The long-term goal is to understand chemical and biological interactions in a chemical mixture that modulate dermal disposition of irritants or chemicals and to be able to predict chemical and biological interactions in a chemically-defined mixture in the workplace. As it is very difficult to experimentally test all commercial cutting fluids or oils, the primary objective of this research project is to investigate the influence of chemical mixtures on the dermal disposition and cutaneous toxicity of several cutting fluid additives and contaminants using a novel experimental paradigm. Complete or partial factorial experiments can be designed to determine the various levels of interactions using appropriate skin models with various levels of biological complexity. The central hypothesis to be tested is that chemical-chemical and chemical- biological interactions can occur on or in the skin which eventually determine the fate of the irritant(s) and thus its potential to cause irritant dermatitis. The rationale for this proposed approach is that many of the chemical additives or components in a cutting fluid formulation behave as solvents, co-solvents, or surfactants, which can modulate percutaneous absorption by altering the normal anatomy and physiology of the skin by discrete mechanisms. The following three specific aims will be pursued to accomplish the stated objectives: 1) Determine statistically significant chemical-chemical and chemical-biological interactions for five component mixtures using three skin model systems possessing increasing levels of biological complexity. Silastic membranes, porcine skin sections, and isolated perfused porcine skin flaps (IPPSFs) will be used to probe for various levels of interactions. (2) Determine interactions with common cutting fluid contaminants, nickel and nitrosodiethanolamine, and a cleansing solvent, trichloroethylene. IPPSFs will be used in these reduced factorial experiments. (3) Using biomarkers of irritation, determine significant changes in epidermal barrier structure and function in skin flaps exposed to mixtures that significantly alter component(s) disposition within skin. These latter experiments will primarily focus on subclinical effects, such as prostaglandin and cytokine release. At the completion of this project, we expect to identify significant interactions between functional components of the mixture that will contribute to a better understanding of additive deposition and irritancy of related cutting fluid products. This experimental approach allows interaction models to be built which can be used to assess other workplace mixtures.
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