Video Documentary: QSARs in REACH? - Uses, issues and priorities

The documentary 'QSARs in REACH?' is based on interviews with regulators, industry and QSAR developers, and addresses some of the key issues and priorities in the further use of QSARs within REACH.

The documentary was first shown at the ORCHESTRA booth at the 2011 SETAC Europe conference in Milan. Here it can be viewed online in 4 short separate sections. The 20+ contributors are listed below and at the end of the final section, with our thanks to them.

Introduction (1 min) & Regulatory perspectives (8 mins)

Interviews with regulators, including ECHA and national regulators on how they see the role and potential of QSAR models within REACH.

What makes a good QSAR model? (9 mins)

Interviews with QSAR developers on the value and limits of QSAR models, to offer an understanding of the core issues of what makes a good QSAR model, the importance of using models appropriately, and how to review or question the outputs.

Industry perspectives. (8 mins)

Interviews with industry representatives on the ways in which they are currently using QSAR models, and their current concerns and priorities for enabling wider use within REACH.

Future directions (4 mins) & List of contributors

Comments from all stakeholders on future directions.

List of contributors who speak in the documentary (in order of appearance).
We are grateful to:

	Professor Wim de Coen Head of Evaluation 1, ECHA
	Dr Doris Hirmann European Chemicals Agency (ECHA)
	Bob Diderich Principal Administrator, Organisation for Economic Co‑operation & Development (OECD)
	Marco Valentini Inspector, Health & Safety Authority, Ireland
	Magnus Lofstedt Environmental Protection Agency, Denmark
	Dr Emilio Benfenati Istituto de Ricerche Farmacologiche “Mario Negri”
	Professor John Dearden Liverpool John Moores University; Medicinal Chemistry
	Professor Nick Price Consultant. Formerly UK Dept. for Environment, Food & Rural Affairs (DEFRA) / FERA Central Science Lab.
	Dr Alessandra Roncaglioni Istituto de Ricerche Farmacologiche “Mario Negri”
	Dr Stéphanie Ringeissen L’Oréal: Head of Modeling & Biological Simulation
	Dr Laura Bigini Cambrex Profarmaco Milano
	Dr Marc Thouin Intertek – Industrial services
	Dr Erwin Annys European Chemical Industry Council (CEFIC)
	Dr Marion Weber CFCS – Consult GmbH
	Dr Maurizio Colombo Lamberti SPA: HSE Manager
	Dr Alexandre Pery Institut National de l’Environnement Industriel et des Risques (INERIS), Paris
	Dr Sandro Marroncelli ChemService S.r.l. Controlli e Ricerche, Milan
	Dr Costanza Rovida Centre for Alternatives to Animal Testing (CAAT) Europe
	Philippe Hubert Institut National de l’Environnement Industriel et des Risques (INERIS), Paris
	Dr Mari-Liis Strik-Ott Molcode Ltd. Estonia

Additional contributors who helped to inform the documentary. We are grateful to:

Professor Giuseppina Gini

Politecnic di Milano, Milan

Ralf Knauf

CentroREACH S.r.l., Milan

Nikolai Nokolov

Technical University of Denmark, National Food Institute, Soeborg

Elena Fioravanzo

S.IN Soluzioni Informatiche S.r.l. Vicenza

Christina Marchiori

General Manager, ChemService S.r.l. Milan

Maria Chiara Neri

Head of Ecotox Unit, ChemService S.r.l. Milan

Claire Mays

Symlog, Paris

Rodolfo Gonella Diaza

Istituto de Ricerche Farmacologiche “Mario Negri”, Milan

Researched, produced and directed by Dr Simon Pardoe, PublicSpace.ac.uk
Additional interviews by Alan Golding and Claire Mays
Filming and post-production by Lisa Cazzato, Simon Pardoe, Alan Golding.

Laboratory images with special thanks to

ChemService S.r.l. Milan
Cambrex Profarmaco Milan
Istituto de Ricerche Farmacologiche “Mario Negri”, Milan

Filmed in: Milan, Paris, Liverpool, York, Lancaster and the English Lake District.
Produced by PublicSpace Ltd. UK for the ORCHESTRA project.
(EC FP7-Cooperation Contract 226521-ORCHESTRA)

Glossary

Related FAQ

What makes a good QSAR model?

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

the model is recognised as scientifically valid;
the substance is included in the applicability domain of the model;
results are adequate for classification and labelling and for risk assessment;
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:

a defined endpoint;
an unambiguous algorithm;
a defined domain of applicability;
appropriate measures of goodness-of-fit, robustness and predictivity;
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.

Further explanation and information

1) For an accessible explanation, see the video documentary ‘QSARs in REACH? Uses, issues and priorities’. Section 1 offers insight into what ECHA and regulators regard as important. Section 2 is called ‘What makes a good QSAR model?’, and from interviews with key QSAR researchers, it offers an introduction to the priorities when selecting and using a QSAR model.

2) This text is adapted from an open access article which offers further discussion of each of the REACH requirements in relation to the use of QSAR models:
Benfenati, E., Gonella Diaza, R., Cassano, A., Pardoe, S., Gini, G., Mays, C., Knauf, R. and Benighaus, L. (2011) The acceptance of in silico models for REACH: Requirements, barriers, and perspectives. Chemistry Central Journal 2011, 5:58 http://journal.chemistrycentral.com/content/5/1/58

3) The platform presentations at the SETAC Europe 2011 conference by Emilio Benfenati, Giuseppina Gini and Alessandra Roncaglioni offer more detailed discussion. These are available as edited videos here.

