Skin Sensitization: Strategies for the Assessment and Management of Risk

D.A. Basketter

Disclosures

The British Journal of Dermatology. 2008;159(2):267-273. 

In This Article

Hazard Characterization

Once a chemical has been identified as a potential skin-sensitization hazard, the immediate next question normally concerns matters of potency - how vigorous a sensitizer is it? In traditional systemic toxicology this means understanding the dose response; this is also true for skin sensitization. However, even more than the dose-response relationship, effort is commonly directed towards understanding thresholds, particularly for the induction of skin sensitization. In each of the guinea pig assays, it is possible to define both an induction and an elicitation threshold, but this always requires additional testing, often in multiple assays, and so is very rarely undertaken. An alternative design for the GPMT was proposed which incorporated a dose-response element at induction, but only a relatively limited body of data was presented and the method was never adopted generally.[33]

In contrast to the guinea pig tests, the standard LLNA design embodied in OECD 429 incorporates an element of dose response and, with the inclusion of additional dose groups, when necessary, the threshold concentration at which the assay becomes positive can be determined.[34] This topic has been thoroughly reviewed recently.[35] In brief, the dose-response curve of the LLNA is interpolated (or occasionally extrapolated[36]), so that the concentration necessary to cause exactly a threefold stimulation of proliferation can be estimated: this is the EC3 value. Recent publications contain EC3 values for approximately 300 skin sensitizers.[37,38,39] In effect, the EC3 value represents an estimate of the relative potency of a skin sensitizer. Some typical examples are given in Table 1 . It is important to remember that the EC3 value is only the threshold for the induction of a significant response in the mouse following three daily applications - hence it may be a measure of relative potency, but it is no more an absolute threshold for the induction of sensitization in the mouse as it is a threshold for human exposure. This topic is dealt with more comprehensively under risk assessment.

Notwithstanding the above caveats, it is nevertheless of particular interest that EC3 values cover some five orders of magnitude, from the most potent allergen assessed, benzo(a)pyrene (EC3=0·0009%) to the very weakest, aniline (EC3=89%).[37] Based on this consideration, several groups have suggested that EC3 values have merit both for regulatory toxicology and for risk assessment/management (see below), including the developers of the LLNA,[40,41,42] the EU,[43] European industry[44] and the World Health Organization.[45] Although many of the schemes proposed differ at the level of fine detail, the underlying principle(s) are identical. In essence, the concept is that rather than chemicals being categorized simply as sensitizing (or not), those that are sensitizing could be grouped according to their relative potency. An example of how this might work is given in Table 2 . It can readily be seen that the chemicals indicated in Table 1 would map into these categories. This type of information could be transferred to safety data sheets, end users etc., and obviously, the more potent allergens could be considered very differently from those chemicals which were definitely sensitizing but whose potency was very low. It is emphasized that the scheme in Table 2 and the examples in Table 1 do not form a detailed recommendation - as mentioned, these have already been made by others. Indeed, it is deliberately slightly different from previous systems. Ultimately, the decision to categorize allergens is both scientific and sociopolitical and will depend on several factors, including the number of categories and the thresholds for these classes, which will depend on an analysis of the available data, a judgement on the degree of protection that is deemed appropriate and the political will of various parties who are aiming to harmonize global regulations in toxicology.[46] Finally, chemicals which fall into the lowest category would not be classified as skin sensitizers, but this group will always contain both true nonsensitizing chemicals as well as substances too weakly sensitizing to be classified, the size of the latter depending again on the sociopolitical view of what level of human health protection is appropriate.

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