Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization

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(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(2)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.

Keywords: QSAR; Skin permeability; Skin sensitization; Skin toxicants; Virtual screening.

Figure 1

Human vs. rodent skin permeability correlation (R² = 0.44, logKp_Human = 0.72*logKp_Rodent − 1.17).

Figure 2

Cluster analysis of the human skin permeability dataset D: dendrogram and heat map of the distance matrix ordered based on structural similarity (blue/violet = similar; yellow/red = dissimilar). The following clusters are noted: (a) carboxylic acids, (b) glycol ethers, and (c) steroids.

Figure 3

Example of a structural transformation of sensitizer n-octanol with low permeability to non-sensitizer octanoic acid with improved permeability. Desired change of property is highlighted by green, undesired – by red; Δ = logKp_parent − logKp_child.