prediction model

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Non-animal Replacements for Acute Toxicity Testing

Carol Barker-Treasure, Kevin Coll, Nathalie Belot, Chris Longmore, Karl Bygrave, Suzanne Avey and Richard Clothier

Current approaches to predicting adverse effects in humans from acute toxic exposure to cosmetic ingredients still heavily necessitate the use of animals under EU legislation, particularly in the context of the REACH system, when cosmetic ingredients are also destined for use in other industries. These include the LD50 test, the Up-and-Down Procedure and the Fixed Dose Procedure, which are regarded as having notable scientific deficiencies and low transferability to humans. By expanding on previous in vitro tests, such as the animal cell-based 3T3 Neutral Red Uptake (NRU) assay, this project aims to develop a truly animal-free predictive test for the acute toxicity of cosmetic ingredients in humans, by using human-derived cells and a prediction model that does not rely on animal data. The project, funded by Innovate UK, will incorporate the NRU assay with human dermal fibroblasts in animal product-free culture, to generate an in vitro protocol that can be validated as an accepted replacement for the currently available in vivo tests. To date, the project has successfully completed an assessment of the robustness and reproducibility of the method, by using sodium lauryl sulphate (SLS) as a positive control, and displaying analogous results to those of the original studies with mouse 3T3 cells. Currently, the testing of five known ingredients from key groups (a surfactant, a preservative, a fragrance, a colour and an emulsifier) is under way. The testing consists of initial range-finding runs followed by three valid runs of a main experiment with the appropriate concentration ranges, to generate IC50 values. Expanded blind trials of 20 ingredients will follow. Early results indicate that this human cell-based test holds the potential to replace aspects of in vivo animal acute toxicity testing, particularly with reference to cosmetic ingredients.
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The Validation of Toxicological Prediction Models

Graeme Archer, Michael Balls, Leon H. Bruner, Rodger D. Curren, Julia H. Fentem, Hermann-Georg Holzhütter, Manfred Liebsch, David P. Lovell and Jacqueline A. Southee

An alternative method is shown to consist of two parts: the test system itself; and a prediction model for converting in vitro endpoints into predictions of in vivo toxicity. For the alternative method to be relevant and reliable, it is important that its prediction model component is of high predictive power and is sufficiently robust against sources of data variability. In other words, the prediction model must be subjected to criticism, leading successful models to the state of confirmation. It is shown that there are certain circumstances in which a new prediction model may be introduced without the necessity to generate new test system data.
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The Importance of the Prediction Model in the Validation of Alternative Tests

Andrew P. Worth and Michael Balls

An overview is presented of the validation process adopted by the European Centre for the Validation of Alternative Methods, with particular emphasis on the central role of the prediction model (PM). The development of an adequate PM is considered to be just as important as the development of an adequate test system, since the validity of an alternative test can only be established when both components (the test system and the PM) have successfully undergone validation. It is argued, however, that alternative tests and their associated PMs do not necessarily need to undergo validation at the same time, and that retrospective validation may be appropriate when a test system is found to be reliable, but the case for its relevance remains to be demonstrated. For an alternative test to be considered "scientifically valid", it is necessary for three conditions to be fulfilled, referred to here as the criteria for scientific relevance, predictive relevance, and reliability. A minimal set of criteria for the acceptance of any PM is defined, but it should be noted that required levels of predictive ability need to be established on a case-by-case basis, taking into account the inherent variability of the alternative and in vivo test data. Finally, in view of the growing shift in emphasis from the use of standalone alternative tests to alternative testing strategies, the importance of making the PM an integral part of the testing strategy is discussed.
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ECVAM’s Activities on Computer Modelling and Integrated Testing

Andrew P. Worth

This paper introduces the basic concepts of quantitative structure-activity relationship (QSAR), expert system and integrated testing strategy, and explains how the analogy between QSARs and prediction models leads naturally to criteria for the validation of QSARs. ECVAM's in-house research programme on QSAR modelling and integrated testing is summarised, along with plans for the validation of QSAR models and expert system rulebases at the European Union level.
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ECVAM’s Activities on Computer Modelling and Integrated Testing

Andrew P. Worth

This paper introduces the basic concepts of quantitative structure-activity relationship (QSAR), expert system and integrated testing strategy, and explains how the analogy between QSARs and prediction models leads naturally to criteria for the validation of QSARs. ECVAM's in-house research programme on QSAR modelling and integrated testing is summarised, along with plans for the validation of QSAR models and expert system rulebases at the European Union level.
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Validation of the Embryonic Stem Cell Test in the International ECVAM Validation Study on Three In Vitro Embryotoxicity Tests

Elke Genschow, Horst Spielmann, Gabriele Scholz, Ingeborg Pohl, Andrea Seiler, Nicole Clemann, Susanne Bremer and Klaus Becker

