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Evaluation of Deltamethrin Kinetics and Dosimetry in the Maturing Rat using a PBPK Model
Citation:
TORNERO-VELEZ, R., A. Mirfazaelian, K. Kim, S. S. Anand, H. J. Kim, W. HAINES, J. V. BRUCKNER, AND J. W. FISHER. Evaluation of Deltamethrin Kinetics and Dosimetry in the Maturing Rat using a PBPK Model. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 244(2):208-217, (2010).
Impact/Purpose:
The National Exposure Research Laboratory′s (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA′s mission to protect human health and the environment. HEASD′s research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA′s strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.
Description:
Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study revealed that blood and brain levels of the neuroactive parent compound were inversely related to age in rats 10, 21, 40 and 90 days old. The objective of the current study was to modify a physiologically-based pharmacokinetic (PBPK) model of DLM disposition in the adult male Sprague-Dawley rat, so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights were estimated with a generalized Michaelis-Menten model. Age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled and the summary equations incorporated into the PBPK model. The model's simulations compared favorably with empirical DLM time-courses in plasma, blood, brain and fat for the four age-groups evaluated (10, 21,40 and 90 days old). Clearance from the blood and tissues increased with age until postnatal day 90 (PND 90). PND 10 pups' area under the 24-h brain concentration time curve (AUC240) was 3.4-fold higher than that of the PND 90 adults. Our maturing rat PBPK model allows for updating with age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals. Hence, this model provides a methodology for risk assessors to consider age-specific adjustments to oral Reference Doses on the basis of PK differences.
URLs/Downloads:
Toxicology and Applied Pharmacology
Evaluation of Deltamethrin Kinetics and Dosimetry in the Maturing Rat using a PBPK Model (PDF, NA pp, 195 KB, about PDF)