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Neurotoxicology. 2008 May;29(3):520-31. doi: 10.1016/j.neuro.2008.02.008. Epub 2008 Feb 23.

Application of in vitro neurotoxicity testing for regulatory purposes: Symposium III summary and research needs.

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European Centre for the Validation of Alternative Methods (ECVAM), Institute of Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.


Prediction of neurotoxic effects is a key feature in the toxicological profile of many compounds and therefore is required by regulatory testing schemes. Nowadays neurotoxicity assessment required by the OECD and EC test guidelines is based solely on in vivo testing, evaluating mainly effects on neurobehavior and neuropathology, which is expensive, time consuming and unsuitable for screening large number of chemicals. Additionally, such in vivo tests are not always sensitive enough to predict human neurotoxicity and often do not provide information that facilitates regulatory decision-making processes. Incorporation of alternative tests (in vitro testing, computational modelling, QSARs, grouping, read-across, etc.) in screening strategies would speed up the rate at which compound knowledge and mechanistic data are available and the information obtained could be used in the refinement of future in vivo studies to facilitate predictions of neurotoxicity. On 1st June 2007, the European Commission legislation concerning registration, evaluation and authorisation of chemicals (REACH) has entered into force. REACH addresses one of the key issues for chemicals in Europe, the lack of publicly available safety data sheets. It outlines a plan to test approximately 30,000 existing substances. These chemicals are currently produced in volumes greater than 1ton/year and the essential data on the human health and ecotoxicological effects are lacking. It is estimated that approximately 3.9 million test animals (including 2.6 million vertebrates) (Hartung T, Bremer S, Casati S, Coecke S, Corvi R, Fortnaer S, et al. ECVAM's response to the changing political environment for alternatives: consequences of the European Union chemicals and cosmetics policies. ATLA 2003;31:473-81) would be necessary to fulfill the requirements of REACH if the development and establishment of alternative methods is not accepted by regulatory authorities. In an effort to reduce animal use and testing costs within this tonnage band, the European Commission has advocated the use of alternative approaches. Neurotoxicity testing is not directly addressed within REACH, however when alerts are observed based on organ specific toxicity studies then neurotoxicity assessment has to be performed. This session at the 11th International Neurotoxicology Association Meeting provided a forum to openly discuss and debate the potential of in vitro testing strategies that could be relevant for neurotoxicity evaluation in the context of regulatory requirements. The EU FP6 project A-Cute-Tox was presented as an example of a possible in vitro testing strategy for prediction of human acute systemic toxicity. Other presentations focused on the characterization of the available in vitro models (cell lines and primary culture) and neuronal specific endpoints, with a special emphasis on electrical activity, metabonomics and modulation of vesicular neurotransmitter release as possible neuronal endpoints relevant for in vitro neurotoxicity testing. Finally, it was underlined that in vitro systems (strategies) that have the potential to be applied for neurotoxicity assessment have to be formally validated under standardised conditions that have been recognised by national and international validation bodies.

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