Terry Wayne Schultz1, Kathryn Rogers, Aynur Osman Aptula. 1. Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4543, USA.
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.
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.
Authors: Fjodor Melnikov; Brian C Geohagen; Terrence Gavin; Richard M LoPachin; Paul T Anastas; Phillip Coish; David W Herr Journal: Neurotoxicology Date: 2020-05-05 Impact factor: 4.294
Authors: Itai Chipinda; Risikat O Ajibola; Moshood K Morakinyo; Tinashe B Ruwona; Reuben H Simoyi; Paul D Siegel Journal: Chem Res Toxicol Date: 2010-05-17 Impact factor: 3.739
Authors: Thomas Luechtefeld; Alexandra Maertens; Daniel P Russo; Costanza Rovida; Hao Zhu; Thomas Hartung Journal: ALTEX Date: 2016-02-11 Impact factor: 6.043
Authors: J Heinrich; I Brüske; C Cramer; U Hoffmann; M Schnappinger; B Schaaf; A von Berg; D Berdel; U Krämer; I Lehmann; O Herbarth; M Borte; A Grübl; C P Bauer; C Beckmann; H Behrendt; J Ring; S Koletzko Journal: Allergol Select Date: 2017-08-04