The influence of the response of skin equivalent systems to topically applied consumer products by epithelial-mesenchymal interactions

A number of diverse in vitro model systems have been employed for the predi ction of irritation potential of test articles. Monolayer systems have prov en to be useful for preliminary screening but are not always capable of dis tinguishing mild effects or adaptable to fully formulated product. Three-di mensional reconstructed skin equivalents integrate cellular toxicity with t he kinetics of exposure and absorption, serving as more realistic models; h owever, it is not obvious which of the three-dimensional models will give t he most predictive response, and which biomarker should be used for an endp oint measurement for different groups of irritants. While evaluating these variables, we have shown that different irritants modulate various cytokine mRNA levels and secretion patterns in a time- and concentration-dependent manner that is unique to each product category. These profiles are also dep endent on keratinocyte-fibroblast interactions. The most predictive combina tions of model systems and biomarkers for each product category were identi fied following comparison to preclinical data and human in vivo skin respon ses. Using a panel of representative consumer products, we identified IL-1 alpha, IL-1ra, IL-8 and GM-CSF release from skin equivalents as being the b est indicators of irritation. (C) 1999 Elsevier Science Ltd. All rights res erved.