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Comparing Toxicological Tipping Points from High-Content Imaging to Rat Subchronic Hepatoxicity Doses
Citation:
Antonijevic, T., T. Knudsen, AND I. Shah. Comparing Toxicological Tipping Points from High-Content Imaging to Rat Subchronic Hepatoxicity Doses. Presented at SOT 57th Annual Meeting and ToxExpo, San Antonio, TX, March 11 - 15, 2018. https://doi.org/10.23645/epacomptox.6836051
Impact/Purpose:
A major challenge to using in vitro high-throughput screening (HTS) data in risk assessment is the identification of toxicological “tipping points” between adaptation and adversity. Toxicological tipping points offer a novel approach for estimating their point of departure and evaluating chemical safety using HTS data.
Description:
A major challenge to using in vitro high-throughput screening (HTS) data in risk assessment is the identification of toxicological “tipping points” between adaptation and adversity. Toxicological tipping points represent a systems threshold, or critical point, beyond which biological pathways invoke permanent perturbations that eventually lead to adverse effects. Previously, we have proposed a formal approach to utilize time-course high-content imaging (HCI) data to identify tipping points in vitro. Here, we analyzed toxicological tipping points for chemicals in rat primary hepatocytes and used quantitative in vitro to in vivo extrapolation (qIVIVE) to compare them with rat subchronic hepatic lowest observed adverse effect levels (LOAELs). First, we selected 88 chemicals from ToxRefDB that produced subchronic effects in rats. Next, we treated rat primary hepatocytes with 10 concentrations (0.2 to 100µM) of these 88 chemicals. We used HCI to measure endoplasmic reticulum stress, mitochondrial function, lysosomal mass, steatosis, apoptosis, DNA texture, nuclear size and cell number at 6 time points (1, 3, 6, 24, 48 and 72h). After processing and normalizing the data to calculate cell-state trajectories produced by each chemical treatment, we examined the occurrence of tipping points. For chemicals that produced tipping points, critical concentrations were estimated and extrapolated to oral equivalent doses using (qIVIVE), and were compared rat subchronic LOAELs for liver effects. Overall, we found 47/88 chemicals produced tipping points while the remaining 41/88 chemicals showed transient perturbations followed by system recovery. For 20/47 chemicals the oral equivalent doses corresponding to tipping points were 5-100 times lower than LOAELs observed in rat subchronic. Our results show the utility of in vitro tipping points as a sensitive estimate of a systems threshold between adaptation and adversity that is supported by in vivo data. Toxicological tipping points offer a novel approach for estimating their point of departure and evaluating chemical safety using HTS data. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: Comparing Toxicological Tipping Points from High-Content Imaging to Rat Subchronic Hepatoxicity Doses
TODOR-SOT2018_POSTER-V2.PDF (PDF, NA pp, 1356.459 KB, about PDF)