Skin Irritation and Sensitization: Mechanisms and New Approaches for Risk Assessment

Abstract

Allergic contact dermatitis (ACD) is a common skin disease with a significant social and economic impact. In contrast to irritation, skin sensitization is a response of the adaptive immune system, in which there is a delayed T-cell-mediated allergic response to chemically modified skin proteins. The chemicals that can covalently modify the skin proteins and trigger an allergic reaction are referred to as haptens or sensitizers. Attempts have been made in many countries to reduce the problems of ACD by the implementation of legislations related to skin-sensitizing chemicals, as well as by the early detection and risk assessment of substances with sensitizing properties. For many years, the simple identification of sensitizing chemicals was performed in guinea pig tests. A murine test, the local lymph node assay (LLNA), has been validated as a replacement for the guinea pig tests. Despite the recent introduction of in vitro methods for the identification of sensitizing chemicals, the LLNA results (when coupled with good exposure data) can be used as the starting point for a quantitative risk assessment. The quantitative risk assessment is aimed to identify the safe use thresholds for any potential skin sensitizer.

Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor-dependent phase I genes

“…Human primary dendritic cells as well as myeloid cell lines are used in in vitro approaches to predict skin sensitization (Basketter et al, 2008;Ott et al, 2010;Python et al, 2009), e.g., the Myeloid U937 Skin Sensitization Test (MUSST), which measures increase of CD86 expression (Ade et al, 2006;Python et al, 2007), the human Cell Line Activation Test (h-CLAT), which assesses increase of CD86 and combined CD54 expression (Sakaguchi et al, 2006), or the Genomic Allergen Rapid Detection (GARD), which is based on a signature of predictive genes differentially regulated in the MUTZ3 cell line when stimulated with sensitizing compared to non-sensitizing compounds (Johansson et al, 2013).…”

“…Human cell lines including THP-1, MUTZ-3 and U937 should undergo similar alterations after activation, which indicate their potential to behave like a DC. In addition to primary DCs, these cell lines are used as an alternative tool to predict skin sensitization (Basketter et al, 2008;Ott et al, 2010;Python et al, 2009).…”

High-Resolution Transcriptional Profiling of Chemical-Stimulated Dendritic Cells Identifies Immunogenic Contact Allergens, but Not Prohaptens

“…Impairment of skin barrier function is frequently associated with cutaneous inflammation resulting in different clinical phenotypes such as allergic contact dermatitis (ACD) [1,2] . ACD represents a common inflammatory skin disease with a cumulative prevalence of 15-20% in the general population of western countries.…”

“…Premarketing skin hazard assessment of newly introduced xenobiotic compounds still mainly relies on in vivo animal testing methods such as the murine local lymph node assay [1] . However, a complete ban on in vivo testing of cosmetic and toiletry ingredients for skin-sensitizing properties will come into force within the European Union in 2013 [15] .…”

“…In particular the second aspect has led to a focus on the chemical-induced stimulation of moDCs, CD34+ progenitor-derived dendritic cells (DCs) or myeloid/DC lines (THP-1, KG-1, MUTZ 3, U-937). These methods assess phenotypic alterations, cytokine secretion or differential gene regulation of the implemented APCs after incubation with the respective test substance [1] .…”