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Quantitative/ Qualitative Structure-Activity Relationships

Qualitative and quantitative structure-activity relationships, collectively referred to as (Q)SARs, are theoretical models that can be used to predict the physicochemical, biological and environmental fate properties of molecules.

A structure-activity relationship (SAR) is a qualitative relationship that relates a (sub)structure to the presence or absence of a property or activity of interest. The substructure may consist of adjacently bonded atoms, or an arrangement of non-bonded atoms that are collectively associated with the property or activity.

A quantitative structure-activity relationship (QSAR) is a mathematical model (often a statistical correlation) relating one or more quantitative parameters derived from chemical structure to a property or activity of interest. QSARs are quantitative models yielding a continuous or categorical result.

(Q)SAR models are playing an increasingly important role in the regulatory assessments of chemicals. For regulatory purposes, it is important that the (Q)SAR models are properly characterised and documented. For this reason, we developed the JRC QSAR Model Database and the QSAR Model Reporting Format (QMRF).

The JRC QSAR Model Database

The JRC QSAR Model Database can be accessed here.
The database provides information on the validity of (Q)SAR models that have been submitted to the JRC. It is intended to help identify valid (Q)SARs for the purposes of regulatory assessments (e.g. REACH).

The database uses a harmonised template (the QSAR Model Reporting Format, see below) for summarising and reporting key information relating to (Q)SAR models. This includes the results of any validation studies. The information is structured according to the OECD principles for the validation of (Q)SAR models (see below).

The contents of the database are openly available online. Submissions to the database must be done using the QSAR Model Reporting Format (QMRF). Upon submission of a QMRF, the JRC will then apply a quality control procedure.
Inclusion of a model in the database does not imply acceptance or endorsement by the JRC or the European Commission. Responsibility for using the models lies with the end-user.
A user manual for the JRC QSAR database is available here.

The QSAR Model Reporting Format

The QSAR Model Reporting Format (QMRF) is a harmonised template for summarising and reporting key information on (Q)SAR models, including the results of any validation studies. The information is structured according to the OECD (Q)SAR validation principles.


A number of resources are available relating to QMRFs:
The user manual for the JRC QSAR database explains the reporting format in detail. Guidelines and a pre-defined protocol is available to assist in the review process of QMRFs which can be downloaded here (PDF).

A QMRF Editor is also available. This is a standalone desktop application and is available from here or Sorceforge net.

Editorial guidelines are also available to assist in the creation of QMRFs. These can be downloaded here.

Specific instructions for the creation of SDF files are available here.

OECD Principles for the validation of (Q)SARs

More information on these principles are available here and can be obtained from the OECD QSAR webpages here and here.

REACH guidance on (Q)SARs

The REACH guidance on (Q)SARs is included in Chapter R.6 of the Guidance on Information Requirements and Chemical Safety Assessment. All of the finalised REACH guidance documents are available on the ECHA website

ECHA has also published a practical guide on how to report (Q)SARs.

More information on the use of (Q)SARs in a regulatory context can be found in the Document area (see below).

 

Historical documents on QSAR

Comparison of the COMMPS Priority Setting Scheme with Total and Partial Ranking Algorithms (May 2007)

In support of the Water Framework Directive, the JRC compared the results obtained with Combined Monitoring-based and Modelling-based Priority Setting (COMMPS) scheme with the results obtained with four ranking methods, including three types of total ranking techniques (Desirability, Utility and Dominance function) and a partial ranking method (Hasse Diagram Technique, HDT).
Download report

Evaluation of (Q)SARs for the Prediction of Eye/Skin Irritation/Corrosion Potential (Oct. 2005 and Feb. 2006)

The German Federal Institute for Risk Assessment (BfR) has developed a QSAR decision support system containing several rulebases for predicting the presence or absence of acute local effects to the skin and the eye. The JRC carried out an assessment of the set of physicochemical exclusion rules for predicting the absence of eye irritation and/or corrosion (I. Tsakovska, T. Netzeva, A. Worth; publication: EUR 21897 EN, Feb. 2006).
With sponsorship from the JRC, a report has been produced by the National Institute of Public Health and Environment (RIVM), NL, on the assessment of one of the set of physicochemical exclusion rules for predicting the absence of skin irritation and/or corrosion (Emiel Rorije, Etje Hulzebos, Oct. 2005).
Download report (Eye)
Download report (Skin)

Review of Non-Commercial (Q)SAR Models for Acute Fish Toxicity (Feb. 2006)

The JRC funded a study to review and evaluate non-proprietary models for acute toxicity to fish. The report of the study, written by Drs Brooke and Crookes (Building Research Establishment, Watford, UK) provides detailed information on a wide range of literature-based models.
Download report (part A)
Download report (part B)

Review of Non-Commercial (Q)SAR Models for Estrogen Receptor and Androgen Receptor Binding (Dec. 2005)

The JRC funded a study to review and evaluate non-proprietary models for ER and AR binding activity. The report of the study, written by Dr Benfenati and colleagues (Mario Negri Institute, Milan), provides detailed information on a wide range of literature-based models. A total of 158 models were evaluated.
Download report

Evaluation of QSAR Models for Aquatic Toxicity (Dec. 2005)

