Recently, attention has been directed to the risk assessment of cutaneous exposure to chemical mixtures rather than to only a single compound since this is the exposure scenario in the environment, residence, and work place. Using acetone or dimethylsulfoxide (DMSO) (80% in water) as a vehicle, percutaneous absorption and cutaneous disposition of parathion (PA) were studied following PA (40 microg/cm2) dosing on isolated perfused porcine skin as mechanistically defined chemical mixtures (MDCM) consisting of the surfactant sodium lauryl sulfate (SLS), the rubefacient methyl nicotinate (MNA), and the reducing agent stannous chloride (SnCl2). A full 2 x 4 factorial design was used to asses treatment effects and potential interactions. More radiolabel was absorbed with DMSO than with acetone albeit an earlier peak flux time but lower peak flux was observed with acetone than with DMSO. The absorption flux rate profiles with DMSO continued increasing but bipeak-featured profiles were observed with acetone. SLS enhanced PA absorption with both DMSO and acetone. The presence of MNA in both vehicles blunted the absorption rate curves without significantly changing total absorption. SnCl2 blocked PA absorption and increased residue level on the skin surface and in the stratum corneum (SC). The venous flux profiles were mixture-dependent and highly reproducible within treatment groups. Higher level interactions were also noted. This study indicated multiple levels of interactive effects on PA absorption which must be incorporated into any effort to identify critical mechanisms which affect risk assessment of topically exposed mixtures. It was suggested that the chemicals selected in a topically applied mixture may have significant effects on the penetration/distribution pattern and percutaneous absorption profile of a toxicant/drug in the mixture. The MDCM approach may be useful in a screening or triage approach to identify mixture components which affect marker chemical absorption as well as identify potential mechanisms which deserve further attention. Risk assessment efforts could then be focused on those mixtures, containing these critical components, which would be expected to have the greatest penetration and absorption.