The second European Workshop of National Platforms on Alternative Methods took place in Brussels on the 27th and 28th of October 2001.
A restricted audience of 60 participants from 15 different countries attended this workshop in order to discuss the implications for animal welfare and the use of alternative methods of the EU strategy on chemicals namely “White Paper for a New EU Chemicals Policy” and to pave the way for launching ecopa as an official non-profit organization. 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 government institutions, a number of guests and speakers from DG Environment, the European Chemicals Bureau as well as government ministries of several European countries was present.
Particularly impressive was the good mood and constructive working attitude among the participants which was highlighted by the official founding of ecopa on Sunday, October 28th, 2001, as an international non-profit organization, registered in Belgium and supported already by 8 members and 6 associate members.
The White Paper for a New EU Chemicals Policy
Prof. Rogiers welcomed the participants and explained the need for the workshop and the potential impact and consequences of the White Paper for a New EU Chemicals Policy regarding additional animal testing which according to some estimates could reach up to 12.6 million animals over the next twenty years. At the core of the controversy lays the intention of the Commission to collect or gain data on approximately 30.000 chemicals in order to assess their potential risks for human health and the environment.
The planned REACH-System would provide for a single, coherent system for new and existing chemicals with three new elements: registration, evaluation and authorization. In particular, high volume chemicals are of great concern. Registration would imply a dossier containing information on the identity and properties of the compound, its uses, production volume, labelling, classification and a preliminary risk assessment. This type of dossier would be sufficient for approximately 80 per cent of the chemicals presently on the market. An estimated 2600 substances of high production volume (over 1000 t) would be registered until 2005, another 2900 substances (100 – 1000 t) until 2008 and finally the rest (20.000 of 1-10 t and 4600 of 10-100 t) until 2012.
It is stated on several occasions in the White Book that the use of non-animal test methods will be maximised and test programmes minimised while the development of new non-animal test methods will be encouraged. However, an important criticism remains that there is no clear and realistic strategy present on how this will be done, in particular avoiding animal testing in favour of using alternative methods. More specifically in the 6th Framework Programme, providing the EU research accents for the coming 6 years, no key topic on the development of alternative methods is being present.
M. Aelvoet, Belgian Minister for Consumer Protection, Public Health and Environment: Opening of Workshop
Mrs. Aelvoet, Belgian Minister for Consumer Protection, Public Health and Environment, expressed her support for the founding of ecopa since its strategy would be based on a European consensus between the different parties involved. She felt that the founding of such an independent non-governmental organisation (NGO), wanting to play a crucial role in the development, promotion and application of alternative methods to the use of experimental animals in research and regulatory testing came at the right time and at the right place. In addition Mrs. Aelvoet pointed out that she saw several areas where ecopa could be of great importance ranging from developing expert opinions and diffusing information on alternative methods to a bridging capacity towards the European Parliament. Assistance to ecopa was offered in order to make access easier to important national and European decision making bodies in relation to alternative methods.
J. Vogelgesang: The White Book Strategy for a Future Chemical Policy: Intentions of the Commission
Dr. Vogelgesang, DG Environment, explained that the EU Chemicals Policy is not a testing programme but essentially an effort to gather the necessary information on chemicals that is quite often readily available within industry and authorities. Only in those cases where insufficient data is available would testing be required involving a minimum of animals.
Regarding the benefits of the REACH-Model, Dr. Vogelgesang explained that equal levels of protection and competitive advantage would be obtained for new and existing substances. The testing requirements for new substances would be increased to production amounts of 1 ton to improve innovation, but without a significant loss of protection. Between 1 and 10 tons, testing would generally be limited to in vitro experiments. It was concluded that the benefits of the New Chemicals Policy would be a high level of protection, improved knowledge, better tracking of chemicals, better use of resources, better reaction to sudden risks, substitution of the most dangerous substances, innovation and better informed choices would be encouraged.
B. Garthoff: The European White Book on Chemicals: Start into an Area of Alternatives to Animal Experimentation?
Dr. Garthoff regretted that in the 6th Framework Programme a perfect opportunity had been missed to provide funding for the development of those in vitro methods that are lacking today but are crucial to reach the objectives as outlined in the White Paper. Since the draft version of the 6th Framework Programme does not include any key provision for the funding of alternative methods, it was announced that the ecopa working group members would address the issue publicly.
