skin sensitisation

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The Adverse Outcome Pathway Concept: A Basis for Developing Regulatory Decision-making Tools

Nathalie Delrue, Magdalini Sachana, Yuki Sakuratani, Anne Gourmelon, Eeva Leinala, Robert Diderich

The Adverse Outcome Pathway (AOP) concept is expected to guide risk assessors in their work to use all existing information on the effects of chemicals on humans and wildlife, and to target the generation of additional information to the regulatory objective. AOPs will therefore be used in the Organisation for Economic Co-operation and Development (OECD) chemical safety programme, as underlying scientific rationales for the development of alternative methods for hazard assessment, such as read-across, in vitro test methods or the development of integrated testing strategies that have the potential to replace animal tests. As a proof-of-concept, the OECD has developed an AOP for skin sensitisation, and as a follow-up has: a) implemented the AOP into the OECD QSAR Toolbox, so that information related to the Key Events (KEs) in the AOP can be used to group chemicals that are expected to act by the same mechanism and hence have the same skin sensitisation potential; b) developed alternative test methods for the KEs, so that ultimately chemicals can be tested for skin sensitisation without the use of animal tests. The development of integrated testing strategies based on the AOP is ongoing. Building on this proof-of-concept, the OECD has launched an AOP development programme with a first batch of AOPs published in 2016. A number of IT tools, which together form an AOP Knowledge Base, are at various stages of development, and support the construction of AOPs and their use in the development of integrated approaches for testing and assessment. Following the publication of the first batch of AOPs, OECD member countries will decide on priorities for their use in supporting the development of tools for regulatory use.
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Skin Sensitisation, Adverse Outcome Pathways and Alternatives

David Basketter

For toxicologists who are in any way associated with skin sensitisation, the last two decades have seen a series of fundamental changes. We have migrated from old-style guinea-pig assays, via the refined and reduced Local Lymph Node Assay (LLNA), to witness the imminent dominance of in vitro and in silico methods. Yet, over the same period, the use of the output data for human safety assurance has evolved from 'black box' risk assessment, via the quantitative risk assessment enabled by the LLNA measurement of potency, to a new period of relative uncertainty. This short review will endeavour to address these topics, all the while keeping a focus on three essential principles: a) that skin sensitisation potential is intrinsic in the molecular structure of the chemical; b) that test methods should have a mechanistic foundation; and finally c) that the only reason for undertaking any skin sensitisation work has to be the protection of human health.
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The Use of Peptide Reactivity Assays for Skin Sensitisation Hazard Identification and Risk Assessment

G. Frank Gerberick

Over the past 20 years or more, investigators have been developing non-animal test methods for use in assessing the skin sensitisation potential of chemicals. In parallel with this effort, the key biological events of skin sensitisation have been well-characterised in an Adverse Outcome Pathway (AOP) proposed by the Organisation for Economic Co-operation and Development (OECD). The key molecular initiating event of this AOP is haptenation or covalent modification of epidermal proteins. In this review, the strengths and limitations of the Direct Peptide Reactivity Assay (DPRA) are described, and the more recently developed Peroxidase Peptide Reactivity Assay (PPRA). The DPRA has been formally validated and incorporated into an OECD Test Guideline (TG442C). The DPRA shows promise for assisting in hazard identification as well as for assessing skin sensitisation potency when used in an integrated testing strategy.
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Nrf2 Activation as a Key Event Triggered by Skin Sensitisers: The Development of the Stable KeratinoSens Reporter Gene Assay

Andreas Natsch and Roger Emter

The 21st century paradigm for toxicology and the adverse outcome pathway concept envisage a future toxicology largely based on mechanistic in vitro assays and relying mainly on cellular models. In the skin sensitisation field, this concept was not intuitive at the beginning. Given the high structural diversity of skin sensitising molecules, classical receptor binding as the molecular initiating event in a cell-based assay could be excluded from the start, leaving the question of how cells could sense potential skin sensitising chemicals and be able to differentiate them from non-sensitisers. When we entered this field in 2006, we realised that, in another emerging field of toxicology, detailed work on the antioxidant/electrophile sensing pathway Keap1/Nrf2/ARE was being performed. We postulated that, based on their intrinsic electrophilicity, a large structural variety of skin sensitisers would activate this pathway. This was demonstrated in a preliminary pilot study with an existing, breast cancer-derived reporter cell line. Broader confirmation of this initial hypothesis then came from a multitude of genome-wide studies, in which sensitiser-induced changes to the transcriptome were investigated. The results showed that this regulatory pathway is indeed the most common regulatory pathway activated by sensitisers at the gene expression level, and the underlying event in keratinocytes has become formalised as a Key Event in the Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway for sensitisation. These studies led to the development of the KeratinoSens® assay, which became the first cell-based in vitro test for skin sensitisation to be endorsed by a European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) statement and an OECD Test Guideline. More recently, a number of studies have further developed this approach into 3-D skin models. Here, we review the underlying mechanism and the development of the KeratinoSens assay. We also present data on the stability of the assay over time, which is a key requirement for a cell-based biological assay to be endorsed in a regulatory context.
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The Adverse Outcome Pathway for Skin Sensitisation: Moving Closer to Replacing Animal Testing

