title: A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.
abstract: Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.
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: Rachel
authors.initials: R
authors.lastname: Hemingway
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Donna S
authors.identifier: 0000-0002-8350-6722
authors.initials: DS
authors.lastname: Macmillan
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Alun
authors.initials: A
authors.lastname: Myden
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Plante
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Tennant
authors.affiliation: Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Vessey
authors.affiliation: Bayer Pharma, Muellerstrasse 178, Wedding, Berlin, D-13342, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steger-Hartmann
authors.affiliation: Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ, 08903, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Gould
authors.affiliation: Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ, 08903, USA.
authors.forename: Jedd
authors.initials: J
authors.lastname: Hillegass
authors.affiliation: Firmenich S.A., Rue de la Bergère 7, Meyrin 2, CH-1217, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Etter
authors.affiliation: Firmenich Inc., POB 5880, Princeton, NJ, 08543, USA.
authors.forename: Benjamin P C
authors.initials: BPC
authors.lastname: Smith
authors.affiliation: GlaxosmithKline, Park Road, Ware, SG12 0DP, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: White
authors.affiliation: International Flavors & Fragrances Inc., 800 Rose Lane, Union Beach, NJ, 07735, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sterchele
authors.affiliation: Janssen Research and Development, Turnhoutseweg 30, Beerse, B-2340, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: De Smedt
authors.affiliation: RIFM, 50 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: O'Brien
authors.affiliation: RIFM, 50 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Parakhia
mesh_terms: D023401:Animal Use Alternatives; D000818:Animals; D003198:Computer Simulation; D066264:Datasets as Topic; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D023441:Local Lymph Node Assay; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations
keywords: Derek Nexus; LLNA; QSAR; local lymph node assay; skin sensitization