Through statements to the Commission and the European Parliament, Dr. Garthoff called on the Commission to earmark at least 20 million Euros in the 6th Framework Programme for the development and validation of alternatives. Furthermore, to feed the outcome of the seven ongoing working groups regarding the White Paper into a yet to be defined process within the DGs, identifying chances and funding schemes for the development of alternative methods. In that regard, the ecopa working group offered its assistance for the identification of the process, the respective experts and the organisation of an appropriate workshop.
R. Taalman: View of the (European) Chemical Industry and CEFIC
Dr. Taalman (CEFIC) acknowledged that the Commission proposed the White Paper as an approach to phase out and substitute the most dangerous substances. Though industry agreed in principle, he stressed that the focus should be on pre-market rather than on pre-manufacturing in order to save time, money and animals. With respect to the timeframe given in the White Paper, he argued that it was too optimistic in all respects. Further, the participants were informed about the global initiative taken by the industry to address emerging and existing health and environmental issues through independent research with the so-called Long Range Research Initiative (LRI).
With respect to animal testing, it was said that CEFIC strongly supports all efforts aiming at limiting them to the utmost possible without compromising human health and/or the environment. Industry is working on the development of alternative methods and is funding projects in this area. Since a future chemicals legislation would be based on exposure, hazard and risk based decisions, research should thus provide results, which could improve the efficacy and scientific base within each of the 3 decision mechanisms. It should also inform policy judgements regarding the balance between the 3 decision mechanisms to meet the current and future economic, environmental and societal needs. He recommended that with respect to exposure based decisions there is a need for the development of cleaner production methods while effective exposure control monitoring of chemical substances in the environment needs to be done. Early warning systems for subtle eco-system changes need to be developed, for example through biomarkers.
U. Sauer: View of the Animal Welfare Associations
Dr. Sauer stated that with respect to the contents of the White Paper there was one key element of prime relevance for animal welfare, namely the promotion of non-animal testing. Yet, she questioned in this context whether the White Paper did enough to ensure safety for humans and the environment and to avoid the use of animal tests. She pointed out that the White Paper actually contained no specifications on how to maximise the use of alternatives and to minimise the use of animal tests or to achieve flexibility in the testing strategy. In particular, the non-animal testing strategy for low production volume chemicals does not specify whether the EU strategy only applies to those chemicals or to others, too. Therefore changes in the White Paper are necessary in the White Paper. A tiered approach seems necessary comprising risk management, safety testing and waiving strategies as well as substantial funding for the development and validation of alternative test methods. The focus should be on tests with the greatest potential to save animals. Dr. Sauer concluded with the view that safety for humans and the environment could be achieved through concrete risk management and new safety testing strategies without animal tests.
Ph. Botham: View of a Toxicologist
Dr. Botham stated that a new chemicals policy is needed in order to achieve a better balance between hazard data and knowledge of exposure and to achieve greater transparency. The Commission tried to address these issues in the White Paper, but that it is not the appropriate strategy to do so. The White Paper for example retains tonnage rather than usage as a main trigger for determining testing requirements and sets unrealistic timelines.
The EU strategy proposed could threaten the competitiveness of the European chemical industry and increase administration costs for the EU and the number of animals being used. Since it is naive to believe that all tests needed could be replaced by alternative methods, it is sound to believe that the number of animals used in addition could be high. Yet, Dr. Botham hinted that there are already a number of possibilities to reduce the number of animal tests even without in vitro alternatives at hand, e.g. data sharing, prioritisation and exceptions. To minimise animal use he suggested identifying the most toxic chemicals to allow prioritisation of risk management and to identify the most important hazard endpoints associated with these chemicals. He also highlighted the need for investment in research, development and validation of alternatives but stressed that it should be based on high quality scientific proposals. He insisted that the protection of human health is paramount and that the development of alternatives cannot be justified on ethical grounds alone. Alternatives can thus only be accepted if they provide equal or even better quality information on hazard or risk to man in comparison to animal tests.
H. Spielmann: View of an Institution for Implementation of Alternatives
Prof. Spielmann argued that the White Paper signified a general improvement since data on hazardous chemicals would be obtained earlier than previously. Calling the new concept a realistic one, he argued that in vitro tests would be cheaper to conduct, would provide the data faster and that costs for industry would be moderate. Within an acceptable time frame the new data would allow both hazard assessment and risk management for existing chemicals. Regulators and industry would thus be able to improve the risk management of hazardous chemicals in Europe. In addition, he stressed that the respective ECVAM working group had elaborated and proposed an integrated testing scheme for existing and new chemicals that would indeed emphasise the use of in vitro methods to reduce the number of animals needed.
