THE USE OF MECHANISTICALLY DEFINED CHEMICAL-MIXTURES (MDCM) TO ASSESSMIXTURE COMPONENT EFFECTS ON THE PERCUTANEOUS-ABSORPTION AND CUTANEOUS DISPOSITION OF TOPICALLY EXPOSED CHEMICALS .2. DEVELOPMENT OF A GENERAL DERMATOPHARMACOKINETIC MODEL FOR USE IN RISK ASSESSMENT

We present a conceptual approach to a general comprehensive mathematic al model to quantify percutaneous absorption of topically applied chem icals in complex mixtures on the basis of biophysical parameters estim ated or measured using in vitro and ex vivo perfused skin preparations . This model addresses mechanistically defined chemical mixtures (MDCM ) which consist of components selected because of their potential to m odulate by various mechanisms the absorption of a marker toxic penetra nt. This model accounts for observed toxicodynamic general and specifi c effects of chemicals, acting single or in concert, on the absorption of any or all components in a defined mixture. We have also included experimental data from an isolated perfused porcine skin flap study wi th topically applied parathion as the marker penetrant and acetone or DMSO as solvent, with methyl nicotinate as a potential rubefacient, so dium laurel sulfate as a surfactant, and stannous chloride as a reduci ng agent in order to provide an illustration of the application and pe rformance of the model. This model supports the MDCM concept that defi ning and then simulating those components of a complex mixture that co uld have a significant impact on the absorption of a marker toxic comp ound would be a useful screening approach in the risk assessment of to pical chemical mixtures. It may also be used to identify critical path ways where chemical mixture component interactions significantly modif y the absorption of the penetrant of interest. (C) 1996 Academic Press , Inc.