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Computational Modeling and Simulation of Developmental Toxicity (EuroTox 2016)
Citation:
Knudsen, T. Computational Modeling and Simulation of Developmental Toxicity (EuroTox 2016). Presented at EUROTOX 2016, Seville, SPAIN, September 04 - 07, 2016. https://doi.org/10.23645/epacomptox.5077591
Impact/Purpose:
Invited Speaker, presentation at EUROTOX 2016, Seville Spain; Workshop, “Enhancing The Quality Of Predictions For Developmental Toxicity Based On Alternative Methods”
Description:
Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative predictions of dose-response and gestational susceptibilities. Disclaimer: does not reflect EPA policy.
URLs/Downloads:
DOI: Computational Modeling and Simulation of Developmental Toxicity (EuroTox 2016)
KNUDSEN_EUROTOX_2016_PRESENTATION.PDF (PDF, NA pp, 3784.75 KB, about PDF)
KNUDSEN_EUROTOX_2016_ABSTRACT.PDF (PDF, NA pp, 88.32 KB, about PDF)