The White Paper signified an improvement of ethics and science since there would be a higher quality of research to replace testing in animals according to the 3Rs concept of Russell & Burch. Increasing research activities would also improve molecular methods since basic research would get more involved. Giving a detailed overview regarding existing alternatives and those under development, it was stressed that further progress is affected by the development of candidate new test methods for prevalidation, the provision of adequate funding, and the availability of experienced laboratories as well as trained personnel to design and manage studies properly. The willingness of industries and regulatory authorities to accept scientifically valid alternative test procedures and testing strategies is another crucial factor.
J. Huggard: Policy on Chemicals: Is there a right or wrong?
Dr. Huggard argued that over the past decades the notion of risk, though difficult to quantify and pin down, had become one of the dominant themes in politics as well as public opinion. There is a general public desire to be protected from any kind of potential risk. This can be found again in the EU chemicals policy and the White Paper. Dr. Huggard said that a non-toxic Europe, enhancing innovation and the competitiveness of the industry as well as creating a clear framework for industry are the key promises of the White Paper, though nobody really knows what a non-toxic Europe actually means.
Regarding the financial impact of the White Paper, he stated that the estimated testing costs of Euro 2.1 billion are only the tip of the iceberg and are in practice detrimental to the promise of enhancing competitiveness. The Commission’s hope to promote innovation is thus a pious hope based on false assumptions, such as that industry needs this spur to develop more profitable products and that it is cheaper to innovate than to defend. He thus predicted a loss of marginal chemicals and a more defensive R&D strategy. Regarding industry testing needs, he commented that a clear framework with standard sets of data sets, unified testing programmes based on validated protocols and cross-jurisdictional acceptance of testing methods is wished. In addition, an authorisation process is needed that only applies to chemicals classified as hazardous under internationally agreed protocols. Socio-economic factors and the evidence approach are also important factors to be considered. As a final remark he posed the questioned whether the net benefit would be worth the efforts.
E. Sandberg: A governmental View: Torn between Health and Environmental Concern and Lab Animal Death
Dr. Sandberg illustrated the Swedish policy on chemicals, which calls for the creation of “a non-toxic environment” as one of its key objectives. This means that the environment should be free from man made substances and metals that represent a threat to the health and biological diversity. The Swedish parliament had also defined an overall objective called the “generation” objective, meaning that the next generation should live in a society in which the main environmental issues ware solved. To achieve this objective the environmental problems need to be solved within the next 10 to 15 years. Due to the given timetable there is a clear need for a speedy evaluation of substances that the existing framework cannot provide. The Swedish government acknowledges that data are required for all HPV and other chemicals.
To avoid unnecessary animal testing a tiered approach for risk assessment is chosen using data sharing and providing for evaluations after each step and the option to waive further testing once the data obtained are sufficient. It is clearly wished that all the required information is available to take the best decisions to protect human health and the environment. Additionally, the issue of animal testing is being addressed by stipulating that animal testing should be reduced by means of developing more alternative methods and more accurate models for accumulative properties. Promotion of the validation of such methods is needed and to this end, funding must also be increased substantially.
E. Walum: Possibilities for Pre-screening Alternatives
Dr. Walum focused on presenting MEIC and ECITTS study results that may lead to future developments of in vitro methods for the assessment of acute systemic toxicity. The MEIC-program is a multicenter program to evaluate the relevance for acute human systemic toxicity of in vitro cytotoxicity tests. He stressed that fundamental to the MEIC-program is the idea that the prediction of systemic toxicity from cytotoxicity data may be improved by adding information on biokinetics. The ECITTS-project aims at defining the criteria for an integrated approach to the prediction of systemic toxicity using computer-based biokinetic models and biological in vitro test methods.
A first study, aiming at predicting LOELs (Lowest Observable Effect Levels) for selected neurotoxic chemicals has been completed and generated encouraging results on the possible methodologies of risk assessment. A test scheme, using highly differentiated human neuroblastoma cells was applied and combined with kinetic simulations and QSAR analysis. He explained that the discrepancy between estimated and experimental LOELs ranged from a factor of two, for low toxic compounds, to a factor of 10, for compounds with a high toxicity. LOELs of the most toxic compounds could only be established after consideration of in vitro test results that were derived from the literature. In addition, it was said that extra information obtained via extended test up protocols on the compound under investigation allows for an estimation of acute, subacute and subchronic toxicity with a high degree of accuracy.
