Introduction and Definitions
Physiology actually represent normal function, which is not really an appropriate label for ACD! Pathology describes the typical behavior of this disease. The basic mechanism of contact allergy is shown in the following figure:

Patch testing represents:
.standardised clinical investigation of possible contact eczema
..patch test concentrations
…evaluations: some are better than others
….is a vital diagnostic tool!

Allergy and thresholds:
Allergy is not an all or none phenomenon; dose response relationships clearly exist for induction and elicitation. Thus for both, “safe” levels can be defined.

We know that thresholds occur for induction and elicitation as:
• not all those exposed are sensitised
• not all those who are sensitised react
• a sensitised individual does not react to any exposure

As an example of the ACD induction dose response, predictive human skin sensitisation tests showed:
  1.0% PPD sensitised 54%
  0.1% PPD sensitised 11%
  0.01% PPD sensitised 7%

Friedmann and co-workers (1990) clearly showed induction dose responses to DNCB, derived an IC50 value and proved it!

The picture below shows an elicitation dose response to 48h patch testing in a subject who is allergic to cinnamic aldehyde. Although a strong reaction occurs at 1.0%, at 0.1%, no significant response can be observed, only the mark made by the Finn chamber.

What determines an elicitation threshold?
• The degree of sensitisation induced
• Individual susceptibility to inflammatory stimuli
• The rate of haptenation at the relevant target site which depends on:
    o skin exposure concentration
    o duration of skin exposure
    o metabolic activation/inactivation
    o individual heterogeneity

However, when you repeat the application of 1.0% PPD in petrolatum the threshold may change compared to that found following single treatment. For example, whilst a single application of 1% PPD for 5 minutes resulted in only 1/19 positive reactions, 5 minutes per day repeated open application of PPD under these conditions generated 8/19 positive allergic reactions; average erythema 1.9 (scale 0-3); average time to react 3-4 days. The quickest to respond were those who reacted to shortest times in patch tests (Hextall JM, et al., 2002).

Elicitation in hand eczema?
Studies in nickel allergic subjects:
• patch testing on hands with mild eczema indicated no greater sensitivity than the back where the threshold in the presence of SLS is about 1 ppm nickel
• 1 ppm nickel, daily 10 minute hand exposure for 1 month in the presence of SLS had no effect
• 10-100 ppm nickel, daily for 10 minutes on the fingers of individuals with hand eczema did elicit allergic reactions over a period of days/weeks

Does irritancy affect ACD?
Yes, but how? And is it always one-way?
Do irritants boost skin penetration?
Do irritants cause non-specific release of signals?
Do irritants disturb proteins and so expose hidden sites for haptenation?
Do irritants stimulate Langerhans cell migration?
Are those more easily irritated at greater risk?
Yes, and ...No – the situation is quite complex.

However, the important consideration is when irritants and allergens are applied at about the same time - then there is almost always a significant increase in allergic sensitivity.

In Europe, an EU expert group is advising on how to incorporate potency/thresholds into regulatory toxicology for allergens. Simple classification for example as extreme, strong, moderate and weak categories may be proposed. Subsequent risk assessment/management will then depend on allergen potency - this seems obvious, but it would be the first time that a structured approach involving potency has been adopted into international regulatory toxicology! For example, the new OECD method, the local lymph node assay (LLNA; Guideline 429) readily lends itself to the measurement of potency. Substantial peer-reviewed publication supports the value of the LLNA as a predictor of the relative human potency of contact allergens. Also, simple strategies to enable guinea pig tests to deliver broad potency classification are being developed by ECETOC. The EU expert group meets in early November 2002.

In conclusion - this is a complex subject, but there already exists a sufficient degree of understanding to permit the predictive identification of potential allergens, to measure their relative human potency and so to enable their risk assessment and thus appropriate risk management. The current burden of disease suggests to me that not everyone yet is doing what they should.

Relevant references
Basketter DA, Blaikie L, Dearman RJ, Kimber I, Ryan CA, Gerberick GF, Harvey P, Evans P, White IR and Rycroft RJG (2000) Use of the local lymph node assay for the estimation of relative contact allergenic potency. Contact Dermatitis, 42, 344-348.

Basketter DA, Evans PE, Gerberick GF and Kimber I (2002) Factors affecting thresholds in allergic contact dermatitis: Safety and regulatory considerations. Contact Dermatitis, 47, 1-6.

Basketter DA, Gerberick GF and Kimber I. (2001) Measurement of allergenic potency using the local lymph node assay. Trends in Pharmacological Sciences, 22, 264-265.

Basketter DA, Lea L, Cooper K, Dickens A, Briggs D, Pate I, Dearman RJ and Kimber I (1999) A comparison of statistical approaches to derivation of EC3 values from local lymph node assay dose responses. J Appl Toxicol, 19, 261-266.

Basketter DA, Lea L, Cooper K, Dickens A, Stocks J, Pate I, Dearman RJ and Kimber I (1999) Thresholds for classification as a skin sensitiser in the local lymph node assay: a statistical evaluation. Food and Chem Toxicol., 37, 1167-1174.

Felter SP, Robinson MK, Basketter DA and Gerberick GF (2002) A review of the scientific basis for default uncertainty factors for use in quantitative risk assessment of the induction of allergic contact dermatitis. Contact Dermatitis, 47, in press.

Felter SP, Ryan CA, Basketter DA and Gerberick GF (2002) Application of the risk assessment paradigm to the induction of allergic contact dermatitis. Regulatory Toxicol Pharmcol, submitted.

Friedman PS (1990) The immunology of allergic contact dermatitis: the DNCB story. Adv. Dermatol., 5, 175-196.

Gerberick GF, Robinson MK, Felter S, White I and Basketter DA. (2001) Understanding fragrance allergy using an exposure-based risk assessment approach. Contact Dermatitis, 45, 333-340.

Gerberick GF, Robinson MK, Ryan CA, Dearman RJ, Kimber I, Basketter DA, Wright Z and Marks JG. (2001) Contact allergenic potency: Correlation of human and local lymph node assay data. Am J Cont Derm, 12, 156-161.

Hextall JM, Algaratnam NJ, Glendinning AK, Holloway DB, Basketter DA and McFadden JP (2002) Dose/time relationships for elicitation of skin allergy to para-phenylenediamine. Contact Dermatitis, 47, in press.

Kimber I and Basketter DA (1997) Contact sensitization: A new approach to risk assessment. Human and Ecological Risk Assessment, 3, 385-395.

OECD (2002). Guidelines for Testing of Chemicals. Guideline No. 429. Skin Sensitisation: The Local Lymph Node Assay. Organisation for Economic Cooperation and Development, Paris.

Robinson MK, Gerberick GF, Ryan CA, McNamee P, White IR and Basketter DA (2000) The importance of exposure estimation in the assessment of skin sensitization risk. Contact Dermatitis, 42, 251-259.

Ryan CA, Gerberick GF, Cruse LW, Basketter DA, Lea LJ, Blaikie L, Dearman RJ, Warbrick EV and Kimber I (2000) Activity of human contact allergens in the murine local lymph node assay. Contact Dermatitis, 43, 95-102.