title: The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals.
abstract: 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.
authors: BioDetection Systems BV, Amsterdam, The Netherlands. Electronic address: bart.van.der.burg@bds.nl.
authors: Bart
authors: B
authors: van der Burg
authors: Danish Technical University, Lyngby, Denmark.
authors: Eva Bay
authors: EB
authors: Wedebye
authors: University of Konstanz, Konstanz, Germany.
authors: Daniel R
authors: DR
authors: Dietrich
authors: Procter & Gamble, Brussels, Belgium.
authors: Joanna
authors: J
authors: Jaworska
authors: Fraunhofer-ITEM, Hannover, Germany.
authors: Inge
authors: I
authors: Mangelsdorf
authors: Simpple, Tarragona, Spain.
authors: Eduard
authors: E
authors: Paune
authors: University of Tübingen, Tübingen, Germany.
authors: Michael
authors: M
authors: Schwarz
authors: National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Utrecht University, Utrecht, The Netherlands.
authors: Aldert H
authors: AH
authors: Piersma
authors: TNO, Zeist, The Netherlands.
authors: E Dinant
authors: ED
authors: Kroese
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity; D000826:Animal Testing Alternatives; D000818:Animals; D003198:Computer Simulation; D004967:Estrogens / Q000633:toxicity; D057166:High-Throughput Screening Assays; D006801:Humans; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity; D055703:Reproductive Physiological Phenomena / Q000187:drug effects*; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D000726:Androgen Antagonists; D004967:Estrogens; D009153:Mutagens; D013723:Teratogens
keywords: Endocrine disruption; In silico; In vitro; Integrated testing; Read accross; Reproductive toxicity