a Cosmetics Division, Office of Cosmetics and Colors (OCAC) , Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA) , MD , USA.
Crit Rev Toxicol. 2017 May;47(5):415-432. doi: 10.1080/10408444.2017.1288025. Epub 2017 Mar 22.
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals.
变应性接触性皮炎（ACD）是一种由重复接触敏化剂引起的迟发型超敏反应（DTH）。一种化学物质作为敏化剂的能力最常通过动物试验进行测试。由于动物在这些方面的使用正逐渐在全球范围内被淘汰，因此需要可靠的体外替代检测方法。目前提出的体外检测方法旨在测试涉及敏化剂对自身蛋白的共价修饰（半抗原化）和将新抗原（半抗原/载体复合物）呈递给免疫系统的不良结局途径（AOP）的四个关键事件。体外检测方法与临床和/或动物数据之间似乎存在不完善的一致性，这表明可能存在 ACD 发展的其他机制。事实上，关于对小分子药物的过敏、小分子化学诱导 HLA-肽交换以用于疫苗接种目的以及化妆品成分诱导自身抗原暴露的研究表明，半抗原/载体非依赖性机制可能促进 DTH 反应。因此，需要额外的适当的体外检测方法，以实现临床和/或动物数据与体外检测方法之间的最大一致性。在本文中，我们将回顾支持 ACD 发展多种机制的证据。我们还将讨论这些多种机制对 AOP 和用于过敏原检测的体外检测方法的影响。我们将提出类似于同种异体反应的反应，通过计算机建模和化合物-HLA 结合的生化测试来辅助，作为更好地预测由于暴露于化妆品成分而引起的 DTH 反应的额外工具。结合提出的测试以及现有的测试，应该可以进一步增强对个体化学品致敏潜力的无动物评估。
