Session E1: Validation of Alternative Test Methods: Recent Progress and New Initiatives

Chairs: William Stokes (USA) and Julia Fentem (UK)

E1: The Principles of Validation and the Ecvam Validation Process
Andrew P. Worth and Michael Balls. ECVAM, Institute for Health & Consumer Protection, Joint Research Centre, European Commission, 21020 Ispra (VA), Italy. andrew.worth@jrc.it.

The validation of a test method is the process by which the relevance and reliability of the method are assessed for a particular purpose. It is an essential stage in the evolution of the method from its development to its acceptance and application for regulatory purposes. The principles according to which alternative tests should be validated have been agreed at an international level, although the actual process by which the validation process is conducted varies between different validation authorities. The aim of this presentation is to summarize the principles of alternative test development and validation and to describe how the internationally agreed upon principles have been applied by the European Centre for the Validation of Alternative Methods (ECVAM), which is responsible for coordinating the validation of alternative methods at the European Union level. The presentation will focus on alternative methods for chemicals testing.

E1: The Interagency Coordinating Committee on the Validation of Alternative Methods (Iccvam): Recent Progress in the Evaluation of New Toxicological Testing Methods
William S. Stokes. NICEATM, Environmental Toxicology Program, National Institute of Environmental Health Sciences, MD EC-17, P. O. Box 12233, Research Triangle Park, NC, 27709, USA. stokes@niehs.nih.gov.

The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was established in 1997, and was subsequently authorized as a permanent committee by the ICCVAM Authorization Act of 2000 (Public Law 106-545). ICCVAM's duties include the technical evaluation of new and alternative test methods, development of recommendations based on these evaluations, and forwarding test recommendations to Federal agencies for their consideration. ICCVAM collaborates with the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) to evaluate the validation status of proposed test methods. Independent scientific peer review panels assess the extent to which established ICCVAM validation and acceptance criteria have been addressed. Expert workshops and panel meetings are convened to develop recommendations for validation of test methods for which there are not yet adequate validation studies. ICCVAM has completed the independent peer review evaluation of: the Local Lymph Node Assay, an alternative method for assessing allergic contact dermatitis; Corrositex®, an in vitro method for assessing skin corrosivity; and the Up-and-Down Procedure, an alternative method for assessing acute oral toxicity. Expert panel evaluations have been completed for an in vitro developmental toxicity screening assay and in vitro screening methods to detect endocrine active compounds, and an expert workshop has reviewed the validation status of in vitro methods for assessing acute systemic toxicity. The acceptance and use of scientifically valid alternative testing methods recommended by ICCVAM is expected to provide for the refinement, reduction, and replacement of animal use while ensuring adequate product safety assessment.

E1: The Zebet Funding Program for the Development of Alternatives to Testing in Animals
H. Spielmann, S. Boy, M. Liebsch, and A. Seiler. Center for Documentation and Evaluation of Alternative Methods to Animal Experiments (ZEBET), 12277 Berlin, Germany. zebet@bgvv.de.

Since 1990, ZEBET, The National German Center for the Documentation and Evaluation of Alternative Methods to Animal Experiments, has funded research in Germany according to the Three R's principle in order to reduce animal testing for regulatory purposes. An annual reported budget of $300,000 allowed ZEBET to fund an average of 10 concurrent projects for 2-3 years. To date, 65 projects have been supported. Most of them were conducted at university laboratories. The program is advertised at the national level, and around 20% of the applications were selected for funding. Several successful projects have initiated validation studies in the field of regulatory toxicology. Other projects that focused on the development of culture methods for monoclonal antibodies, embryonic stem cells, transgenic cell lines, human tissues and organs, and human skin models have also been funded. A considerable number of projects funded by the German government via ZEBET achieved both success and international recognition, including scientific awards for refining, reducing, or replacing testing in animals.

E1: The New Look of the Validation of Test Methods
Hiroshi Ono. Hatano Research Institute, Food and Drug Safety Center, Hadano, Kanagawa, 257-8523 Japan. ono.h@fdsc.or.jp.

Validation of the test method is a process to provide evidence that a new test is useful, or sufficiently reliable and relevant, to predict toxicities of concern for chemicals in place of the corresponding existing toxicity test. The OECD conference held in Stockholm, in March 2002, yielded fruitful discussion about issues relating to validation that had arisen after the previous workshop in Solna, in 1996. A full-scale validation is a large project that requires significant financial and human resources. There are special difficulties in appointing an independent peer review panel. The Stockholm Conference has extended the discussion to newer approaches. New technology of molecular biology has made considerable progress recently, and such research efforts in the area of toxicology are becoming substantiated as toxicogenomics. It is not premature to have concern about the procedure and about how to validate the usefulness of such a new approach to chemical toxicity.

E1: The Third FRAME Toxicity Committee: Working Toward Greater Implementation of Alternatives in Toxicity Testing
R. Combes, M. Jackson, M. Balls, L. Bansil, M. Barratt, D. Bell, P. Botham, C. Broadhead, R. Clothier, E. George, J. Fentem, I. Indans, G. Loizu, V. Navaratnam, V. Pentreath, B. Phillips, H. Stemplewski, and J. Stewart. FRAME, Nottingham NG1 4EE, England. frame@frame.org.uk.

The First FRAME Toxicity Committee, formed in 1979, published its report in 1982, and a discussion of this was published in 1983. A second committee, formed in 1988, reported its work in 1990, and a discussion of this was published in 1991. The work of these committees was extremely successful and influential in laying the foundation for many later productive activities in alternatives research. A Third FRAME Toxicity Committee was formed in 1999, comprising a wide range of experts, augmented by several working groups, focusing on a number of specific issues. There is much scope for the further implementation of the Three R's in toxicity testing, especially due to recent plans for the large-scale testing of high-production volume, hormonally active and existing chemicals, and the increasing use of transgenic animal models. The activities of the Third FRAME Toxicity Committee in response to these challenges will be reviewed.