Primary cutaneous irritancy represents a major cause of dermatologic mobidity in our society. No accepted and reliable in vitro model for primary irritancy in human skin currently exists. The present methods of screening products for potential irritancy by industries involved in the manufacture of consumer products is limited to in vivo techniques using animals and human volunteers. Development of a clinically relevant in vitro system to screen protential irritants would humane as well as cost effective. Before any assay for such screening purposes is developed, however, some basic information concerning the mechanisms of these reactions must be delineated. At present, the body of data concerning these reactions is surprisingly small. The overall objectives of these proposed studies is to elucidate the cellular mechanisms by which certain physical and chemical agents produce primary irritant reactions in human skin. The proposed studies will examine the effects of three types of cutaneous irritants-ultraviolet irradiation, phorbol ester tumor promoters, and non-promoting chemical irritants - in a human epidermal keratinocyte culture system. Specifically, we plan to assay the following irritant induced membrane related effects: a) Metabolism of saturated fatty acids, unsaturated fatty acids and polar head groups of membrane phospholipids. b) Production of arachidonic acid derived mediators of inflammation. c) Induction of alteration in selected aspects of proliferation and differentiation. Finally, we plan to define those in vitro aspects of primary cutaneous irritancy which best correlate with this response in man so as to identify assay systems which can be utilized for predictive in vitro testing of potential irritants.
