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

Timchalk-C; Kousba-A; Poet-TS
Toxicologist 2003 Mar; 72(S-1):305
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.
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
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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
Performing Organization
Battelle Memorial Institute, Richland, Washington