A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response
Corresponding Author
Robert M. Park
Division of Science Integration, National Institute for Occupational Safety and Health, 1090 Tusculum Ave, MS C-15, Cincinnati, OH, USA
Address correspondence to Robert Park, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Division of Science Integration, Risk Evaluation Branch, 1090 Tusculum Ave, MS C-15, Cincinnati OH 45226-1998, USA; tel: +1-513-533-8572; fax: +1-513-533-8224; rhp9@cdc.gov.
Search for more papers by this authorCorresponding Author
Robert M. Park
Division of Science Integration, National Institute for Occupational Safety and Health, 1090 Tusculum Ave, MS C-15, Cincinnati, OH, USA
Address correspondence to Robert Park, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Division of Science Integration, Risk Evaluation Branch, 1090 Tusculum Ave, MS C-15, Cincinnati OH 45226-1998, USA; tel: +1-513-533-8572; fax: +1-513-533-8224; rhp9@cdc.gov.
Search for more papers by this authorAbstract
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.
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