Next generation risk assessment for skin allergy: Decision making using new approach methodologies.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment (SARA) that do not require new animal test data and better quantify uncertainties. Significant progress has been made in the development of New Approach Methodologies (NAMs), non-animal test methods, for assessment of skin sensitisation and there is now focus on their application to derive potency information for use in Next Generation Risk Assessment (NGRA). The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data. Here we have applied the SARA model within our weight of evidence NGRA framework for skin allergy to three case study materials in four consumer products. Highlighting how to structure the risk assessment, apply NAMs to derive a point of departure and conclude on consumer safety risk. NGRA based upon NAMs were, for these exposures, at least as protective as the historical risk assessment approaches. Through such case studies we are building our confidence in using NAMs for skin allergy risk assessment.

A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.

Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model. SARA uses Bayesian statistics to provide a human relevant point of departure and risk metric for a given chemical exposure based upon input data that can include both NAMs and historical in vivo studies. Regardless of whether NAM or in vivo inputs were used, the model predicted that the face cream and deodorant exposures were low and high risk respectively. Using only NAM data resulted in a minor underestimation of risk relative to in vivo. Coumarin is a predicted pro-hapten and consequently, when applying this mechanistic understanding to the selection of NAMs the discordance in relative risk could be minimized. This case study demonstrates how integrating a computational model and generating bespoke NAM data in a weight of evidence framework can build confidence in safety decision making.

Cellular control of abscess formation: role of T cells in the regulation of abscesses formed in response to Bacteroides fragilis.

Although abscesses are a major sequela of infection, little is known about which cellular events initiate and which prevent this pathologic response. These studies are the first to indicate a role for T cells in the important pathogenic process of abscess development and also in immunity to abscesses induced by Bacteroides fragilis. We have shown that T cells initiate the formation of abscesses in mice after i.p. challenge with B. fragilis. These T cells bear both Ly-1 and Ly-2 surface markers. Nude mice (which have been shown by others to have T cell or T cell precursors) are also able to form abscesses. Cyclophosphamide-treated mice (with depressed T cell function) were not capable of developing abscesses. Reconstitution with normal or nude mouse spleen cells restored this ability. However, reconstitution with anti-Thy-1.2-treated, anti-Ly-1, or anti-Ly-2-treated spleen cells (or a mixture of the two cell populations) failed to allow abscess formation after bacterial challenge. Immunity to abscesses caused by B. fragilis requires two T cells. The first Ly-1-2+ T cell has an IJ surface marker and has been shown to release a small m.w. soluble factor (ITF) that is antigen specific. Immunity to abscesses, however, depends on the interaction of ITF with a second Ly-1-2+ T cell, demonstrated in reconstitution experiments with nude mice. The data presented document a critical role for T cells in abscess induction and suggest the existence of a suppressor-like T cell circuit in immunity to abscesses.