Grantee Research Project Results
2002 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, 2002 through December 31, 2003
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 Pharmacokinetic/Pharmacodynamic (PBPK/PD) model for organophosphate 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 organophosphate insecticide exposures.
Progress Summary:
During Year 2 of the project, the development of a neonatal rat PBPK/PD model has continued to advance (Timchalk, et al., 2003; Timchalk, et al., 2002). In addition, the capability to quantitate biomarkers of dosimetry and response in spot saliva samples has been established (Kousba, et al., 2003). Ongoing research has resulted in the publication of 2 peer-reviewed manuscripts with a third submitted for publication, and 11 presentations at numerous national meetings and several invited seminars.
To enable the PBPK/PD model to adequately describe age-dependent changes in metabolism and esterase levels, a series of scaling algorithms has been developed based on available data in the literature, as well as from experimental data derived from this project. In addition, model validation has been conducted using available data from the literature to compare dosimetry and dynamic response following exposure to a range of chlorpyrifos doses (Timchalk, et al., 2003; Timchalk, et al., 2002); a number of in vivo studies likewise are being initiated to provide additional age-dependent dosimetry and dynamic response data for model validation.
To establish the potential utility of saliva as a biological matrix for noninvasive biomonitoring of chlorpyrifos, a number of in vitro (Kousba, et al., 2003) and in vivo (Timchalk, et al., 2003) studies have been conducted. These experiments have been used to characterize the salivary ChE activity (primarily butyrylcholine esterase) and quantitate the levels of chlorpyrifos and its major metabolite, trichlorpyridinol in rat saliva and blood following in vivo exposure to a range of chlorpyrifos doses. Saliva ChE activity demonstrated an in vivo dose-dependent inhibition and was comparable to the plasma ChE inhibition kinetics. Likewise, trichlorpyridinol was readily detected in saliva, and although the saliva concentrations were less than in the blood, the overall kinetic profile paralleled the response in the blood. These in vivo experiments suggest that it may be possible to use saliva for quantitation of dosimetry and dynamic response following exposure to chlorpyrifos. Efforts are underway to modify the PBPK/PD model to incorporate a salivary gland compartment. Once fully developed, the model should predict systemic dosimetry and dynamic response based on a limited sampling of saliva.
Future Activities:
Year 3 of the project will involve research that will focus on obtaining additional in vivo age-dependent data for model validation. In addition, samples of human saliva will be obtained for a range of ages (children-adult), and the ChE activity will be characterized. Finally, attempts will be made to appropriately scale the age-dependent rodent PBPK/PD model to accommodate human neonates and children.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 33 publications | 7 publications in selected types | All 7 journal articles |
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Kousba AA, Poet TS, Timchalk C. Characterization of the in vitro kinetic interaction of chlorpyrifos-oxon with rat salivary cholinesterase: a potential biomonitoring matrix. Toxicology 2003;188(2-3):219-232. |
R828608 (2002) R828608 (Final) |
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Poet TS, Wu H, Kousba AA, Timchalk C. In vitro rat hepatic and intestinal metabolism of the organophosphate pesticides chlorpyrifos and diazinon. Toxicological Sciences 2003;72(2):193-200. |
R828608 (2002) 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.