Dialogue and Collaboration: A Personal View on Laboratory Animal Welfare Developments in General, and on ECVAM's First Decade in Particular

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 207-210 ◽  
Author(s):  
Herman B.W.M. Koëter
Keyword(s):  
National Level ◽  
In Vitro Tests ◽  
Practical Application ◽  
Animal Testing ◽  
Validation Process ◽  
Personal View ◽  
Ld50 Test ◽  
The Three Rs ◽  
Regulatory Acceptance

A personal view is presented on progress made during the last 25 years in applying the Three Rs ( reduction, refinement, replacement) to animal testing in regulatory toxicology, with an emphasis on “good moments” (for example, international workshops on the principles and practical application of the validation process and on regulatory acceptance) and “not-so-good moments” (for example, the time taken to accept alternatives to the LD50 test and to accept in vitro tests for skin absorption as OECD Test Guidelines). The importance of dialogue and cooperation between international coordinating centres and scientific activities at the national level is stressed, as exemplified by the work of ECVAM during its first decade.

The Use of Biomarkers as Alternatives to Current Animal Tests on Food Chemicals

1998 ◽  
Vol 26 (4) ◽  
pp. 421-480
Author(s):  
Krys Bottrill
Keyword(s):  
Animal Studies ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
In Vitro Test ◽  
Animal Testing ◽  
Dietary Biomarkers ◽  
Recent Developments ◽  
Mechanistic Basis ◽  
The Three Rs

Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.

Research on the development of alternatives to animal testing for pharmaceutical products and international standardisation

Impact ◽  
2021 ◽  
Vol 2021 (8) ◽  
pp. 44-45
Author(s):  
Hajime Kojima
Keyword(s):  
Research Group ◽  
Pharmaceutical Products ◽  
In Vitro Assays ◽  
Animal Testing ◽  
3 Dimensional ◽  
Alternatives To Animal Testing ◽  
Gene Assay ◽  
Innovative Work ◽  
Regulatory Acceptance

Scientists are working to develop new and innovative alternatives to animal testing that don't rely on the use of animals. Takao Ashikaga, Hajime Kojima and Yoko Hirabayashi are part of JaCVAM which works to promote the use of alternatives to animal testing. The goal is to replace, reduce or refine (3Rs) the use of animal under International harmonization. Hirabayashi is also the representative of a research group that is funded by the AMED and the representative of a research group funded by the MHLW. A challenge the researchers are facing in their quest to ensure the welfare of experimental animals and also ensure the safety of various pharmaceutical and chemicals is the lack of biomarkers to more accurately predict toxicity for regulatory acceptance. This means that without animal testing more costly and complex non-animal methods are required and presents a barrier to the adoption of non-animal methods for international standerisation. As such, there is a need to develop an easy way to obtain a lot of information. Hirabayashi and the team are working on the development of AI that can be used to evaluate the safety of different compounds. The researchers are developing in vitro assays such as ordinary 2-dimensional culture, 3-dimensional culture including organoids or spheroids, reporter gene assay and organ-on-a chip; and in silico assays such as computer toxicology using QSAR and Read Across. The researchers hope that their innovative work will contribute to the 3Rs, benefiting animal welfare for regulatory use.

Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 91-109 ◽  
Author(s):  
Robert Combes ◽  
Christina Grindon ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Decision Tree ◽  
Systemic Toxicity ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
The European Union ◽  
Animal Testing ◽  
Pbpk Modelling ◽  
Joint Research Project ◽  
The Eu

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, 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 REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

HYDRAULICS AND IN VITRO HEMOLYSIS TEST OF A MAGLEV IMPLANTABLE VENTRICULAR ASSIST DEVICE

2017 ◽  
Vol 17 (07) ◽  
pp. 1740023
Author(s):  
GUANGHUI WU ◽  
CHUANGYE XU ◽  
XIUJIAN LIU ◽  
CHANGYAN LIN ◽  
LIN YANG ◽  
...  
Keyword(s):  
Left Ventricular Assist Device ◽  
Ventricular Assist Device ◽  
Left Ventricular ◽  
Hydrodynamic Performance ◽  
In Vitro Tests ◽  
Animal Testing ◽  
Assist Device ◽  
Ventricular Assist ◽  
Left Ventricular Assist

