The Dermal Absorption of Selected Agricultural and Industrial Chemicals Through Porcine Skin with Emphasis on Chemical Mixture Effects

Abstract

The stratum corneum is the primary barrier to dermal absorption and the processes of absorption include partitioning into, and diffusion through, the lipid matrix of the stratum corneum. These studies were aimed at furthering our understanding of these processes and modeling dermal absorption. We used 11 industrial and agricultural compounds, including 14C labeled phenol, 4-nitrophenol, pentachlorophenol, dimethyl parathion, parathion, chloropyrifos, fenthion, triazine, atrazine, simazine and propazine, and 24 solvent mixtures consisting of combinations of water, ethanol, propylene glycol, sodium lauryl sulphate and methyl nicotinate. Study methods included in vitro partitioning using isolated stratum corneum and permeability studies, Fourier transform infrared spectroscopy, multivariate clustering techniques, transmission electron microscopy and light microscopy. A model of dermal absorption was developed using a physiological-based (PBPK) approach. Ethanol and ethanol/water mixtures altered the stratum corneum through lipid extraction, rather than through disruption of lipid order. Partitioning was primarily determined by relative compound solubility between the stratum corneum lipids and the donor solvent. Permeability reflected the result of successive, complex processes and was not consistently correlated with stratum corneum partitioning. These results demonstrated the potential of using large datasets to identify consistent solvent and chemical mixture effects. Diffusion cell studies were conducted to validate the PBPK model under a variety of conditions including different dose ranges (6.3-106.9 mg/cm2 for parathion; 0.8-23.6 mg/cm2 for fenthion; 1.6-39.3 mg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5-120 ml for ethanol; 20-80 ml for 2-propanol and acetone), occlusion versus open to atmosphere dosing, and corneocyte removal by tape-stripping. The study demonstrated the utility of PBPK models for studying dermal absorption, which can be useful as explanatory and predictive tools; and may be used for in silico hypotheses generation and limited hypotheses testing. These data have direct relevance to topical chemical exposure risk assessments.