An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential. SAR QSAR Environ Res 18(5-6):515-541

European Chemicals Bureau TP582, IHCP, Joint Research Centre, European Commission, Ispra, Italy.
SAR and QSAR in Environmental Research (Impact Factor: 1.6). 07/2007; 18(5-6):515-41. DOI: 10.1080/10629360701427872
Source: PubMed


Skin sensitisation potential is an endpoint that needs to be assessed within the framework of existing and forthcoming legislation. At present, skin sensitisation hazard is normally identified using in vivo test methods, the favoured approach being the local lymph node assay (LLNA). This method can also provide a measure of relative skin sensitising potency which is essential for assessing and managing human health risks. One potential alternative approach to skin sensitisation hazard identification is the use of (Quantitative) structure activity relationships ((Q)SARs) coupled with appropriate documentation and performance characteristics. This represents a major challenge. Current thinking is that (Q)SARs might best be employed as part of a battery of approaches that collectively provide information on skin sensitisation hazard. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here we focus on three models (TOPKAT, Derek for Windows and TOPS-MODE), and evaluate their performance against a recently published dataset of 211 chemicals. The current strengths and limitations of one of these models is highlighted, together with modifications that could be made to improve its performance. Of the models/expert systems evaluated, none performed sufficiently well to act as a standalone tool for hazard identification.

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    • "There is a continuing imperative to develop new appropriates to skin sensitization testing that obviate the need for animals. Three tests have now been validated for the purposes of hazard identification , Direct Peptide Reactivity Assay (DRPA), KeratinoSens and the Quantitative structure–activity relationship model (QSAR) (Patlewicz et al., 2007, Gerberick et al., 2004, Emter et al., 2010). However, to date, there are no in vitro or silico methods (including those identified above) that provide information on relative potency. "
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    ABSTRACT: Sensitization to chemicals resulting in an allergy is an important health issue. The current gold-standard method for identification and characterization of skin-sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in-vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro-haptens, respiratory sensitizers, non-sensitizing chemicals (including skin-irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non-sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNγ production, respectively. Collectively, the data suggests the human in-vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 08/2015; DOI:10.1002/jat.3197 · 2.98 Impact Factor
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    • "One general factor that is believed to influence reactivity and skin sensitising potential is chemical structure. It has been suggested that the modest sensitising activity of methacrylates is attributable to the a-methyl substitution of the a-b double bond that in turn destabilises the Michael transition state reducing capacity to react with glutathione and protein-SH groups (Greim et al., 1995; Patlewicz et al., 2007). This is in contrast to the situation that pertains to the structurally related acrylates that show rates of glutathione reactivity that are at least two orders of magnitude higher than seen with the methacrylates (McCarthy et al., 1994), and stronger reactivity in guinea pig assays (Greim et al., 1995), and the LLNA (Dearman et al., 2007). "
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    ABSTRACT: There is continued interest in, and imperatives for, the classification of contact allergens according to their relative skin sensitising potency. However, achieving that end can prove problematic, not least when there is an apparent lack of concordance between experimental assessments of potency and the prevalence allergic contact dermatitis as judged by clinical experience. For the purpose of exploring this issue, and illustrating the important considerations that are required to reach sound judgements about potency categorisation, the lower alkyl methacrylate esters (LAM) have been employed here as a case study. Although the sensitising potential of methyl methacrylate (MMA) has been reviewed previously, there is available new information that is relevant for assessment of skin sensitising potency. Moreover, for the purposes of this article, analyses have been extended to include also other LAM for which relevant data are available: ethyl methacrylate (EMA), n-butyl methacrylate (nBMA), isobutyl methacrylate (iBMA), and 2-ethylhexyl methacrylate (EHMA). In addressing the skin sensitising activity of these chemicals and in drawing conclusions regarding relative potency, a number of sources of information has been considered, including estimates of potency derived from local lymph node assay (LLNA) data, the results of guinea pig assays, and data derived from in silico methods and from recently developed in vitro approaches. Moreover, clinical experience of skin sensitisation of humans by LAM has also been evaluated. The conclusion drawn is that MMA and other LAM are contact allergens, but that none of these chemicals has any more than weak skin sensitising potency. We have also explored here the possible bases for this modest sensitising activity. Finally, the nature of exposure to LAM has been reviewed briefly and on the basis of that information, together with an understanding of skin sensitising potency, a risk assessment has been prepared.
    Regulatory Toxicology and Pharmacology 10/2014; 70(1). DOI:10.1016/j.yrtph.2014.06.013 · 2.03 Impact Factor
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    • "Derek for Windows and TOPKAT are examples that have been used for several years. This type of predictive tool allows the user to input a chemical structure and obtain a readout of the chemical constructs that could potentially lead to sensitization [74]. Challenges with this type of modeling include the analysis of chemicals requiring metabolic activation. "
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    ABSTRACT: Allergic contact dermatitis is the second most commonly reported occupational illness, accounting for 10% to 15% of all occupational diseases. This highlights the importance of developing rapid and sensitive methods for hazard identification of chemical sensitizers. The murine local lymph node assay (LLNA) was developed and validated for the identification of low molecular weight sensitizing chemicals. It provides several benefits over other tests for sensitization because it provides a quantitative endpoint, dose-responsive data, and allows for prediction of potency. However, there are also several concerns with this assay including: levels of false positive responses, variability due to vehicle, and predictivity. This report serves as a concise review which briefly summarizes the progress, advances and limitations of the assay over the last decade.
    Journal of Allergy 06/2011; 2011(1687-9783):424203. DOI:10.1155/2011/424203
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