Grantee Research Project Results
2003 Progress Report: Development of a Physiologically Based Pharmacokinetic/ Pharmacodynamic (PBPK/PD) Model to Quantitate Biomarkers of Exposure for Organophosphate Insecticides
EPA Grant Number: R828608Title: Development of a Physiologically Based Pharmacokinetic/ Pharmacodynamic (PBPK/PD) Model to Quantitate Biomarkers of Exposure for Organophosphate Insecticides
Investigators: Timchalk, Charles , Campbell, James A. , Poet, Torka
Institution: Pacific Northwest National Laboratory
EPA Project Officer: Aja, Hayley
Project Period: January 1, 2001 through December 31, 2003 (Extended to December 31, 2004)
Project Period Covered by this Report: January 1, 2003 through December 31, 2004
Project Amount: $733,174
RFA: Biomarkers for the Assessment of Exposure and Toxicity in Children (2000) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The objective of this research project is to develop and validate a Physiologically Based Pharmacokinetic/Pharmacodynamic (PBPK/PD) model for the organophosphorus insecticide, chlorpyrifos. This model will be useful to quantitate biomarkers of dosimetry and pharmacodynamic response (i.e., acetylcholinesterase ([AChE]) inhibition) in young rats and children. It is hypothesized that an age-dependent decrement in both CYP450 and esterase-mediated detoxification of organophosphates correlates with the increased sensitivity of young animals and potentially children. The PBPK/PD model will integrate age-dependent changes in metabolism and pharmacodynamic response and will facilitate quantitative biomonitoring for organphosphate insecticide exposures.
Progress Summary:
During Year 3 of the project, we developed a neonatal rat PBPK/PD model that has continued to advance. The research was focused on conducting a series of in vivo and in vitro experiments in neonatal rats (postnatal days 5, 12, and 17). These experiments included quantifying the blood concentration time course of chlorpyrifos and the major metabolite trichloropyridinol as well as the time course of cholinesterase inhibition in the blood and brain following exposure to chlorpyrifos (1 and 10 mg/kg). Ongoing research has resulted in the publication of two peer-reviewed manuscripts and another has been accepted and another submitted for publication. The research also has been presented at four national meetings/seminars and a fifth presentation is scheduled for March 2005.
To better understand the dynamics of cholinesterase (ChE) inhibition and to obtain reasonable parameter estimates for model development, in vitro studies have focused on determining the bimolecular inhibition rate constants and the potential impact of binding to a peripheral site on AChE (Kousba, et al., 2004a; Kousba, et al., 2004b). In addition, in vitro metabolism studies have been conducted to establish metabolic parameter estimates and the impact of potential coexposures to structurally related organophosphorus insecticides (Wu, et al., 2004). We also have published in vivo results (Timchalk, et al., 2004) demonstrating that saliva ChE activity was inhibited in a dose-dependent manner and was comparable to the plasma ChE inhibition kinetics. In addition, it was demonstrated that trichlorpyridinol was detected readily in saliva, and the overall kinetic profile paralleled the response in the blood. These results strongly suggest that the utility of saliva as a biomonitoring matrix for organophosphorus insecticides is feasible.
Future Activities:
We will focus on the completion of the age-dependent rodent PBPK/PD model and will prepare to extend this modeling to accommodate gestational and lactational exposures to these insecticides.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
Other project views: | All 33 publications | 7 publications in selected types | All 7 journal articles |
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Campbell JA, Timchalk C, Kousba AA, Wu H, Valenzuela BR, Hoppe EW. Negative ion chemical ionization mass spectrometry for the analysis of 3,5,6-trichloro-2-pyridinol in saliva of rats exposed to chlorpyrifos. Analytical Letters 2005;38(6):939-949. |
R828608 (2003) R828608 (Final) |
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Kousba AA, Sultatos LG, Poet TS, Timchalk C. Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics: potential role of a peripheral binding site. Toxicological Sciences 2004;80(2):239-248. |
R828608 (2003) R828608 (Final) |
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Timchalk C, Poet TS, Kousba AA, Campbell JA, Lin Y. Noninvasive biomonitoring approaches to determine dosimetry and risk following acute chemical exposure: analysis of lead or organophosphate insecticide in saliva. Journal of Toxicology and Environmental Health-Part A 2004;67(8-10):635-650. |
R828608 (2003) R828608 (Final) |
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Timchalk C, Poet TS, Hinman MN, Busby AL, Kousba AA. Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat. Toxicology and Applied Pharmacology 2005;205(1):31-42. |
R828608 (2003) R828608 (Final) |
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Supplemental Keywords:
risk, risk assessment, health effects, human health, sensitive populations, susceptibility, neonate, toxics, agriculture, pesticide,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Toxicology, Genetics, Health Risk Assessment, pesticides, Environmental Microbiology, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Physical Processes, Children's Health, genetic susceptability, health effects, pesticide exposure, pharmacodynamic model, sensitive populations, detoxification, biomarkers, PBPK model, age-related differences, gene-environment interaction, exposure, children, pharmacokinetic models, insecticides, toxicity, genetic polymorphisms, human exposure, PBPK modeling, pharmacokinetc model, biological markers, exposure assessment, organophosphate pesticides, biochemical research, human health risk, environmental hazard exposuresRelevant Websites:
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.