van der Burg Bart, Wedebye Eva Bay, Dietrich Daniel R, Jaworska Joanna, Mangelsdorf Inge, Paune Eduard, Schwarz Michael, Piersma Aldert H, Kroese E Dinant
BioDetection Systems BV, Amsterdam, The Netherlands.
Danish Technical University, Lyngby, Denmark.
Reprod Toxicol. 2015 Aug 1;55:114-23. doi: 10.1016/j.reprotox.2015.01.008. Epub 2015 Feb 2.
There is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible.
迫切需要用于生殖毒性测试的快速测试策略，以避免使用动物。欧盟框架计划7项目ChemScreen旨在以务实的方式填补这一空白，最好使用经过验证的现有工具，并将其置于创新的替代测试策略中。在我们的方法中，我们将受生殖毒物影响的关键过程的知识与此类影响的作用机制基础的知识相结合。我们使用计算机模拟方法对化学品进行相关毒性效应的预筛选，以减少测试需求。对于那些需要测试的化学品，我们建立了一个体外筛选小组，其中包括机械高通量方法和测量更综合终点的低通量试验。开发了计算机模拟药代动力学模块，用于通过不同暴露途径进行快速暴露预测。这些用于匹配体外和体内暴露水平的模块大大提高了体外试验的预测性。作为进一步的步骤，我们给出了如何使用现有数据预测化学品生殖毒性的示例。我们对小组组成部分进行了正式验证，还使用了更具创新性的方式，通过作用机制方法验证测试小组。我们积极致力于推动监管机构接受所开发的工具，将其作为实际应用的关键一步，包括用于类推目的的案例研究。通过这种方法，在动物使用和相关成本方面实现大幅节省似乎非常可行。
