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Buckley L.A.,Eli Lilly and Company | Chapman K.,National Center for the Replacement | Burns-Naas L.A.,Pfizer | Todd M.D.,Pfizer | And 2 more authors.
International Journal of Toxicology | Year: 2011

Selection of a pharmacologically responsive species can represent a major challenge in designing nonclinical safety assessment programs for many biopharmaceuticals (eg, monoclonal antibodies (mAbs)). Frequently, the only relevant species for nonclinical testing of mAbs is the non-human primate (NHP). This situation, coupled with a rapidly increasing number of mAb drugs in development, has resulted in a significant increase in the number of NHPs used in nonclinical safety assessment. Apart from ethical considerations related to responsible animal use, there is a clear need for more efficient and innovative approaches to drug discovery and development; these factors drive the need to investigate alternative approaches and strategies for the safety assessment. This review summarizes important scientific and regulatory perspectives derived from presentations and audience discussions in an educational forum at the 2010 annual American College of Toxicology meeting regarding opportunities for employing alternative approaches to minimize NHP use in mAb drug development. © 2011 American College of Toxicology.


Smith A.C.,Anglia Ruskin University | Smith A.C.,University of Stirling | Surridge A.K.,University of Cambridge | Prescott M.J.,University of Stirling | And 4 more authors.
Animal Behaviour | Year: 2012

The colour vision polymorphism of most New World primates is a model system to study the function of colour vision. Theories for the evolution of primate trichromacy focus on the efficient detection and selection of ripe fruits and young leaves among mature leaves, when trichromats are likely to be better than dichromats. We examined whether colour vision status affected insect capture in groups of tamarins (Saguinus spp.) in captivity and in the field. Trichromatic tamarins caught more prey than dichromats, but dichromats caught a greater proportion of camouflaged prey than trichromats. The prey caught did not differ in size between the two visual phenotypes. Thus two factors may contribute to the maintenance of the genetic polymorphism of middle- to long-wavelength photopigments in platyrrhines: the advantage in finding fruit and leaves, which supports the maintenance of the polymorphism through a heterozygote advantage, and the dichromats' exploitation of different (e.g. camouflaged) food, which results in frequency-dependent selection on the different colour vision phenotypes. © 2011 The Association for the Study of Animal Behaviour.


Seidle T.,Humane Society International | Seidle T.,University of Konstanz | Robinson S.,Astrazeneca | Holmes T.,Covance | And 4 more authors.
Toxicological Sciences | Year: 2010

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or refining the use of animals, and (3) recommendations for future work in this area. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Creton S.,National Center for the Replacement | Weltje L.,BASF | Hobson H.,Hill International | Wheeler J.R.,Hill International
Chemosphere | Year: 2013

Fish bioconcentration tests are time consuming, expensive, and use many animals. Alternative methods that replace, reduce or refine the use of fish for BCF testing would therefore be of value. Test guidelines generally require that bioconcentration factors (BCFs) are determined at two exposure concentrations. However, recent revisions to the OECD Test Guideline for BCF testing (TG 305) provide the option to use only one exposure concentration, when justification is provided, although two concentrations may still be required for some regulatory purposes. Analysis of 55 studies on plant protection products demonstrates that BCF values do not significantly differ between the two exposure concentrations. This analysis therefore provides evidence to support the revision of OECD TG 305, and in particular provides justification for using the one test concentration approach for plant protection product active substances. © 2012 Elsevier Ltd.


Burden N.,National Center for the Replacement | Creton S.,Environmental Protection Authority | Weltje L.,BASF | Maynard S.K.,Hill International | Wheeler J.R.,Dow AgroSciences
Regulatory Toxicology and Pharmacology | Year: 2014

Fish bioconcentration test guidelines generally require that bioconcentration factors (BCFs) are determined at two exposure concentrations. However, recent revisions to the OECD test guideline for bioconcentration testing (TG 305) provide the option to use only one exposure concentration, when justification is provided, although two concentrations may still be required for some regulatory purposes. Recently, this justification has been demonstrated for plant protection product active ingredients. To determine whether this justification has a broader validity for general chemicals, an analysis of 236 BCF studies on general chemicals was conducted. The results presented here again demonstrate that BCF values do not significantly differ between concentrations when more than one concentration is used. This relationship is particularly strong for BCFs ≥1000. L/kg, which is beneficial, since only chemicals with BCFs >2000. L/kg may require regulatory action. This analysis therefore provides a data-driven rationale for using the one test concentration approach for general chemical substances and thus could contribute to a substantial reduction in the use of fish in bioconcentration tests. © 2014 The Authors.


