Review of Data Sources, QSARs and Integrated Testing Strategies for Skin Sensitisation

This review collects information on sources of skin sensitisation data and computational tools for the estimation of skin sensitisation potential, such as expert systems and (quantitative) structure-activity relationship (QSAR) models. The review also captures current thinking of what constitutes an integrated testing strategy (ITS) for this endpoint. The emphasis of the review is on the usefulness of the models for the regulatory assessment of chemicals, particularly for the purposes of the new European legislation for the Registration, Evaluation, Authorisation and Restriction of CHemicals (REACH), which entered into force on 1 June 2007. Since there are no specific databases for skin sensitisation currently available, a description of experimental data found in various literature sources is provided. General (global) models, models for specific chemical classes and mechanisms of action and expert systems are summarised. This review was prepared as a contribution to the EU funded Integrated Project, OSIRIS. LIST OF ABBREVIATIONS CEFIC European Chemical Industry Council DC Dendritic Cells EC3 Concentration (weight percent) giving a stimulation index value of 3 in the LLNA EC European Commission ECB European Chemicals Bureau ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals ECVAM European Centre for Validation of Alternative Methods ELUMO Energy of the Lowest Unoccupied Molecular Orbital EPA Environmental Protection Agency ESIS European chemical Substances Information System (ECB) EU European Union F Fischer Statistic FCA Freunds Complete Adjuvant GPMT Guinea Pig Maximisation Test HMT Human Maximisation Test HOMO Highest occupied molecular orbital HPV High Production Volume ICCA International Council of Chemical Associations ICCVAM Interagency Coordinating Committee on the Validation of Alternative Methods ITS Integrated (Intelligent) Testing Strategy JRC Joint Research Centre k Rate constant Ka Acid Dissociation Constant LC Langerhans Cells LLNA Local lymph node assay LUMO Lowest unoccupied molecular orbital MLR Multiple Linear Regression MO Molecular Orbital MSIAT Modified Single Injection Adjuvant Test MW Molecular Weight OECD Organisation for Economic Co-operation and Development PCA Principal Components Analysis pEC3 Negative logarithm of EC3 on a molar basis. Calculated as log [(molecular weight)/EC3] Q 2 Predictive ability of a model QMM Quantitative Mechanistic Model QMRF (Q)SAR Model Reporting Format QSAR Quantitative Structure-Activity Relationship R 2 Goodness of fit RAI Relative Alkylation Index REACH Registration Evaluation and Authorisation of CHemicals RIP REACH Implementation Project SAR Structure-Activity Relationship SB Schiff Base SI Stimulation index σ*: sigma* Taft substituent constant SMILES Simplified Molecular Line Entry system SN2 Substitution reaction, nucleophilic, bimolecular SNAr Substitution reaction, nucleophilic, aromatic TG Test Guideline TIMES-SS TIssue MEtabolism Simulator for Skin Sensitisation