A Simple Physiologically Based Toxicokinetic Model for Multi-Route <i>In Vitro–In Vivo</i> Extrapolation

Many chemicals found in the environment and commerce have been characterized for potential hazards by using in vitro screens. Translating concentrations that cause bioactivity into real-world exposures, in other words, in vitro–in vivo extrapolation (IVIVE), requires chemical-specific parameters and mathematical models. An administered (for example, oral) equivalent dose rate (milligrams per kilogram per day) that causes steady-state human plasma concentrations (micromolar) equivalent to bioactive in vitro concentrations can be derived using a simple IVIVE equation. Herein, we explain how this IVIVE equation approximates a physiologically based toxicokinetic (PBTK) model. Through the derivation of the steady-state solution of the PBTK model, we show how the simple IVIVE equation approximates relevant flows and tissues. We then extend the simple IVIVE equation by modifying the oral exposure PBTK model to include gas inhalation and exhalation. Gas exhalation increases clearance, potentially allowing more accurate prediction of the oral equivalent dose for semivolatile organic chemicals. The revised IVIVE equations also allow prediction of inhalation equivalent doses, in other words, the parts per million concentration that would cause steady-state human plasma concentrations equivalent to bioactive in vitro concentrations. Through comparison to an inhalation PBTK model, new simple IVIVE equations for plasma concentration have been developed, describing exhaled oral and inhalation doses.