Citation:

Wambaugh, J., M. Hughes, C. Ring, D. MacMillan, J. Ford, T. Fennell, S. Black, R. Snyder, N. Sipes, B. Wetmore, J. Westerhout, Woodrow Setzer, R. Pearce, J. Simmons, AND R. Thomas. Evaluating In Vitro-In Vivo Extrapolation of Toxicokinetics. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 163(1):152-169, (2018). https://doi.org/10.1093/toxsci/kfy020

Impact/Purpose:

This paper describes in vivo evaluation of high throughput in vitro predictions for toxicokinetics (HTTK). In tandem with high throughput toxicity screening (e.g., ToxCast) and high throughput exposure estimates (e.g., ExpoCast), HTTK methods provide critical information for risk-based chemical prioritization. In the past HTTK methods have been largely evaluated with pharmaceutical data. EPA/NHEERL and RTI conducted new in vivo experiments using an optimized study design to provide evaluation for chemicals more commonly associated with environmental exposure. These new data and analyses quantify and reduce uncertainty associated with the use of HTTK.

Description:

Identifying priority chemicals among the thousands present in the environment ideally relies upon risk analysis incorporating toxicity assessments, exposure potential, and toxicokinetics (TK). Relatively high throughput, in vitro TK (HTTK) pharmaceutical methods have been adapted for these chemicals. However, limitations with the predictive ability of HTTK methods are known to exist, particularly for non-pharmaceuticals. Here we report on new, in vivo TK experiments in rat for 26 chemicals more commonly associated with non-therapeutic and/or unintentional exposure. These chemicals, and an additional 19 chemicals from previously published in vivo rat studies, were systematically analyzed to estimate relevant TK parameters (e.g., volume of distribution, elimination rate). Our analysis created a library of TK parameters for 38 chemicals for which rat-specific in vitro HTTK data were also available. We then performed direct evaluation of TK in vitro-in vivo extrapolation (IVIVE) for rat. We evaluated four key aspects of TK: assumed oral bioavailability, estimated clearance, predicted volume of distribution, and predicted uncertainty. While no pharmaceutical was absorbed at less than 10% efficiency, fraction bioavailable for more environmentally-relevant chemicals was as low as 0.5%. Previous evaluations of HTTK have often used one-compartment models for in vivo data, while we determined that the plasma concentration time-course for many of the chemicals were better described using a two-compartment model with distribution and elimination phases. We observe that IVIVE performs much better for some TK metrics (e.g., average or maximum plasma concentration) than other properties (e.g., elimination rate). Predictive performance improved when data on fraction bioavailable was used.

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