Development of a Physiologically Based Pharmacokinetic/ Pharmacodynamic (PBPK/PD) Model to Quantitate Biomarkers of Exposure for Organophosphate Insecticides

EPA Grant Number: R828608
Title: 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, Pacific Northwest Division
EPA Project Officer: Mustra, David
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 , Health Effects , Human Health , Health

Description:

This project will entail 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.

Approach:

A PBPK/PD model has been developed for CPF and will be modified by incorporating age-dependent physiological and metabolic parameters to adequately describe the blood and tissue time-course of CPF, and the metabolites CPF-oxon and trichloropyridinol (TCP) and the inhibition of target esterase in young rats and children. Once developed the model will be utilized to quantitate biomarkers of exposure and response during neonatal/juvenile development. The model will be validated and refined as necessary through focused in vivo/in vitro experimentation. CPF will be administered as single oral doses of 1 and 10 mg/kg of body weight to neonatal Sprague-Dawley rats and the pharmacokinetic (PK) and PD response will be determined over a 3 ?12 hour post-dosing period at 4, 12 and 21 days of age. These doses encompass a linear to non-linear metabolic response. Based on the results of these studies the PBPK/PD model will be further refined. The model will be expanded to assess intermittent low-dose exposure to CPF during neonatal/juvenile development in rats. The PK/PD response will also be evaluated in vivo following a repeated (7d/wk, for 3 wks) 1 mg CPF/kg of body weight oral dose through 21 days of age. To facilitate development of a human child PBPK/PD model, human metabolic parameters will be determined in vitro for CYP450-, A-esterase- and CaE-mediated metabolism of CPF using tissues obtained from children. The rodent model will be modified to extrapolate dosimetry and PD response from young animals to human children. Studies will likewise be conducted in rodents to quantitate dosimetry, using saliva as a biomonitoring matrix for CPF metabolites.

Expected Results:

1) A PBPK/PD model that can be used to quantitate biomarkers of dosimetry and response in children following intermittent low dose exposure to OPs. 2) Refinement and validation of the PBPK/PD model through the acquisition of focused in vivo and in vitro experiments. 3) A strategy for utilizing non-invasive (i.e. saliva) biological samples for quantitation of dosimetry. 4) The model can be modified to address differences in human response associated with both inter-individual and extrinsic variability. 5) This PBPK/PD model can be modified to assess aggregate and cumulative exposures.

Publications and Presentations:

Publications have been submitted on this project: View all 33 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 7 journal articles for this project

Supplemental Keywords:

Health effects, biomarkers of exposure, vulnerability, neurotoxicity, pesticide, cumulative effects, agriculture, human health, genetic polymorphisms., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Toxicology, Genetics, Health Risk Assessment, pesticides, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, 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 exposures

Relevant Websites:

Synthesis Report of Research from EPA’s Science to Achieve Results (STAR) Grant Program: Feasibility of Estimating Pesticide Exposure and Dose in Children Using Biological Measurements (PDF) (42 pp, 3.87 MB)

Progress and Final Reports:

2001 Progress Report
2002 Progress Report
2003 Progress Report
Final Report