A detailed report is presented on the performance of the embryonic stem cell test (EST) in a European Centre for the Validation of Alternative Methods (ECVAM)-sponsored formal validation study on three in vitro tests for embryotoxicity. Twenty coded test chemicals, classified as non-embryotoxic, weakly embryotoxic or strongly embryotoxic on the basis of their in vivo effects in animals and/or humans, were tested in four laboratories. The outcome showed that the EST can be considered to be a scientifically validated test, which is ready for consideration for use in assessing the embryotoxic potentials of chemicals for regulatory purposes.
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Validation of the Rat Limb Bud Micromass Test in the International ECVAM Validation Study on Three In Vitro Embryotoxicity Tests

Horst Spielmann, Elke Genschow, Nigel A. Brown, Aldert H. Piersma, Aart Verhoef, Marielle Q.I. Spanjersberg, Hannele Huuskonen, Francoise Paillard and Andrea Seiler

A detailed report is presented on the performance of the rat limb bud micromass (MM) test in a European Centre for the Evaluation of Alternative Methods (ECVAM)-sponsored formal validation study on three in vitro tests for embryotoxicity. Twenty coded test chemicals, classified as non-embryotoxic, weakly embryotoxic or strongly embryotoxic on the basis of their in vivo effects on animals and/or humans, were tested in four laboratories. The outcome showed that the MM test is an experimentally validated test, which holds promise for use for identifying strongly embryotoxic chemicals, but which needs to be improved before it can be recommended for use for regulatory purposes.
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Validation of the Postimplantation Rat Whole-embryo Culture Test in the International ECVAM Validation Study on Three In Vitro Embryotoxicity Tests

Aldert H. Piersma, Elke Genschow, Aart Verhoef, Marielle Q.I. Spanjersberg, Nigel A. Brown, Madeleine Brady, Angie Burns, Nicole Clemann, Andrea Seiler and Horst Spielmann

A detailed report is presented on the performance of the postimplantation rat whole-embryo culture (WEC) test in a European Centre for the Validation of Alternative Methods (ECVAM)-sponsored formal validation study on three in vitro tests for embryotoxicity. Twenty coded test chemicals, classified as non-embryotoxic, weakly embryotoxic or strongly embryotoxic on the basis of their in vivo effects in animals and/or humans, were tested in four laboratories. The outcome showed that the WEC test can be considered to be a scientifically validated test, which is ready for consideration for use in assessing the embryotoxic potentials of chemicals for regulatory purposes.
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An Exploratory Study of Two Caco-2 Cell Models for Oral Absorption: A Report on Their Within-laboratory and Between-laboratory Variability, and Their Predictive Capacity

Pilar Prieto, Sebastian Hoffmann, Valentina Tirelli, Francesco Tancredi, Isabel González, Marival Bermejo and Isabella De Angelis

In 2005, the European Centre for the Validation of Alternative Methods (ECVAM) sponsored a study aimed at evaluating the reproducibility (between-laboratory and within-laboratory variability) and the predictive capacity of two in vitro cellular systems — the Caco-2/ATCC parental cell line and the Caco- 2/TC7 clone — for estimating the oral fraction absorbed (Fa) in humans. Two laboratories, both of which had experience with Caco-2 cultures, participated in the study. Ten test chemicals with documented in vivo oral absorption data were selected. Atenolol, cimetidine and propranolol were included as reference compounds for low, medium and high intestinal absorption, respectively. Transport experiments were independently carried out in the two laboratories, according to an agreed protocol. The apparent permeability coefficient (Papp) was calculated in either the apical to basolateral (absorption) or the basolateral to apical (efflux) direction. To investigate the involvement of possible active transport processes, experiments were also performed in the presence of sodium azide plus 2-deoxy-D-glucose in the donor compartment. Before performing the permeability experiments, the highest concentration that did not impair barrier integrity was identified for each test chemical in both cell models, by applying the chemicals together with a marker of the paracellular pathway. In addition, barrier integrity was assessed by measuring the trans-epithelial electrical resistance. All the permeability data obtained were independently analysed. Reproducibility was assessed for the seven substances for which sufficient data were available. Within-laboratory variability was based on coefficient of variation (CV) values. Median CV values of 10.4% and 14.7% were found for the two laboratories. Concerning between- aboratory reproducibility, comparable response levels were obtained for the three reference compounds and for paracetamol, while, for the other chemicals, the results were less reproducible — in particular, for compounds known to be actively transported. The Papp values obtained for both cell lines were comparable for identical experimental conditions. Despite the limited number of substances tested, the predictive capacity was investigated by using two mathematical models available in the literature. Good estimations of the human Fa were obtained for five well-absorbed compounds, while moderately and poorly absorbed compounds were overestimated. It is proposed that a confirmatory study addressing the main results, including power considerations, would now be useful.
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