• Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

      Fritsche, Ellen; Grandjean, Philippe; Crofton, Kevin M; Aschner, Michael; Goldberg, Alan; Heinonen, Tuula; Hessel, Ellen V S; Hogberg, Helena; Bennekou, Susanne Hougaard; Lein, Pamela J; Leist, Marcel; Mundy, William R; Paparella, Martin; Piersma, Aldert H; Sachana, Magdalini; Schmuck, Gabriele; Solecki, Roland; Terron, Andrea; Monnet-Tschudi, Florianne; Wilks, Martin F; Witters, Hilda; Zurich, Marie-Gabrielle; Bal-Price, Anna (2018-02-12)
      This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.
    • Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity.

      Bal-Price, Anna; Hogberg, Helena T; Crofton, Kevin M; Daneshian, Mardas; FitzGerald, Rex E; Fritsche, Ellen; Heinonen, Tuula; Hougaard Bennekou, Susanne; Klima, Stefanie; Piersma, Aldert H; Sachana, Magdalini; Shafer, Timothy J; Terron, Andrea; Monnet-Tschudi, Florianne; Viviani, Barbara; Waldmann, Tanja; Westerink, Remco H S; Wilks, Martin F; Witters, Hilda; Zurich, Marie-Gabrielle; Leist, Marcel (2018-02-23)
      Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).