Quantitative structure-activity relationships: sulfonate esters in the local lymph node assay

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after metabolic activation, with appropriate skin proteins. For direct acting electrophilic compounds, this ability can be modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity parameters. The development of predictive quantitative structure-activity relationships (QSAR) models of skin sensitization, using mechanism-based physicochemical parameters, has been greatly facilitated by the introduction of the murine local lymph node assay (LLNA), which is able to describe the extent of the biological response in objective and quantitative terms. In the present work, sensitization response data in the LLNA is generated for a series of 6 sulfonate esters. An RAI-based hybrid QSAR/dose-response relationship is derived using a negative hydrophobicity coefficient in the RAI expression, to model the effect of retention of the hydrophobic test chemicals in the stratum corneum. Dose-response analyses are used to estimate EC3 and EC20 values as quantitative indices of skin sensitization potential for each compound, and regression analysis is applied to develop QSARs correlating these EC3 and EC20 values with an RAI-based parameter. The high statistical quality of these QSARs demonstrates both the consistency of the LLNA method for generating high quality skin sensitization data, and the value of the RAI approach in development of mathematical models for skin sensitization.