Integrated Decision-tree Testing Strategies for Skin Corrosion and Irritation with Respect to the Requirements of the EU REACH Legislation

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 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 environmental (aquatic) toxicity testing. The manuscript reviews tests based on fish cells and cell lines, fish embryos, lower organisms, and the many expert systems and QSARs for aquatic toxicity testing. Ways in which reduction and refinement measures can be used are also discussed, including the Upper Threshold Concentration — Step Down (UTC) approach, which has recently been retrospectively validated by ECVAM and subsequently endorsed by the ECVAM Scientific Advisory Committee (ESAC). It is hoped that the application of this approach could reduce the number of fish used in acute toxicity studies by around 65–70%. Decision-tree style integrated testing strategies are also proposed for acute aquatic toxicity and chronic toxicity (including bioaccumulation), followed by a number of recommendations for the future facilitation of aquatic toxicity testing with respect to environmental risk assessment.

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An Evaluation of the Proposed OECD Testing Strategy for Skin Corrosion

Alternatives to Laboratory Animals ◽

10.1177/026119299802600512 ◽

1998 ◽

Vol 26 (5) ◽

pp. 709-720 ◽

Cited By ~ 4

Author(s):

Andrew P. Worth ◽

Julia H. Fentem ◽

Michael Balls ◽

Philip A. Botham ◽

Rodger D. Curren ◽

...

Keyword(s):

Skin Irritation ◽

Alternative Methods ◽

Advisory Group ◽

Chemical Toxicity ◽

Testing Strategy ◽

Animal Testing ◽

Ph Measurements ◽

Testing Strategies

The use of testing strategies which incorporate a range of alternative methods and which use animals only as a last resort is widely considered to provide a reliable way of predicting chemical toxicity while minimising animal testing. The widespread concern over the severity of the Draize rabbit test for assessing skin irritation and corrosion led to the proposal of a stepwise testing strategy at an OECD workshop in January 1996. Subsequently, the proposed testing strategy was adopted, with minor modifications, by the OECD Advisory Group on Harmonization of Classification and Labelling. This article reports an evaluation of the proposed OECD testing strategy as it relates to the classification of skin corrosives. By using a set of 60 chemicals, an assessment was made of the effect of applying three steps in the strategy, taken both individually and in sequence. The results indicate that chemicals can be classified as corrosive (C) or non-corrosive (NC) with sufficient reliability by the sequential application of three alternative methods, i.e., structure-activity relationships (where available), pH measurements, and a single in vitro method (either the rat skin transcutaneous electrical resistance (TER) assay or the EPISKIN™ assay). It is concluded that the proposed OECD strategy for skin corrosion can be simplified without compromising its predictivity. For example, it does not appear necessary to measure acid/alkali reserve (buffering capacity) in addition to pH for the classification of pure chemicals.

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

Alternatives to Laboratory Animals ◽

10.1177/026119290803600108 ◽

2008 ◽

Vol 36 (1) ◽

pp. 65-80 ◽

Cited By ~ 1

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Risk Assessment ◽

Decision Tree ◽

Endocrine Disruption ◽

Reproductive Toxicity ◽

Toxicity Testing ◽

Alternative Methods ◽

The European Union ◽

Animal Testing ◽

Testing Strategies

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

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s10 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 123-138 ◽

Cited By ~ 8

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Risk Assessment ◽

Decision Tree ◽

Endocrine Disruption ◽

Reproductive Toxicity ◽

Toxicity Testing ◽

Alternative Methods ◽

The European Union ◽

Animal Testing ◽

Testing Strategies

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 Skin Sensitisation with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s07 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 75-89 ◽

Cited By ~ 7

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Decision Tree ◽

In Vitro Tests ◽

The European Union ◽

Testing Strategy ◽

Animal Testing ◽

Joint Research ◽

Skin Sensitisation ◽

Joint Research Project ◽

The Eu

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 end-points 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

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s08 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 91-109 ◽

Cited By ~ 4

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

Alternatives to Laboratory Animals ◽

10.1177/026119290002800108 ◽

2000 ◽

Vol 28 (1) ◽

pp. 29-40 ◽

Cited By ~ 2

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.

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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

Alternatives to Laboratory Animals ◽

10.1177/026119290803600107 ◽

2008 ◽

Vol 36 (1) ◽

pp. 45-63 ◽

Cited By ~ 12

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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Development and use of in vitro alternatives to animal testing by the pharmaceutical industry 1980–2013

Toxicology Research ◽

10.1039/c5tx00123d ◽

2015 ◽

Vol 4 (5) ◽

pp. 1297-1307 ◽

Cited By ~ 25

Author(s):

Jen-Yin Goh ◽

Richard J. Weaver ◽

Libby Dixon ◽

Nicola J. Platt ◽

Ruth A. Roberts

Keyword(s):

Pharmaceutical Industry ◽

Animal Testing ◽

Genetic Toxicology ◽

Safety Testing ◽

Safety Pharmacology ◽

Alternatives To Animal Testing ◽

Ich Guidelines ◽

Preclinical Safety

An analysis of the use ofin vitrotechniques in preclinical safety testing revealed a marked increase to >180 000 tests/year by 2012. Step changes in uptake were notable in the three main areas of ADME, safety pharmacology and genetic toxicology, correlated with relevant ICH guidelines.

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Integrated Decision-tree Testing Strategies for Mutagenicity and Carcinogenicity with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s05 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 43-63 ◽

Cited By ~ 6

Author(s):

Robert Combes ◽

Christina Grindon ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

In Silico ◽

Alternative Methods ◽

Background Information ◽

Weight Of Evidence ◽

Future Research ◽

The European Union ◽

In Vitro Methods ◽

Testing Scheme ◽

Testing Strategies

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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