Skin Sensitization: What is it? Why is it important? What are the challenges?

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Skin Sensitization

Skin Sensitization: What is it? Why is it important? What are the challenges?

Ian Kimber, University of Manchester and G. Frank Gerberick, Procter & Gamble

Published: December 6, 2007

About the Author(s)
Ian Kimber is currently Professor and Chair of Toxicology at the University of Manchester. Previous to that he was Head of Research and Principal Fellow at the Syngenta Central Toxicology Laboratory. He has broad research interests based around immunotoxicology, allergy and skin biology with specific research themes currently including: the pathogenesis of food allergy, the stimulation of T lymphocyte responses by skin sensitising chemicals and respiratory allergens, and the molecular regulation of Langerhans cell function and the roles played by these cells in the orchestration of cutaneous immune responses. In addition, Professor Kimber has active interests in the development, validation and application of novel predictive test methods in toxicology, and in research that seeks to reduce, refine and replace the use of animals in safety assessment.

Professor Kimber holds, and has held, a wide variety of positions on national and international expert and scientific advisory committees. Currently these include the following: UK Medical Research Council Training and Career Development Board, UK Medicine and Health Regulatory Agency Committee for Safety of Devices, Programme Advisor Food Standards Agency, and member OECD Expert Committee on Sensitisation.

He has published over 500 research papers, review articles and book chapters and serves currently on the editorial boards of toxicology, immunology, dermatology and pathology journals.

Professor Kimber has received a number of awards and prizes. These include: the SmithKline Beecham Laboratory Animal Welfare Prize (2000), the 9th Robert A Scala Award in Toxicology, the Doerenkamp-Zbinden Foundation Prize for Realistic Animal Protection in Biomedical Research (2001), Society of Toxicology Enhancement of Animal Welfare Award (2003), and Society of Toxicology Immunotoxicology Career Achievement Award (2005).

Dr. Ian Kimber
University of Manchester
Michael Smith Building
Oxford Rd
Manchester, M13 9PT
UK
E-mail: ian.kimber@manchester.ac.uk

Dr. Frank Gerberick
Procter & Gamble
Miami Valley Innovation Center
Cincinnati, OH 45253
E-mail: gerberick.gf@pg.com

Skin sensitization resulting in allergic contact dermatitis is a common occupational and environmental health issue. Many hundreds of chemicals have been implicated as skin sensitizers, and allergic contact dermatitis is without doubt the most common manifestation of immunotoxicity in humans.

In common with all forms of allergic disease, contact allergy develops in two phases and is by definition dependent upon the stimulation of an immune response. The first phase – or induction phase – is initiated when an inherently susceptible individual is exposed (usually at the skin surface) to an amount of contact allergen sufficient to trigger a cutaneous immune response resulting in immunological priming. A subject that has acquired skin sensitization now has the ability to mount an accelerated and more aggressive secondary immune response if contact is made with the same allergen again at the same or a distant skin site. This second phase – or elicitation phase – is associated with a localised cutaneous inflammatory reaction at the site of skin exposure that is characterized clinically as allergic contact dermatitis.

Allergic contact dermatitis is not life-threatening, but can be associated with considerable morbidity. Sensitisation is life-long, or at least long-lasting, and can result in the need for redeployment if acquired to chemicals in the workplace.

There is, therefore, a continuing and important need for the accurate identification and characterization of chemicals that have the potential to cause skin sensitization. Initially guinea pig methods were favoured for the purposes of hazard identification, the most widely applied being the Guinea Pig Maximization Test (1) and the Occluded Patch Test (2). More recently, the murine local lymph node assay (LLNA) has been introduced and validated as an alternative to traditional guinea pig test methods, and has been assigned an OECD test guideline (No 429) (3).

The LLNA identifies skin sensitizing chemicals as a function of their ability to provoke T lymphocyte proliferative responses in lymph nodes draining the site of topical exposure. Chemicals are classified as being contact allergens if, at one or more test concentrations, a 3-fold or greater proliferative response is induced in draining lymph nodes compared with concurrent control values (3). The approach employed by the LLNA, wherein activity is measured with respect to events during the induction phase of sensitisation, contrasts with guinea pig tests where sensitisation potential is determined as a function of the ability of chemicals to induce and elicit dermal hypersensitivity reactions (1, 2).

