title: TIMES-SS--a promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity.
abstract: The TImes MEtabolism Simulator platform used for predicting Skin Sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a Consortium comprising industry and regulators. The model was developed with the aim of minimizing animal testing and to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs. Here, we describe the extent to which the five OECD principles are met and in particular the results from an external evaluation exercise that was recently carried out. As part of this exercise, data were generated for 40 new chemicals in the murine local lymph node assay (LLNA) and then compared with predictions made by TIMES-SS. The results were promising with an overall good concordance (83%) between experimental and predicted values. Further evaluation of these results highlighted certain inconsistencies which were rationalized by a consideration of reaction chemistry principles for sensitization. Improvements for TIMES-SS were proposed where appropriate. TIMES-SS is a promising tool to aid in the evaluation of skin sensitization hazard under legislative programs such as REACH.
authors.affiliation: European Chemicals Bureau, TP 582, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, 21020 Ispra, VA, Italy. grace.patlewicz@jrc.it
authors.forename: Grace
authors.initials: G
authors.lastname: Patlewicz
authors.forename: Sabcho D
authors.initials: SD
authors.lastname: Dimitrov
authors.forename: Lawrence K
authors.initials: LK
authors.lastname: Low
authors.forename: Petra S
authors.initials: PS
authors.lastname: Kern
authors.forename: Gergana D
authors.initials: GD
authors.lastname: Dimitrova
authors.forename: Mike I H
authors.initials: MI
authors.lastname: Comber
authors.forename: Aynur O
authors.initials: AO
authors.lastname: Aptula
authors.forename: Richard D
authors.initials: RD
authors.lastname: Phillips
authors.forename: Jay
authors.initials: J
authors.lastname: Niemelä
authors.forename: Charlotte
authors.initials: C
authors.lastname: Madsen
authors.forename: Eva B
authors.initials: EB
authors.lastname: Wedebye
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.forename: Paul T
authors.initials: PT
authors.lastname: Bailey
authors.forename: Ovanes G
authors.initials: OG
authors.lastname: Mekenyan
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D003198:Computer Simulation; D005062:European Union; D007509:Irritants / Q000737:chemistry*; D023441:Local Lymph Node Assay; D051379:Mice; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects; D023422:Skin Irritancy Tests / Q000379:methods
chemical_list: D007509:Irritants