hazard identification

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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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Introduction to the EU REACH Legislation

Christina Grindon and Robert Combes

FRAME initiatives on the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals, first proposed as a White Paper in 2001, are summarised. These initiatives considered the scientific and animal welfare issues raised by the REACH proposals, and resulted in a number of suggestions for improvement, many of which seem to have been adopted during the current progress of the legislation through the European Council and European Parliament.
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A Review of the Status of Alternative Approaches to Animal Testing and the Development of Integrated Testing Strategies for Assessing the Toxicity of Chemicals under REACH — A Summary of a DEFRA-funded Project Conducted by Liverpool John Moores University and FRAME

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

Liverpool John Moores University and FRAME were recently awarded a DEFRA tender to conduct a review of the status of alternative approaches to animal testing, and to recommend further research with regard to the forthcoming European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The outcome of the project is summarised, including the prospects for in vitro and in silico testing, areas where reduction and refinement could be applied, and how decision-tree integrated testing strategies could be used to reduce the number of animals needed to fulfil the testing requirements of the REACH system. This paper is a prelude to a series of individual papers on detailed suggestions for applying non-animal methods to each of the major toxicity endpoints in REACH.
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Introduction to the EU REACH Legislation

Christina Grindon and Robert Combes

FRAME initiatives on the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals, first proposed as a White Paper in 2001, are summarised. These initiatives considered the scientific and animal welfare issues raised by the REACH proposals, and resulted in a number of suggestions for improvement, many of which seem to have been adopted during the current progress of the legislation through the European Council and European Parliament.
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