Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling

EPA Grant Number: R830800
Title: 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. , Bartlett, Michael G. , Delp, Michael D. , 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: Pascual, Pasky
Project Period: February 1, 2003 through January 31, 2007 (Extended to January 31, 2008)
Project Amount: $749,991
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Health Effects , Children's Health

Description:

The overall objective of the proposed project is to develop and validate a systematic quantitative approach for reducing uncertainty in risk assessments of pesticide exposures of children. Vulnerability of infants and children may be the result of exposure during periods of: (a) sequenced biochemical and morphological events in growing tissues that alter pesticide pharmacodynamics; and (b) physiological and biochemical changes that affect the absorption and disposition of chemicals. The focus of the proposed project is on the latter category of events. Particular attention will be paid to maturation of: the GI mucosal barrier to absorption; the blood-brain barrier; plasma protein binding; tissue blood flows and volumes, including adipose tissue; and metabolism.

Approach:

(1) Use the results of pharmacokinetic experiments in adult rats with deltamethrin (DLM), a representative pyrethroid insecticide, and published physiological and biochemical parameter values to develop a physiologically-based pharmacokinetic (PBPK) model for DLM and its major metabolites in the mature animal. (2) Characterize maturational changes in major physiological and chemical-specific indices in developing rats. (3) Define the dose-dependent metabolism and kinetics of DLM in developing rats. Employ these data and the measured age-dependent physiological and biochemical indices to construct and validate a PBPK model appropriate for neonatal to sexually-mature animals. (4) Utilize the model to: (a) predict the internal dosimetry of DLM in developing animals; and (b) test hypotheses about the role of specific immaturities in altered target organ deposition (e.g., limited adipose tissue and metabolic capacity, coupled with increased oral absorption and blood-brain barrier penetration, result in greater deposition of DLM in the brain of neonates).

Expected Results:

A validated PBPK model of DLM for different age-groups would provide reliable estimates of the bioavailability and target organ doses of this commonly-used pyrethroid insecticide. It is EPA policy that an extra 10X safety factor may be applied in children's risk assessments of pesticides. The ability to forecast how much of an exposure/dosage adjustment must be made to achieve equivalent brain DLM levels in children and adults can help provide a scientific basis for this practice. The currently proposed work should result in significant advances in our understanding of biological determinants that play the most important roles in the internal (e.g., brain) dosimetry of DLM and other lipid-soluble chemicals. Physiological values obtained here for growing rats may be effectively utilized in subsequent PBPK modeling of additional pyrethroids and other chemicals.

Publications and Presentations:

Publications have been submitted on this project: View all 29 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 12 journal articles for this project

Supplemental Keywords:

children, sensitive population, toxicokinetics, PBPK modeling, metabolism, bioavailability, internal exposure/dose, pyrethroids, insecticides, toxics., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, ENVIRONMENTAL MANAGEMENT, PESTICIDES, Toxicology, Genetics, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Biochemistry, Environmental Monitoring, Physical Processes, 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 risk

Progress and Final Reports:

2003 Progress Report
2004 Progress Report
2005 Progress Report
2006 Progress Report
Final Report