Thumbnail
Access Restriction
Open

Author Alves, Vinicius M. ♦ Muratov, Eugene ♦ Fourches, Denis ♦ Strickland, Judy ♦ Kleinstreuer, Nicole ♦ Andrade, Carolina H. ♦ Tropsha, Alexander
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ACCURACY ♦ CORRELATIONS ♦ DATASETS ♦ DESIGN ♦ HUMAN POPULATIONS ♦ MODIFICATIONS ♦ MOLECULAR STRUCTURE ♦ OECD ♦ OPTIMIZATION ♦ PERMEABILITY ♦ RANDOMNESS ♦ RODENTS ♦ SCREENING ♦ SENSITIZERS ♦ SIMULATION ♦ SKIN ♦ STRUCTURE-ACTIVITY RELATIONSHIPS
Abstract Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R{sup 2} = 0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q{sup 2}{sub ext} = 0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential. - Highlights: • It was compiled the largest publicly-available skin permeability dataset. • Predictive QSAR models were developed for skin permeability. • No concordance between skin sensitization and skin permeability has been found. • Structural rules for optimizing sensitization and penetration were established.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-04-15
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 284
Issue Number 2


Open content in new tab

   Open content in new tab