Terry W. Schultz, Gergana Dimitrova, Sabcho Dimitrov and Ovanes G. Mekenyan

This article outlines the work of the Organisation for Economic Co-operation and Development (OECD) that led to being jointly awarded the 2015 Lush Black Box Prize. The award-winning work centred on the development of 'The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins'. This Adverse Outcome Pathway (AOP) has provided the mechanistic basis for the integration of skin sensitisation-related information. Recent developments in integrated approaches to testing and assessment, based on the AOP, are summarised. The impact of the AOP on regulatory policy and on the Three Rs are discussed. An overview of the next generation of the skin sensitisation AOP module in the OECD QSAR Toolbox, based on more-recent work at the Laboratory of Mathematical Chemistry, is also presented.
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Evaluation of Non-animal Methods for Assessing Skin Sensitisation Hazard: A Bayesian Value-of-Information Analysis

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Maria Leontaridou, Silke Gabbert, Ekko C. Van Ierland, Andrew P. Worth and Robert Landsiedel

This paper offers a Bayesian Value-of-Information (VOI) analysis for guiding the development of non-animal testing strategies, balancing information gains from testing with the expected social gains and costs from the adoption of regulatory decisions. Testing is assumed to have value, if, and only if, the information revealed from testing triggers a welfare-improving decision on the use (or non-use) of a substance. As an illustration, our VOI model is applied to a set of five individual non-animal prediction methods used for skin sensitisation hazard assessment, seven battery combinations of these methods, and 236 sequential 2-test and 3-test strategies. Their expected values are quantified and compared to the expected value of the local lymph node assay (LLNA) as the animal method. We find that battery and sequential combinations of non-animal prediction methods reveal a significantly higher expected value than the LLNA. This holds for the entire range of prior beliefs. Furthermore, our results illustrate that the testing strategy with the highest expected value does not necessarily have to follow the order of key events in the sensitisation adverse outcome pathway (AOP).

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Local Tolerance Testing Under REACH: Accepted Non-animal Methods Are Not on Equal Footing with Animal Tests

Ursula G. Sauer, Erin H. Hill, Rodger D. Curren, Susanne N. Kolle, Wera Teubner, Annette Mehling and Robert Landsiedel

In general, no single non-animal method can cover the complexity of any given animal test. Therefore, fixed sets of in vitro (and in chemico) methods have been combined into testing strategies for skin and eye irritation and skin sensitisation testing, with pre-defined prediction models for substance classification. Many of these methods have been adopted as OECD test guidelines. Various testing strategies have been successfully validated in extensive in-house and inter-laboratory studies, but they have not yet received formal acceptance for substance classification. Therefore, under the European REACH Regulation, data from testing strategies can, in general, only be used in so-called weight-of-evidence approaches. While animal testing data generated under the specific REACH information requirements are per se sufficient, the sufficiency of weight-of-evidence approaches can be questioned under the REACH system, and further animal testing can be required. This constitutes an imbalance between the regulatory acceptance of data from approved non-animal methods and animal tests that is not justified on scientific grounds. To ensure that testing strategies for local tolerance testing truly serve to replace animal testing for the REACH registration 2018 deadline (when the majority of existing chemicals have to be registered), clarity on their regulatory acceptance as complete replacements is urgently required.

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An Integrated Decision-tree Testing Strategy for Skin Sensitisation with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This report presents some of the results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This report focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for skin sensitisation testing. The manuscript reviews in vitro tests based on protein-ligand binding, dendritic/Langerhans cells and T-lymphocyte activation, and also the QSAR models and expert systems available for this endpoint. These tests are then incorporated into an integrated, decision-tree testing strategy, which also includes the Local Lymph Node Assay (in its original and new reduced protocols) and the traditional guinea-pig tests (which should only be used as a last resort). The aim of the strategy is to minimise the use of animals in testing for skin sensitisation, while satisfying the scientific and logistical demands of the EU REACH legislation.
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An Integrated Decision-tree Testing Strategy for Skin Sensitisation with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This report presents some of the results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This report focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for skin sensitisation testing. The manuscript reviews in vitro tests based on protein-ligand binding, dendritic/Langerhans cells and T-lymphocyte activation, and also the QSAR models and expert systems available for this endpoint. These tests are then incorporated into an integrated, decision-tree testing strategy, which also includes the Local Lymph Node Assay (in its original and new reduced protocols) and the traditional guinea-pig tests (which should only be used as a last resort). The aim of the strategy is to minimise the use of animals in testing for skin sensitisation, while satisfying the scientific and logistical demands of the EU REACH legislation.
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