The role of physiologi cally based kinetic modeling in interpreting the results of in vitro cell-based toxicity ass ays

INTRODUCTION

The risk a chemical poses to human health is a function of its potential to damage cells (toxicocynamics), coupled with the concentration to which cells are exposed in vivo (toxicokinetics) (Figure 1).

Figure 1: The toxicokinetic and toxicodynamic processes that link between external exposure and adverse health outcomes

Cell-based in vitro assays measure the former. The latter is dependent on the biokinetic properties of the chemical and often needs to be predicted using in silico mathematical models. Physiologically-based kinetic (PBK) models are important tools for simulating the toxicokinetics of a chemical compounds and predicting internal chemical concentrations at the organ, cellular and even subcellular levels for a given human exposure scenarios¹.

EXPERIMENTAL METHODS

PBK models are in silico mathematical models that conceptualize the body as a system of interconnected compartments coupled by differential equations that describe the processes that govern the fate and transport of compounds between these compartments. Parameter values for these models are set a priori based on a combination of experimental data and theoretical knowledge of the compound, human anatomy and human physiology.

RESULTS AND DISCUSSION

PBK models for predicting chemical concentrations in cardiac tissue have been developed². These can be adapted to account for the characteristics of different in vitro models, as well as the putative molecular targets and key events associated with the toxicodynamics of the chemical compound being studied.

CONCLUSION

PBK models are useful tools for predicting of time-concentrations profiles of chemicals in heart tissues to allow a meaningful interpretation of in vitro concentration-response data and predict in vivo outcomes.

REFERENCES

Paini, A., Leonard, J.A., et al. Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making, Computational Toxicology, Volume 9, 2019, Pages 61-72, ISSN 2468-1113,

https://doi.org/10.1016/j.comtox.2018.11.002.

Tylutki, Z., Szlęk, J., Polak, S.  CardiacPBPK: A tool for the prediction and visualization of time-concentration profiles of drugs in heart tissue, Computers in Biology and Medicine, Volume 115, 2019, 103484, ISSN 0010-4825, https://doi.org/10.1016/j.compbiomed.2019.103484