ATLA 32, 2004

/ATLA 32, 2004

The Case for Taking Account of Metabolism when Testing for Potential Endocrine Disruptors In Vitro

Robert D. Combes

Legislation in the USA, Europe and Japan will require that chemicals are tested for their ability to disrupt the hormonal systems of mammals. Such chemicals are known as endocrine disruptors (EDs), and will require extensive testing as part of the new European Union Registration, Evaluation and Authorisation of Chemicals (REACH) system for the risk assessment of chemicals. Both in vivo and in vitro tests are proposed for this purpose, and there has been much discussion and action concerning the development and validation of such tests. However, to date, little interest has been shown in incorporating metabolism into in vitro tests for EDs, in sharp contrast to other areas of toxicity testing, such as genotoxicity, and, ironically, such in vitro tests are criticised for not modelling in vivo metabolism. This is despite the existence of much information showing that endogenous and exogenous steroids are extensively metabolised by Phase I and Phase II enzymes both in the liver and in hormonally active tissues. Such metabolism can lead to the activation or detoxification of steroids and EDs. The absence of metabolism from these tests could give rise to false-positive data (due to lack of detoxification) or false-negative data (lack of activation). This paper aims to explain why in vitro assays for EDs should incorporate mammalian metabolising systems. The background to ED testing, the test methods available, and the role of mammalian metabolism in the activation and detoxification of both endogenous and exogenous steroids, are described. The available types of metabolising systems are compared, and the potential problems in incorporating metabolising systems into in vitro tests for EDs, and how these might be overcome, are discussed. It is recommended that there should be: a) an assessment of the intrinsic metabolising capacity of cell systems used in tests for EDs; b) an investigation into the relevance of using the prostaglandin H synthase system for metabolising EDs; and c) a feasibility study into the generation of genetically engineered mammalian cell lines expressing specific metabolising enzymes, which could also be used to detect EDs.
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Laboratory Animal Science Association (LASA) Alternatives Section Meeting — Designing to Reduce and Refine: Strategies and Successes

Sylvia Vaughan

On 30 March 2004, scientists from across the UK attended the Laboratory Animal Science Association (LASA) Alternatives Section meeting, Designing to reduce and refine: strategies and successes, held at AstraZeneca R&D, Charnwood, UK.
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2017-01-09T06:32:46+00:00

Editorial: Animal Experimentation and Alternatives in the Age of Extremism

Michael Balls

In my plenary lecture at the 2nd World Congress on Alternatives and Animal Use in the Life Sciences,1 held in 1996, I said that the Three Rs concept of Russell and Burch seemed to be going through a series of ages similar to the great ages of human civilisation, but in decades rather than in centuries, and in a different order. Thus, for the Three Rs, the 1950s was the Age of Renaissance, the 1960s the Age of Darkness, the 1970s the Age of Reason, and the 1980s the Age of Reformation — and I then saw the 1990s as the Age of Revolution (?).
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2017-01-09T06:32:47+00:00

News & Views

ATLA Staff Writer

Could Scientific Viewpoints Decide the US Presidency?
Genomics and the Meaning of Life
Quantum Dots: A Quantum Leap for Animal Models
Improving Public Awareness of Biotechnological Advances: Call for Information and Illustrations for the FRAME Website
The Future of Organ Transplantation
Re-homing Primates: The Consequences of Zero-tolerance to Primate Research
RNA Interference and Lentiviruses: Knocked-down but Not Out
Dimming Down Animal Numbers by Lighting Up Cancer Research
OncoMouse Patent Restricted
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2017-01-09T06:32:48+00:00

ECVAM News & Views

ATLA Staff Writer

ECVAM Task Forces
ECVAM Workshop
ECVAM Scientific Advisory Committee (ESAC)
Press Conference of European Research Commissioner Philippe Busquin
ECVAM Publications
Integrated Project on Reproductive Toxicity (ReProTect)
11th International Workshop on Quantitative Structure–Activity Relationships in the Human Health and nvironmental Sciences (QSAR 2004)
ECVAM’s Activities within the Joint Research Centre Enlargement Action
Conference Genomics and Alternatives to Animal Use 2004
ECETOC/LRI/ECVAM Scientific Workshop on Alternative Testing Approaches in Environmental Risk Assessment
Update on the ECVAM Validation Study on In Vitro Tests for Acute Skin Irritation
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2017-01-09T06:32:49+00:00 Tags: |

A Scientific and Animal Welfare Assessment of the OECD Health Effects Test Guidelines for the Safety Testing of Chemicals Under the European Union REACH System

Robert D. Combes, Ian Gaunt and Michael Balls

We have assessed each of the OECD Health Effects Test Guidelines (TGs) that were included in an annex to the Internet consultation issued by the European Commission relating to the Registration, Evaluation and Authorisation of Chemicals (REACH) legislation for the testing of new and existing chemical substances. Each guideline has been analysed with respect to its design and its scientific and animal welfare implications, the extent to which it makes use of modern techniques, and its suitability to be used in the REACH system for the testing of large numbers of chemicals. The scientific basis of the test and its justification are considered, as well as the numbers of animals required, and the potential adverse effects on them. The prospects and possibilities for applying the Three Rs (reduction, refinement and replacement) to each of the TGs are also discussed. We have proposed an overall testing strategy for how these TGs and other methods could best be deployed for chemicals testing, should it be necessary to fill data gaps. Certain TGs have been omitted from the strategy, when we have considered them to be unnecessary for chemicals testing. A series of recommendations has been made for improving the TGs with regard to both their scientific content and ways in which they could be better designed in relation to optimising the use of the animals concerned, and minimising adverse welfare consequences to them. Our investigations show that there is an urgent need to update the TGs to reflect modern techniques and methods, and to use current approaches for applying refinement strategies to improve the scientific and animal welfare aspects of the procedures used. Improvements can and should be made in all aspects of toxicity testing, from sample preparation, and animal housing, care and feeding, to dose formulation, test material administration, and the histopathological and clinical analysis of tissue samples. Opportunities for streamlining individual assays are very limited, but testing could be made more efficient by: a) only undertaking studies that provide relevant data; b) making greater use of screens and preliminary testing; c) applying some tests simultaneously to the same animals; d) using one sex; and e) eliminating redundant tests. In conclusion, it is clear that, as they stand, the OECD Health Effects TGs are unsuitable for use in the European Union REACH system, for which potentially very large numbers of laboratory animals will be needed for the testing of a very large number of chemicals.
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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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Third EU Report on the Statistics on Animals Used for Experimental and Other Scientific Purposes: Trends, Problems, Conclusions

Ursula G. Sauer, Horst Spielmann and Brigitte Rusche

A brief overview is given of the data published in the third report on the number of animals used for scientific purposes in the European Union (EU), in 1999. In comparison to the second EU statistical report, the meaningfulness of the data has been greatly improved, since 14 EU Member States have now used the “EU tables”. Even though the total number of animals officially reported in the EU for 1999 (9.81 million animals) is lower than the number reported for 1996 in the second report (11.65 million animals), an increase in animal numbers was observed in several Member States. Repeatedly, the use of transgenic animals was considered to be the cause for this. Most national authorities provided some comments on the data they submitted. However, the quality of these accompanying notes varies considerably, with the comments provided by The Netherlands, Finland, Sweden, Austria, Denmark and the United Kingdom containing the most-detailed remarks on their data.
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