Skin sensitization, prediction

Table 10 includes the results for skin irritation. No clear results have been obtained. All models are in agreement only for the absence of irritative potential of BDE 100. Multiple results from ToxTree are due to the five different alerts used by the model (Schiff base formation, SNAr, Acyl transfer agent, skin sensitization, and Michael acceptor). A global evaluation of ToxTree data could suggest that all the analyzed compounds are not able to induce skin sensitization. These predictions are in clear contrast with that obtained by applying CAESAR and in partial agreement with the results of Toxsuite. 

Patlewicz, Gv et alv TIMES-SS — A promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity, Reg. Toxicity Pharmacol., 48, 225, 2007. 

Botham, RA. et al., Skin sensitization—a critical review of predictive test methods in animals and man, Fd. Chem. Toxic., 29, 275, 1991. 

D. A. Basketter, G. F. Gerberick, and I. Kimber. Strategies for identifying false positive responses in predictive skin sensitization tests. Food Chem. Toxicol. 36 327-333 (1998). 

DEREK Expert system for the prediction of toxicity (genotoxicity, carcinogenicity, skin sensitization, etc.)... 

It should be noted that, although respiratory allergens tested so far were positive in current tests evaluating the skin sensitization potential, skin sensitization potency data available from current test methods do not predict respiratory sensitization potency in general. 

Substances, which are skin or eye irritating or corrosive after single exposure (Section 4.5) should be suspected of inducing local effects upon repeated respiratory exposure to low concentrations. In contrast, local effects reported from skin sensitization studies as well as dermal repeated dose toxicity studies are not predictive of local effects on the respiratory tract. In addition, observations from irritation and/or sensitization studies as well as repeated dose inhalation toxicity studies are not predictive of local effects on the skin upon repeated dermal exposure (EC 2003). 

In the context of skin sensitization bioavailability can be seen as the capacity of the compound to reach the viable epidermis, where it interacts with keratinocytes and Langerhans cells. This capacity is dependent on its molecular weight and solubility in polar and apolar solvents [115]. Importantly, potency prediction solely on the basis of cell culture models (steps 3 and 4) does not account for skin penetration rate and may thus wrongly predict potency in vivo. Possible in vitro approaches to detect allergic capacity of chemicals/pharmaceuticals are presented in Table 18.5. 

Predictive identification of human skin sensitization thresholds. Contact Dermatitis, 53, 260-267. 

Roberts, D. W., Aptula, A. O., Patlewicz, G. (2006) Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the Schiff base applicability domain for skin sensitization. Chem Res Toxicol 19, 1228-1233. 

Predictive tests on the potential of the compound to cause skin sensitization are essential. The introduction of new potent sensitizers must be avoided. So far only animal tests are sufficiently reliable to predict a low sensitizing potential, although alternatives can exclude potent sensitizers. 

The skin permeability of this chemical is low the log Kp value from the reasoning algorithm is -6.856 and the chemical is known to give a weak response in the guinea pig maximization test, which indicates an equivocal response in mammals. This information leads to the prediction from the software that skin sensitization in humans is doubtful. 

Payne, M.P and Walsh, P.T., Structure-activity relationships for skin sensitization potential development of structural alerts for use in knowledge-based toxicity prediction systems, J. Chem. Inf. Comput. Sci., 34, 154-161, 1994. 

This test uses an in vitro human dendritic cell culture to obtain information of the potential for various chemicals to induce allergic contact dermatitis. This test is used as an alternative to the Local Lymph node assay (LLNA) to minimize or replace the use of live animal testing for predicting skin sensitization (Kimber et al. 2002, see below). The test allows for evaluation of skin sensitization by examining the presence of cell surface markers on Periperal Blood Mononuclear Cell (PBMC)-derived dendritic cells (DC) that are known to be involved in the development of allergic contact dermatitis. 

This test using animals seems to be the most frequently used predictive test for the identification of skin-sensitizing chemicals or for chemicals prone to cause allergic contact dermatitis. While it is most frequently used for general dermatological investigations, results... 

Your chemical is expected to be a strong skin sensitizer because it contains an alert associated with activity by a mechanism that is widely accepted, and it is within the prediction space for QSAR model XXX, which predicts activity well above the threshold for labeling under EU regulations. ... 

Currently better predictions can be obtained for mutagenicity, carcinogenicity, skin sensitivity, and primary irritancy than for hepatoxicity, cardiotoxicity,... 

Advances in the understanding of the immunobiology of skin sensitization have led to the establishment of predictive in vivo tests which not only identify sensitizing hazards but also characterize their potency. Recently, appreciation of the underlying biology has also resulted in the development of mechanistically based in vitro alternatives which offer the prospect of the replacement of current in vivo methods. Assays under active validation include the Direct Peptide Reactivity Assay (DPRA), the human Cell Line Activation Test (h-CLAT), and KeratinoSens. None of the methods have a sufficient level of accuracy or freedom from applicability domain limitations to allow them to act as a standalone replacement. Consequently, it will be necessary to consider how to deploy these assays, perhaps in combination and/or in a structured assessment of skin sensitization hazard, to ensure at least the same level of predictive accuracy as the in vivo methods. However, a challenge remains the capacity of these methods to provide potency information on skin-sensitizing chemicals has yet to be assessed. This is an essential requirement for future risk assessment without use of animal models if we are to retain the same level of human health protection that is currently delivered. 

Essentially all of the early methods for the prediction of skin sensitization potential involved the use of guinea pig models. Many methods were proposed and these have been reviewed in detail some years ago [10, 11]. All of the methods followed the same general principles in that procedures were undertaken over a period of 1-3 weeks exposing groups of guinea pigs to the test substance either by... 

Extensive reviews concerning the opportunities for the development of in vitro sensitization methods already exist [41-44], These reviews show that essentially all of the methods address one or other of the key mechanistic steps in the induction of skin sensitization—and these are nicely represented in the OECD adverse outcome pathway description [45], From this large body of work, three methods have emerged whose initial promise has been substantiated by demonstration not only of their predictive merits but also by verification of their robustness in terms of inter-laboratory transferability and within and between laboratory reproducibility [46]. The three methods are the direct peptide reactivity assay (DPRA) [47, 48], KeratinoSens [49, 50], and the human Cell Line Activation Test (h-CLAT) [51-53]. The first of these, the DPRA, addresses the question of chemical reactivity, the second investigates an aspect of keratinocyte activation... 

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