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Validation Successes: Chemicals

Horst Spielmann and Manfred Liebsch

The ECVAM validation concept, which was defined at two validation workshops held in Amden (Switzerland) in 1990 and 1994, and which takes into account the essential elements of prevalidation and biostatistically defined prediction models, has been officially accepted by European Union (EU) Member States, by the Federal regulatory agencies of the USA, and by the OECD. The ECVAM validation concept was introduced into the ongoing ECVAM/COLIPA validation study of in vitro phototoxicity tests, which ended successfully in 1998. The 3T3 neutral red uptake in vitro phototoxicity test was the first experimentally validated in vitro toxicity test recommended for regulatory purposes by the ECVAM Scientific Advisory Committee (ESAC). It was accepted by the EU into the legislation for chemicals in the year 2000. From 1996 to 1998, two in vitro skin corrosivity tests were successfully validated by ECVAM, and they were also officially accepted into the EU regulations for chemicals in the year 2000. Meanwhile, in 2002, the OECD Test Guidelines Programme is considering the worldwide acceptance of the validated in vitro phototoxicity and corrosivity tests. Finally, from 1997 to 2000, an ECVAM validation study on three in vitro embryotoxicity tests was successfully completed. Therefore, the three in vitro embryotoxicity tests, the whole embryo culture (WEC) test on rat embryos, the micromass (MM) test on limb bud cells of mouse embryos, and the embryonic stem cell test (EST) including a permanent embryonic mouse stem cell line, are considered to be scientifically valid and appropriate for routine use in laboratories of the European pharmaceutical and chemicals industries.
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ecopa: A Powerful Concept in the Way Forward for Alternative Methods

Vera Rogiers

ecopa, the European Consensus-Platform on Alternatives, is an international not-for-profit organisation, based in Belgium and complying with Belgian Law. It is the only quadripartite organisation that promotes the Three Rs at the European level. Ecopa brings together national consensus platforms on alternative methods. Consensus means that all parties concerned are represented, including animal welfare, industry, academia and government. Ecopa currently includes the National Platforms of 14 EU Member States (or future Member States; eight full members, namely, Austria, Belgium, Finland, Germany, The Netherlands, Spain, Switzerland and the UK, and six associate members, being the Czech Republic, Denmark, Italy, Norway, Poland and Sweden). Ecopa also has three working groups, concerned with: a) the 6th Framework Programme of the EC for Research, Technological Development and Demonstration Activities; b) the EC White Paper Strategy for a Future EU Chemicals Policy; and c) the formation of educational programmes on alternative methods within the EU. Ecopa is thus uniquely placed and has huge expertise to offer to the debate around political topics, including the White Paper, the 6th Framework Programme, and the 7th Amendment of the EU Cosmetics Directive. Ecopa should be considered a key stakeholder by the European Commission and Parliament, and it is essential that the views of ecopa are fully incorporated into future legislation. Recently, the ecopa working groups made a strong common statement on the Chemicals Policy White Paper and made a number of recommendations to the Commission based on scientific, practical and realistic grounds. These are to be found on the ecopa Web site (http://ecopa.tsx.org/ or http://ecopa.vub.ac.be).
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Experience with the HET-CAM Method in the Routine Testing of a Broad Variety of Chemicals and Formulations

Arnhild Schrage, Armin O. Gamer, Ben van Ravenzwaay and Robert Landsiedel

Data on eye irritation are generally needed for the hazard identification of chemicals. For the routine testing of a broad variety of chemicals and formulations, we have used the Hen’s Egg Test- Chorioallantoic Membrane (HET-CAM) method. In the course of a tiered-testing strategy, and due to the lack of global regulatory acceptance of the HET-CAM method, we have also performed the Rabbit Eye Irritation test according to OECD Test Guideline 405. Of the 145 substances tested, 76% were classified as non-irritant/mild irritant and 13% were identified as irritant in vivo, according to the EU classification system (61% and 28%, respectively, with the GHS classification). The remaining 11% were severe irritants in vivo, based on the irreversibility of the effects and not due to sufficiently high irritation scores in the three days following application. The retrospective analysis revealed that the overall accuracy of the HET-CAM assay was 65% and the overall rates of false-negatives (FN) and false-positives (FP) were 50% and 33%, respectively. The HET-CAM assay was sufficiently specific (few FP) for water-soluble substances, but failed to identify nearly all the severe irritants within this group. In contrast, it was highly sensitive (no FN) for non-soluble and oil-soluble substances, but the specificity for this group was rather low. Therefore, we conclude that the HET-CAM assay is not useful in our tiered-testing strategy for eye irritation testing. However, for water-insoluble substances, it might be applicable in combination with another in vitro method, provided that regulatory acceptance is gained.
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