Citation:

Patlewicz, G., J. Wambaugh, S. Felter, T. Simon, AND R. Becker. Utilizing Threshold of Toxicological Concern (TTC) with High Throughput Exposure Predictions (HTE) as a Risk-Based Prioritization Approach for thousands of chemicals. Computational Toxicology. Elsevier B.V., Amsterdam, Netherlands, 7:58-67, (2018). https://doi.org/10.1016/j.comtox.2018.07.002

Impact/Purpose:

Proof of concept study to explore the utility of coupling HTE estimates with TTC values as part of a risk based screening approach to prioritise thousands of chemicals

Description:

Regulatory agencies across the world are facing the challenge of performing risk-based prioritization of thousands of chemicals in commerce. Here, we present an approach using the Threshold of Toxicological Concern (TTC) combined with heuristic high-throughput exposure (HTE) modelling to identify those chemicals for which human exposures are sufficiently low that they could be considered of lower priority for further evaluation. We started with 7968 chemicals with previously modeled median and upper 95% credible interval (UCI) total daily median exposure rates. As an initial proof of concept, assuming none of the 7986 were excluded from the TTC approach, we found fewer than 5% of these chemicals had UCI exposures > the Cramer Class III TTC (1.5 μg/kg-day). Here, we expand upon that work using the TTC workflow of Kroes et al (2004) to profile the 7986 chemicals using known TTC exclusions and structural alerts, and compared UCI exposures to the appropriate class-specific TTC. For risk-based prioritization, chemicals with exposures > TTC would be ranked as higher priority for further evaluation whereas substances with exposures < TTC would be ranked as lower priority. None of the substances categorized as Cramer Class I (1294) or Cramer Class II (332) exceeded their respective TTC values. For Cramer Class III, 58 of the 3214 substances and 1 of the 102 acetylcholinesterase inhibitors exceeded their TTC values. The modeled UCI exposures for the vast majority of the 1853 chemicals with genotoxicity structural alerts exceeded the TTC of 0.0025 μg/kg-day, but only 79 substances exceeded this TTC using median exposure values. For substances for which UCI exposures exceed relevant TTC values, we highlight possible approaches could be considered for further evaluation. Overall, coupling TTC with HTE offers promise as a pragmatic first step in ranking substances as part of a risk-based screening approach.

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