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In vitro-in vivo extrapolation (IVIVE) for neurodevelopment: Toxico-kinetics and in vitro point of departure evaluation of putative developmental neurotoxicants
Citation:
Kreutz, A., T. Shafer, K. Paul-Friedman, J. Wambaugh, AND B. Wetmore. In vitro-in vivo extrapolation (IVIVE) for neurodevelopment: Toxico-kinetics and in vitro point of departure evaluation of putative developmental neurotoxicants. FutureTox V, Chapel Hill, NC, May 10 - 11, 2022. https://doi.org/10.23645/epacomptox.19701313
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Description:
In vitro new approach methodologies (NAMs) that screen for developmental neurotoxicity (DNT) hold great potential over traditional DNT studies for risk assessment. However, alongside additional uncertainties, these assays lack two key barriers that modulate concentrations at the site of brain development—the fetoplacental and blood brain barriers—leading to gaps in translating in vitro potency values to in vivo concentrations in the brain during windows of susceptibility for neurodevelopment. To address this, we developed a customized IVIVE approach. To estimate human equivalent doses that could elicit DNT-relevant bioactivity, IVIVE was performed using physiologically-based pharmacokinetic modeling during these windows of susceptibility—15 and 24 gestation weeks, and 2 weeks and 1 year of age. This approach incorporated in vitro toxicokinetic data to predict maximal concentrations (Cmax) in target tissues for chemicals screened in DNT NAMs. Administered equivalent doses (AEDs) were calculated from Cmax predictions and bioactivity data using reverse dosimetry. For chemicals with in vivo DNT data, AEDs overlapped with doses that elicited in vivo DNT effects at comparable lifestages, suggesting this approach holds potential for setting testing priorities. Incorporation of external exposure allowed derivation of bioactivity:exposure ratios—an ad hoc margin of exposure estimate for risk prioritization. To reduce uncertainty, we have incorporated three additional elements: enzyme-specific clearance to assess the impact of metabolic ontogenies, a lactational model to assess the impact of breastfeeding, and a fetoplacental transport model to derive fetal-tissue level concentrations. This abstract does not necessarily represent the views or policies of EPA.
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DOI: In vitro-in vivo extrapolation (IVIVE) for neurodevelopment: Toxico-kinetics and in vitro point of departure evaluation of putative developmental neurotoxicants
FUTURETOX_KREUTZ_042722_STICS.PDF (PDF, NA pp, 783.489 KB, about PDF)