In silico methods
In silico is an expression that means "performed using a computer simulation" and was coined in 1989 during the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico by a mathematician from National Autonomous University of Mexico (UNAM).
Quantitative Structure-Activity Relationship (QSAR) are computer-based models for the prediction of toxicological, biological and physico-chemical properties. QSAR models aim at establishing, if it exists, the relationship between structural-derived properties of chemicals and their properties, such as toxicity. For the relationship between the activity and the chemical information a mathematical function is used. The chemical information can be given by chemical descriptors or fragments. Many thousands of chemical descriptors have been proposed, constitutional, geometrical, physico-chemical, topological, etc. In the specific case of the evaluation of a qualitative relationship, for instance between the presence of a certain chemical fragment and the occurrence of a certain toxicity effect, the typical name is structure-activity relationship (SAR). (Q)SAR is used sometimes to refer to both QSAR and SAR. Here we will present QSAR and SAR together, using the acronym QSAR.
Regulatory context
In Europe, mainly two regulations have clearly taken a position about the use of in silico models:
- The cosmetic directive (76/768/EEC) established that by 2013 all in vivo models will be banned for testing, and many of them have been banned for cosmetics already.
- The REACH legislation (907/2006/EC) foresees use of in silico models.
In other cases, such as plant protection products and pharmaceuticals, tests on animals have to be done, at least on the parent compound. However, some tools have been developed to study ecotoxicity of metabolites and degradation products of pesticides (more info could be find at the EC project DEMETRA) website.
The REACH legislation
In December 2006 the European Community adopted a new regulation addresses the production circulation of chemical substances in the European territory, and their potential impacts on both human health and the environment. This new regulation is called REACH (Registration, Evaluation, Authorisation and restriction of Chemicals) and states that for each chemical circulating in the European territory, a complete dossier on physico-chemical, biological and toxicological properties has to be compiled. In order to prevent an over-usage of animal testing, REACH regulation foresees and promotes the use of alternative methods (such as QSAR) stating that:
"Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data from structurally related substances (read-across approach) shall be assessed first."
REACH (907/2006/EC), Annex VII
In silico methods and REACH
REACH legislation foresees the use of alternative in silico methods such as QSAR and Read-Across. Regarding Qualitative or Quantitative structure-activity relationship ((Q)SAR), Annex XI states that:
Results obtained from valid qualitative or quantitative structure-activity relationship models ((Q)SARs) may indicate the presence or absence of a certain dangerous property. Results of (Q)SARs may be used instead of testing when the following conditions are met:
- results are derived from a (Q)SAR model whose scientific validity has been established,
- the substance falls within the applicability domain of the (Q)SAR model,
- results are adequate for the purpose of classification and labelling and/or risk assessment, and
- adequate and reliable documentation of the applied method is provided.
The Agency in collaboration with the Commission, Member States and interested parties shall develop and provide guidance in assessing which (Q)SARs will meet these conditions and provide examples.
REACH (907/2006/EC), Annex XI
Thus, these are the requirements according to REACH. Three of them refers to the QSAR model, and one on its use for a specific compound.
These principles are also expressed in four of the OECD principles for the QSAR validation, whereas we notice that there is no explicit mention of the fifth OECD principle within REACH.
For more inforation, visti the About In-silico/Regulatory Context section of ORCHESTRA project official we portal.
