Contact dermatitis · 2009
Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain.
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Schultz Terry Wayne, Rogers Kathryn, Aptula Aynur Osman
Аннотация
BACKGROUND: Eliminating animal testing for skin sensitization is a significant challenge in consumer safety risk assessment. To be able to perform resilient risk assessments in the future, one will need alternative approaches to fill the data gaps.
OBJECTIVES: To this end, we propose a subcategory-based read-across approach to estimate and rank skin sensitization potential of chemicals. The example described here is for the mechanism of Michael-type nucleophilic addition with subcategories being limited to carbonyl-containing compounds.
PATIENTS/METHODS: In this approach, in silico tools based on structural alerts were used to determine both the mechanism of protein binding and the relative subcategories within that mechanism.
RESULTS: Fifty compounds previously evaluated in the in vivo mouse local lymph node assay (LLNA) were placed in 10 subcategories defined by their polarized alpha,beta-unsaturated substructure. To offset the limitations and skewness of the published in vivo data, in chemico glutathione (GSH) depletion data also were included.
CONCLUSIONS: It was shown that the read-across approach can be successfully used to rank qualitatively skin sensitization potential of an untested carbonyl-containing Michael acceptor chemical by using subcategories. Moreover, the use of the more resilient in chemico GSH depletion data added further support to the read-across result.
OBJECTIVES: To this end, we propose a subcategory-based read-across approach to estimate and rank skin sensitization potential of chemicals. The example described here is for the mechanism of Michael-type nucleophilic addition with subcategories being limited to carbonyl-containing compounds.
PATIENTS/METHODS: In this approach, in silico tools based on structural alerts were used to determine both the mechanism of protein binding and the relative subcategories within that mechanism.
RESULTS: Fifty compounds previously evaluated in the in vivo mouse local lymph node assay (LLNA) were placed in 10 subcategories defined by their polarized alpha,beta-unsaturated substructure. To offset the limitations and skewness of the published in vivo data, in chemico glutathione (GSH) depletion data also were included.
CONCLUSIONS: It was shown that the read-across approach can be successfully used to rank qualitatively skin sensitization potential of an untested carbonyl-containing Michael acceptor chemical by using subcategories. Moreover, the use of the more resilient in chemico GSH depletion data added further support to the read-across result.
Предметные рубрики MeSH
Animal Testing AlternativesAnimalsCatalytic DomainDermatitis, Allergic ContactDermatitis, IrritantDisease Models, AnimalGlutathioneGuinea PigsHumansImmunizationIrritantsLocal Lymph Node AssayMiceModels, ChemicalProtein BindingRisk FactorsSensitivity and SpecificitySeverity of Illness IndexSkin Irritancy TestsToxicity Tests