The derivation of quantitative correlations between skin sensitisation and physio-chemical parameters for alkylating agents, and their application to experimental data for sultones

Abstract

Quantitative relationships are derived, for skin sensitisation by alkylating agents, between sensitisation potential (as measured by the number of animals responding in a given test) and physico-chemical parameters. A composite parameter, the relative alkylation index ( RAI), which is a function of chemical reactivity (measured in vitro), lipophilicity (as expressed by a partition coefficient measured in vitro) and dose administered, is used as a relative measure of the extent of in vivo alkylation produced by a given dose of a given alkylating agent. The number of animals rendered sensitive in the induction stage of a sensitisation test is related to RAI i (the subscript i referring to induction) by a double sigmoid curve whereby as RAI i is increased from a low value the number of animals rendered sensitive increases, until induction of tolerance begins to predominate and further increase in RAI i gives a decrease in the number of animals sensitive. It is argued that the number of animals responding in the challenge stage of a sensitisation test will depend on the number of animals sensitised, the extent to which they are sensitised, and on RAI c the RAI value applying to the challenge process. It is argued that a plot of RAI c,50 , the RAI c value required to produce a response in 50% of the test animals challenged, against RAI i , should be U-shaped. These theoretically derived correlations are shown to apply to experimental data on skin sensitisation by saturated sultones and by unsaturated sultones.