Skin Sensitization: Modeling Based on Skin Metabolism Simulation and Formation of Protein Conjugates

Abstract

A quantitative structure-activity relationship (QSAR) system for estimating skin sensitization potency has been developed that incorporates skin metabolism and considers the potential of parent chemicals and/or their activated metabolites to react with skin proteins. A training set of diverse chemicals was compiled and their skin sensitization potency assigned to one of three classes. These three classes were, significant, weak, or nonsensitizing. Because skin sensitization potential depends upon the ability of chemicals to react with skin proteins either directly or after appropriate metabolism, a metabolic simulator was constructed to mimic the enzyme activation of chemicals in the skin. This simulator contains 203 hierarchically ordered spontaneous and enzyme controlled reactions. Phase I and phase II metabolism were simulated by using 102 and 9 principal transformations, respectively. The covalent interactions of chemicals and their metabolites with skin proteins were described by 83 reactions that fall within 39 alerting groups. The SAR/QSAR system developed was able to correctly classify about 80% of the chemicals with significant sensitizing effect and 72% of nonsensitizing chemicals. For some alerting groups, three-dimensional (3D)-QSARs were developed to describe the multiplicity of physicochemical, steric, and electronic parameters. These 3D-QSARs, so-called pattern recognition-type models, were applied each time a latent alerting group was identified in a parent chemical or its generated metabolite(s). The concept of the mutual influence amongst atoms in a molecule was used to define the structural domain of the skin sensitization model. The utility of the structural model domain and the predictability of the model were evaluated using sensitization potency data for 96 chemicals not used in the model building. The TIssue MEtabolism Simulator (TIMES) software was used to integrate a skin metabolism simulator and 3D-QSARs to evaluate the reactivity of chemicals thus predicting their likely skin sensitization potency.

The Guidance Document for Using the OECD (Q)SAR Application Toolbox to Develop Chemical Categories According to the OECD Guidance on Grouping Chemicals

“…Nevertheless, as the examples provided below demonstrate, either approach can be used successfully. (Dimitrov et al, 2005).…”

“…The core of the skin metabolism model is a set of 203 principal transformations defined on the basis of empirical and theoretical knowledge and hence peer-reviewed by human experts (Dimitrov et al, 2005). The principal transformations were separated into two major classes: nonrate determining and rate determining reactions.…”

Integrated Testing Strategies for Skin Sensitization Hazard and Potency Assessment—State of the Art and Challenges

“…Physico-chemical properties (water solubility and fraction ionized) define bioavailability oriented applicability domains of individual assays. Further, the ITS-3 uses TIMES [37] to form in silico hypothesis about potency as well as a way to assess a chemical's potential for being a pre-or pro-hapten. Data outside applicability domains are excluded from the integrated prediction or in case of pre-or pro-haptenation are treated with caution in the prediction process.…”

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

“…TIMES-SS is a commercial software package developed by LMC that offers toxicity predictors for several endpoints as well as some metabolism simulators. 134 In contrast to the OECD QSAR Toolbox, TIMES-SS uses some quantum mechanics descriptors such as HOMO-LUMO gaps and electronegativity, which are calculated at the semi-empirical level with the embedded MOPAC software. The skin simulator also includes extra features with respect to the one on the OECD QSAR Toolbox that make it a more powerful tool and the data output is more verbose.…”