The JRC carried out research to evaluate the possibility of using QSAR predictions for regulatory purposes. In these two reports, QSAR models for aquatic toxicity are analyzed (M. Pavan, A. Worth, T. Netzeva). Publications: EUR 21749 EN (2005) and EUR 21750 EN (2005).
Preliminary Analysis of an Aquatic Toxicity Dataset and Assessment of QSAR Models for Narcosis Comparative Assessment of QSAR Models for Aquatic Toxicity

The Characterisation of (Q)SARs: Preliminary Guidance (Nov. 2005)

In November 2004, the OECD Member Countries and the European Commission adopted five principles for the validation of (Q)SARs intended for use in the regulatory assessment of chemicals. This report provides preliminary guidance on how to characterise (Q)SARs according to the OECD validation principles, and is based on the best understanding of the JRC authors at the time of writing (November 2005). Publication: EUR 21866 EN.
Download report

QSAR Decision Support System (Sept. 2005)

The JRC funded a scoping study for the development of an international QSAR Decision Support System (DSS), i.e. a computer-based system to provide authorities and industry with (Q)SAR tools that can be used to support hazard and risk assessments. The report of the scoping study, written by Professor Gini (Milan Polytechnic), provides background information that will be useful for the future development of the DSS.
Download report

A Series of Papers on Applicability Domain Methods (Feb. 2005)

 The Joint Research Centre sponsored a series of papers to review methods for assessing the applicability domains of SARs and QSARs. This work was done by Dr Joanna Jaworska (Procter & Gamble, Belgium) in collaboration with Dr Tom Aldenberg (RIVM, NL) and Dr Nina Nikolova (Bulgarian Academy of Sciences, Bulgaria).

Download overview of the four papers

Review of methods for QSAR applicability domain estimation by the training set (Paper 1)

An approach to determining applicability domain for QSAR group contribution models: an analysis of SRC KOWWIN (Paper 2)

Joint applicability domain and predictive uncertainty in QSAR Regression (Paper 3)

Discussion on the difference between SAR and QSAR (Paper 4)

Evaluation of Different Statistical Approaches for the Validation of QSARs (Nov. 2004)

The validation of QSARs has been a subject of intense debate within the academic regulatory and regulated communities. The questions discussed refer to: a) the validation principles that should be followed; b) the methods and approaches that can be used to apply the principles; c) the criteria for establishing scientific validity of models; and d) the flexibility and pragmatism that should be applied in the "real-world" use of QSARs for regulatory purposes (P. Gramatica, University of Insubria, Varese, Italy).
Download paper

Reports of the ICCA/CEFIC workshop on the Regulatory Acceptance of QSARs for Human Health and Environmental Endpoints (2003)

A scientific workshop entitled "Regulatory Acceptance of (Q)SARs for Human Health and Environmental Endpoints", hosted by the European Centre for Ecotoxicology and Toxicology of Chemicals and organized by the International Council of Chemical Associations (ICCA) and the European Chemical Industry Council (CEFIC)) was held on 4-6 March 2002 in Setubal, near Lisbon, Portugal.
Jaworska et al (2003). Workshop summary

Eriksson et al (2003). Methods for reliability, uncertainty assessment, and  applicability evaluations of classification and regression based QSARs

Cronin et al (2003). Use of quantitative structure-activity relationships in international decision-making frameworks to predict ecological effects and environmental fate of chemical substances

Cronin et al (2003). Use of quantitative structure-activity relationships in international decision-making frameworks to predict health effects of chemical substances

Overview of Structure-Activity Relationships for Environmental Endpoints (1995)

The report presents an overview of QSARs for sorption, degradation, and ecotoxicity. All these parameters play an important role in the evaluation of risks of chemicals in the environment.
Part 1: General outline and procedure
Part 2: Descriptions of selected models

Predictions of the Aquatic Toxicity of High-Production-Volume Chemicals (1993)

The predictions are based on: a) a scheme to classify chemicals into four different classes; b) a set of QSAR equations for different endpoints of ecotoxicity; c) extrapolation methods for calculation of safe level at the ecosystem level; d) an equilibrium partitioning model (J. Bol, H.J.M. Verhaar, C.J. Van Leeuwen and J.L.M. Hermens).
Part A: Introduction and Methodology
Part B: Predictions

The US/EC Joint Project on Evaluation of (Q)SARs (1989)

In 1989, the OECD organised a workshop on Notification Schemes for New Chemicals, during which it was recommended that the (Q)SARs in use by the US EPA should be evaluated in terms of their predictive power. It was recommended that this should be achieved by applying (Q)SARs to chemicals for which test data had been obtained in the context of the EU New Chemicals notification scheme, so that QSAR predictions could be compared with independent experimental data. To follow up this recommendation, the US EPA and the European Commission undertook a joint project in which predictions for 144 substances were made by using the US EPA (Q)SARs for a wide variety of physicochemical properties, ecotoxicological effects and human health effects. The study identified promising areas for the wider application of (Q)SARs, such as biodegradation and acute toxicity to fish and Daphnia, as well as areas where further work was needed, such as the development of
(Q)SARs for human health effects. The outcome of the US/EC project was published as OECD Environment Monograph no. 88.