Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain
Article first published online: 6 JAN 2009
© 2008 The Authors Journal compilation © 2008 Blackwell Munksgaard
Volume 60, Issue 1, pages 21–31, January 2009
How to Cite
Schultz, T. W., Rogers, K. and Aptula, A. O. (2009), Read-across to rank skin sensitization potential: subcategories for the Michael acceptor domain. Contact Dermatitis, 60: 21–31. doi: 10.1111/j.1600-0536.2008.01473.x
- Issue published online: 6 JAN 2009
- Article first published online: 6 JAN 2009
- Accepted for publication 19 August 2008
- glutathione reactivity;
- Michael acceptors;
- skin sensitization;
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 α,β-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.