integrated testing strategy

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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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Acute Oral Toxicity Testing: Scientific Evidence and Practicability Should Govern Three Rs Activities

Roland Buesen, Uwe Oberholz, Ursula G. Sauer and Robert Landsiedel

Acute oral toxicity is determined for regulatory hazard classification or non-classification. The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) recommends the following modules for acute oral toxicity testing: a) the use of the in vitro 3T3 Neutral Red Uptake (NRU) test to identify substances not requiring classification and to estimate starting doses for in vivo acute oral toxicity studies; and b) the use of data from sub-acute toxicity studies to identify substances not requiring classification. However, the application of these modules in a regulatory context would require a predefined, validated and formally accepted testing strategy and data interpretation procedure, which are not available. Furthermore, the application of the 3T3 NRU assay for starting dose estimations could in fact increase the number of animals used. Finally, only very few substances exist for which data from sub-acute or other repeated dose studies are available, but data from acute studies are not. Therefore, in practice, the prediction of acute toxicity by using sub-acute toxicity data is generally irrelevant. It could even lead to a risk of overdosing in the range-finding study, which may result in the death of many or all of the animals used.

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The In ChemicoIn Silico Interface: Challenges for Integrating Experimental and Computational Chemistry to Identify Toxicity

Mark T.D. Cronin, Fania Bajot, Steven J. Enoch, Judith C. Madden, David W. Roberts and Johannes Schwöbel

A number of toxic effects are brought about by the covalent interaction between the toxicant and biological macromolecules. In chemico assays are available that attempt to identify reactive compounds. These approaches have been developed independently for pharmaceuticals and for other nonpharmaceutical compounds. The assays vary widely in terms of the macromolecule (typically a peptide) and the analytical technique utilised. For both sets of methods, there are great opportunities to capture in chemico information by using in silico methods to provide computational tools for screening purposes. In order to use these in chemico and in silico methods, integrated testing strategies are required for individual toxicity endpoints. The potential for the use of these approaches is described, and a number of recommendations to improve this extremely useful technique, in terms of implementing the Three Rs in toxicity testing, are presented.
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The Use of Mechanisms and Modes of Toxic Action inIntegrated Testing Strategies: The Report and Recommendations of a Workshop held as part of the European Union OSIRIS Integrated Project

J. Arie Vonk, Romualdo Benigni, Mark Hewitt, Monika Nendza, Helmut Segner, Dik van de Meent1 and Mark T.D. Cronin

This report on The Potential of Mode of Action (MoA) Information Derived from Non-testing and Screening Methodologies to Support Informed Hazard Assessment, resulted from a workshop organised within OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-test and Test Information), a project partly funded by the EU Commission within the Sixth Framework Programme. The workshop was held in Liverpool, UK, on 30 October 2008, with 35 attendees. The goal of the OSIRIS project is to develop integrated testing strategies (ITS) fit for use in the REACH system, that would enable a significant increase in the use of non-testing information for regulatory decision making, and thus minimise the need for animal testing. One way to improve the evaluation of chemicals may be through categorisation by way of mechanisms or modes of toxic action. Defining such groups can enhance read-across possibilities and priority settings for certain toxic modes or chemical structures responsible for these toxic modes. Overall, this may result in a reduction of in vivo testing on organisms, through combining available data on mode of action and a focus on the potentially most-toxic groups. In this report, the possibilities of a mechanistic approach to assist in and guide ITS are explored, and the differences between human health and environmental areas are summarised.
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Comparing In Vivo, In Vitro and In Silico Methods and Integrated Strategies for Chemical Assessment: Problems and Prospects

Emilio Benfenati, Giuseppina Gini, Sebastian Hoffmann and Robert Luttik

The RAINBOW workshop addressed the background for the integration of in vivo, in vitro and computer-based (in silico) methods, to facilitate the study of the toxic properties of chemicals. On the basis of these discussions, we prepared the present paper, outlining the strengths, weaknesses, opportunities and threats of each approach, both alone and integrated into a single testing strategy. The current scheme for evaluation of chemicals needs to be reshaped, in the face of the much larger numbers of chemicals which need to be examined and the availability of a diversified set of tools.
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