A small implantable centrifugal left ventricular assist device, the CH-VAD (CH Biomedical Inc, JiangSu, China), featuring a magnetically levitated impeller is under development. The goal of this study is to validate hydrodynamic performance and hemocompatibility of the pump through in vitro studies. The hydraulic performance was quantified experimentally by using in vitro circulation loop system, and it turned out that the pump could deliver 5[Formula: see text]L/min under a pressure of 100[Formula: see text]mmHg at a rotational speed of approximate 3400[Formula: see text]rpm. A series of in vitro tests were established according to ASTM F1841, the standard practice for the assessment of hemolysis in continuous-flow blood pumps. The results showed that the average normalized index of hemolysis (NIH) value of the VAD was 0.0007[Formula: see text][Formula: see text][Formula: see text]0.0003[Formula: see text]mg/dL. The magnetic levitation left ventricular assist device (LVAD) has good hemolytic performance and stable mechanical property. These acceptable performance results supported proceeding initial acute animal testing conditions.

The Future of ECVAM: A Personal Perspective

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 239-241
Author(s):  
Michael Balls
Keyword(s):  
Alternative Methods ◽  
Personal Perspective ◽  
Practical Application ◽  
Validation Process ◽  
The Future ◽  
Chemicals Policy ◽  
The Three Rs ◽  
Made In

Progress made in the practical application of the validation process is summarised, and some of the remaining problems are considered. Highlights of the first ten years of ECVAM are reviewed, and ECVAM's activities as a route of communication on the Three Rs are discussed. Finally, some suggestions are made for maintaining ECVAM's momentum in the future, especially in relation to the challenge and opportunity for alternative methods afforded by the new EU Chemicals Policy.

Ocular Safety: A Silent (In Vitro) Success Story

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 69-74 ◽  
Author(s):  
Rodger D. Curren ◽  
John W. Harbell
Keyword(s):  
Raw Materials ◽  
Test Methods ◽  
In Vitro Tests ◽  
High Dose ◽  
Animal Testing ◽  
Animal Test ◽  
Ocular Irritation ◽  
Irritation Test ◽  
Dose Levels

Ocular irritation testing has been one of the animal test methods most criticised by animal welfare advocates. Additional criticism has arisen from within the scientific community, based on the variability of the animal test results and the questionable relevance of the extremely high dose levels employed. As a result, the Draize eye irritation test has been one of the main targets for in vitro replacement. Despite extensive efforts, however, there is still no in vitro method that is fully validated as a regulatory replacement. In spite of this, many individual companies are using diverse in vitro ocular irritation tests to gain important safety and efficacy information about their products and raw materials, eliminating the need for animal testing in the process. This is done in a safe fashion by applying intelligent testing paradigms. ECVAM has played a major role in this success, through its many programmes that have emphasised the importance of understanding the true toxicological need, and then using in vitro tests to provide that information. Thus, even in the absence of a successfully validated regulatory assay, the desired result of reducing animal testing is being met.

Local Irritation/Corrosion Testing Strategies: Development of a Decision Support System for the Introduction of Alternative Methods

2000 ◽  
Vol 28 (1) ◽  
pp. 29-40 ◽  
Author(s):  
Stephan Zinke ◽  
Ingrid Gerner ◽  
Gabriele Graetschel ◽  
Eva Schlede
Keyword(s):  
Decision Support ◽  
Decision Support System ◽  
Support System ◽  
Chemical Properties ◽  
Alternative Methods ◽  
In Vitro Tests ◽  
The European Union ◽  
Animal Testing ◽  
Property A

The notification procedure for new chemicals of the European Union (EU) requires protocols on physicochemical and toxicological tests for the evaluation of physico-chemical properties and probable toxic effects of each notified substance. In order to reduce the amount of animal testing, alternative methods should be introduced into toxicity testing. Therefore, we have developed a rule-based decision support system (DSS) for the prediction of the local corrosive/irritant properties of new chemicals. To this end, data on more than 1000 substances were examined, which resulted in approximtely 180 “exception-rules” of the kind IF (physicochemical property) A THEN not (toxic) Effect B. In addition, the structural formulae of the chemicals were analysed, which resulted in approximately 160 “structure-rules” of the kind IF Substructure A THEN Effect B. The DSS can predict (based on theoretical structure-activity relationships) whether a chemical produces: a) corrosive effects (i.e. no testing is necessary; b) might have corrosive effects (i.e. no animal testing, in vitro tests are suitable); and c) will produce no effects or only marginal effects (i.e. animal tests are necessary based on current EU legislation for hazard assessment purposes). In addition, the DSS provides reliable data for legal classification and labelling based on a specific result.

