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Development of a neonatal rat physiologically based pharmokinetic/pharmacodynamic (PBPK/PD) model for chlorpyrifos.

Authors
Timchalk-C; Kousba-A; Poet-TS
Source
Toxicologist 2003 Mar; 72(S-1):305
NIOSHTIC No.
20033143
Abstract
Juvenile rats are more susceptible than adults to the high dose effects of organophosphate (OP) insecticides, like chlorpyrifos (CPF); therefore, it is assumed that infants and children are likewise more susceptible. Age-dependent differences are primarily a function of metabolic capacity for several important enzyme systems. This includes CYP450 activation to CPF-oxon, and detoxification to trichloropyridinol (TCP), as well as B-esterase (B-EST) and A-esterase (A-EST) detoxification of CPF-oxon to TCP. A PBPK/PD model describing the time-course of CPF, CPF-oxon, and the inhibition of acetylcholinesterase (AChE) in adult rats and humans was modified to allometrically scale (based on body weight) the agedependent development of CYP450 and A-EST enzyme activity. The model provided a good simulation of brain and RBC AChE inhibition in post-natal day (PND) 17 rats orally administered 15 mg/kg CPF. The model was used to simulate concentrations of CPF-oxon in the brain of neonatal rats (PND4) following single acute oral exposure to a range of CPF doses (0.5-50 mg/kg). Doses greater than 5 mg/kg resulted in theoretical concentrations of CPF-oxon in the brain of PND4 rats that was greater than in adults, this difference increased with dose. Doses less than 1 mg/kg resulted in brain CPF-oxon concentrations in PND4 rats that were similar to theoretical adult AUCs. The model simulation suggests that neonatal rats are more sensitive than adults to the effects of acute high dose exposures. However, the model also indicates that even though neonatal rats have lower metabolic capacity, it is adequate to detoxify CPF at relevant environmental exposure levels. These simulations are consistent with differences in the acute toxicity response noted between neonatal and adult rats following exposure to CPF. This model represents an important starting point in the development of a PBPK/PD model to better define the potential of CPF to cause neurotoxicity in sensitive populations, such as infants and children.
Keywords
Models; Phosphates; Pesticides; Insecticides; Exposure-levels; Bioactivation; Detoxification; Blood-samples; Liver-cells; Metabolic-rate; In-vitro-studies; Dosimetry; Pesticides-and-agricultural-chemicals; Laboratory-animals; Animal-studies; Animals
CAS No.
2921-88-2
Publication Date
20030301
Document Type
Abstract
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2003
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
ISSN
1096-6080
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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