZV.

Dr. Maciej Stepnik
Poland

Dr. Stepnik said that in 1999 a programme supported by the Ministry of Health lead to the establishment of the “The National Centre for Alternative Methods in Toxicity Assessment” (NCAM) at the Nofer Institute of Occupational Medicine.

The aim of NCAM was the dissemination of the idea of applying alternative methods for toxicity assessment to replace, reduce and/or refine experiments on animals. Thus the main objectives were the collection and distribution of data on the concept and use of alternative methods, the promotion of the co-operation research centres employing the alternative methods and the Information exchange on research projects conducted in Poland and in other countries. Additional objectives were the organisation of workshops and conferences as well as the editing and distribution of the newsletter “Vitryna”.

He further explained that the “Vitryna” quarterly was an official publication of the National Centre of Alternative Methods in Toxicity Assessment, being supported by the Ministry of Health under a long-term governmental programme called “Health and Safety in Work Environment”. He added that the newsletter contained information on the history and development of the 3R concept, information on the implementation of alternative methods in research centres and their promotion among scientists in Poland, information of the activities of the National and Regional Ethics Committees. In addition, the newsletter contained international news on the activities of ECVAM and national centers for alternative methods as well as information on institutions employing alternative methods and legislation regarding alternatives to animal testing, etc.

Closing Dr. Stepnik added that there was also a home page available that among others provided reports on activities of Polish research centres employing alternative methods. He added that NCAM had recently worked out “Training materials for toxicity assessment using alternative methods”, which after consultations would be disseminated among university teachers as a multi-medial presentation on CD. These materials would cover various aspects of history, development and present status of alternative methods in the world. Perhaps in 2004 the NCAM would contact the various parties in order to establish a national consensus platform in Poland.

Prof. Ove Svendsen:
Denmark

Prof. Svendsen commenced by giving a few figures pointing out that the number of laboratory animals being used in Denmark per year was around 350.000. Since 1999 Prof. Thorn and himself had followed the development of ecopa and passed the message to the Danish government leading to a hearing in 2001 that was attendedby representatives from several ministries as well as members of parliament.

Then there had been another public hearing in June of 2003 that was a fairly big meeting focusing on the issue of alternative methods. He had also been invited and given the opportunity to present ecopa. By the end of the day the establishment of a Danish platform was recognised as a main priority. Yet, he stated that the process had slowed down again with the government ministries presently contacting other countries with established platforms to obtain information. Despite the slowdown Prof. Svendsen expressed his hope that a platform could probably be established in 2004.

Dr. Dag Marcus Eide:
Norway

Dr. Eide reported that the Norwegian National Consensus Platform was not established yet, although the government had already promised money and made a proposition announcing the plans for establishing a Platform.

Regarding the overall situation in Norway he then explained that 1.5 million of Norwegian experimental animals were fish, while less than 60 000 rodents and rabbits were used for research. He stressed that the ethical issues about fish were different from mammals. Most of the fish would be used for the development and testing of fish drugs. Most of the fish counted as experimental animals would actually be used for consumption, thus, they were not what was normally considered to be an experimental animal. Dr Eide emphasized that this would pose special questions for the platform regarding the equal importance of all 3Rs with respect to the use of fish.

Regarding the formation of a platform he added that the 4 pillars had not been established yet, although the animal rights organisations and the government representatives, as the Norwegian animal research board, had made common action.

Current discussion would focus on the question of where to locate the platform secretariat geographically. The Ministry of Agriculture had suggested that it should be on the west coast and thus closer to fish research, while the organisations and the Research Board wanted it in Oslo and thus closer to the rodent research and lab animal specialists. A decision had not been taken yet. As a closing remark, Dr. Eide stressed that the Norwegian animal research board was committed to establishing a Norwegian platform.

Dr. Isabelle Fabre
France

Dr. Fabre explained that her agency, Agence Française de Sécurité des Produits de Santé, had worked to set up groups in the past such as one on alternative methods in cosmetics. However, she felt that it was now time to establish a national consensus platform in France comprising all four parties. Though it was very difficult to motivate the French government, she was hopeful that such a platform could be established in the near future and perhaps even this year. This was due to the fact that there was a new ministry on the environment in place that appeared to be much more motivated.

Confirmation of the final ecopa Statutes and the Board Elections as of June 2003

Regarding the confirmation of the ecopa statutes Prof. Maier pointed out that a copy of the version as to be published in the Moniteur Belge was included in the annex of the workshop booklet. This version was in Flemish but not in English though, and Prof. Rogiers explained that the Belgian Ministry had requested a Flemish version in addition to the English one since the approval and publication of the statutes would be on the basis of the Flemish version.

Thus she had prepared a Flemish translation with the help of the juridical department of Johnson & Johnson which was then accepted by the Belgian Ministry. But due to a change of government in Belgium and a change in legislation affecting international not-for-profit organisat ons took much longer than anyone would have expected. Thus the statutes were published only a week prior to the workshop. She added that it was important to get the statutes approved and published. Now that this was the case it would always be possible to make changes at the next AGM if there was anything in the Flemish version that was misleading from the English one and thus needed to be corrected.