scholarly journals Efficacité des anthelminthiques usuels contre les strongles digestifs chez les ovins au centre de la Côte d’ivoire

2020 ◽  
Vol 14 (2) ◽  
pp. 378-389
Author(s):  
Alain Gérard Ambroise Apala ◽  
Amoin Marie Amélie Clarisse Komoin-Oka ◽  
Kouakou Rufin Assare ◽  
Gédéon Amian ◽  
Kouakou Eliezer N’goran
Keyword(s):  
Cote D'ivoire ◽  
Côte D’Ivoire ◽  
National Level ◽  
Fecal Excretion ◽  
In Vitro Tests ◽  
Cote D’Ivoire ◽  
Faecal Excretion ◽  
Côte D'ivoire

Les données recueillies lors des études menées par certains chercheurs ont donné des prévalences élevées à l’infestation des strongles dans certaines régions de la Côte d’Ivoire, laissant soupçonner une diminution de l’efficacité des anthelminthiques dans les élevages ovins. Nous avons supposé que les moyens de lutte contre les strongles deviennent moins efficaces. C’est donc pour confirmer cette baisse de l’efficacité des traitements anthelminthiques, en déterminer les causes et proposer des solutions pour enrayer ce phénomène que cette étude a été réalisée. Elle s’est déroulée dans 12 élevages répartis dans 8 localités du centre de la Cote d’Ivoire. Elle visait à évaluer par des tests in vivo de réduction de l’excrétion fécale des oeufs (FECRT), la sensibilité des strongles gastro intestinaux aux anthelminthiques usuels, afin de vérifier l’apparition de cas de résistance. La molécule la plus utilisée était l’Albendazole, suivie du Lévamisole, puis de l’Ivermectine. L’Ivermectine a été testée dans un seul élevage, le Lévamisole dans 4 élevages et l’Albendazole dans 10 élevages. Les analyses coprologiques ont permis l’identification d’oeufs de strongles, de Trichuris sp, de Strongyloides sp, de Moniezia sp et d’ookystes du genre Eimeria. Avec l’Ivermectine, le taux de réduction de l’excrétion fécale (FECR) des oeufs de strongles a été de 100% dans le seul élevage où il a été testé. Avec le Lévamisole, le FECR a été de 100% dans 2 élevages et il était compris entre 92 et 99% dans les 2 autres élevages. Avec l’Albendazole, le FECR a été de 100% dans 7 élevages ; il était compris entre 94 et 99% dans 2 élevages, et entre 70 et 96% dans un élevage. Des autopsies ont permis d’identifier les espèces de strongles ; il s’agissait d’Haemonchus sp, Trichostrongylus sp, Cooperia sp et Oesophagostomum sp. Les animaux autopsiés provenant des élevages où le FECR était inférieur à 100%, hébergeaient un nombre de vers plus important que les animaux des autres élevages. Ce travail a permis de démontrer que la résistance aux anthelminthiques ne s’est pas encore installée dans les élevages ovins au centre de la Côte d’Ivoire. Un tel travail doit être étendu à l’échelle national avec des tests in vitro, afin de mieux cerner l’état des lieux, et par la même occasion sensibiliser l’ensemble des éleveurs sur les différentes pratiques à adopter afin de retarder voire empêcher la mise en place de la résistance dans nos différentes fermes en Côte d’Ivoire. Mots clés : Efficacité, anthelminthiques, strongles digestifs, ovins, Côte d’Ivoire. English Title: Efficacy of common anthelmintics against digestive strongles in sheep in central of Côte d’IvoireThe data collected during the studies carried out by some researchers gave high prevalence to the infestation of strongles in certain regions of Côte d'Ivoire, suggesting a decrease in the efficacy of anthelmintics in sheep farming. We have assumed that the means of combating strongles become less effective. This study was therefore carried out to confirm this drop in the effectiveness of anthelmintic treatments, to determine the causes and to propose solutions to curb this phenomenon. It took place in 12 farms spread over 8 localities in the center of Côte d’Ivoire. It aimed to evaluate, by in vivo tests for the reduction of faecal excretion of eggs (FECRT), the sensitivity of gastrointestinal strongyles to the usual anthelmintics, in order to check the appearance of cases of resistance. The most used molecule was Albendazole, followed by Levamisole and then Ivermectin. Ivermectinwas tested in a single farm, Levamisole in 4 farms and Albendazole in 10 farms. Coprology analyzes identified eggs of strongyles, Trichuris sp, Strongyloides sp, Moniezia sp and Oookies of the genus Eimeria. With Ivermectin, the rate of fecal excretion reduction (FECR) of strongle eggs was 100% in the one farm where it was tested. With Levamisole, the FECR was 100% in 2 farms and it was between 92 and 99% in the 2 other farms. With Albendazole, the FECR was 100% in 7 farms; it was between 94 and 99% in 2 farms, and between 70 and 96% in a farm. Autopsies identified species of strongyles; these were Haemonchus sp, Trichostrongylus sp, Cooperia sp and Oesophagostomum sp. Autopsied animals from farms where the  FECR was less than 100% harbored a larger number of worms than animals from other farms. This work has made it possible to demonstrate that resistance to anthelmintics has not yet taken hold in sheep farming in the center of Côte d'Ivoire. Such work must be extended to the national level with in vitro tests, in order to better understand the inventory, and at the same time make all the breeders aware of the different practices to adopt in order to delay or even prevent the resistance set up in our different farms in Ivory Coast.Keywords: Efficacy, anthelmintics, digestive strongles, sheep, Côte d'Ivoire.  

