High-throughput PBTK models for in vitro to in vivo extrapolation

ABSTRACT

Introduction

Toxicity data are unavailable for many thousands of chemicals in commerce and the environment. Therefore, risk assessors need to rapidly screen these chemicals for potential risk to public health. High-throughput screening (HTS) for in vitro bioactivity, when used with high-throughput toxicokinetic (HTTK) data and models, allows characterization of these thousands of chemicals.

Areas covered

This review covers generic physiologically based toxicokinetic (PBTK) models and high-throughput PBTK modeling for in vitro-in vivo extrapolation (IVIVE) of HTS data. We focus on ‘httk’, a public, open-source set of computational modeling tools and in vitro toxicokinetic (TK) data.

Expert opinion

HTTK benefits chemical risk assessors with its ability to support rapid chemical screening/prioritization, perform IVIVE, and provide provisional TK modeling for large numbers of chemicals using only limited chemical-specific data. Although generic TK model design can increase prediction uncertainty, these models provide offsetting benefits by increasing model implementation accuracy. Also, public distribution of the models and data enhances reproducibility. For the httk package, the modular and open-source design can enable the tool to be used and continuously improved by a broad user community in support of the critical need for high-throughput chemical prioritization and rapid dose estimation to facilitate rapid hazard assessments.

KEYWORDS:

• Generic physiologically based toxicokinetic models
• high-throughput
• in vitro to in vivo extrapolation
• modeling software tools
• open source tools
• physiologically-based toxicokinetics
• toxicokinetics

Article highlights

• In vitro high-throughput screening (HTS) to efficiently assess potential chemical risk to public health requires toxicokinetics (TK) for in vitro-in vivo extrapolation (IVIVE)

• Physiologically based TK models (PBTK) support extrapolation in chemical risk assessment, including IVIVE

• The high-throughput toxicokinetics (HTTK) method uses generic PBTK models that can be parameterized for thousands of chemicals with in vitro TK data

• The U.S. Environmental Protection Agency (U.S. EPA) provides HTTK methods through the publicly available software package called ‘httk’

• HTTK facilitates HTS of chemical libraries for potential risk using only limited data

This box summarizes key points contained in the article.

Acknowledgement

The authors thank Drs. Elaina Kenyon and Todd Zurlinden for their helpful U.S. EPA internal reviews of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was funded by the U.S. Environmental Protection Agency through its Office of Research and Development