A. Vedani: In Silico Prediction of Harmful Effects triggered by Chemicals
Prof. Vedani explained that the objective is to establish a virtual laboratory on the Internet to allow for an in silico estimation of harmful effects triggered by drugs, chemicals and their metabolites. The current database includes validated models for five biological targets – the receptors of aryl hydrocarbons, 5HT-2A, cannabinoids, GABA-A, and steroids. It will be continuously extended to include surrogates for any bioregulator known or presumed to mediate harmful effects. Free access to this virtual laboratory will allow any interested party to estimate the harmful potential of a given substance prior to its synthesis. This is achieved by generating the three-dimensional structure of the compound and its possible metabolites in the computer, followed by calculating their binding affinity towards each receptor surrogate in the database. Only compounds/metabolites passing through this surrogate battery without displaying a significant affinity towards any member are cleared for synthesis and pre-clinical studies. Prof. Vedani concluded that this way potentially harmful compounds could be withdrawn from the evaluation pipeline before in vivo test are conducted, hence contributing to the reduction of animal testing in chemical and pharmaceutical research and development.
Podium Discussion: The Way Forward?
During the following podium discussion, moderated by Dr. Bansil, the discussants Dr. Walum, Mrs. Gabrielson, Dr. Vollmer and Prof. Bolt, addressed questions and issues regarding the White Paper. Various speakers stressed that the Commission had indeed addressed the issues but that there still remains a major need to develop suitable strategies on how the use of animals can be minimised in a realistic way.
Another step is the validation of existing alternative methods that have been validated yet and to speed up this process. There also was agreement on the need for expert groups such as ecopa and ECVAM to identify which methods are ready for prevalidation or validation, need to be improved or are missing and therefore require further research. In addition, speakers highlighted the necessity of more resources including funding for research, which needs to become a priority in the 6th Framework Programme allocating 20 million EURO to this purpose. The dialogue showed that all parties concerned were mutually committed and had a role to play either financially or scientifically. The discussants agreed that more consideration to the 3Rs should be brought into the White Paper. In addition, attention should also go to the possibility to use of human data. A general agreement existed for a tiered strategy. It was also pointed out that there is a need for more education on alternatives and their availability with particular emphasis on informing small and medium sized companies.
Foundation of ecopa
The foundation of ecopa proceeded in several stages. The working group that had been established during the first ecopa workshop made a list of criteria in order to join ecopa as a member. Questionnaires were sent around to the member states that expressed there interested. These were evaluated prior to the second workshop. On this basis, the ecopa working group elaborated a list of national consensus platforms and proposed to the assembled platform representatives to accept Germany, Austria, Switzerland, Great Britain and the Netherlands as full members since they met all criteria. These platforms were then admitted as full members of ecopa.
With respect to the national consensus platforms of Belgium, Finland and Spain it was acknowledged that they did not yet meet all criteria at the present stage. However, it was concluded that they were likely to meet all criteria within the next 12 months. It was therefore suggested and agreed to admit these three platforms under the condition that compliance with the criteria would be reassessed within one year (temporary membership).
In addition, the Czech Republic, Denmark, Italy, Norway, Poland and Sweden that had all sent representatives, wanted to join ecopa as associate members. In each of these countries there are national consensus platforms currently being developed with the aim of meeting all criteria for full membership by the end of next year.
Prior to the foundation of ecopa, the draft statutes were thoroughly discussed taking all remarks into consideration that had been made by the national consensus platforms prior and during the workshop. The revised statutes will be reviewed by a lawyer to ensure compliance with the Belgian law for international non-profit organizations before submitting them to the platforms once more. Within the next six months the final statutes shall then be published in the Official Belgian Journal, which will mark the formal completion of the ecopa foundation process.
Furthermore the ecopa members took the initiative to establish two new working groups:
One group, headed by Mrs. K. Gabrielson (S) will focus on the issue of animal testing and the use of alternative methods with respect to the EC White Paper for a New EU Chemicals Policy.
The second group, headed by Dr. Jan van der Valk (NL) and assisted by Prof. A. Smith (N) will concentrate on developing information and education programmes on alternative methods such as a lecture for university students as well as contributing to the ecopa website (http://ecopa.vub.ac.be) as a main source of information on alternative methods.
In addition, the already existing working group will continue its work with respect to the statutes as well as step up its efforts to get an explicit notion for the promotion and funding (!) of developing alternative methods to be included in the 6th EU Framework Programme.