Grantee Research Project Results
2003 Progress Report: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
EPA Grant Number: R830800Title: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
Investigators: Bruckner, J. V. , Delp, Michael D. , Bartlett, Michael G. , Fisher, Jeffrey W.
Current Investigators: Bruckner, J. V. , Bartlett, Michael G.
Institution: University of Georgia , Texas A & M University
Current Institution: University of Georgia
EPA Project Officer: Hahn, Intaek
Project Period: February 1, 2003 through January 31, 2007 (Extended to January 31, 2008)
Project Period Covered by this Report: February 1, 2003 through January 31, 2004
Project Amount: $749,991
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
The objective of this research project is to develop and validate a systematic quantitative approach (i.e., physiologically-based pharmacokinetic [PBPK] model) for predicting internal dosimetry of deltamethrin (DLM) (a representative pyrethroid insecticide) in maturing rats as a model for exposure in children.
Progress Summary:
The major accomplishment in Year 1 of the project was the development and validation of rapid, sensitive methods for analysis of DLM in the blood and tissue of animals. Existing procedures were not suitable for accurate measurement of DLM in very small biological samples (e.g., micro blood and tissue specimens taken from preweanling and adult rats). Therefore, a high-performance liquid chromatography technique was developed and optimized for quantitation of DLM and 3-phenoxybenzoic acid (PBA), one of its major metabolites, in serum (Ding, et al., 2004a). The limit of quantitation was found to be 100 ng/ml (ppb). This procedure was utilized to monitor the time course of DLM and PBA in the blood for up to 12 hours following oral dosing of rats with DLM. The procedure was adapted for measurement of DLM, PBA, and a third metabolite, 3-phenoxybenzyl alcohol, in maternal plasma, amniotic fluid, and placental and fetal tissues (Ding, et al., 2004b). A liquid chromatography tandem mass spectrometry (LC-MS-MS) method, with even greater sensitivity and specificity, is under development.
The aforementioned analytical techniques may have broad applications in a number of fields as the methods for DLM also should work well for a number of other pyrethroids. The methods would be quite useful in determining whether specific pyrethroids or their metabolites accumulate in food chains or in the human body. Because levels of pyrethroids and metabolites can be measured in a variety of body fluids and tissues, such procedures could be utilized in regional or national exposure monitoring efforts by the U.S. Environmental Protection Agency and other agencies. The Centers for Disease Control and Prevention (CDC) currently is employing a LC-MS-MS procedure to measure pyrethroid metabolites in urine as part of its National Health and Nutrition Examination Survey program. The CDC intends to start monitoring parent compounds in serum using gas chromatography-MS this year. Interactions with their analytical staff reveal that some features of our own procedures (e.g., simplicity, rapidity, small sample volumes) can be advantageous in studies involving children as well as small laboratory animals.
Future Activities:
During the next reporting period, we will:
- characterize the pharmacokinetics and metabolism of DLM in adult and immature rats of selected ages;
- and establish the age dependency of key physiological parameters needed for input into a PBPK model.
Blood and tissue time-course data for a graduated series of DLM doses in different age groups will be obtained and used for model construction and validation. It also will be necessary to investigate the manner in which DLM is metabolized. The limited information that is available suggests that esterase-catalyzed hydrolysis and cytochrome P450-mediated hydroxylation (with subsequent conjugation) play important roles. In vitro studies will be performed to learn which plasma and liver esterases and which liver P450 isozymes are involved. Subsequent experiments will be conducted to determine metabolic rate constants. Other PBPK model input parameters to be measured in selected age groups of immature rats include body weight, organ volumes, body fat content, and tissue:blood partition coefficients.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 29 publications | 12 publications in selected types | All 12 journal articles |
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Ding Y, White CA, Muralidhara S, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolite 3-phenoxybenzoic acid in male rat plasma by high-performance liquid chromatography. Journal of Chromatography B 2004;810(2):221-227. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
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Ding Y, White CA, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolites, 3-phenoxybenzoic acid and 3-phenoxybenzyl alcohol, in maternal plasma, amniotic fluid, and placental and fetal tissues by HPLC. Journal of Liquid Chromatography & Related Technologies 2004;27(12):1875-1892. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
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Supplemental Keywords:
modeling, internal exposure, pharmacokinetics, metabolism, toxicology, health effects, human health, risk assessment, susceptible populations, children, pesticides, insecticides, pyrethroids, toxics, sensitive population, toxicokinetics, PBPK modeling, bioavailability, internal exposure/dose, environmental management, health, physical aspects, biochemistry, children’s health, environmental microbiology, epidemiology, genetics, health risk assessment, pesticide types, physical processes, risk assessments, susceptibility/sensitive population/genetic susceptibility, age-related differences, animal model, biochemical research, biological markers, biomarkers, detoxification, developmental effects, environmental hazard exposures, exposure, exposure assessment, gene-environment interaction, genetic polymorphisms, human exposure, human health risk, metabolic study, organophosphate pesticides, pesticide exposure, pharmacodynamic model, pharmacokinetic model, risk-based model,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Toxics, PESTICIDES, Toxicology, Genetics, Health Risk Assessment, Risk Assessments, Environmental Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Physical Processes, Environmental Monitoring, Children's Health, genetic susceptability, Pesticide Types, Risk Assessment, health effects, pesticide exposure, pharmacodynamic model, sensitive populations, detoxification, biomarkers, age-related differences, gene-environment interaction, exposure, animal model, developmental effects, metabolic study, children, pharmacokinetic models, insecticides, toxicity, genetic polymorphisms, PBPK modeling, pharmacokinetc model, metabolism, biological markers, risk based model, exposure assessment, organophosphate pesticides, biochemical research, environmental hazard exposures, human health riskRelevant Websites:
http://www.rx.uga.edu/main/home/httpd/html/index.html Exit
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.