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Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model

Rogelio Tornero-Velez1, Ahmad Mirfazaelian, Kyu-Bong Kim

  • 1National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. tornero-velez.rogelio@epa.gov

Toxicology and Applied Pharmacology
|January 5, 2010
PubMed

Insights

Immature rats show higher susceptibility to pyrethroid insecticides due to increased deltamethrin (DLM) brain levels. A modified pharmacokinetic model accurately predicts DLM distribution across different rat ages, aiding risk assessment.

Area of Science:

  • Toxicology
  • Pharmacokinetics
  • Computational Biology

Background:

  • Immature rats exhibit greater susceptibility to pyrethroid neurotoxicity compared to adults.
  • Deltamethrin (DLM) exposure leads to age-dependent differences in blood and brain concentrations.
  • Existing physiologically based pharmacokinetic (PBPK) models require age-specific modifications for accurate dosimetry in developing organisms.

Purpose of the Study:

  • To adapt an existing PBPK model for DLM disposition in adult rats to predict neurotoxicant dosimetry during maturation.
  • To incorporate age-specific physiological parameters and metabolic clearance rates into the PBPK model.
  • To validate the modified PBPK model against empirical data in rats of different ages.

Main Methods:

  • Modified a PBPK model of deltamethrin (DLM) disposition in adult Sprague-Dawley rats.
  • Incorporated age-specific organ weights and age-dependent oxidative/hydrolytic clearance using a generalized Michaelis-Menten growth model.
  • Simulated DLM time-courses in plasma, blood, brain, and fat for rats aged 10, 21, 40, and 90 days.

Main Results:

  • The PBPK model accurately simulated DLM disposition across the evaluated age groups.
  • Postnatal day 10 (PND 10) pups exhibited a 3.8-fold higher area under the 24-h brain concentration-time curve (AUC(0-24h)) compared to PND 90 adults.
  • Model predictions showed favorable comparison with empirical DLM concentration-time data.

Conclusions:

  • The developed maturing rat PBPK model accurately predicts pyrethroid dosimetry in young and aged individuals.
  • The model facilitates age-specific adjustments to risk assessment parameters, such as oral Reference Doses, based on pharmacokinetic differences.
  • This PBPK modeling approach provides a valuable tool for evaluating age-related risks of pyrethroid exposure.

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