A future approach to measuring relative skin sensitising potency: a proposal

Abstract

Current approaches to skin sensitisation risk assessment are dependent upon the availability of information regarding two fundamental parameters. Firstly, data relating to the relative skin sensitising potency of the chemical, and secondly, information regarding likely conditions of human exposure. During the past two decades, much has been achieved in terms of refining methods capable of informing these parameters. For example, the development of the local lymph node assay (LLNA) has made it possible to predict skin sensitising hazard, and to determine relative skin sensitising potency, in a way that was not possible previously. Taken together with accurate information about predicted exposure, such potency data can be used to facilitate the derivation of effective risk assessments. However, although the LLNA provides an integrated assessment of skin sensitising activity, it does require the use of experimental animals and there is growing enthusiasm for designing robust alternative approaches that will reduce or obviate that need. Progress is being made in defining alternative experimental strategies that avoid animal use, but it is clear that accurate characterisation of skin sensitisation hazards will require the effective integration of various sources of information. For this reason, we exemplify here one possible approach that, in theory, provides a framework for not only the identification of skin sensitising chemicals, but also the estimation of relative sensitising potency. This paradigm depends upon development of an understanding of the various biological, biochemical and chemical factors that impact on the allergenic properties of chemicals and the acquisition of skin sensitisation, and an ability to measure these in vitro.

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

“…Other types of assays are in development and include peptide reactivity and single cellbased assays using, for example, human keratinocytes and dendritic cells (DC). They assess the activation of the innate immune system and of the antioxidant response which are hallmarks of the reactivity of such chemicals [16][17][18][19][20][21][22][23]. The innate immune response is essential for both the sensitization to the chemical and the subsequent adaptive T-cellmediated immune response upon further contacts [18][19][20].…”

“…The innate immune response is essential for both the sensitization to the chemical and the subsequent adaptive T-cellmediated immune response upon further contacts [18][19][20]. In the single cell-based assays the sensitization potential of chemicals is tested by measuring, for example, chemicalinduced antioxidant responses [21,22] or IL-18 production in keratinocytes [23] or the induction of activation markers such as CD86 on the cell surface of DC [16,17].…”

“…They can be easily incorporated into tiered risk assessment strategies [16]. Protein-reactive small chemicals efficiently induce T-cell responses and B-cell responses, but the role of antibodies in the pathogenesis of ACD and ADR is not clear and is a matter of controversy.…”

“…From this research we have already identified and will identify key mechanisms and pathways that are being successfully incorporated in novel in vitro assays in immunotoxicology [17]. This will help to build a tiered strategy with a battery of assays that cover the different steps from sensitization to elicitation of chemical-induced disease [16,17]. Past efforts using T cells in the study of immune responses to chemicals…”

Characterization of skin sensitizing chemicals: A lesson learnt from nickel allergy

“…We and others have drawn attention to the fact that the effective acquisition of skin sensitization is dependent upon a number of biological "hurdles" being cleared after encounter with a chemical allergen on the skin (Dearman and Kimber, 2003;Jowsey et al, 2006 of the immune system can be effected. In addition, it is necessary that the chemical is able to form stable associations with protein to provide an immunogenic hapten-protein conjugate.…”