Creton S.,National Center for the Replacement | Clook M.,Chemicals Regulation Directorate | Wheeler J.R.,Hill International
Chemosphere | Year: 2014

In order to minimise animal testing, this paper explores the feasibility of the "threshold approach" that has been recently developed by the Organisation for Economic Cooperation and Development (OECD). Essentially the approach uses a limit test at a single threshold concentration determined by the results of Daphnia and algae tests. If no mortality is observed in the limit test the fish acute value can be expressed as greater than the threshold value. However, if mortality is observed a full concentration-response test is triggered. In order to assess the applicability of the approach to plant protection products (PPP), a database of 185 products (fish, Daphnia and algae endpoints) was constructed and the threshold approach retrospectively applied. However, this analysis did not take into account the use of the data in the regulatory process. To assess whether the "threshold approach" could be used for PPPs the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) held a workshop in December 2010. This meeting brought together representatives from a number of European regulators and researchers as well as industry to discuss the applicability of the approach. The outcome of this discussion is presented in the paper. © 2013 Elsevier Ltd.


O'Connor E.C.,Pfizer | Chapman K.,National Center for the Replacement | Butler P.,Pfizer | Mead A.N.,Pfizer
Neuroscience and Biobehavioral Reviews | Year: 2011

The self-administration model is the primary non-clinical approach for assessing the reinforcing properties of novel compounds. Given the now frequent use of rats in self-administration studies, it is important to understand the predictive validity of the rat self-administration model for use in abuse liability assessments. This review of 71 drugs identifies high concordance between findings from rat self-administration studies and two clinical indicators of abuse liability, namely reports of positive subjective-effects and the DEA drug scheduling status. To understand the influence of species on concordance we compare rodent and non-human primate (NHP) self-administration data. In the few instances where discrepancies are observed between rat data and the clinical indicators of abuse liability, rat self-administration data corresponds with NHP data in the majority of these cases. We discuss the influence of genetic factors (sex and strain), food deprivation state and the study design (acquisition or drug substitution) on self-administration study outcomes and highlight opportunities to improve the predictive validity of the self-administration model. © 2010 Elsevier Ltd.


Creton S.,National Center for the Replacement | Douglas M.,Dow AgroSciences | Wheeler J.R.,Hill International | Hutchinson T.H.,CEFAS - Center for Environment, Fisheries and Aquaculture Science
Toxicology Letters | Year: 2010

Ecotoxicity testing of pesticide active ingredients and formulated plant protection products (PPPs) prior to their commercial use is required by authorities around the world. Such studies are important for the conduct of risk assessments to protect wildlife and the environment, but they should only be conducted when their use is scientifically justified. One test of questionable scientific merit is the chronic fish toxicity test when conducted with formulated PPPs, which is a potential requirement under European legislation: chronic exposure to the formulated product per se rarely occurs in the environment and therefore it is generally not possible to use the data from chronic formulation studies in a meaningful risk assessment. A recent survey of European crop protection companies to explore the scientific merits and regulatory drivers for chronic fish toxicity studies has shown that current practice in deciding on the need for chronic fish toxicity testing of formulated PPPs varies substantially between companies. The most commonly cited reason for conducting such studies was solely to meet regulatory requirements. We conclude that chronic formulation testing is rarely if ever scientifically justified, and recommend that the forthcoming revision of the EU Aquatic Toxicology Guidance Document takes account of this by including a requirement that justification must be provided for conducting the test, rather than the current situation where the onus is on the registrant to provide a justification for not conducting the test. © 2010 Elsevier Ireland Ltd.


Percie Du Sert N.,National Center for the Replacement | Rice A.S.C.,Imperial College London | Rice A.S.C.,Chelsea and Westminster Hospital NHS Foundation Trust
British Journal of Pharmacology | Year: 2014

Neuropathic pain remains an area of considerable unmet clinical need. Research based on preclinical animal models has failed to deliver truly novel treatment options, questioning the predictive value of these models. This review addresses the shortcomings of rodent in vivo models commonly used in the field and highlights approaches which could increase their predictivity, including more clinically relevant assays, outcome measures and animal characteristics. The methodological quality of animal studies also needs to be improved. Low internal validity and incomplete reporting lead to a waste of valuable research resources and animal lives, and ultimately prevent an objective assessment of the true predictivity of in vivo models. © 2014 The British Pharmacological Society.


Burden N.,National Center for the Replacement | Chapman K.,National Center for the Replacement | Sewell F.,National Center for the Replacement | Robinson V.,National Center for the Replacement
Journal of the American Association for Laboratory Animal Science | Year: 2015

The National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is an independent scientific organization that is based in the United Kingdom, which was set up by the government to lead the discovery and application of new technologies and approaches that minimize the use of animals in research and improve animal welfare. The NC3Rs uses a range of strategies to improve and advance science through application of the 3Rs. These include funding basic research, open innovation (CRACK IT), and programs run by inhouse scientists. We present several case studies from the NC3Rs portfolio, featuring asthma research, the use of nonhuman primates in monoclonal antibody development, and CRACK IT. Finally, we anticipate the future, as we use our experience to move into new research fields and expand toward international collaboration. Here we highlight how equipping scientists with relevant and emerging 3Rs tools can help overcome the challenges and limitations of the use of animals in research to the benefit of the whole bioscience community. Copyright 2015 by the American Association for Laboratory Animal Science.

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