Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model.
Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study (Kim et al., in press) 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 (Mirfazaelian et al., 2006), so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights and age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled with a generalized Michaelis-Menten model for growth 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). PND 10 pups' area under the 24-h brain concentration time curve (AUC(0-24h)) was 3.8-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.
Tornero-Velez
Rogelio
R
National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. tornero-velez.rogelio@epa.gov
Mirfazaelian
Ahmad
A
Kim
Kyu-Bong
KB
Anand
Sathanandam S
SS
Kim
Hyo J
HJ
Haines
Wendy T
WT
Bruckner
James V
JV
Fisher
Jeffrey W
JW
D000367:Age Factors; D000375:Aging / Q000097:blood / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D008954:Models, Biological; D009570:Nitriles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology; D011722:Pyrethrins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin