The importance of exposure estimation in the assessment of skin sensitization risk

The development of new ingredients and products for the consumer market requires a thorough assessment of their potential for skin sensitization and the possible clinical manifestation of allergic contact dermatitis. The process by which low molecular weight chemicals induce and elicit skin sensitization reactions is complex and dependent on many factors relevant to the ability of the chemical to penetrate the skin, react with protein, and trigger the cell-mediated immune response. These major factors include inherent potency, chemical dose, duration and frequency of exposure, vehicle or product matrix, and occlusion. The fact that a chemical is a contact allergen does not mean that it cannot be formulated into a consumer product at levels well tolerated by most individuals. Many common ingredients (e.g., fragrances, preservatives) are known skin allergens. However, all allergens show dose-response and threshold characteristics. Therefore, one should be able to incorporate these chemicals into products at levels that produce acceptably low incidences of skin sensitization under foreseeable conditions of exposure. The critical exposure determinant for evaluating skin sensitization risk is dose per unit area of skin exposed. Use of this parameter allows for comparative assessments from different types of skin sensitization tests (including cross-species comparisons), and, at least for known potent allergens, there is remarkable similarity in threshold dose/unit area determinations across species. The dose/unit area calculation enables a judgment of the sensitization risk for different product types. This is illustrated using the chemical preservative methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) as a case study.