In vitro approaches to the identification and characterization of skin sensitizers.
ABSTRACT Allergic contact dermatitis (ACD) is to a considerable extent a preventable disease. Limitation of ACD can be achieved by correct detection of skin sensitizers, characterization of potency, understanding of human skin exposure, and the application of adequate risk assessment and management strategies. A range of methods now exist that have been proven to be very accurate in terms of the predictive identification of chemicals that possess skin sensitizing properties. In addition, certain methods, notably the local lymph node assay (LLNA), also deliver valuable information of the relative potency of identified sensitizers. Great use can be made of this potency information in the application of quantitative risk assessments (although of course such assessments depend also on the availability of accurate data on human skin exposure). However, the challenge now to be faced is how to obtain the same quality of information on the potency of skin sensitizing chemicals using solely in vitro and in silico methods. With the forthcoming elimination of in vivo tests, the opportunities being exploited for in vitro test development focus on key elements of the sensitization process, such as peptide binding and dendritic cell activation. What has to then be addressed is how information from such in vitro assays is integrated, together with data on epidermal bioavailability, to deliver an assessment of the allergen potency.
SourceAvailable from: Rosette Van Den Heuvel[Show abstract] [Hide abstract]
ABSTRACT: Chemical sensitization remains an important environmental and occupational health issue. A wide range of substances have been shown to possess the ability to induce skin sensitization or respiratory sensitization. As a consequence, there is a need to have appropriate methods to identify sensitizing agents. Although a considerable investment has been made in exploring opportunities to develop methods for hazard identification and characterization, there are, as yet, no validated nonanimal methods available. A state of the art of the different in vitro approaches to identify contact and respiratory capacity of chemicals is covered in this chapter.EXS 01/2012; 101:289-314. DOI:10.1007/978-3-7643-8340-4_10
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ABSTRACT: T lymphocytes mediate skin sensitisation and allergic contact dermatitis. Not unexpectedly, therefore, there is considerable interest in the use of T lymphocyte-based assays as alternative strategies for the identification of skin sensitising chemicals. However, in addition to accurate identification of hazards the development of effective risk assessments requires that information is available about the relative skin sensitising potency of contact allergens. The purpose of this article is to consider the relationships that exist between the characteristics of T lymphocyte responses to contact allergens and the effectiveness/potency of sensitisation. We propose that there are 3 aspects of T lymphocyte responses that have the potential to impact on the potency of sensitisation. These are: (a) the magnitude of response, and in particular the vigour and duration of proliferation and the clonal expansion of allergen-reactive T lymphocytes, (b) the quality of response, including the balance achieved between effector and regulatory cells, and (c) the breadth of response and the clonal diversity of T lymphocyte responses. A case is made that there may be opportunities to exploit an understanding of T lymphocyte responses to contact allergens to develop novel paradigms for predicting skin sensitising potency and new approaches to risk assessment.Toxicology 11/2011; 291(1-3):18-24. DOI:10.1016/j.tox.2011.11.007 · 3.75 Impact Factor
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ABSTRACT: Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et al., 2011) and its independent review (Hartung et al., 2011), the present report proposes a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals. Five whitepapers were commissioned addressing toxicokinetics, skin sensitization, repeated-dose toxicity, carcinogenicity, and reproductive toxicity testing. An expert workshop of 35 participants from Europe and the US discussed and refined these whitepapers, which were subsequently compiled to form the present report. By prioritizing the many options to move the field forward, the expert group hopes to advance regulatory science.ALTEX: Alternativen zu Tierexperimenten 01/2012; 29(1):3-91. · 4.09 Impact Factor