Skin sensitization, false positives and false negatives: experience with guinea pig assays.
ABSTRACT The advent of the local lymph node assay (LLNA), and efforts to develop in vitro alternatives for the identification of skin sensitizing chemicals has focused attention on the issue of false positive and false negative results. In essence, the question becomes 'what is the gold standard?' In this context, attention has focused primarily on the LLNA as this is now the preferred assay for skin sensitization testing. However, for many years prior to introduction of the LLNA, the guinea pig maximization test and the occluded patch test of Buehler were the methods of choice. In order to encourage a more informed dialogue about the relative performance, accuracy and applicability of the LLNA and guinea pig tests, we have here considered the extent to which guinea pig methods were themselves subject to false positives and negative results. We describe and discuss here well-characterized examples of instances where both false negatives (including abietic acid and eugenol) or false positives (including vanillin and sulfanilic acid) have been recorded in guinea pig tests. These and other examples are discussed with particular reference to the fabrication of a gold standard dataset that is required for the validation of in vitro alternatives.
- SourceAvailable from: David W Roberts[Show abstract] [Hide abstract]
ABSTRACT: Since the OECD published the Adverse Outcome Pathway (AOP) for skin sensitization, many efforts have focused on how to integrate and interpret nonstandard information generated for key events in a manner that can be practically useful for decision making. These types of frameworks are known as Integrated Approaches to Testing and Assessment (IATA). Here we have outlined an IATA for skin sensitization which focuses on existing information including non testing approaches such as QSAR and read-across. The IATA was implemented into a pipeline tool using OASIS technology to provide a means of systematically collating and compiling relevant information which could be used in an assessment of skin sensitization potential. A test set of 100 substances with available skin sensitization information was profiled using the pipeline IATA. In silico and in chemico profiling information alone was able to correctly predict skin sensitization potential, with a preliminary accuracy of 73.85%. Information from other relevant endpoints (e.g. Ames mutagenicity) was found to improve the accuracy (to 87.6%) when coupled with a reaction chemistry mechanistic understanding. This pipeline platform could be useful in the assessment of skin sensitization potential and marks a step change in how non testing approaches can be practically applied.Regulatory Toxicology and Pharmacology 06/2014; · 2.14 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Healthcare workers are in an occupational sector that is at high risk for contact dermatitis. The major irritants are wet work, detergents, disinfectants, antiseptics and plastic materials. The principal allergens are vulcanization additives in medical gloves, cleaning agents, conservatives, antiseptics, disinfectants, drugs, and, in dental workers, acrylates. Medical advice for prevention should be based on promoting maximal reduction of cutaneous contact with irritants and complete avoidance of skin contact with the relevant allergens. Preventive education programs on hand washing, wearing gloves, and the use of protective creams are recommended.Revue Française d'Allergologie 04/2013; 53(3):212–217. · 0.35 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The TImes MEtabolism Simulator platform for predicting Skin Sensitisation (TIMES-SS) is a hybrid expert system, first developed at Bourgas University using funding and data from a consortium of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs. The model estimates semi-quantitative skin sensitisation potency classes and has been developed with the aim of minimising animal testing, and also to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. In 2007 an external validation exercise was undertaken to fully address these principles. In 2010, a new industry consortium was established to coordinate research efforts in three specific areas: refinement of abiotic reactions in the skin (namely autoxidation) in the skin, refinement of the manner in which chemical reactivity was captured in terms of structure-toxicity rules (inclusion of alert reliability parameters) and defining the domain based on the underlying experimental data (study of discrepancies between local lymph node assay Local Lymph Node Assay (LLNA) and Guinea Pig Maximisation Test (GPMT)). The present paper summarises the progress of these activities and explains how the insights derived have been translated into refinements, resulting in increased confidence and transparency in the robustness of the TIMES-SS predictions.SAR and QSAR in environmental research 05/2014; · 1.68 Impact Factor