Gavin Maxwell and Cameron MacKay
We have developed an in silico model of the induction of skin sensitisation, in order to characterise and quantify the contribution of each pathway to the overall biological process. This analysis has been used to guide our research on skin sensitisation and in vitro test development programmes, and provides a theoretical rationale for the interpretation and integration of non-animal predictive data for risk assessment (RA) purposes. The in vivo mouse Local Lymph Node Assay (LLNA) is now in widespread use for the evaluation of skin sensitisation potential and potency. Recent changes in European Union (EU) legislation (i.e. the 7th Amendment to the EU Cosmetics Directive) have made the development of nonanimal approaches to provide the data for skin sensitisation RA a key business need. Several in vitro predictive assays have already been developed for the prediction of skin sensitisation. However, these are based on the determination of a small number of pathways within the overall biological process, and our understanding of the relative contribution of these individual pathways to skin sensitisation induction is limited. To address this knowledge gap, a “systems biology” approach has been used to construct a computer-based mathematical model of the induction of skin sensitisation, in collaboration with Entelos, Inc. The biological mechanisms underlying the induction phase of skin sensitisation are represented by nonlinear ordinary differential equations and defined by using information from over 500 published papers. By using the model, we have identified knowledge gaps for future investigative research, and key factors that have a major influence on the induction of skin sensitisation (e.g. TNF-α production in the epidermis). The relative contribution of each of these key pathways has been assessed by determining their contributions to the overall process (e.g. sensitiser-specific T-cell proliferation in the draining lymph node). This information provides a biologically-relevant rationale for the interpretation and potential integration of diverse types of non-animal predictive data. Consequently, the Skin Sensitisation Physiolab® (SSP) platform represents one approach to integration that is likely to prove an invaluable tool for hazard evaluation in a new framework for consumer safety RA.
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