risk assessment

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Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

Liverpool John Moores University and FRAME conducted a 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 the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.
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An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and 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 repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which
could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivostudies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.
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The Role of Laboratory and Field Leaching Tests in Hazard Identification for Solid Materials

Uuve Kirso, Natalya Irha, Janek Reinik, Gary Urb and Margit Laja

The use of various in vitro toxicity assays for testing environmental solid samples is dependent on the availability of reliable methods for the sampling and pretreatment of the material. This study focuses on the evaluation of leaching behaviour as a first step in the context of the toxicity testing of solid environmental matter. Spent shale, from oil shale retorting, was chosen as a suitable example of deposited solid waste material. For the generation of leachate in the laboratory setting, a standard two-stage batch–leaching test was applied to the samples of technogenic waste. In the field, a new type of lysimeter, which does not disturb the surface, was used for in situ leachate collection. The chemical composition of water extracts was found to be different under field conditions, as compared with the laboratory experiments. Thus, the hazard identification of a solid technogenic waste by in vitro toxicological tests applied to laboratory leachates would not be the best solution. The content of hazardous ingredients could be underestimated if only laboratory tests are used. For risk assessment concerned with solid waste materials, the generation of leachate by using field lysimeters is recommended.
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The New EU REACH Regulation Has Finally Been Adopted: Is This the End of the Campaign Trail… or Just the Beginning?

Christina Grindon

The final EU REACH legislation has recently been adopted. This article considers the progress that has been made toward reducing the numbers of animals likely to be required to fulfil the testing requirements, and also considers the benefits to animal welfare and science that have arisen since the original REACH system proposals were published in 2003. Several positive changes have been made, including: the use of exposure-based testing; the requirement for scientific justification of any proposed animal testing; mandatory data sharing; and the fact that the EU is to take responsibility for the development and validation of alternative methods. While these changes are to be commended, there is still much room for improvement, particularly with respect to the adoption of integrated testing strategies that make maximum use of non-animal approaches to expedite the risk assessment process of existing chemicals, with the use of refined and updated animal tests only as a last resort.
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Proposed Integrated Decision-tree Testing Strategies for Mutagenicity and Carcinogenicity in Relation to the EU REACH Legislation

Robert Combes, Christina Grindon, Mark T.D. Cronin, David W. Roberts and John Garrod

Liverpool John Moores University and FRAME recently conducted a 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 the REACH system. This paper focuses on the prospects for using alternative methods (both in vitro and in silico) for mutagenicity (genotoxicity) and carcinogenicity testing — two toxicity endpoints, which, together with reproductive toxicity, are of pivotal importance for the REACH system. The manuscript critically discusses well-established testing approaches, and in particular, the requirement for short-term in vivo tests for confirming positive mutagenicity, and the need for the rodent bioassay for detecting non-genotoxic carcinogens. Recently-proposed testing strategies focusing on non-animal approaches are also considered, and our own testing scheme is presented and supported with background information. This scheme makes maximum use of pre-existing data, computer (in silico) and in vitro methods, with weight-of-evidence assessments at each major stage. The need for the improvement of in vitro methods, to reduce the generation of false-positive results, is also discussed. Lastly, ways in which reduction and refinement measures can be used are also considered, and some recommendations are made for future research to facilitate the implementation of the proposed testing scheme.
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Why ‘Suitable’ In Vitro Methods, as Defined in the Final EU REACH Legislation, are an Inappropriate Basis for Risk Assessment

Robert D. Combes

The final text of the REACH legislation, that has recently been published by the European Parliament, and which will come into force in the middle of 2007, implies that results obtained from so-called ‘suitable’ in vitro methods could be used for testing. It is also stated that a ‘suitable’ test is one that has been deemed to be ready to enter a validation study — for example, according to criteria specified by ECVAM. It is argued that, because the wording of the legal text is too vague and imprecise, it is totally unsatisfactory, mainly because it seems to endorse the application of non-validated methods for regulatory risk assessment. While their use might be suitable for providing information for classification in a weightof- evidence approach, setting safe dose levels should only ever be based on the use of data from a properly validated test method. This concern, and other problems raised by the final legislation, is discussed, and recommendations are made which could avoid the premature use of potentially unsuitable methods for risk assessment, whilst ensuring that potentially suitable tests can be used for this purpose, once they have been formally validated.
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Integrated Decision-tree Testing Strategies for Skin Corrosion and Irritation with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

Liverpool John Moores University and FRAME recently conducted a 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 the REACH system. This report focuses on how to maximise the use of alternative methods (both in vitro and in silico) for skin corrosion and irritation testing within a tiered testing strategy. It considers the latest developments in in vitro testing, with particular reference to the reconstituted skin models which have now been now been successfully validated and independently endorsed as suitable for both skin corrosivity and irritancy testing within the EU.
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An Integrated Decision-tree Testing Strategy for Skin Sensitisation with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This report presents some of the results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, 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 the REACH system. This report focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for skin sensitisation testing. The manuscript reviews in vitro tests based on protein-ligand binding, dendritic/Langerhans cells and T-lymphocyte activation, and also the QSAR models and expert systems available for this endpoint. These tests are then incorporated into an integrated, decision-tree testing strategy, which also includes the Local Lymph Node Assay (in its original and new reduced protocols) and the traditional guinea-pig tests (which should only be used as a last resort). The aim of the strategy is to minimise the use of animals in testing for skin sensitisation, while satisfying the scientific and logistical demands of the EU REACH legislation.
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Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

Robert Combes, Christina Grindon, Mark T.D. Cronin, David W. Roberts and John F. Garrod

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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Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

Liverpool John Moores University and FRAME conducted a 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 the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.
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