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Burden N.,NC3Rs | Aschberger K.,European Commission - Joint Research Center Ispra | Chaudhry Q.,University of Chester | Clift M.J.D.,University of Fribourg | And 7 more authors.
Nano Today | Year: 2016

Due to the plethora of nanomaterials being manufactured, it is crucial that their effects on human health are understood. It is not feasible to assess the safety of all nanomaterials using animal-based toxicity tests. There are also scientific, business, legislative and ethical drivers to reconsider the use of such toxicity tests. Utilising non-traditional methods has the potential to improve the human relevance of nanosafety assessment, reduce the numbers of animals that are used, and shift the paradigm to a '21st century' approach that exploits recent scientific and technological advances. This article considers how application of the 3Rs principles can be used as a framework to support and guide this paradigm shift in the short, medium and long-term. Bringing the community together to facilitate the transition is necessary to ensure that tangible impacts are made on the efficiency and robustness of the nanosafety assessment process. © 2016 The Authors.


PubMed | GSK., Health Canada., U.S. FDA., ASCR. and 7 more.
Type: | Journal: Pharmeuropa bio & scientific notes | Year: 2016

The International Workshop on Alternatives to the Murine Histamine Sensitization Test for Acellular Pertussis Vaccines: Progress and Challenges in the Replacement of HIST was held on 24 August 2014, in Prague, Czech Republic, as a satellite meeting to the 9th World Congress on Alternatives and Animal Use in the Life Sciences. Participants discussed the progress and challenges associated with the development, validation, and implementation of in vitro assays as replacements for the histamine sensitisation test (HIST) for acellular pertussis vaccines. Discussions focused on the consistency approach, the necessary framework for regulatory acceptance of a harmonised method, and recent international efforts towards the development of in vitro assays to replace the HIST. Workshop participants agreed that acceptable alternatives to the HIST should be based on ADP ribosylation-mediated cell intoxication and therefore that the CHO cell clustering assay, which measures cell intoxication, should be further pursued and developed as a possible replacement for the HIST. Participants also agreed to continue ongoing multinational discussions involving national and international standardisation authorities to reach consensus and to organise collaborative studies in this context for assay characterisation and calibration of reference materials.


PubMed | NC3Rs, BASF, Dow AgroSciences and Hill International
Type: | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2016

The European Plant Protection Products Regulation 1107/2009 requires that registrants establish whether pesticide metabolites pose a risk to the environment. Fish acute toxicity assessments may be carried out to this end. Considering the total number of pesticide (re-) registrations, the number of metabolites can be considerable, and therefore this testing could use many vertebrates. EFSAs recent Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters outlines opportunities to apply non-testing methods, such as Quantitative Structure Activity Relationship (QSAR) models. However, a scientific evidence base is necessary to support the use of QSARs in predicting acute fish toxicity of pesticide metabolites. Widespread application and subsequent regulatory acceptance of such an approach would reduce the numbers of animals used. The work presented here intends to provide this evidence base, by means of retrospective data analysis. Experimental fish LC50 values for 150 metabolites were extracted from the Pesticide Properties Database (http://sitem.herts.ac.uk/aeru/ppdb/en/atoz.htm). QSAR calculations were performed to predict fish acute toxicity values for these metabolites using the US EPAs ECOSAR software. The most conservative predicted LC50 values generated by ECOSAR were compared with experimental LC50 values. There was a significant correlation between predicted and experimental fish LC50 values (Spearman rs=0.6304, p<0.0001). For 62% of metabolites assessed, the QSAR predicted values are equal to or lower than their respective experimental values. Refined analysis, taking into account data quality and experimental variation considerations increases the proportion of sufficiently predictive estimates to 91%. For eight of the nine outliers, there are plausible explanation(s) for the disparity between measured and predicted LC50 values. Following detailed consideration of the robustness of this non-testing approach, it can be concluded there is a strong data driven rationale for the applicability of QSAR models in the metabolite assessment scheme recommended by EFSA. As such there is value in further refining this approach, to improve the method and enable its future incorporation into regulatory guidance and practice.


PubMed | Public Health England, INERIS, WIL Research, Harlan Laboratories and 14 more.
Type: Journal Article | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2015

Acute inhalation studies are conducted in animals as part of chemical hazard identification and characterisation, including for classification and labelling purposes. Current accepted methods use death as an endpoint (OECD TG403 and TG436), whereas the fixed concentration procedure (FCP) (draft OECD TG433) uses fewer animals and replaces lethality as an endpoint with evident toxicity. Evident toxicity is defined as clear signs of toxicity that predict exposure to the next highest concentration will cause severe toxicity or death in most animals. A global initiative including 20 organisations, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has shared data on the clinical signs recorded during acute inhalation studies for 172 substances (primarily dusts or mists) with the aim of making evident toxicity more objective and transferable between laboratories. Pairs of studies (5 male or 5 female rats) with at least a two-fold change in concentration were analysed to determine if there are any signs at the lower dose that could have predicted severe toxicity or death at the higher concentration. The results show that signs such as body weight loss (>10% pre-dosing weight), irregular respiration, tremors and hypoactivity, seen at least once in at least one animal after the day of dosing are highly predictive (positive predictive value > 90%) of severe toxicity or death at the next highest concentration. The working group has used these data to propose changes to TG433 that incorporate a clear indication of the clinical signs that define evident toxicity.


