title: Predicting chemically-induced skin reactions. Part I: QSAR models of skin sensitization and their application to identify potentially hazardous compounds.
abstract: Repetitive exposure to a chemical agent can induce an immune reaction in inherently susceptible individuals that leads to skin sensitization. Although many chemicals have been reported as skin sensitizers, there have been very few rigorously validated QSAR models with defined applicability domains (AD) that were developed using a large group of chemically diverse compounds. In this study, we have aimed to compile, curate, and integrate the largest publicly available dataset related to chemically-induced skin sensitization, use this data to generate rigorously validated and QSAR models for skin sensitization, and employ these models as a virtual screening tool for identifying putative sensitizers among environmental chemicals. We followed best practices for model building and validation implemented with our predictive QSAR workflow using Random Forest modeling technique in combination with SiRMS and Dragon descriptors. The Correct Classification Rate (CCR) for QSAR models discriminating sensitizers from non-sensitizers was 71-88% when evaluated on several external validation sets, within a broad AD, with positive (for sensitizers) and negative (for non-sensitizers) predicted rates of 85% and 79% respectively. When compared to the skin sensitization module included in the OECD QSAR Toolbox as well as to the skin sensitization model in publicly available VEGA software, our models showed a significantly higher prediction accuracy for the same sets of external compounds as evaluated by Positive Predicted Rate, Negative Predicted Rate, and CCR. These models were applied to identify putative chemical hazards in the Scorecard database of possible skin or sense organ toxicants as primary candidates for experimental validation.
authors.affiliation: Laboratory of Molecular Modeling and Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO 74605-220, Brazil; Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Alves
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Laboratory of Theoretical Chemistry, A.V. Bogatsky Physical-Chemical Institute NAS of Ukraine, Odessa 65080, Ukraine.
authors.forename: Eugene
authors.initials: E
authors.lastname: Muratov
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Fourches
authors.affiliation: ILS/Contractor Supporting the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), P.O. Box 13501, Research Triangle Park, NC 27709, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Strickland
authors.affiliation: ILS/Contractor Supporting the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), P.O. Box 13501, Research Triangle Park, NC 27709, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
authors.affiliation: Laboratory of Molecular Modeling and Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO 74605-220, Brazil.
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: alex_tropsha@unc.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D016208:Databases, Factual; D017449:Dermatitis, Allergic Contact / Q000209:etiology* / Q000276:immunology; D015386:Hazardous Substances / Q000506:poisoning*; D006801:Humans; D008956:Models, Chemical; D018448:Models, Immunological; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D012984:Software
chemical_list: D015386:Hazardous Substances
keywords: QSAR; Skin sensitization; Skin toxicants; Virtual screening