title: Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4543, USA.
authors.forename: Terry Wayne
authors.initials: TW
authors.lastname: Schultz
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rogers
authors.forename: Aynur Osman
authors.initials: AO
authors.lastname: Aptula
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D020134:Catalytic Domain; D017449:Dermatitis, Allergic Contact / Q000175:diagnosis / Q000276:immunology; D017453:Dermatitis, Irritant / Q000175:diagnosis / Q000276:immunology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000276:immunology / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D007114:Immunization / Q000379:methods; D007509:Irritants / Q000633:toxicity*; D023441:Local Lymph Node Assay; D051379:Mice; D008956:Models, Chemical; D011485:Protein Binding / Q000276:immunology; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D023422:Skin Irritancy Tests / Q000379:methods*; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D007509:Irritants; D005978:Glutathione