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Article
Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain
Contact dermatitis (2009)
  • Terry W Schultz, University of Tennessee - Knoxville
  • K Rogers
  • A O Aptula
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. 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.

Keywords
  • Animal Testing Alternatives methods,
  • Animals,
  • Catalytic Domain,
  • Dermatitis,
  • Allergic Contact diagnosis,
  • Dermatitis,
  • Allergic Contact immunology,
  • Dermatitis,
  • Irritant diagnosis,
  • Dermatitis,
  • Irritant immunology,
  • Disease Models,
  • Animal,
  • Glutathione immunology,
  • Glutathione toxicitym,
  • Guinea Pigs,
  • Humans,
  • Immunization/methods,
  • Irritants/toxicity,
  • Local Lymph Node Assay,
  • Mice,
  • Models,
  • Chemical,
  • Protein Binding/immunology,
  • Risk Factors,
  • Sensitivity and Specificity,
  • Severity of Illness Index,
  • Skin Irritancy Tests methods,
  • Toxicity Tests methods
Publication Date
2009
Citation Information
Terry W Schultz, K Rogers and A O Aptula. "Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain" Contact dermatitis Vol. 60 (2009)
Available at: http://works.bepress.com/terry_schultz/9/