Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment

Toxicology. 2015 Jun 5;332:94-101. doi: 10.1016/j.tox.2014.05.012. Epub 2014 Jun 5.


High-throughput in vitro toxicity screening provides an efficient way to identify potential biological targets for environmental and industrial chemicals while conserving limited testing resources. However, reliance on the nominal chemical concentrations in these in vitro assays as an indicator of bioactivity may misrepresent potential in vivo effects of these chemicals due to differences in clearance, protein binding, bioavailability, and other pharmacokinetic factors. Development of high-throughput in vitro hepatic clearance and protein binding assays and refinement of quantitative in vitro-to-in vivo extrapolation (QIVIVE) methods have provided key tools to predict xenobiotic steady state pharmacokinetics. Using a process known as reverse dosimetry, knowledge of the chemical steady state behavior can be incorporated with HTS data to determine the external in vivo oral exposure needed to achieve internal blood concentrations equivalent to those eliciting bioactivity in the assays. These daily oral doses, known as oral equivalents, can be compared to chronic human exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. This review will describe the use of QIVIVE methods in a high-throughput environment and the promise they hold in shaping chemical testing priorities and, potentially, high-throughput risk assessment strategies.

Keywords: High-throughput screening; Quantitative in vitro-to-in vivo extrapolation; Reverse dosimetry.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Administration, Oral
  • Animal Testing Alternatives
  • Animals
  • Biotransformation
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Hepatocytes / metabolism
  • High-Throughput Screening Assays*
  • Humans
  • In Vitro Techniques*
  • Models, Biological*
  • Monte Carlo Method
  • Pharmacokinetics*
  • Risk Assessment
  • Risk Factors
  • Toxicity Tests / methods*
  • Toxicology / methods*