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A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response
Author(s) -
Park Robert M.
Publication year - 2020
Publication title -
risk analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.972
H-Index - 130
eISSN - 1539-6924
pISSN - 0272-4332
DOI - 10.1111/risa.13547
Subject(s) - toxicokinetics , simple (philosophy) , nonlinear system , dynamics (music) , biological system , statistical physics , computer science , biochemical engineering , environmental science , engineering , physics , biology , bioinformatics , philosophy , epistemology , acoustics , quantum mechanics , pharmacokinetics
Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.