The In Vitro Acute Skin Irritation of Chemicals: Optimisation of the EPISKIN Prediction Model within the Framework of the ECVAM Validation Process

2005 ◽  
Vol 33 (4) ◽  
pp. 329-349 ◽  
Author(s):  
José Cotovio ◽  
Marie-Hélène Grandidier ◽  
Pascal Portes ◽  
Roland Roguet ◽  
Gilles Rubinstenn
Keyword(s):  
Prediction Model ◽  
Mtt Assay ◽  
Skin Irritation ◽  
Membrane Damage ◽  
Clinical Signs ◽  
Alternative Methods ◽  
In Vitro Tests ◽  
Validation Process

In view of the increasing need to identify non-animal tests able to predict acute skin irritation of chemicals, the European Centre for the Validation of Alternative Methods (ECVAM) focused on the evaluation of appropriate in vitro models. In vitro tests should be capable of discriminating between irritant (I) chemicals (EU risk: R38) and non-irritant (NI) chemicals (EU risk: “no classification”). Since major in vivo skin irritation assays rely on visual scoring, it is still a challenge to correlate in vivo clinical signs with in vitro biochemical measurements. Being particularly suited to test raw materials or chemicals with a wide variety of physical properties, in vitro skin models resembling in vivo human skin were involved in prevalidation processes. Among many other factors, cytotoxicity is known to trigger irritation processes, and can therefore be a first common event for irritants. A refined protocol (protocol15min–18hours) for the EPISKIN model had been proposed for inclusion in the ECVAM formal validation study. A further improvement on this protocol, mainly based on a post-treatment incubation period of 42 hours (protocol15min–42hours), the optimised protocol, was applied to a set of 48 chemicals. The sensitivity, specificity and accuracy with the MTT assay-based prediction model (PM) were 85%, 78.6% and 81.3% respectively, with a low rate of false negatives (12%). The improved performance of this optimised protocol was confirmed by a higher robustness (homogeneity of individual responses) and a better discrimination between the I and NI classes. To improve the MTT viability-based PM, the release of a membrane damage marker, adenylate kinase (AK), and of cytokines IL-1α and IL-8 were also investigated. Combining these endpoints, a simple two-tiered strategy (TTS) was developed, with the MTT assay as the first, sort-out, stage. This resulted in a clear increase in sensitivity to 95%, and a fall in the false-positive rate (to 4.3%), thus demonstrating its usefulness as a “decision-making” tool. The optimised protocol proved, both by its higher performances and by its robustness, to be a good candidate for the validation process, as well as a potential alternative method for assessing acute skin irritation.

Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1) ◽  
pp. 45-63 ◽  
Author(s):  
Robert Combes ◽  
Christina Grindon ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Decision Tree ◽  
Systemic Toxicity ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
The European Union ◽  
Animal Testing ◽  
Pbpk Modelling ◽  
Joint Research Project ◽  
The Eu

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, 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 REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

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