4) Detailed guidance from ECHA is available in two key guides:

Guidance on information requirements and chemical safety assessment: Chapter R.6: QSARs and grouping of chemicals. 2008: 12-13
ECHA. Practical guide 5: How to report (Q)SAR. 2009: 2-4

Are in silico methods / QSAR models accepted by REACH?

REACH explicitly encourages innovation in toxicity evaluation. The development of alternative methods is one of the purposes of REACH.

The legislation sets out conditions specifically for the use of QSAR models, and the European Chemicals Agency (ECHA) offers detailed guidance. Even the introductory ‘Guidance in a nutshell’ on substance registration advises industry to ‘collect QSAR estimated results for the substance if suitable models are available’ as an initial step.

However, acceptability depends on both the model and on how it is used in practice. See ‘What makes a good QSAR model?’

Further information:

1) FAQ: ‘What makes a good QSAR model?’

2) The video interview with Professor Wim de Coen, Head of Evaluation 1 at ECHA, provides insight into ECHA’s thinking on in silico methods / QSAR models and their current uses.

3) The documentary ‘QSARs in REACH? Uses, issues and priorities’, offers perspectives from regulators (section 1), model developers (section 2), and industry representatives (section 3).

4) The following open access article offers further detail:
Benfenati, E., Gonella Diaza, R., Cassano, A., Pardoe, S., Gini, G., Mays, C., Knauf, R. and Benighaus, L. (2011) The acceptance of in silico models for REACH: Requirements, barriers, and perspectives. Chemistry Central Journal 2011, 5:58 http://journal.chemistrycentral.com/content/5/1/58

5) The many ECHA guides referring to the use of QSAR models include:

ECHA (2009) Practical guide 5: How to report (Q)SAR. http://echa.europa.eu/doc/publications/practical_guides/pg_report_qsars.pdf
ECHA (2008) Guidance on information requirements and chemical safety assessment: Chapter R.6: QSARs and grouping of chemicals.

Why are in silico methods not yet used widely in REACH?

QSARs have been used for decades in the development of pharmaceuticals, where a drug is to be developed to achieve a particular biological action. Our interest here is in the reverse use, where the chemical is known, and the biological action is to be predicted. That too has been the focus of research for decades. But here we are concerned specifically with their use for evaluating toxicity within the regulatory framework of REACH, and it is early days.

In practice, the use of in silico methods by European industry within REACH is still limited. There are three key practical issues that can delay their use. They are highly inter-connected.

(i) Progress in developing models for regulatory use: The limitations for model development are primarily the lack of good available experimental data as the basis for developing models. The results of the many thousands of past animal experiments carried out or commissioned by industry are held as confidential by industry. (The regulatory demand for the transparency of QSAR models inevitably requires that they not only reveal the experimental data used to develop the model, but also make available for independent review the details of how the experimental results were achieved.) In his video interview (see documentary, part 4) Professor John Dearden made a plea to industry to release that data.

A positive development is that it is now clearer to QSAR developers than ever before, exactly what is expected of QSAR models for regulatory use. The regulatory framework of REACH, the OECD principles and the ECHA guidelines effectively work together to increase the demands on models in terms of rigour, reliability and transparency.

(ii) Uptake by industry and consultants: uptake requires awareness of the models available, confidence in their reliability and confidence in regulatory acceptance if they are used. (See the FAQ: ‘Do in silico methods require expertise, or can anyone use them?’) The use of in silico methods for REACH also involves a simultaneous shift from simply using in vivo methods as an accepted form of evidence, to using different and complementary sources of evidence.

(iii) Acceptance in practice by regulators (ECHA and the national competent authorities): The ultimate responsibility of regulators is to protect human health and the environment, so there is some caution in accepting the use of alternative methods. The experience of European regulators in using QSARs is also still limited.

The regulation has made the shift to animal testing being ‘only as a last resort’, but process requires confidence, shared expertise and communication between these three major stakeholders. It may be encouraged by wider interest among industry shareholders, publics, and policy makers, in realisation that there are alternatives to animal testing.

Further information

1) The video interview with Professor Wim de Coen, Head of Evaluation 1 at ECHA, provides further accessible insight into ECHA’s thinking on QSARs and their current uses.

2) ECHA have reported on the use of alternative methods up to June 2011:
ECHA (2011) Use of Alternatives to Testing on Animals for the REACH Regulation
http://echa.europa.eu/publications/alternatives_test_animals_2011_en.asp

3) The documentary video ‘QSARs in REACH? Uses, issues and priorities’ includes perspectives from each group of stakeholders (Part 1 – Regulators; Part 2 – Developers; Part 3 – Industry; Part 4 – Future directions).

4) The platform presentations at the SETAC Europe 2011 conference by Simon Pardoe outlined of the current challenges to industry of using QSAR models, and what is needed to enable the learning ‘case-by-case’. This is on video here.

5) A list of possible QSAR models for REACH is available at the ANTARES web site: http://www.antares-life.eu Note: the models in this list should not be considered as necessarily valid for REACH; they must be evaluated in terms of a particular intended use. (See FAQ: ‘What makes a good QSAR model?’)

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