PhD course: Use of QSAR models

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Date: 
Tue, 2011-08-23 (All day)

Practical use of the CAESAR models for legislative purposes.
Copenhagen (DK), August 23rd, 2011

Learn more here: http://www.receto.dk/Nyheder/2011/PhD_course_QSAR%20models.aspx

Related FAQ

What makes a good QSAR model?

According to REACH regulation (Annex XI) an assessment using a QSAR model is valid if:

  1. the model is recognised as scientifically valid;
  2. the substance is included in the applicability domain of the model;
  3. results are adequate for classification and labelling and for risk assessment;
  4. adequate documentation of the methods is provided.’

These four ‘conditions’ are specific to the regulatory context, and address important scientific and practical aspects of the use of in silico models.  It is important to note that the four conditions are not just about the model, but also about the particular chemicals it is used for in an assessment, the particular regulatory function it is used for, and how well the model and its use are documented.  

A QSAR model is built on a set of experimental data for particular chemicals (a ‘training set’) and it is trialled by testing other chemicals for which there is also experimental data available (the ‘test set’).  In this way a QSAR model is designed to evaluate a particular set of chemicals in relation to a particular endpoint.  So while it could be used for other chemicals outside this ‘applicability domain’, the evaluation of those chemicals will have a higher level of uncertainty.  

For this reason, REACH and ECHA do not provide approval for models: each use of QSAR models has to be evaluated on its own merit, on a case-by-case basis.  

The first of the four conditions above is nevertheless about the model itself.  In the implementation of REACH, ECHA and others usefully refer to the five OECD principles for QSAR models.  The OECD stated that ‘to facilitate the consideration of a (Q)SAR model for regulatory purposes, it should be associated with the following information:

  1. a defined endpoint;
  2. an unambiguous algorithm;
  3. a defined domain of applicability;
  4. appropriate measures of goodness-of-fit, robustness and predictivity;
  5. a mechanistic interpretation, if possible.’

These five principles refer to the rigour of the model and the transparency of the information provided by the model developer.  The REACH demand to provide ‘adequate documentation of the models’ and their use, is central to demanding and ensuring the quality of models and the quality of their use, now and in the future.  It is ultimately about enabling the regulator to evaluate the chemical safety assessments independently in the interest of human health and the environment.

Are QSAR models expensive, or free to use?

The CAESAR and VEGA platforms have been produced from EC-funded research, and are therefore freely available for use.  The software can be downloaded. Furthermore, predicted values for more than four million chemicals will be made freely available.

The Danish Environmental Protection Agency has created and made available a database with predictions from more than 70 (Q)SAR models on endpoints for physico-chemical properties, fate, eco-toxicity, absorption, metabolism and toxicity.  More than half of all the estimates are for mammalian (human) toxicity endpoints and include commercial data sets from TOPKAT and MULTICASE as well as models developed in-house.  A structure set of about 166.000 discrete organic chemicals, including almost half of the (around) 100,000 EINECS substances, has been batched through the models, and the results are integrated in the database.  (EINECS: European INventory of Existing Commercial chemical Substances.)

The US Environmental Protection Agency made available a series of QSAR models, within the EPISuite and the T.E.S.T. platforms.

The EC funded ANTARES project is evaluating existing models which could be used for REACH, many of which are free to use.  Hundreds of possible models have been identified and listed, which theoretically could be used for tens of REACH endpoints.

The EU Joint Research Centre has promoted the availability of reliable computer-based estimation methods for use in the regulatory assessment of chemicals.  Within the JRC Institute for Health and Consumer Protection (IHCP), the European Chemicals Bureau (ECB) developed a range of freely available software.  One of the aims of the IHCP is to support the implementation of EU chemicals policy (including the safety assessment of industrial chemicals, chemicals in consumer products, pesticides and biocides) through the development, assessment and application of computational (in silico) methods. 

Typically in such QSAR models, the training set used to develop the model, the algorithm, and other aspects of the model are open for scrutiny by the regulator.   However, in commercially available software the full documentation of each model may not be available.  Indeed, the algorithm and the training set used to build the model are often confidential.  Despite this, the use of commercial programs has not been explicitly criticised by regulatory authorities.  In reality, commercial programs have been used in the USA and Europe, because of their ease of use, their availability and because they represent a major source of QSAR models.  We do not foresee restrictions in their use, and in our opinion it would be a pity to renounce these models.  However, it is likely that in the case of two similar models being available, one commercial and one freely available, the user will prefer the second one.  Within REACH, it also seems likely that the regulators will demand more transparency from the commercial models, and/or prefer the use of fully documented models.

What are in silico methods?

In silico methods simply means computer-based methods.  In this context they are computer-based methods for assessing the toxicity of chemicals.  

In silico methods involve using databases of existing experimental data on the toxicity of chemicals.  That data is used to predict the toxicity of chemicals which are similar to those already tested.   The advantage of in silico methods is that they make it possible to assess the toxicity of large numbers of chemicals quickly using a database and software on a desktop computer, whereas assessments were formerly only possible from long and expensive tests in laboratories.  However, the main limitation is in the amount of existing data available; much is held by industry as confidential, and in some areas (such as long term toxicities for mammals) the amount of existing data of high quality is limited.  

In silico methods are widely used (including by regulators in the US) to screen and identify chemicals for priority testing in the laboratory. They are also used in addition to available laboratory data to generate a stronger ‘weight of evidence’.  In silico methods include QSAR models, ‘Read across’ and Virtual Screening.

The term in silico contrasts with in vivo and in vitro.  In vivo methods involve testing chemicals on living organisms, including invertebrates, fish and animals.  In vitro methods involve test-tube research, where (for example) instead of putting the chemical on the skin or in the eye of an animal, the chemical is put in a test tube with some living skin cells or eye cells taken from an animal.  Both in silico and in vitro methods are known as ‘alternative methods’.  In silico methods make use of existing data from in vivo and in vitro tests.

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