Physiological fidelity or model parsimony? The relative performance of reverse-toxicokinetic modeling approaches

Physiologically-based toxicokinetic (PBTK) models are often developed to facilitate in vitro to in vivo extrapolation (IVIVE) using a top-down, compartmental approach, favoring architectural simplicity over physiological fidelity despite the lack of general guidelines relating model design to dynamical predictions. Here we explore the impact of design choice (high vs. low fidelity) on chemical distribution throughout an animal's organ system.

We contrast transient dynamics and steady states of three previously proposed PBTK models of varying complexity in response to chemical exposure. The steady states for each model were determined analytically to predict exposure conditions from tissue measurements. Steady state whole-body concentrations differ between models, despite identical environmental conditions, which originates from varying levels of physiological fidelity captured by the models. These differences affect the relative predictive accuracy of the inverted models used in exposure reconstruction to link effects-based exposure data with whole-organism response thresholds obtained from in vitro assay measurements.

Our results demonstrate how disregarding physiological fideltiy in favor of simpler models affects the internal dynamics and steady state estimates for chemical accumulation within tissues, which, in turn, poses significant challenges for the exposure reconstruction efforts that underlie many IVIVE methods. Developing standardized systems-level models for ecological organisms would not only ensure predictive consistency among future modeling studies, but also ensure pragmatic extrapolation of in vivo effects from in vitro data or modeling exposure-response relationships.