Skin Sensitization Testing in Potency and Risk Assessment

Abstract

The purpose of this article is to review, and make recommendations for, the use of relevant skin sensitization test methods, for the purposes of determination of relative potency and the threshold dose necessary for the induction of skin sensitization, and for risk assessment. In addressing the first area, the utility of three guinea pig tests (the guinea pig maximization test, the occluded patch test, and the open epicutaneous test) of the local lymph node assay (LLNA) and of human volunteer testing for the assessment of relative potency and identification of thresholds for sensitization were considered. The following conclusions were drawn. (1) Although attempts have been made to modify the guinea pig maximization test for the purposes of deriving dose-response relationships, this method is usually unsuitable for determination of relative sensitizing potency. (2) Guinea pig methods that do not require the use of adjuvant and which employ a relevant route of exposure (the occluded patch test and the open epicutaneous test) are more appropriate for the assessment of relative skin-sensitizing potency. (3) The LLNA is suitable for the determination of relative skin sensitizing potency, and the adaptation of this method for derivation of comparative criteria such as EC3 values (the estimated concentration of test chemical required to induce a stimulation index of 3 in the LLNA) provides an effective and quantitative basis for such measurements. (4) For all the methods identified above, potency is assessed relative to other chemical allergens of known skin sensitizing potential. The estimation of likely threshold concentrations is dependent upon the availability of suitable benchmark chemicals of known potency for human sensitization. (5) Human testing (and specifically, the Human Repeat Insult Patch Test) can provide information of value in confirming the absence of skin sensitizing activity of formulations and products under specific conditions of use and exposure. Based on the above, the following recommendations are made. (1) If results are already available from suitable guinea pig tests, then judicious interpretation of the data may provide information of value in assessing relative skin sensitizing potency. This option should be explored before other analyses are conducted. (2) The LLNA is the recommended method for new assessments of relative potency, and/or for the investigation of the influence of vehicle or formulation on skin sensitizing potency. (3) Whenever available, human skin sensitization data should be incorporated into an assessment of relative potency. With respect to risk assessment, the conclusion drawn is that all the available data on skin-sensitizing activity in animals and man should be integrated into the risk-assessment process. Appropriate interpretation of existing data from suitable guinea pig studies can provide valuable information with respect to potency, as the first step in the development of a risk assessment. However, for de novo investigations, the LLNA is the method favored fo...

The local lymph node assay and the assessment of relative potency: status of validation

“…2 primary uses are suggested for this type of data. First, as has already been proposed by both industry (38) and regulatory (39) expert groups, potency data can lead to improvements in hazard classification and thus risk management. Second, potency data can facilitate improved risk assessments for skin sensitization (40)(41)(42)(43)(44).…”

Evaluation of Allergenicity of Constituents of Myoga Using the Murine Local Lymph Node Assay

“…Activity is judged as a function of the induction, rather than the elicitation phase of sensitization. Specifically, LLNAmeasures the ability of topically applied chemicals to induce proliferative responses by draining proliferated lymph node cells in mice (15). The hypersensitivity reaction can be recognized as T lymphocyte-dependent cellular immune responses.…”

“…The hypersensitivity reaction can be recognized as T lymphocyte-dependent cellular immune responses. The defining event during the induction phase of skin sensitization is stimulation within draining lymph nodes of proliferative responses by allergen-reactive T lymphocytes (15) .…”

Effect of Prolonged Repeated Exposure to Formaldehyde Donors with Doses Below the EC3 Value on Draining Lymph Node Responses

“…The quantitative data obtained in the LLNA might be of use as a starting point for the risk assessment of individual chemicals rather then an identification as sensitizer or non-sensitizer (Kimber et al, 2001;Basketter et al, 2005aBasketter et al, , 2005b. This opens the possibility for sensitizers to perform a more in-depth risk assessment to estimate relatively safe exposure levels for ingredients in consumer products.…”