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Biomedical subjects

Michael Balls

Publications and source records attributed to Michael Balls.

At least 19 recordsLinked to original sources
PubMed2006

The FRAME alternatives laboratory database. 1. In vitro basal cytotoxicity determined by the Kenacid blue total protein assay.

A database of over 280 chemicals has been compiled by using a mouse 3T3-L1 fibroblast-like cell line in exponential growth, exposed to chemicals for 72 hours in a 96-well tissue culture plate format, and determining cell number via the Kenacid blue (KB) assay for total protein. Ranking the chemicals according to their basal cytotoxicity, expressed as the concentration (mM) that inhibits increase in total cellular protein over 72 hours by 50% (the ID50 value) shows a wide range of ID50 values, from 0.00003 mM to 10,096 mM. This information includes the results for MEIC chemicals 1-50, and we have now added basal cytotoxicity data for 23 of the next 25 MEIC chemicals. When the neutral red uptake (NRU) assay was performed with the same cell cultures, before the KB assay, very similar indications of basal cytotoxicity were obtained. Comparisons between the results with 3T3-L1 cells and with a human fibroblast-like cell line, BCL-D1 showed a significant difference in order of magnitude of the ID50 value for only 5 of 52 chemicals. However, there was a difference in ID50 value of more than one order of magnitude for 8 of 24 chemicals tested with an undifferentiated teratocarcinoma cell line, F9.

3T3 Cells↗
PubMed2006

An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system.

In its White Paper, Strategy for a Future Chemicals Policy, published in 2001, the European Commission (EC) proposed the REACH (Registration, Evaluation and Authorisation of CHemicals) system to deal with both existing and new chemical substances. This system is based on a top-down approach to toxicity testing, in which the degree of toxicity information required is dictated primarily by production volume (tonnage). If testing is to be based on traditional methods, very large numbers of laboratory animals could be needed in response to the REACH system, causing ethical, scientific and logistical problems that would be incompatible with the time-schedule envisaged for testing. The EC has emphasised the need to minimise animal use, but has failed to produce a comprehensive strategy for doing so. The present document provides an overall scheme for predictive toxicity testing, whereby the non-animal methods identified and discussed in a recent and comprehensive ECVAM document, could be used in a tiered approach to provide a rapid and scientifically justified basis for the risk assessment of chemicals for their toxic effects in humans. The scheme starts with a preliminary risk assessment process (involving available information on hazard and exposure), followed by testing, based on physicochemical properties and (Q)SAR approaches. (Q)SAR analyses are used in conjunction with expert system and biokinetic modelling, and information on metabolism and identification of the principal metabolites in humans. The resulting information is then combined with production levels and patterns of use to assess potential human exposure. The nature and extent of any further testing should be based strictly on the need to fill essential information gaps in order to generate adequate risk assessments, and should rely on non-animal methods, as far as possible. The scheme also includes a feedback loop, so that new information is used to improve the predictivity of computational expert systems. Several recommendations are made, the most important of which is that the European Union (EU) should actively promote the improvement and validation of (Q)SAR models and expert systems, and computer-based methods for biokinetic modelling, since these offer the most realistic and most economical solution to the need to test large numbers of chemicals.

Journal Article↗
PubMed2006

A critical assessment of the European Commission's proposals for the risk assessment and registration of chemical substances in the European Union.

In May, 2003, the European Commission published detailed proposals relating to its 2001 White Paper--Strategy for a Future Chemicals Policy. The White Paper described a new registration system called the REACH (Registration, Evaluation and Authorisation of Chemicals) system, for both new and existing chemicals. Subsequently, these detailed proposals were available for an eight-week consultation period for stakeholders to voice their views and concerns. In this paper, we describe our reactions to the Commissions more-detailed proposals. These include the creation of a European Chemicals Agency to implement the REACH system in conjunction with Competent Authorities (CAs) in Member States and the Commission itself. Unfortunately, many of our concerns and suggestions, previously voiced and shared with several other key stakeholders, remain unanswered, but are as relevant as when the White Paper was published. In particular, we are concerned about the lack of a clear and coherent strategy. There is no guidance for registrants on intelligent testing to maximise the use of non-animal approaches to safety testing, based on a combination of factors for estimating exposure levels, rather than mainly on production volumes. We are also concerned about the absence of a clear programme for the development, improvement and validation of new alternative methods, in conjunction with the Commissions own unit, the European Centre for the Validation of Alternative Methods, as well as other organisations with relevant expertise and experience, including FRAME. Finally, we explain why such measures should be introduced, together with clearer guidelines for the respective roles of the Agency, the CAs and the Commission in implementing and harmonising the REACH system at the European Union and Member State levels. A series of recommendations are made, to improve the situation and to improve the risk assessment process.

Journal Article↗
PubMed2006

FRAME and the Royal Commission on Environmental Pollution: common recommendations for assessing risks posed by chemicals under the EU REACH system.

