A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response

Details

• Alternative Title:
  Risk Anal
• Personal Author:
  Park, Robert M.
• Description:
  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.
• Keywords:
  Animals Dose Response Homeostasis Hormesis Humans Inactivation, Metabolic Models, Biological Nonlinear Dynamics PBPK Simulation Toxicokinetics Uncertainty Upregulation

  More +
• Source:
  Risk Anal. 40(12):2561-2571
• Pubmed ID:
  32632964
• Pubmed Central ID:
  PMC7748990
• Document Type:
  Journal Article
• Funding:
  CC999999/Intramural CDC HHSUnited States/
• Volume:
  40
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:afdf986f8f9a5ccf628458db9152054a4836b0e2807406b48e3b2d322ee7f1e2
• Download URL:
  https://stacks.cdc.gov/view/cdc/99061/cdc_99061_DS1.pdf
• File Type:
  [PDF - 1.76 MB ]