Further evaluation of the quantitative structure-activity relationship for skin-sensitizing alkyl transfer agents

The biological activity of skin-sensitizing chemicals can be expressed in terms of physicochemical properties which relate to the propensity of those chemicals to behave as electrophiles and which describe their ability to partition into the epidermis and between compartments within it. For defined series of chemicals, it has proved possible to express such structure-activity relationships quantitatively. Such quantitative relationships can provide valuable insights into the mechanisms of skin sensitization and/or are of use in predictive toxicology. In the present work the quantitative structure-activity relationship (QSAR) previously derived for a series of alkyl transfer agents based on alkanesulfonate leaving groups has been critically examined in the light of skin sensitization data obtained for new members of that series and also for alkyl transfer agents based on different leaving groups. The QSAR predictions were broadly accurate, but demonstrated that further refinement was both necessary and possible. In particular, the physicochemical parameters which relate to the disposition of the chemical in the epidermis, i.e., its penetration through the stratum corneum, cell surface/cytoplasmic distribution and the associated dynamics, will need to be understood more fully in order to enhance the precision of the QSAR and its predictive power.