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CORDIS - Résultats de la recherche de l’UE

Structure-activity relationships leading experts in mutagenicity and carcinogenicity

Final Report Summary - SCARLET (Structure-activity relationships leading experts in mutagenicity and carcinogenicity)

The concept of a relationship between the structure and the toxic activity of chemical mutagens and carcinogens has been widely investigated. Structure-activity concepts have also been exploited to make safer chemicals. Whereas for academic purposes even studies based on biased data sets may provide useful information, the extensive regulatory use of (Q)SARs foreseen by e.g. REACH requires that the models fulfil severe quality criteria. Unfortunately, this ideal situation is not a common occurrence in toxicology.

This project aimed at organising a debate as well as a workshop including leading experts in order to critically review the situation in the field of (Q)SARs for mutagenicity and carcinogenicity and to provide indications on hot topics issues to be further investigated. SCARLET was multidisciplinary and multisectorial. Regulators, scientists, problem holders, animal welfare experts, citizen organisations and chemical industry participated.

SCARLET discussed, during a workshop organised in April 2008 in Milan, the state-of-the-art of in silico models for carcinogenicity and mutagenicity. The discussion started with an overview of the new in vitro experimental approaches. A major issue is the occurrence of false negatives and positives. The precautionary principle is pointing towards a conservative approach, which tends to eliminate chemicals with positive results, but the use of batteries of in vitro methods is progressively eliminating most of the compounds, with an increasing number of false positives. Nevertheless, in vitro methods are used for regulatory purposes, and they are required information within many evaluation protocols and laws.

It was mentioned that when the Ames test was originally introduced, it was severely criticised, as not suitable to replace carcinogenicity studies. Today it is widely accepted that mutagenicity studies are a valid support to the general evaluation of the genotoxicity studies. It is expected that a similar evolution will also happen for in silico methods. Indeed, there is a knowledge gap on the carcinogenicity and mutagenicity evaluation of the chemical compounds. Any useful piece of information should be used to limit toxic effects. Alternative methods, such as in vitro and in vivo methods, can contribute to cover this knowledge gap.

During the workshop, the positions of industry and regulators were discussed. Pharmaceutical companies, chemical, cosmetics and food industries have needs, which are partly similar, partly different. Different regulations apply, which are country-specific. In Europe the regulation for cosmetics is progressively banning all animal experiments. Thus, only alternative methods will be used. The situation is different for pharmaceutical companies, which will continue using animals. The REACH regulation is promoting the use of methods alternative to animal models. However, their reliability has to be proved. Furthermore, in United States (US) certain in silico models are used when providing data for the Food and Drug Administration, which are not so popular in Europe.

Regulators and industry may have different attention to false negatives (of high concern for regulators) and false positives (which cause ban of certain compounds which have industrial interest, but no toxicity). Furthermore, the overall evaluation of a certain chemical compound may varry in the different industrial sectors, considering for instance the balance between the risk and the benefits, or whether the compound is a natural food component.

In such a broad scenario, with different components, not only theoretical, but also related to the application and use, complex, multiple solutions exist. The challenge is to tackle the problem in its complexity, taking advantage of the new tools offered by new assays and the omics techniques. The concept of toxicity profiles has gained new prominence. In silico methods can benefit from this increased information and better contribute to carcinogenicity studies.