Asked by Prof. Maier all 11 ecopa members unanimously confirmed the statutes with the representatives of the National Consensus Platforms being: Prof. Walter Pfaller, (Austria), Dr. JP Beaufays (Belgium), Dr. Dagmar Jírová (Czech Republic), Prof. Hanna Tähti (Finland), Dr. Bernward Garthoff (Germany), Dr. Annalaura Stammati (Italy), Dr. Wim de Leeuw (The Netherlands), Prof. José Castell (Spain), Mrs. Karin Gabrielson (Sweden), Prof. Peter Maier (Switzerland) and Dr. Jane Smith (United Kingdom).

Regarding the confirmation of the board elections Prof. Maier recalled that the board elections had been performed in writing in June 2003. He added that all the elected board members had expressed their willingness to serve on the board in a written response. All but one of them was attending this meeting with Prof. Coenraad Hendriksen being the only exception due to other commitments that had kept him from coming.

Asked by Prof. Maier all 11 ecopa members unanimously confirmed the board as elected in June 2003 with the representatives of the National Consensus Platforms being: Prof. Walter Pfaller, (Austria), Dr. JP Beaufays (Belgium), Dr. Dagmar Jírová (Czech Republic), Prof. Hanna Tähti (Finland), Dr. Bernward Garthoff (Germany), Dr. Annalaura Stammati (Italy), Dr. Wim de Leeuw (The Netherlands), Prof. José Castell (Spain), Mrs. Karin Gabrielson (Sweden), Prof. Peter Maier (Switzerland) and Dr. Jane Smith (United Kingdom).

All the elected board members present at the AGM accepted their election and expressed their readiness to serve on the first ecopa board for a two-year period. With respect to Prof. Hendriksen it was agreed to notify him in writing that the results of the board elections had been confirmed at the AGM and to request a written response in which he would express the acceptance of his election.

The newly elected and confirmed ecopa board thus comprised the following persons:

  • Prof. Vera Rogiers (President)
  • Prof. José Castell (Vice-President)
  • Dr. Bernward Garthoff (Treasurer)
  • Prof. Peter Maier (Delegate)
  • Mrs. Karin Gabrielson (Delegate)
  • Prof. Walter Pfaller (Delegate)
  • Dr. Arthur van Iersel (Delegate)
  • Dr. Flavia Zucco (3-R-Expert)
  • Prof. C.M. Hendriksen (3-R-Expert)
  • Prof. Horst Spielmann (3-R-Expert)

Furthermore Prof. Maier provided information on the 6th World Congress on Alternatives saying that ecopa had been approached and asked by the Board of the Alternative Congress Trust (ACT) during the 4th World Congress in New Orleans to organise the 6th World Congress. It was then agreed that he would organise the 6th World Congress in Spain in 2008 with the active support of ecopa. He continued that in October of 2003 there was a letter of the Japanese Society of Alternatives to Animal Experiments to Prof. Spielmann that offered to host the 6th World Congress in Japan. He added that ecopa was then asked by the ACT to organise a congress at a later stage such as 2011. Prof. Maier stressed that a letter should be written to the ACT to inform them that ecopa could not undertake such a long-term commitment at the present stage. The other representatives agreed and it was unanimously decided that the ecopa board would write such a letter to the Board of the ACT.

Prof. Maier than closed the AGM and thanked all members for their active participation.

ecopa-Activities
Splitting-up of participants in three groups to work on proposals for ecopa initiatives with guidance by Prof. Spielmann, Prof. Castell and Dr. Jan van der Valk

Prof. Tjard de Cock Buning presented the results of the first group that had worked on proposals on how to address the issue of ethics in alternative guidelines. Then Prof. Castell illustrated the results of the second group that had focused on matters related to establishing further national consensus platforms to be followed by Dr. Jan van der Valk presenting the results of the third group that had dealt with matters related to education and information programmes on alternatives.

Taking up the various suggestions that were elaborated in the three groups, the participants decided on the following action plan for 2004 to be taken up by ecopa. Regarding the issue of ethics it was agreed that ecopa would address the problem that not all animals used for alternatives were currently being covered by the Directive 86/609/ EEC. This issue would be brought up by ecopa in the framework of the current revision of Directive 86/609/EEC. In addition the ecopa working group on ethics would put efforts into organising a workshop on ethics in alternatives. With respect to the promotion of establishing further NCPs it was decided to prepare an information guide that would provide interest parties with practical information on setting up a platform based on the experiences gained in other countries that Prof. Tjard de Cock Buning presented the results of the first group that had worked on proposals on how to address the issue of ethics in alternative guidelines. Then Prof Castell illustrated the results of the second group that had focused on matters related to establishing further national consensus platforms to be followed by Dr. Jan van der Valk presenting the results of the third group that had dealt with matters related to education and information programmes on alternatives.

Taking up the various suggestions that were elaborated in the three groups, the participants decided on the following action plan for 2004 to be taken up by ecopa. Regarding the issue of ethics it was agreed that ecopa would address the problem that not all animals used for alternatives were currently being covered by the Directive 86/609/ EEC. This issue would be brought up by ecopa in the framework of the current revision of Directive 86/609/EEC. In addition the ecopa working group on ethics would put efforts into organising a workshop on ethics in alternatives. With respect to the promotion of establishing further NCPs it was decided to prepare an information guide that would provide interest parties with practical information on setting up a platform based on the experiences gained in other countries.