ABSTRACT
A number of diverse in vitro model systems have been employed for the prediction of irritation potential of test articles. Monolayer systems have proven to be useful for preliminary screening but are not always capable of distinguishing mild effects or adaptable to fully formulated product. Three-dimensional reconstructed skin equivalents integrate cellular toxicity with the kinetics of exposure and absorption, serving as more realistic models; however, it is not obvious which of the three-dimensional models will give the most predictive response, and which biomarker should be used for an endpoint 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 dependent on keratinocyte-fibroblast interactions. The most predictive combinations of model systems and biomarkers for each product category were identified following comparison to preclinical data and human in vivo skin responses. Using a panel of representative consumer products, we identified IL-1alpha, IL-1ra, IL-8 and GM-CSF release from skin equivalents as being the best indicators of irritation.
ABSTRACT
We have previously evaluated the measurement of viability and cytokine release from skin equivalents, for predicting the skin irritation potential of topically applied surfactants and demonstrated that IL-1alpha and interleukin-1 receptor antagonist (IL-1ra) release from epidermal skin equivalents correlates with skin irritation potential. In this study, the utility of the model was confirmed by the evaluation of cleansing bars and cleansing lotions that exhibited varying degrees of irritation potential as determined by exaggerated arm wash human clinical studies. Epidermal equivalents were exposed to increasing concentrations of the cleansing bars and cleansing liquids and viability and release of IL-1alpha and IL-1ra were measured. Loss of viability was used to identify the stronger irritants of the products tested. A linear correlation was demonstrated between IL-1alpha and IL-1ra secretion and human irritation data, demonstrating that the model can correctly predict the irritation potential of soap and surfactant products. These results show that this in vitro model is useful for rank ordering the irritation potential of mild consumer products and for demonstrating enhanced mildness in products with minor differences.
