title: Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization.
abstract: The goal of eliminating animal testing in the predictive identification of chemicals with the intrinsic ability to cause skin sensitization is an important target, the attainment of which has recently been brought into even sharper relief by the EU Cosmetics Directive and the requirements of the REACH legislation. Development of alternative methods requires that the chemicals used to evaluate and validate novel approaches comprise not only confirmed skin sensitizers and non-sensitizers but also substances that span the full chemical mechanistic spectrum associated with skin sensitization. To this end, a recently published database of more than 200 chemicals tested in the mouse local lymph node assay (LLNA) has been examined in relation to various chemical reaction mechanistic domains known to be associated with sensitization. It is demonstrated here that the dataset does cover the main reaction mechanistic domains. In addition, it is shown that assignment to a reaction mechanistic domain is a critical first step in a strategic approach to understanding, ultimately on a quantitative basis, how chemical properties influence the potency of skin sensitizing chemicals. This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed.
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.forename: Grace
authors.initials: G
authors.lastname: Patlewicz
authors.forename: Petra S
authors.initials: PS
authors.lastname: Kern
authors.forename: Frank
authors.initials: F
authors.lastname: Gerberick
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Ryan
authors.forename: David A
authors.initials: DA
authors.lastname: Basketter
authors.forename: Aynur O
authors.initials: AO
authors.lastname: Aptula
mesh_terms: D000465:Algorithms; D000826:Animal Testing Alternatives; D000818:Animals; D016208:Databases, Factual / Q000145:classification / Q000706:statistics & numerical data*; D003875:Drug Eruptions / Q000175:diagnosis / Q000209:etiology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D023441:Local Lymph Node Assay; D051379:Mice; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D018675:Toxicity Tests / Q000379:methods / Q000639:trends
chemical_list: D004364:Pharmaceutical Preparations