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Use of Threshold of Toxicological Concern (TTC) with High Throughput Exposure Predictions as a Risk-Based Screening Approach to Prioritize More Than Seven Thousand Chemicals (ASCCT)
Citation:
Patlewicz, G., John F. Wambaugh, S. Felter, T. Simon, AND R. Becker. Use of Threshold of Toxicological Concern (TTC) with High Throughput Exposure Predictions as a Risk-Based Screening Approach to Prioritize More Than Seven Thousand Chemicals (ASCCT). Presented at American Society for Cellular and Computational Toxicology (ASCCT), Gaithersburg, MD, September 21 - 22, 2017.
Impact/Purpose:
We present results of an approach for risk-based prioritization using the Threshold of Toxicological Concern (TTC) combined with high-throughput exposure (HTE) modelling. This analysis indicates promise for employing the TTC and HTE as a pragmatic first step in a risk-based prioritization approach for chemical safety evaluations.
Description:
Here, we present results of an approach for risk-based prioritization using the Threshold of Toxicological Concern (TTC) combined with high-throughput exposure (HTE) modelling. We started with 7968 chemicals with calculated population median oral daily intakes characterized by an upper 95% credible interval (UCI). Substances were profiled using known TTC exclusions and structural alerts using the workflow of Kroes et al (2004). UCI oral daily intakes were compared to the chemical class-specific TTC. For Cramer Class I, 0 of 1294 substances had UCIs greater than TTC; for Cramer Class II 0 of 332 had UCIs above TTC; for Cramer Class III 58 of 3214 UCIs were greater than TTC; and for cholinesterase inhibitors 1 of 102 had a UCI above the TTC. For the 1853 chemicals with potential genotoxicity structural alerts, modeled UCI exposures for the vast majority exceeded the TTC of 0.15 μg/day (using median exposure values, only 79 were above the TTC). Using the ICH TTC value for mutagenic impurities of 1.5 μg/day (corresponding to an individual excess lifetime cancer risk of 1x10-5), the UCI exposure values of 333 substances greater than this TTC (using the median exposure values 19 were above the ICH TTC). For substances that exceed TTCs, we discuss options for subsequent evaluation depending on the decision context. Overall, this analysis indicates promise for employing the TTC and HTE as a pragmatic first step in a risk-based prioritization approach for chemical safety evaluations. This abstract does not reflect EPA policy.