Grantee Research Project Results
2001 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: Battelle Memorial Institute
Current 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, 2001 through December 31, 2002
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:
This project involves development and validation of a PBPK/PD model for the organophosphate (OP) insecticide chlorpyrifos (CPF) to quantitate biomarkers of dosimetry and pharmacodynamic (PD) 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 OPs correlates with the increased sensitivity of young animals to OPs. The PBPK/PD model will integrate age-dependent changes in metabolism and PD response, and will facilitate quantitative biomonitoring for OP exposures.
Progress Summary:
During the project's first year, a number of important accomplishments have been achieved in several research areas, including: analytical analysis, in vitro metabolism, preliminary in vivo pharmacokinetic and pharmacodynamic studies, and the modification of the PBPK/PD model to incorporate age-dependent metabolism and esterase levels. Analytical methods utilizing gas chromatography/mass spectrometry (GC/MS) and GC/electron capture detector (GC/ECD) were established for the in vivo and in vitro analysis of CPF, CPF-oxon, and trichloropyridinol (TCP) (Campbell, et al., 2002). In addition, spectrophotometric assays for AChE and butyrlcholinesterase (BChE) have been established for both in vitro determination of inhibition rate constants, and for assessing in vivo inhibition following CPF exposure.
In vitro metabolism studies have been completed to determine the CYP450 metabolism kinetics for CPF in rat microsomes prepared from both liver and gastrointestinal enterocytes (Wu, et al., 2002). These new data suggest that CPF can undergo metabolism prior to being absorbed, and the results may provide additional perspective on low-dose bioavailability. Work to conduct similar experiments to compare liver and enterocytes A-esterase metabolism kinetics is underway.
To obtain needed B-esterase (AChE/BChE) inhibition constants and reactivation rates, a series on in vitro esterase inhibition studies was conducted with CPF-oxon using brain and saliva as sources of AChE and BChE, respectively. These studies suggest that esterase activity in saliva is low, relative to other tissue compartments (plasma/brain), but is quantifiable and may have some utility in biomonitoring. In addition, it appears that the B-esterase activity is primarily BChE.
Initially, in vivo pharmacokinetic/pharmacodynamic studies were conducted in adult rats to assess the relationship between the concentration of CPF and TCP in blood and saliva over a range of doses and to compare the extent of ChE inhibition in these same tissues. The preliminary results are encouraging and suggest that TCP is eliminated in the saliva and may be a useful biomonitoring endpoint. Samples currently are being analyzed to assess the extent of saliva ChE inhibition relative to the observed inhibition in plasma following in vivo exposure to CPF.
The CPF PBPK/PD model that was developed to assess dosimetry and dynamic response in both adult rats and humans has been modified to enable scaling of age-dependent parameters for CYP450 activation and detoxification as well as A-esterase detoxification of CPF-oxon (Timchalk, et al., 2002). Initial simulations have been conducted and compared to available published ChE inhibition kinetics in the neonatal rat. Based on these comparisons, the PBPK/PD model simulates the differences in ChE inhibition between neonatal and adult rats. Further model refinement is ongoing.
Future Activities:
We will obtain additional age-dependent parameter estimates utilizing in vitro approaches and initiate a series on in vivo validation studies where neonatal rats will be exposed to a range of CPF doses. In addition, the pharmacokinetics and pharmacodynamics will be evaluated.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
| Other project views: | All 33 publications | 7 publications in selected types | All 7 journal articles |
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Timchalk C, Kousba A, Poet TS. Monte Carlo analysis of the human chlorpyrifos-oxonase (PON1) polymorphism using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. Toxicology Letters 2002;135:(1-2):51-59. |
R828608 (2001) R828608 (Final) |
Exit Exit |
Supplemental Keywords:
risk, risk assessment, health effects, human health, sensitive populations, susceptibility, infant, children, toxics, agriculture, pesticides., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Physical Processes, pesticides, Risk Assessments, genetic susceptability, Environmental Microbiology, Children's Health, Biochemistry, Toxicology, Genetics, health effects, sensitive populations, toxicity, PBPK modeling, environmental hazard exposures, PBPK model, biological markers, detoxification, pharmacokinetc model, age-related differences, human exposure, organophosphate pesticides, pesticide exposure, insecticides, pharmacokinetic models, genetic polymorphisms, children, exposure, pharmokinetic models, gene-environment interaction, human health risk, biomarkers, exposure assessment, pharmacodynamic modelRelevant 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.