Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization

Abstract

High(er) throughput toxicokinetics (HTTK) encompasses in vitro measures of key determinants of chemical toxicokinetics and reverse dosimetry approaches for in vitro-in vivo extrapolation (IVIVE). With HTTK, the bioactivity identified by any in vitro assay can be converted to human equivalent doses and compared with chemical intake estimates. Biological variability in HTTK has been previously considered, but the relative impact of measurement uncertainty has not. Bayesian methods were developed to provide chemical-specific uncertainty estimates for 2 in vitro toxicokinetic parameters: unbound fraction in plasma (fup) and intrinsic hepatic clearance (Clint). New experimental measurements of fup and Clint are reported for 418 and 467 chemicals, respectively. These data raise the HTTK chemical coverage of the ToxCast Phase I and II libraries to 57%. Although the standard protocol for Clint was followed, a revised protocol for fup measured unbound chemical at 10%, 30%, and 100% of physiologic plasma protein concentrations, allowing estimation of protein binding affinity. This protocol reduced the occurrence of chemicals with fup too low to measure from 44% to 9.1%. Uncertainty in fup was also reduced, with the median coefficient of variation dropping from 0.4 to 0.1. Monte Carlo simulation was used to propagate both measurement uncertainty and biological variability into IVIVE. The uncertainty propagation techniques used here also allow incorporation of other sources of uncertainty such as in silico predictors of HTTK parameters. These methods have the potential to inform risk-based prioritization based on the relationship between in vitro bioactivities and exposures.

Predictive Performance of Next Generation Physiologically Based Kinetic (PBK) Model Predictions in Rats Based on In Vitro and In Silico Input Data

“…Particularly, for highly lipophilic compounds, like permethrin and resmethrin, the in vitro input data led to underpredictions by the PBK model. These results indicate the importance of standardizing and harmonizing the in vitro approaches to obtain robust results, including in vitro protocol adjustments to work with very lipophilic compounds ( Ferguson et al , 2019 ; Wambaugh et al , 2019 ).…”

External Scientific Report on the Interpretation of Data from the Developmental Neurotoxicity In Vitro Testing Assays for Use in Integrated Approaches for Testing and Assessment

“…Data gaps in IVIVE for developmental toxicity, including DNT, include a need to incorporate placental transfer, and in addition estimating brain concentrations and the fetal and postnatal development of the blood brain barrier. Oral equivalents calculated from in vitro assays can be combined with human exposure estimates for large numbers of chemicals to develop risk-based prioritizations (Wambaugh et al 2019). IVIVE can also be used for single chemical assessments.…”

New Approach Methods to Evaluate Health Risks of Air Pollutants: Critical Design Considerations for In Vitro Exposure Testing

“…To date, in vitro measures of toxicokinetics for volatile compounds have not been included in chemical risk prioritizations [163,169,170] because both bioactivity and kinetic data cannot be obtained using the same methods as previously implemented for the non-volatile and semi-volatile compounds that make up the majority of high-throughput screening libraries [164,171]. The development of a generic PBTK modeling framework that can concurrently handle higher throughput data on semi-and non-volatile chemicals with lower throughput data on volatile chemicals would enable comparison of chemical risk rankings across these diverse chemistries.…”