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.
"Keeping in mind that an integrated test strategy will only be meaningful if the methods included cover a broad variety of different endpoints, it is very likely that by using a combination of methods, the majority of the limitations addressed above will be overcome. Although reliable nonanimal methods for the prediction of sensitization hazard are within reach, at least for a large number of chemicals, potency estimation is still an unresolved issue for risk assessment when using the currently available in vitro methods (Basketter and Kimber 2010). Finally, most of the data generated from in vitro alternative methods so far derive from experiments with single substances. "
[Show abstract][Hide abstract] ABSTRACT: Contact allergies are complex diseases, and it is estimated that 15-20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers.
Archives of Toxicology 06/2012; 86(8):1273-95. DOI:10.1007/s00204-012-0867-6 · 5.98 Impact Factor
"More recently, 7/9 nonsensitizing irritating compounds (oleic acid, linoleic acid, linolenic acid, undecylenic acid, maleic acid, squalene, and octinol) tested positive in the LLNA with the highest SI value of each substance between the range of 4.4–16.1 . It is important to point out that these types of limitations are not unique to the LLNA and have also been associated with GPT for skin sensitization  as well as with human patch test studies . "
[Show abstract][Hide abstract] 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
"These options are accepted in the registration dossier when backed by robust scientific justification (ECHA, 2008). negative results, as the test interpretation requires experience and expertise (Basketter et al., 2009). The LLNA takes advantage of a much more standardised procedure, in which the final outcome relies on an instrumental measurement that is much less prone to subjective interpretation. "
[Show abstract][Hide abstract] ABSTRACT: The Local Lymph Node Assay (LLNA) is the official method for assessing the allergic contact dermatitis potential of chemicals for the purposes of REACH regulation. The LLNA went through a validation process that allowed the delineation of a robust protocol for performing new tests. The OECD accepted this method in 2002 and published OECD TG 429. The European Chemical Agency (ECHA) recently published data that were submitted in the registration dossiers of chemicals. This database was analysed to determine how testing laboratories apply OECD TG 429. This analysis comes after a detailed analysis of four full study reports that were also prepared for REACH purposes. Although the majority of the tests are fully compliant with OECD TG 429, some showed major deviations, and a number of others used more animals than necessary. This suggests that in vivo tests need to be planned more carefully and consciously to obtain meaningful results with the minimum animal number necessary.
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