PubMed | Hill International, NC3Rs, University of Plymouth, Cefas Fisheries Laboratory and 6 more.
Type: Journal Article | Journal: Integrated environmental assessment and management | Year: 2016

The ecotoxicity testing of chemicals for prospective environmental safety assessment is an area in which a high number of vertebrates are used across a variety of industry sectors. Refining, reducing, and replacing the use of animals such as fish, birds, and amphibians for this purpose addresses the ethical concerns and the increasing legislative requirements to consider alternative test methods. Members of the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) Ecotoxicology Working Group, consisting of representatives from academia, government organizations, and industry, have worked together over the past 6 y to provide evidence bases to support and advance the application of the 3Rs in regulatory ecotoxicity testing. The group recently held a workshop to identify the areas of testing, demands, and drivers that will have an impact on the future of animal use in regulatory ecotoxicology. As a result of these discussions, we have developed a pragmatic approach to prioritize and realistically address key opportunity areas, to enable progress toward the vision of a reduced reliance on the use of animals in this area of testing. This paper summarizes the findings of this exercise and proposes a pragmatic strategy toward our key long-term goals-the incorporation of reliable alternatives to whole-organism testing into regulations and guidance, and a culture shift toward reduced reliance on vertebrate toxicity testing in routine environmental safety assessment. Integr Environ Assess Manag 2016;12:417-421. 2015 SETAC.


Burden N.,NC3Rs | Mahony C.,Procter and Gamble | Muller B.P.,Symrise AG | Terry C.,Dow AgroSciences | And 2 more authors.
Toxicology | Year: 2015

There are currently several factors driving a move away from the reliance on in vivo toxicity testing for the purposes of chemical safety assessment. Progress has started to be made in the development and validation of non-animal methods. However, recent advances in the biosciences provide exciting opportunities to accelerate this process and to ensure that the alternative paradigms for hazard identification and risk assessment deliver lasting 3Rs benefits, whilst improving the quality and relevance of safety assessment. The NC3Rs, a UK-based scientific organisation which supports the development and application of novel 3Rs techniques and approaches, held a workshop recently which brought together over 20 international experts in the field of chemical safety assessment. The aim of this workshop was to review the current scientific, technical and regulatory landscapes, and to identify key opportunities towards reaching these goals. Here, we consider areas where further strategic investment will need to be focused if significant impact on 3Rs is to be matched with improved safety science, and why the timing is right for the field to work together towards an environment where we no longer rely on whole animal data for the accurate safety assessment of chemicals. © 2015 Z.


PubMed | NC3Rs, University of Plymouth, Dow AgroSciences and Organisation for Economic Co-operation and Development
Type: | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2016

Fish toxicity testing has been conducted since the 1860s in order to help define safe levels of chemical contaminants in lakes, rivers and coastal waters. The historical emphasis on acute lethality testing of chemicals has more recently focussed on long term sublethal effects of chemicals on fish and their prey species. Fish toxicity testing is now embedded in much environment legislation on chemical safety while it is recognized that animal use should be Replaced, Reduced and Refined (the 3Rs) where possible. The OECD Fish Toxicity Testing Framework provides a useful structure with which to address the needs of environmental safety assessment whilst implementing the 3Rs. This commentary aims to promote the implementation of the recommendations of the OECD Fish Toxicity Testing Framework.


News Article | December 20, 2016
Site: www.eurekalert.org

Researchers have won a major new grant award for a study that will help to improve the welfare of live fish used in scientific tests. After rodents, fish are the second most commonly used animal in laboratory research and testing. However, the methods currently used for monitoring their welfare such as checking activity levels, stress hormones post mortem and clinical signs, are of limited value. These methods can often be ambiguous, invasive and provide feedback too late for researchers to act on. Scientists specialising in animal behaviour, cognition and welfare from the University of Lincoln, UK, have secured grant funding of more than £300,000 to devise an effective new tool for assessing the welfare of fish. Funded by the NC3Rs (National Centre for the Replacement Refinement & Reduction of Animals in Research), the project will develop and validate an automated 'social network' analysis tool using computer systems that will monitor changes in social interactions within groups of zebrafish and rainbow trout, and identify those changes which provide early warning signs of compromised welfare. The research will also examine how interventions designed to improve welfare, such as enriching the fishes' environment, impact on their behaviour. The three-year project will be led by Dr Oliver Burman, together with his co-investigator Dr Thomas Pike - both from the School of Life Sciences at the University of Lincoln. Dr Burman said: "Fish are increasingly popular as a research model, and we know that they can experience pain and demonstrate aversive behaviour when involved in scientific studies. There is therefore a clear and urgent need to identify ways in which we can refine the procedures used to assess fish welfare." The project will build up an extensive bank of knowledge and data about how groups of zebrafish and rainbow trout interact with each other in different conditions. Observations of the frequency, strength, type and direction of their associations with each other will be analysed to reveal to what extent deviations from their normal behaviour can inform us about their wellbeing. Dr Pike explained: "By developing a system that immediately recognises and alerts us to the first signs of distress, we hope to be able to ensure that fish welfare is protected whenever they are used in a scientific study." The funding was awarded as part of the NC3Rs 2016 project grant competition, which supports new approaches to reducing reliance on animals in research and improving animal welfare.

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