title: Can currently available non-animal methods detect pre and pro-haptens relevant for skin sensitization?
abstract: Predictive testing to characterize substances for their skin sensitization potential has historically been based on animal tests such as the Local Lymph Node Assay (LLNA). In recent years, regulations in the cosmetics and chemicals sectors have provided strong impetus to develop non-animal alternatives. Three test methods have undergone OECD validation: the direct peptide reactivity assay (DPRA), the KeratinoSens™ and the human Cell Line Activation Test (h-CLAT). Whilst these methods perform relatively well in predicting LLNA results, a concern raised is their ability to predict chemicals that need activation to be sensitizing (pre- or pro-haptens). This current study reviewed an EURL ECVAM dataset of 127 substances for which information was available in the LLNA and three non-animal test methods. Twenty eight of the sensitizers needed to be activated, with the majority being pre-haptens. These were correctly identified by 1 or more of the test methods. Six substances were categorized exclusively as pro-haptens, but were correctly identified by at least one of the cell-based assays. The analysis here showed that skin metabolism was not likely to be a major consideration for assessing sensitization potential and that sensitizers requiring activation could be identified correctly using one or more of the current non-animal methods.
authors: US Environmental Protection Agency, National Center for Computational Toxicology, Research Triangle Park, NC, USA. Electronic address: patlewicz.grace@epa.gov.
authors: Grace
authors: G
authors: Patlewicz
authors: European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, Ispra, VA, Italy.
authors: Silvia
authors: S
authors: Casati
authors: DABMEB Consultancy Ltd, Sharnbrook, Bedfordshire, UK.
authors: David A
authors: DA
authors: Basketter
authors: European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, Ispra, VA, Italy.
authors: David
authors: D
authors: Asturiol
authors: Liverpool John Moores University, School of Pharmacy and Biomolecular Sciences, Liverpool, UK.
authors: David W
authors: DW
authors: Roberts
authors: Institute of Chemistry, CNRS UMR 7177 and University of Strasbourg, Strasbourg, France.
authors: Jean-Pierre
authors: JP
authors: Lepoittevin
authors: European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, Ispra, VA, Italy.
authors: Andrew P
authors: AP
authors: Worth
authors: European Commission, Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit, Ispra, VA, Italy.
authors: Karin
authors: K
authors: Aschberger
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D002460:Cell Line; D016208:Databases, Factual; D017449:Dermatitis, Allergic Contact / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006241:Haptens / Q000633:toxicity*; D006801:Humans; D007509:Irritants / Q000633:toxicity*; D023441:Local Lymph Node Assay; D015203:Reproducibility of Results; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D023422:Skin Irritancy Tests / Q000379:methods*; D057188:Workflow
chemical_list: D006241:Haptens; D007509:Irritants
keywords: Adverse Outcome Pathway; DPRA; KeratinoSens™; Pre-hapten; Pro-hapten; Reaction mechanistic domain; Skin sensitization; h-CLAT