title: Predicting skin sensitisation using a decision tree integrated testing strategy with an in silico model and in chemico/in vitro assays.
abstract: There is a pressing need for non-animal methods to predict skin sensitisation potential and a number of in chemico and in vitro assays have been designed with this in mind. However, some compounds can fall outside the applicability domain of these in chemico/in vitro assays and may not be predicted accurately. Rule-based in silico models such as Derek Nexus are expert-derived from animal and/or human data and the mechanism-based alert domain can take a number of factors into account (e.g. abiotic/biotic activation). Therefore, Derek Nexus may be able to predict for compounds outside the applicability domain of in chemico/in vitro assays. To this end, an integrated testing strategy (ITS) decision tree using Derek Nexus and a maximum of two assays (from DPRA, KeratinoSens, LuSens, h-CLAT and U-SENS) was developed. Generally, the decision tree improved upon other ITS evaluated in this study with positive and negative predictivity calculated as 86% and 81%, respectively. Our results demonstrate that an ITS using an in silico model such as Derek Nexus with a maximum of two in chemico/in vitro assays can predict the sensitising potential of a number of chemicals, including those outside the applicability domain of existing non-animal assays.
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK. Electronic address: donna.macmillan@lhasalimited.org.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Macmillan
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Canipa
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Martyn L
authors.initials: ML
authors.lastname: Chilton
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Richard V
authors.initials: RV
authors.lastname: Williams
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Barber
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D003198:Computer Simulation; D016208:Databases, Factual; D003663:Decision Trees; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D017453:Dermatitis, Irritant / Q000209:etiology*; D006801:Humans; D007509:Irritants / Q000737:chemistry / Q000633:toxicity*; D051188:Knowledge Bases; D015203:Reproducibility of Results; D012867:Skin / Q000187:drug effects*; D023422:Skin Irritancy Tests / Q000379:methods*; D012984:Software; D013329:Structure-Activity Relationship; D057188:Workflow
chemical_list: D007509:Irritants
keywords: DPRA; Derek Nexus; In silico assessment; Integrated testing strategy; KeratinoSens; LuSens; Skin sensitisation; U-SENS; h-CLAT