Grantee Research Project Results
Final 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 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 was 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 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.
Summary/Accomplishments (Outputs/Outcomes):
There currently is a significant concern and focus over the potential increased sensitivity of infants and children to the toxic effects of chemicals. The importance of this issue is highlighted by the National Research Council’s report Pesticides in the Diets of Infants and Children and the passage of the Food Quality Protection Act. It is recognized that children are not just “small adults,” but rather a unique subpopulation that may be particularly vulnerable to chemical insult. Age-dependent changes in a child’s physiology (i.e., body size, blood flow, organ functions) and metabolic capacity may impact significantly their response to a chemical insult, resulting in either beneficial or detrimental effects. Clear age-dependent variability in the capacity to detoxify environmental chemicals has been established in both animals and humans. The current risk assessment paradigms, however, may not consider adequately the implications of these differences on the risk to infants and children. Biologically based modeling offers a unique opportunity to integrate age-dependent changes into a comprehensive model that is capable of quantifying dose and response across all ages.
To address these questions, the project team has developed successfully an age-dependent PBPK/PD model for the organophosphorus insecticide chlorpyrifos and the characterization of saliva as a potential biological matrix for quantifying both dosimetry and cholinesterase inhibition in rats. The results from this project indicate that the age-dependent rat model quantitatively behaves consistently with the general understanding of organophosphorus insecticide toxicity (young vs. old animals). Overall, the modeling results are consistent with experimental findings in the neonatal and adult rats. Secondly, the model suggests that neonatal rats are more sensitive quantitatively to the high-dose acute effects of organophosphorus insecticide exposure; however, at low environmentally relevant exposure levels the neonatal rat is not substantially more sensitive than adult rats.
Conclusions:
The completion of this initial model represents an important milestone in developing and applying computational models for assessing age-dependent differences in dosimetry and dynamic response. Future research must entail further development and validation of this model with the ultimate goal of developing a model that is capable of predicting biological response in infants and children following variable intermittent exposures to insecticides at environmentally relevant exposures.
Journal Articles on this Report : 7 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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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, 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, toxicity, environmental hazard exposures, sensitive populations, PBPK modeling, PBPK model, biological markers, detoxification, pharmacokinetc model, age-related differences, organophosphate pesticides, pesticide exposure, human exposure, insecticides, genetic polymorphisms, pharmacokinetic models, children, exposure, pharmokinetic models, gene-environment interaction, human health risk, exposure assessment, pharmacodynamic model, biomarkersRelevant 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.