The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

Abstract

a b s t r a c tThere 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.

Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

“…Different types of test batteries have been recently presented: they may consist of molecular-based assays, like in the ToxCast program (Sipes et al 2011 ; Padilla et al 2012 ) or cell-based assays, as, for example, in the ReProTect (Schenk et al 2010 ) or ChemScreen (van der Burg et al 2014 , 2015 ) projects.…”

Adverse outcome pathways: opportunities, limitations and open questions

“…Examples include predictive systems of developmental toxicity mediated by chemicals that inhibit migration of neural crest cells (Zimmer et al 2012(Zimmer et al , 2014Smirnova et al 2014;Nyffeler et al 2017) that block neurite growth (Stiegler et al 2011;Krug et al 2013b) or compromise the regulation of genes normally up-or downregulated during normal embryonic development (Krug et al 2013a;Rempel et al 2015). Other important examples are interferences with nuclear receptors and developmental signaling pathways (van der Burg et al 2015a(van der Burg et al , 2015bBal-Price et al 2015a, b, 2017, the generation of oxidative stress (Schildknecht et al 2009(Schildknecht et al , 2011(Schildknecht et al , 2017Krug et al 2014) and endoplasmic reticulum stress.…”

In silico prediction of toxicity and its applications for chemicals at work

“…A rapid test strategy for reproductive toxicity testing, avoiding the use of animals, combines knowledge of important processes affected by reproductive toxicants with the knowledge of the mechanical basis of those effects. As an additional step, examples were generated of how to predict the reproductive toxicity of chemicals using available data, formal validation of panel components was performed, and mechanical approaches used to test and verify, using more innovative approaches [49]. In summary, any approach that provides the information needed to establish an in silico tool for the safety assessment of chemicals can identify and predict a variety of toxicities from chemicals.…”