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SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated around harnessing knowledge about toxicological modes-of-action and an organisational model was developed that combines crowd-sourcing with individual excellence. The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built. This is done on three levels: (i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological mode-of-actions leading to adverse outcomes; (ii) adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects; (iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios, the ab initio prediction and the read-across approach, are addressed with respective case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from the efforts of designing the case studies and is discussed in the context of international developments focussing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing., JRC.I.5-Systems Toxicology

This is the report of the first workshop on the Validation of Toxicogenomics-based Test Systems held in Ispra, Italy on 11-12 December 2003. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicological test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technological experts, regulators, and the principal validation bodies, and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would serve as the basis for the future validation of the technology when it reached the appropriate stage. Due to the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas included (a) biological validation of toxicogenomics-based test methods for regulatory decision-making, (b) technical and bioinformatics aspects related to validation, and (c) validation issues as they relate to regulatory acceptance and utilization of toxicogenomics-based test methods. This report summarizes the discussions and details the recommendations for future direction and priorities., JRC.I.2-Validation of biomedical testing methods

The local lymph node assay (LLNA) and modifications thereof were recently recognized by the OECD as stand-alone methods for the detection of skin-sensitizing potential. However, although the validity of the LLNA was acknowledged by the ICCVAM, attention was drawn to one major problem, i.e., the possibility of false positive results caused by non-specific cell activation as a result of inflammatory processes in the skin (irritation). This is based on the fact that inflammatory processes in the skin may lead to non-specific activation of dendritic cells, cell migration and non-specific proliferation of lymph node cells. Measuring cell proliferation by radioactive or non-radioactive methods, without taking the irritating properties of test items into account, leads thus to false positive reactions. In this paper, we have compared both endpoints: (1) cell proliferation alone and (2) cell proliferation in combination with inflammatory (irritating) processes. It turned out that a considerable number of tests were “false positive” to the definition mentioned above. By excluding such false positive results the LLNA seems not to be more sensitive than relevant guinea pig assays. These various methods and results are described here.