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eGenero, Investigators Brochure and Protocol, at http://www.mhra.gov.uk.

repel, F., 1974. Klin. Wochenschr. 52, 511–515.

oi:10.1016/j.tox.2006.11.026

n silico modelling of skin sensitisation

. MacKay 1,a, S. Bajaria 2,a, G. Shaver 2,a,

. Kudrycki 2, S. Ramanujan 2, T. Paterson 2,

. Friedrich 2, G. Maxwell 1, I. Jowsey 1, D. Lockley 1,. Reynolds 1, J. Fentem 1

Unilever, Safety and Environmental Assurance Centre,harnbrook, Bedfordshire MK44 1LQ, UK 2 Entelos,oster City, CA 94404, USA

-mail address: cameron.mackay@unilever.comC. MacKay).

The 7th Amendment to the EU Cosmetics Direc-ive and the proposed new EU Chemicals RegulationREACH) challenge the use of animal tests for evaluat-ng the safety of chemicals and consumer products. Oneoxicological endpoint for which there are no currentlyccepted non-animal methods is the induction of skinensitisation. For this endpoint, the mouse local lymphode assay is now in widespread use. It is postulated thatew technologies will, in future, when applied in con-unction with new experimental (non-animal) models,nable the generation of different types of data that cane interpreted via new risk assessment paradigms for therotection of human health (Fentem et al., 2004).

In this study, a “systems biology” approach (Lewis etl., 2001; Rullman et al., 2005) has been used to constructcomputer-based mathematical model of the induc-

ion of skin sensitisation. The resulting model (the Skinensitisation Induction (SSI) PhysioLab® platform)omprises a large-scale system of nonlinear ordinary dif-erential equations representing biological mechanismsnderlying the induction phase of skin sensitisation. The

hysioLab platform models the following key events: (1)hemical exposure in the epidermis; (2) epidermal cellctivation and cytokine production; (3) chemical uptakend processing by epidermal Langerhans cells (LCs);

(2007) 100–103 103

(4) LC traffic to the draining lymph node (LN); (5) anti-gen presentation and costimulation in the LN, and (6)the resulting CD4+ and CD8+ T cell responses. Theeffects of 8 chemicals (dinitrocholrobenzene, oxazolone,isoeugenol, cinnamic aldehyde, hexyl cinnamic alde-hyde, hydroquinone, p-aminobenzoic acid, and glycerol)were represented in the model. Both qualitative andquantitative information from a total of 496 papersin the contemporary literature were utilised. In orderto calibrate the model, available quantitative data wasincorporated in order that the model could reproduce keyresults from 35 published experiments (e.g. keratinocytecytokine response to chemical stimulus). The model wasthen checked to ensure that the system-level physiolog-ical behaviours associated with chemical-induced skinsensitisation were reproducible, by using a set of 30experiments taken from 14 published papers (distinctfrom those used for calibration purposes).

The results of sensitivity analysis of the Physiolabplatform identified several factors as having a majorinfluence on the induction of skin sensitisation. Theseinclude TNF-alpha production in the epidermis, theexpression of LC co-stimulatory molecules, the numberof specific T-cell clones and their affinity for antigen.This initial analysis has provided an understanding ofthe major sources of variability and uncertainty in ourcurrent knowledge, and highlighted knowledge gaps forfuture investigative research. The in silico model appearsto provide an appropriate platform for biologically rel-evant integration of data from existing and new in vitrotests for risk assessment purposes.

References

Fentem, J., Chamberlain, M., Sangster, B., 2004. ATLA 32, 617–623.

Lewis, A.K., Paterson, T., Leong, C.C., Defranoux, N., Holgate, S.T.,Stokes, C.L., 2001. Int. Arch. Allergy Immunol. 124, 282–286.

Rullman, J.A.C., Struemper, H., Defranoux, N.A., Ramanujan, S.,Meeuwisse, C.M.L., van Elas, A., 2005. IEE Proc. Syst. Biol. 152,

256–262.

a Equal contributing authors.

doi:10.1016/j.tox.2006.11.027