Comparison of In Vivo, Ex Vivo, and In Vitro Dermal Absorption Models: Pentachlorophenol (PCP) Studies with Multiple Media. G. L. Qiao and J. E. Riviere, Cutaneous Pharmacology and Toxicology Center, North Carolina State University, Raleigh, NC 27606
PCP is one of the most heavily applied fungicides or pesticides and one of the most commonly detected environmental contaminants in the human. To quantify experimental model differences for data extrapolation in risk assessment, PCP dermal absorption and disposition in different media were studied in in vivo (whole pig, n=3), ex vivo (Isolated Perfused Porcine Skin Flap, n=4), in vitro (flow through diffusion cell, n=7) porcine skin, as well as in vitro human skin cell culture models. 14C-PCP was dosed at 40 g/cm2 in different media including ethanol, acetone, water-based, and soil-based mixtures. Model similarities or differences in PCP absorption and tissue disposition were assessed while counting for the dosing medium impacts. Generally, the diffusion cell absorption data with the human skin cell culture system overestimated and had a much earlier peaking time (15-60 min) than other models. The pig skin diffusion cell and IPPSF data were better correlated to the in vivo findings although some differences were observed. The model differences may be better quantified by applying dermatopharmacokinetic modeling approach and PCP metabolism studies. Across all model systems used, we found significant model-dependent dosing medium effects on dermal absorption and disposition. Greater medium-dependencies in absorption, penetration, and absorption efficiency were observed with pig skin model than with human skin cell culture system. Dose dependency in terms of PCP absorption from soil might be experimental model-dependent, which increases the complexity of data extrapolation and dermal risk assessment. Therefore, the model-dependent application medium effect and the medium-dependent experimental model differences were studied, and the mechanisms of the interactions between absorption model and application medium were explored.
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