The ECVAM international validation study on in vitro embryotoxicity tests:: Results of the definitive phase and evaluation of prediction models
The ECVAM international validation study on in vitro embryotoxicity tests:: Results of the definitive phase and evaluation of prediction models
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DOI：
10.1177/026119290203000204
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发表时间：
2002-03-01
影响因子：
2.7
通讯作者：
Becker, K
中科院分区：
文献类型：
--
作者：
Genschow, E;Spielmann, H;Becker, K
从1996年到2000年，ZEBET（BgVV动物实验替代方法文件和评价中心，柏林，德国）协调了欧洲替代方法验证中心（ECVAM）关于三种胚胎毒性试验的预验证和验证研究：a）采用胚胎干细胞系（EST）的试验; B）微团（MM）试验;和c）植入后大鼠全胚胎培养试验（WEC试验）。本研究的主要目的是评估这三种体外试验在区分无胚胎毒性、弱胚胎毒性和强胚胎毒性化合物方面的性能。该研究的第一阶段（1997年）被设计为预验证阶段，用于优化试验方案，并建立胚胎毒性化合物体内和体外数据的综合数据库。第二阶段（1998-2000年）涉及一项正式的验证试验，在盲法条件下对从数据库中选出的20种测试化合物进行验证，这些化合物被编码并分发给参与的实验室。在验证研究的初步阶段，对20种化学品中的6种进行了测试，这些化学品显示出潜在的胚胎毒性。这些结果被用来定义新的生物统计学为基础的预测模型（PM）的MM和WEC测试，并评估那些以前开发的EST。下一步，使用验证研究最终阶段剩余14种化学品的结果评价PM。三项体外胚胎毒性试验证明适用于测试具有不同胚胎毒性潜力（无胚胎毒性、弱胚胎毒性和强胚胎毒性）的各种化学品。根据管理团队定义的验收标准，三项体外胚胎毒性试验的重现性可接受。根据管理团队在正式验证研究前定义的性能标准，体外数据和体内数据得出的胚胎毒性潜力之间的一致性对于EST和WEC（PM2）试验良好，对于MM试验和WEC（PM 1）试验充分。当将EST的PM应用于正式验证研究确定阶段获得的体外数据时，在78%的实验中对化学品进行了正确分类。对于MM和WEC测试，PM分别提供了70%和80%（PM2）的正确分类。而且，非常重要的是，在三项体外试验的每一项中，使用强胚胎毒性化学品获得了极好的预测性（100%，WEC试验的PM 1除外，79%被认为是良好的）。
From 1996 to 2000, ZEBET (Centre for Documentation and Evaluation of Alternative Methods to Animal Experiments at the BgVV, Berlin, Germany) coordinated the European Centre for the Validation of Alternative Methods (ECVAM) prevalidation and validation study on three embryotoxicity tests: a) a test employing embryonic stem cell lines (EST); b) the micromass (MM) test; and c) the postimplantation rat whole-embryo culture assay (WEC test). The main objectives of the study were to assess the performance of these three in vitro tests in discriminating between non-embryotoxic, weakly embryotoxic and strongly embryotoxic compounds. Phase I of the study (1997) was designed as a prevalidation phase, for test protocol optimisation, and for the establishment of a comprehensive database of in vivo and in vitro data on embryotoxic compounds. Phase II (1998-2000) involved a formal validation trial, conducted under blind conditions on 20 test compounds selected from the database, which were coded and distributed to the participating laboratories. In the preliminary phase of the validation study, six chemicals out of the 20, which showed embryotoxic potential, were tested. These results were used to define new biostatistically based prediction models (PMs) for the MM and WEC tests, and to evaluate those developed previously for the EST. As a next step, the PMs were evaluated by using the results for the remaining 14 chemicals of the definitive phase of the validation study. The three in vitro embryotoxicity tests proved to be applicable to testing a diverse group of chemicals with different embryotoxic potentials (non-embryotoxic, weakly embryotoxic, and strongly embryotoxic). The reproducibility of the three in vitro embryotoxicity tests were acceptable according to the acceptance criteria defined by the Management Team. The concordances between the embryotoxic potentials derived from the in vitro data and from the in vivo data were good for the EST and the WEC (PM2) test, and sufficient for the MM test and the WEC (PM1) tests according to the performance criteria defined by the Management Team before the formal validation study. When applying the PM of the EST to the in vitro data obtained in the definitive phase of the formal validation study, chemicals were classified correctly in 78% of the experiments. For the MM and the WEC tests, the PMs provided 70% and 80% (PM2) correct classifications, respectively. And, very importantly, an excellent predictivity (100%, except for PM1 of the WEC test, with 79%, considered as good) was obtained with strongly embryotoxic chemicals in each of the three in vitro tests.