This document discusses recommendations made by FRAME and the Royal Commission on Environmental Pollution (RCEP) with regard to the current European Commission proposals on the Registration, Evaluation and Authorisation of Chemicals (REACH) system for assessing the risks of chemicals to humans, wildlife and the environment. Of several common aims and recommendations, the two most important are: a) the greater use of non-animal testing methods, especially computational prediction methods (for example, [quantitative] structure-activity relationships, expert systems and biokinetic modelling) for prioritising chemicals for hazard assessment; and b) the greater use of intelligent exposure-based targeted risk assessment, with less emphasis being placed on tonnage-triggers. FRAME has produced a decision-tree testing scheme to illustrate the way in which these approaches could be used, together with in vitro test methods. This scheme has been slightly modified to take account of proposals subsequently made by the RCEP. In addition, FRAME points out that new and improved computational methods are needed through more coordinated research, and that these and existing methods need to be validated. The similarities between the independent publications of FRAME and the RCEP add weight to the recommendations that each have made concerning the implementation of the REACH system.

Journal Article↗
PubMed2006

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.

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.

Journal Article↗
PubMed2005

Toxicity testing: creating a revolution based on new technologies.

Biotechnology is evolving at a tremendous rate. Although drug discovery is now heavily focused on high throughput and miniaturized screening, the application of these advances to the toxicological assessment of chemicals and chemical products has been slow. Nevertheless, the impending surge in demands for the regulatory toxicity testing of chemicals provides the impetus for the incorporation of novel methodologies into hazard identification and risk assessment. Here, we review the current and likely future value of these new technologies in relation to toxicological evaluation and the protection of human health.

Animal Testing Alternatives↗
PubMed2005

The need for a formal invalidation process for animal and non-animal tests.

A plethora of regulations require that many chemicals and chemical products are tested for efficacy and/or toxicity. When permitted to operate effectively and without bias, the ECVAM/ICCVAM/OECD validation process can be used to independently establish that new animal and non-animal test procedures are sufficiently relevant and reliable for their stated purposes and should be considered for regulatory use. However, the validation process is under threat because of vested interests of various kinds, and it is clear that many currently-accepted animal tests and candidate animal and non-animal tests do not, and could never, meet the agreed criteria for necessity, test development, prevalidation, validation and acceptance. We therefore need an invalidation process to parallel and protect the validation process, so that such methods could be independently reviewed and declared irrelevant and/or unreliable for their claimed purposes. An additional advantage of such a process would be that valuable resources would no longer be wasted in attempts to secure the acceptance of inherently inadequate tests.

Animal Use Alternatives↗
PubMed2005

Intelligent testing strategies for chemicals testing -- a case of more haste, less speed?

The prospects for using (Q)SAR modelling, read-across (chemical) and other non-animal approaches as part of integrated testing strategies for chemical risk assessment, within the framework of the EU REACH legislation, are considered. The potential advantages and limitations of (Q)SAR modelling and read-across methods for chemical regulatory risk assessment are reviewed. It is concluded that it would be premature to base a testing strategy on chemical-based computational modelling approaches, until such time as criteria to validate them for their reliability and relevance by using independent and transparent procedures, have been agreed. This is mainly because of inherent problems in validating and accepting (Q)SARs for regulatory use in ways that are analogous to those that have been developed and applied for in vitro tests. Until this issue has been resolved, it is recommended that testing strategies should be developed which comprise the integrated use of computational and read-across approaches. These should be applied in a cautious and judicious way, in association with available tissue culture methods, and in conjunction with metabolism and biokinetic studies. Such strategies should be intelligently applied by being driven by exposure information (based on bioavailability, not merely on production volume) and hazard information needs, in preference to a tick-box approach. In the meantime, there should be increased efforts to develop improved (Q)SARs, expert systems and new in vitro methods, and, in particular, ways to expedite their validation and acceptance must be found and prospectively agreed with all major stakeholders.

Animal Testing Alternatives↗
PubMed2005

The use of non-human primates in biological and medical research: evidence submitted by FRAME to the Academy of Medical Sciences/Medical Research Council/Royal Society/Wellcome Trust Working Group.

The Academy of Medical Sciences, the Medical Research Council, the Royal Society and the Wellcome Trust are undertaking a study into the use of non-human primates in biological and medical research. An independent working group of scientific experts, led by Sir David Weatherall, aims to produce a report summarising the findings of this study, early in 2006. The trends in primate research, and the nature and effects of recent and proposed changes in the global use of non-human primates in research, will be investigated. The associated ethical, welfare and regulatory issues, and the role and impact of the Three Rs principles of refinement, reduction and replacement will also be reviewed. As part of this study, a call for evidence was made. The evidence submitted by FRAME emphasised that the use of non-human primates for fundamental research or for regulatory testing still fails to take into account the fact that, although non-human primates are anatomically and physiologically similar to humans, they are not necessarily relevant models for studies on human disease or human physiology. FRAME continues to believe that we have a duty to ensure that these animals are not used without overwhelming evidence that they are the only suitable and relevant models for use in work of undeniable significance.

Acquired Immunodeficiency Syndrome↗