Skin Allergy

Mechanistic understanding of the key events that drive skin sensitisation has recently been documented as an Adverse Outcome Pathway (AOP) and a range of data integration approaches have been proposed to characterise sensitiser potential or potency using non-animal test method data. Despite this progress our ability to combine these non-animal hazard data with exposure information to inform risk assessment decisions (i.e. to establish a safe level of human exposure for a sensitising chemical) remains a key gap.  Our aim is to apply our mechanistic understanding of skin sensitisation to improve our ability to make risk assessment decisions.  Central to our approach is mathematical modelling of the response and evaluation of model output against available clinical data on sensitisation. Our current model outputs naïve CD8+ T cell activation as a surrogate measure for sensitisation induction in humans (See Figure 1).

Figure 1: Model scope relative to Skin Sensitisation AOP

skin

Ordinary differential equations are used to model key events of the AOP: skin penetration (chemical diffusion and partitioning), haptenation of protein nucleophiles and antigen processing and presentation by skin dendritic cells (see Figure 2).

Figure 2: Model Schematic

skin1

Biological parameters are taken from the immunological literature with human data used where possible.  Bioavailability and chemical-specific parameters are derived from bespoke in vitro experiments and from sensitiser-specific literature.  The model has been used to simulate a study published previously by Friedmann et al. in which 132 healthy volunteers were exposed to one of five doses of the contact allergen 2,4-dinitrochlorobenzene.  Clinical research and additional modelling is currently underway with a number of academic partners to inform future model development.

Latest Presentation

Applying the Skin Sensitisation AOP to Human Health Risk Assessment

Latest Publications

Maxwell G, MacKay C, Cubberley R, Davies M, Gellatly N, Glavin S, Gouin T, Jacquoilleot S, Moore C, Pendlington R, Saib O, Sheffield D, Stark R, Summerfield V (2014) Applying the skin sensitisation adverse outcome pathway (AOP) to quantitative risk assessment, Toxicology in Vitro 28, 8–12

http://www.ncbi.nlm.nih.gov/pubmed/24184331

MacKay C, Davies M, Summerfield V, Maxwell G (2013). From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitisation risk assessment ALTEX, 30, 473-486

http://www.ncbi.nlm.nih.gov/pubmed/24173169

Dr. Gavin Maxwell