title: Development and prevalidation of a list of structure-activity relationship rules to be used in expert systems for prediction of the skin-sensitising properties of chemicals.
abstract: The new European Union (EU) chemicals policy, as described in the White Paper entitled Strategy for a Future Chemicals Policy, has identified a need for computer-based tools suitable for predicting the hazardous properties of chemicals. Two sets of structural alerts (fragments of chemical structure) for the prediction of skin sensitisation hazard classification ("R43, may cause sensitisation by skin contact") have been drawn up, based on sensitising chemicals from a regulatory database (containing data for the EU notification of new chemicals). These alerts comprise 15 rules for chemical structures deemed to be sensitising by direct action of the chemicals with cells or proteins within the skin, and three rules for substructures that act indirectly, i.e. requiring chemical or biochemical transformation. The predictivity rates of the rules were found to be good (positive predictivity, 88%; false-positive rate, 1%; specificity, 99%; negative predictivity, 74%; false-negative rate, 80%; sensitivity, 20%). Because of the confidential nature of the regulatory database, the rules are supported by examples of sensitising chemicals taken from the "Allergenliste" now held by the Federal Institute for Risk Assessment (BfR) and the DEREK for Windows expert system. The rules were prevalidated against data not used for their development. As a result of the prevalidation study, it is proposed that the two sets of structural alerts should be taken forward for formal validation, with a view to incorporating them into regulatory guidelines.
authors.affiliation: Federal Institute for Risk Assessment (BfR), Thielallee 88-92, 14191 Berlin, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Gerner
authors.forename: Martin D
authors.initials: MD
authors.lastname: Barratt
authors.forename: Stephan
authors.initials: S
authors.lastname: Zinke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schlegel
authors.forename: Eva
authors.initials: E
authors.lastname: Schlede
mesh_terms: D000826:Animal Testing Alternatives; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003201:Computers; D003877:Dermatitis, Contact / Q000209:etiology; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D018675:Toxicity Tests / Q000379:methods / Q000592:standards