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

Risk Assessment

Once a skin-sensitization hazard has been identified and characterized, the real action to protect human health can begin. There is no more powerful tool in the hands of toxicologists than risk assessment. The aim is to determine a level of exposure to the allergen which will not result in the induction of sensitization, often referred to as primary prevention. However the risk assessment is completed, the key starting points are an understanding of the relative potency of the sensitizer compared with other contact allergens and the nature, extent, frequency and duration of skin exposure. Two types of risk assessment can then be recognized, a comparative approach and a more recent quantitative approach. These are now described briefly with suitable references for those who wish to dig deeper.

Relative potency information on a skin sensitizer, such as an EC3 value, can be compared with that available for other skin sensitizers. Where these latter sensitizers have been employed safely in defined exposure situations, then it may be judged that a newer chemical of similar or indeed lower potency could be used in their place. In effect, what is being done is that the variables/unknowns associated with the relationship between skin exposure to a sensitizer of known potency, and the resultant likelihood of ACD being elicited, are regarded as 'constants' in the comparison of a known sensitizer in an existing use with a new sensitizer which is being used in the same situation. For example, the weak sensitizing potency of cocoamidopropyl betaine (CAPB) is well understood in terms of data from predictive models and clinical data.[32] Significantly, the very limited extent to which it causes clinical allergy through use in rinse-off products such as shower gels at levels up to approximately 10% is also quite well understood. Thus, were a novel material to be proposed for use in shower gels, CAPB could be employed as a potential benchmark. Similarly, the much stronger sensitizing potency of (chloro)methylisothiazolinone also is well understood in predictive models and in humans: there are dose-response studies in mice, guinea pigs and humans.[47,48] Furthermore, there are data on acceptable and unacceptable use concentrations and product types.[49] All of these data represent a valuable source of benchmark data for use in risk assessment.

Recently, a more quantitative approach to skin sensitization risk assessment has been promulgated. In essence, this is founded on the traditional toxicology approach of identifying a no effect level (NOEL) in a predictive model and then appropriate reduction of this NOEL to provide an indication of human exposure limits below which the adverse effect, in this case the induction of skin sensitization, should not occur. The approach indicates safe exposure levels for individual sensitizing chemicals under well-defined exposure conditions; exposure is expressed in dose per unit area and is calculated per diem. Comprehensive details of this new approach have been delineated in a short series of publications.[50,51,52,53] Given the difficulties concerning the conduct of predictive human testing (the human repeated insult patch test), this quantitative approach relies heavily on the direct prediction of NOELs from LLNA EC3 values. Several publications now support the validity of this relationship.[41,42,54,55,56,57,58] Quantitative risk assessment for skin-sensitizing chemicals has been deployed to demonstrate the inappropriately high level of exposure to a preservative, methyldibromo glutaronitrile, providing an independent demonstration of the utility of the approach.[59] A generic overview of this new quantitative risk assessment strategy is outlined in Figure 2. The strengths and limitations of this new approach have not been fully worked out, but the assessment does follow the same principles of risk assessment commonly applied in toxicology for very many years to all systemic endpoints. It is challenging ultimately to consider how in vitro alternatives will deliver the quality of information required to populate quantitative risk assessments in the future.[60]

Figure 2.

Simplified flow diagram for the conduct of a risk assessment using animal-derived skin sensitization potency data. LLNA, local lymph node assay; GPMT, guinea pig maximization test; HRIPT, human repeated insult patch test.

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