European Centre for the Validation of Alternative Methods ECVAM

European Centre for the Validation of Alternative Methods (ECVAM), six in vitro systems for chronic neurotoxicity testing are recommended for further consideration (Worth and Balls 2002). These are described as in vitro models that may be suitable for long-term toxicity testing. The systems are... 

In vitro tools could be used alone or in test batteries with increased potency of the description of cellular events and changes. The chapter provides a brief introduction on the components of an in vitro system, the main differences between models for research and models for testing and a list of validated alternative methods according to the European Centre for the Validation of Alternative Methods (ECVAM) (http // ecvam.jrc.it/, http //ecvam.jrc.ec.europa.eu/) evaluation. 

An important point, made by the European Centre for the Validation of Alternative Methods (ECVAM), is that these 3 aspects (3Rs) should not be considered as alternatives that could replace each other, but as parts of an integrated system which should lead to progress in the development of non-animal tests and testing strategies. Another important key point recently defined by ECVAM is that the use of existing information must be maximized instead of testing methods. 

Alternative tests will have to be validated scientifically and established as acceptable by industry and the regulators before being used for registration. The EU body which undertakes this validation process is the European Centre for the Validation of Alternative Methods (ECVAM), and the US equivalent is the Interagency Co-ordinating Committee on the Validation of Alternative Methods (ICCVAM). 

To test the irritancy potential of substances, two tests which can reliably distinguish between skin corrosives and noncorrosives are endorsed by the European Centre for the Validation of Alternative Methods (ECVAM). The testing procedures are based on the transcutaneous electrical resistance (TER) measurements of rat skin and on a human skin model. Both test systems [141-145] will be briefly outlined below. Nevertheless, these tests are not suited for the group of mild irritants which do not induce an acute effect on the barrier function. For those substances, new markers need to be evaluated. First results are available for heat shock protein 27 where higher levels were observed in skin models after exposure to mildly irritating chemicals [146, 147]. 

One key issue is the requirement for animal testing. The report and recommendations of the European Centre for the Validation of Alternative Methods (ECVAM) workshop (Leahy et al., 1997) clearly state that a major priority is to reduce the number of animals used in pharmacokinetic studies in drug development. As much information as possible should be obtained from alternative sources, such as computer modeling or using data already generated for similar compounds. 

A European Centre for the Validation of Alternative Methods (ECVAM) was created by a Communication from the Commission to the Council and the Parliament in 1991, pointing to a requirement in Directive 86/609/EEC for the protection of animals used for experimental and other scientific purposes, which requires that the Commission and the Member States should actively support the development, validation, and acceptance of methods which could reduce, refine, or replace the use of laboratory animals [11]. As defined in the Communication of the European Commission to Council and the European Parliament, the duties of ECVAM are ... 

Worth A and Balls M (eds.) (2002) Alternative (non-animal) methods for chemical testing Current status and future prospects. A report prepared by ECVAM and the ECVAM Working Group on Chemicals. European Commission, Institute for Health and Consumer Protection, European Centre for the Validation of Alternative Methods (ECVAM). Alternatives to Laboratory Animals 30(Suppl. 1) 1-125. 

Eurther, The European Commission s Joint Research Centre (JRC), Institute for Health and Consumer Protection in Ispra, Italy is partnering in several initiatives to establish an international framework for the development, validation, and implementation of QSAR models that are useful for regulatory purposes. Within the JRC, the work involves the European Chemicals Bureau (ECB) and the European Centre for the Validation of Alternative Methods (ECVAM, in addition to external partners, such as the OECD. 

The list of alternative tests for reproductive toxicity, at variable stage of development, is fairly long given the complexity of the reproductive cycle and the multiple cell types and functions involved. An official source of information on alternative test development is the website of the European Centre for the Validation of Alternative Methods (ECVAM) (http //ecvam-dbalm.jrc.ec. europa.eu/ updated to 15 June 2013). Forty methods are listed for the area of reproductive toxicity. They are split into four categories effects on female fertility (n = 8), effects on male fertility n= 10), developmental toxicity (n = 21), and genotoxicity-mutagenicity (n= 1). Only eight of these methods have been developed up to fully defined protocols that can be downloaded from the same website ... 

Since Intestinal absorption and Intestinal and hepatic first-pass metabolism are the major processes limiting bloavallablllty, the majority of the methods described below will focus on appropriate models for these processes. Nevertheless, It should be emphasized that other barriers, notably the blood-brain barrier (BBB) and virtually all organ-related membrane barriers, also need to be considered when Investigating the distribution of a compound throughout the body and ultimately Its tissue bloavallablllty. A recent study by the European Centre for the Validation of Alternative Methods (ECVAM) compared In vitro BBB methods and characterized several models In relation to In vivo studies Immortalized BBB-derlved endothelial cell lines (SV-ARBEC, MBEC4), non-BBB-derlved cell lines (MDCK, Caco-2, ECV-C6), and primary cells derived from BBB. In all cases, the correlations between In vitro and In vivo assays were low [36], and, moreover, most In vitro methods lacked at least some of the features of the In vivo barrier [37, 38]. Therefore, animal studies will continue to play a major role In studies of the BBB. 

Worth, A.P., Hartung, T, and van Leeuwen, C.J. (2004b). The role of the European Centre for the Validation of Alternative Methods (ECVAM) in the validation of (Q)SARs, SAR and QSAR in Environmental Research, 15, 345-358. 

Katoh M, Hamajima F, Ogasawara T, Hata K. 2010. Assessment of human epidermal model LabCyte EPI-MODEL for in vitro skin irritation testing according to European Centre for the Validation of Alternative Methods (ECVAM)-validated protocol. J. Toxicol. Sci. 34(3) 327. 

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