BTS working party report on in vitro toxicology

Fielder, R.J.; Atterwill, C.K.; Anderson, Diana; Boobis, Alan R.; Botham, Philip A.; Chamberlain, M.; Combes, Robert; Duffy, Paul; Lewis, Richard; Lumley, Cynthia E.; Kimber, Ian; Newall, D.R.

doi:10.1177/096032719701600101

Cited by 24 publications

(15 citation statements)

References 2 publications

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“…There are no current or pending guidelines issued by the regulatory authorities for in vitro neurotoxicity testing (2,3), but several in vitro screening tests for neurotoxicity have been developed and evaluated (2,4,5). In 1994, the European Centre for the Validation of Alternative Methods (ECVAM) proposed a tiered approach consisting of three tiers for in vitro neurotoxicity testing (2), which has been further developed (6).…”

Section: Introductionmentioning

confidence: 99%

Organotypic Brain Slice Cultures: An Efficient and Reliable Method for Neurotoxicological Screening and Mechanistic Studies

Noraberg

2004

Altern Lab Anim

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This paper reviews the current state of the use of organotypic brain slice cultures for neurotoxicological and neuropharmacological screening and mechanistic studies, as exemplified by excitotoxin application. At present, no in vitro systems have been approved by the regulatory authorities for neurotoxicity testing. For the evaluation of the slice culture method, organotypic hippocampal slice cultures were exposed to toxic doses of the excitotoxins, glutamate, N-methyl-D-aspartate (NMDA), kainic acid and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and the glial toxin, DL-α-aminoadipic acid (DL-AAA). Neuronal cell death was quantified by propidium iodide (PI) uptake, and visualised by Fluoro-Jade (FJ) staining. General cell death was monitored by lactate dehydrogenase (LDH) release into the culture medium. EC50 values for the different compounds, based on PI uptake after exposure for 48 hours in entire cultures, were: glutamate, 3.5mM; DL-AAA, 2.3mM; kainic acid, 13μM; NMDA, 11μM; and AMPA, 3.7μM. In the slice cultures, the hippocampal subfields displayed the same differences in vulnerability as those observed in vivo. When subfield analysis was performed on the cultures, the CA1 subfield was most susceptible to glutamate, NMDA and AMPA, while CA3 was most susceptible to kainic acid. The amount of LDH release for DL-AAA was about four times that of L-glutamate, in accordance with the additional toxic effect on glial cells, which was also found by confocal microscopy to stain for FJ. In conclusion, it was found that organotypic brain slice culture, combined with standardised protocols and quantifiable markers, such as PI and FJ staining, is a relevant and feasible in vitro system for neurotoxicity testing. Considering the amount and quality of the available published data, it is recommended that the brain slice culture method could be subjected to pre-validation and formal validation for inclusion in a tiered in vitro neurotoxicity testing scheme to supplement and replace conventional animal tests.

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Section: Introductionmentioning

confidence: 99%

Organotypic Brain Slice Cultures: An Efficient and Reliable Method for Neurotoxicological Screening and Mechanistic Studies

Noraberg

2004

Altern Lab Anim

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“…The alternative methods available to date have been effective in refining and reducing animal testing (11,(29)(30)(31). Replacing animal tests is much more challenging (7,8,24,32,33). The reason is probably that integrating and interpreting effects in alternative models in terms of human health has proven to be very difficult (11,12,22).…”

Section: Discussionmentioning

confidence: 99%

The Feasibility of Replacing Animal Testing for Assessing Consumer Safety: A Suggested Future Direction

2004

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At present, we are unable to use much of the data derived from alternative (non-animal) tests for human health risk assessment. This brief Comment outlines why it is plausible that new paradigms could be developed to enable risk assessment to support consumer safety decisions, without the need to generate data in animal tests. The availability of technologies that did not exist 10 years ago makes this new approach possible. The approach is based on the concept that data and information derived from applying existing and new technologies to non-animal models can be interpreted in terms of harm and disease in man. A prerequisite is that similar data and information generated in a clinical setting are available to permit this “translation”. The incorporation of this additional translation step should make it possible to use data and information generated in non-animal models as inputs to risk assessment. The new technologies include genomics, transcriptomics, proteomics and metabonomics. Their application to in vitro and human “models” enables large amounts of data to be generated very quickly. The processing, interpretation and translation of these data need to be supported by powerful informatics capabilities and statistical tools. The use of integrated “systems biology” approaches will further support the interpretation by providing better understanding of the underlying biological complexity and mechanisms of toxicity. Clinical medicine is using the opportunities offered by the new ‘omics’ technologies to advance the understanding of disease. The application of these technologies in clinical medicine will generate massive amounts of data that will need processing and interpretation to allow clinicians to better diagnose disease and understand the patients’ responses to therapeutic interventions. Support from clinical epidemiology will be essential. If these data and information can be made generally accessible in an ethical and legal way, they should also permit the “translation” of experimental non-animal data, so that they can then be used in risk assessment.

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“…The use of integrated testing schemes has become particularly widespread in the pharmaceutical and agrochemical industries, where large numbers of candidate test substances need to be tested and screened to filter out those likely to be found toxic in subsequent testing (9). The use of integrated testing schemes contributes to the Three Rs, since scientifically advanced, replacement methods are used for all test substances initially.…”

Section: The Concept Of Integrated Testing Strategiesmentioning

confidence: 99%

Integrated Testing Strategies for Use with Respect to the Requirements of the EU REACH Legislation

et al. 2008

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Integrated testing strategies have been proposed to facilitate the process of chemicals risk assessment to fulfil the requirements of the proposed EU REACH system. Here, we present individual, decision-tree style, strategies for the eleven major toxicity endpoints of the REACH system, including human health effects and ecotoxicity. These strategies make maximum use of non-animal approaches to hazard identification, before resorting to traditional animal test methods. Each scheme: a) comprises a mixture of validated and non-validated assays (distinguished in the schemes); and b) decision points at key stages to allow the cessation of further testing, should it be possible to use the available information to classify and label and/or undertake risk assessment. The rationale and scientific justification for each of the schemes, with respect to the validation status of the tests involved and their individual advantages and limitations, will be discussed in detail in a series of future publications.

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BTS working party report on in vitro toxicology

Cited by 24 publications

References 2 publications

Organotypic Brain Slice Cultures: An Efficient and Reliable Method for Neurotoxicological Screening and Mechanistic Studies

Organotypic Brain Slice Cultures: An Efficient and Reliable Method for Neurotoxicological Screening and Mechanistic Studies

The Feasibility of Replacing Animal Testing for Assessing Consumer Safety: A Suggested Future Direction

Integrated Testing Strategies for Use with Respect to the Requirements of the EU REACH Legislation

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