Although it can be argued that there are now available animal models that provide for the needs of skin sensitization hazard identification, there is a real requirement for the purposes of risk assessment to have some understanding of relative potency. Although a case can be made that an appreciation of potency is relevant for all forms of safety assessment, it is particularly the case with respect to skin sensitizers. This is because there is reason to believe that skin sensitising chemicals vary by up to 5 orders of magnitude with regard to their relative potency. Effective risk assessment, and appropriate risk management strategies, rely therefore on information about relative sensitising activity, and the preferred approach currently for providing this is derivation of an EC3 value from analysis of LLNA dose responses (4).

This approach is based on an appreciation that not only does lymph node cell proliferation provide a marker for sensitizing activity, it also correlates causally and quantitatively with the extent to which sensitization is acquired. It is possible therefore to determine relative sensitizing potency as a function of the vigour of induced proliferative responses and for this purpose an EC3 value is derived – this being the amount of chemical required to stimulate a 3-fold increase in lymph node cell proliferation compared with controls (4).

Hazard and risk assessment for skin sensitization is therefore relatively well-served by animal test methods. However, there is interest now in defining new approaches that will allow a reduction or refinement of animal use, or that will allow the replacement of animals altogether. Although it has been proposed recently that a cut-down or reduced version of the LLNA might in some circumstances allow for further refinement and reduction of animal use for hazard identification (but not potency assessment) (5), the real focus is on the development of non-animal methods.

Recent progress has been summarised elsewhere and readers are directed to the following articles for information on recent and current progress (6-11). It is against this background that we hope that debate can be encouraged in the AltTox.org Forum.
©2007 Ian Kimber & G. Frank Gerberick

References
  1. Magnusson, B. & Kligman, A.M. (1970). Allergic Contact Dermatitis in the Guinea Pig. Charles C Thomas, Springfield, IL.
  2. Buehler, E.V. (1965). Delayed contact hypersensitivity in the guinea pig. Arch. Dermatol. 91, 171-177.
  3. Kimber, I., Dearman, R.J., Basketter, D.A., Ryan, C.A. & Gerberick, G.F. (2002). The local lymph node assay: past, present and future. Contact Derm. 47, 315-328.
  4. Basketter, D.A., Gerberick, F. & Kimber, I. (2007). The local lymph node assay and the assessment of relative potency: status of validation. Contact Derm. 57, 70-75.
  5. Kimber, I., Dearman, R.J., Betts, C.J., Gerberick, G.F., Ryan, C.A., Kern, P.S., Patlewicz, G. & Basketter, D.A. (2006). The local lymph node assay and skin sensitization: a cut-down screen to reduce animal requirements? Contact Derm. 54, 181-185.
  6. Kimber, I., Pichowski, J.S., Betts, C.J., Cumberbatch, M., Basketter, D.A. & Dearman, R.J. (2001). Alternative approaches to identification and characterization of chemical allergens. Toxicol. In Vitro. 15, 307-312.
  7. Kimber, I., Cumberbatch, M., Betts, C.J. & Dearman, R.J. (2004). Dendritic cells and skin sensitization hazard assessment. Toxicol. In Vitro. 18, 195-202.
  8. Ryan, C.A., Gerberick, G.F., Gildea, L.A., Hulette, B.C., Betts, C.J., Cumberbatch, M., Dearman, R.J. & Kimber, I. (2005). Interactions of contact allergens with dendritic cells: opportunities and challenges for development of navel approaches to hazard assessment. Toxicol. Sci. 88, 4-11.
  9. Jowsey, I.R., Basketter, D.A., Westmoreland, C. & Kimber, I. (2006). A future approach to measuring relative skin sensitising potency: a proposal. J. Appl. Tox. 26, 341-350.
  10. Patlewicz, G., Aptula, A.O., Uriarte, E., Roberts, D.W., Kern, P.S., Gerberick, G.F., Kimber, I., Dearman, R.J., Ryan, C.A. & Basketter, D.A. (2007). An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential. SAR QSAR Environ. Res. 18, 515-541.
  11. Gerberick, G.F., Vassallo, J.D., Foertsch, L.M., Price, B.B., Chaney, J.G. & Lepoittevin, J.P. (2007). Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicol. Sci. 97, 417-427.