ACKNOWLEDGEMENTS Research personnel were funded both by ORD and by the American Chemistry Council Long-range Research Initiative (ACC-LRI). The views expressed in this poster are those of the authors and do not necessarily reflect the views of the U.S. Environmental Protection Agency. Applying a Tiered Risk-based Approach to Prioritizing Thousands of Chemicals for Further Evaluation: A Comparison of Current High Throughput Computational Approaches Chantel I. Nicolas1, Kamel Mansouri1, Patrick D. McMullen2, Rebecca A. Clewell1, Miyoung Yoon1, Martin B. Phillips1, Grace Patlewicz2, John F. Wambaugh2, and Harvey J. Clewell III1* 1ScitoVation, Research Triangle Park, NC and 2National Center for Computational Toxicology, U.S. Environmental Protection Agency, RTP, NC INTRODUCTION There is a need to prioritize thousands of environmental chemicals for further testing with the help of current computational technologies. Here we present a case study on applying a risk-based approach to chemical prioritization based on an initial triage by ranking the ratios between ExpoCast1 high-throughput exposure estimates and Thresholds of Toxicological Concern (TTCs)2. To demonstrate the applicability of TTCs for the initial triage, 358 ToxCast3 chemicals were processed as follows: 1) oral equivalent doses (OEDs)4 were calculated based on ToxCast bioactivity measurements and available metabolism data for estimating in vivo clearance, 2) TTC values were determined using the Cramer1 classification system, 3) OEDs and TTCs were then compared with available ExpoCast exposure estimates to determine their respective activity:exposure ratios (AERs). TTCs were lower than OEDs for 349 (97%) of the evaluated ToxCast compounds, implying that TTCs can serve as a conservative estimate of hazard in the absence of chemical- specific data. The TTC approach was then applied to a curated dataset of ~45,000 chemicals. In order to ground-truth the results, we curated an ensemble of compounds with established points of departure (e.g., no observed adverse effect levels (NOAELs)). TTC values were lower than NOAELs for all 128 compounds that overlap with the chemical database and have published NOAEL values based on a daily oral exposure. This study demonstrated the utility of exploiting computational approaches as part of a tiered risk-based approach to prioritize thousands of chemicals. This abstract does not necessarily reflect U.S. EPA policy. REFERENCES 1. Investigate whether TTC-based chemical prioritization approach is relevant for environmental chemicals of interest. 2. Compare TTC-based chemical prioritization to ToxCast OED-based chemical prioritization. 3. Ground-truth prioritization results by comparing available regulatory points of departure to TTC and OEDs OBJECTIVES Figure 9. Margin of exposures (MoEs) for top 50 ranking CERAPP compounds in grey dots (Cramer TTC Class III). 24 of these are ToxCast compounds, 3 have data necessary for HT-IVIVE, and 0 are ToxCast active compounds that also have data for employing HT-IVIVE. MoEs were calculated by dividing the Class 3 TTC (0.0015 mg/kg/d) by the upper 95% bounds on the ExpoCast SEEM2 exposure estimates in mg/kg/d. Some compound names were truncated for display. The breakdown of CERAPP compounds per Cramer class was roughly 82% (36773), 3% (1410), and 15% (6847), for Class III, Class II, and Class I, respectively (Figure 7a). Median margin of exposures for the three classes was 51.2, 392.1, and 1409.1 respectively (Figure 7b). Roughly 1000 chemicals have TTC-derived MoE of less than 10, while 164 have a margin of exposure of less than 1. These results are consistent with the a previous study10 comparing Cramer classes across compounds with biomonitoring data from the National Health and Nutrition Examination Survey (NHANES)11; 66% of NHANES compounds are in Cramer Class III. Furthermore, this study also illustrated that MoEs of less than 1 are feasible (58 compounds). Overall, TTC’s were more protective than