Citation:

OKINO, M. S., F. W. POWER, J. B. KNAAK, R. TORNERO-VELEZ, C. LUNCHICK, A. LOWIT, J. N. BLANCATO, AND C. C. DARY. USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION. Presented at Socieity of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.

Impact/Purpose:

Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:

1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.

Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;

Designing and implementing the graphical user interface for added features.

Refining the exposure interface to handle various sources of exposure information;

Providing tools for post processing as well as for uncertainty and variability analyses;

Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.

2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.

Examples of the applications are:

exposure of children to pesticides

study design

route-to-route extrapolation

species extrapolation

experimental data analysis

relationship between parametric uncertainty and the distribution of model results

validity of scaling methods within species

validity of scaling methods from one species to another species

reduction of uncertainty factors for risk assessment

Description:

A physiologically based pharmacokinetic (PBPK) model was developed to investigate exposure scenarios of children to carbaryl following turf application. Physiological, pharmacokinetic and pharmacodynamic parameters describing the fate and effects of carbaryl in rats were scaled to establish the model structure for exposure to humans. Adjustments were made for differences in metabolism and physiology between children and adults. Michaelis-Menten kinetics were used to describe the metabolism of carbaryl to yield biomarkers of metabolism, including urinary 1-naphthol. Bimolecular rate constants, ki (pM^-1 hr^-1), were used to describe inhibition of acetylcholinesterase by the parent chemical. Rates for enzyme synthesis and reactivation were interposed within compartments to account for depletion of the enzymes. Exposure by hand-to-mouth activities for toddlers, and by dermal exposure for older children resulted in no observable cholinesterase inhibition (>99% of basal activity) in the brain and blood. Peak concentrations of carbaryl in the brain remained below the brain peaks observed in rats at the no observable adverse effect level (NOAEL) by an order-of-magnitude. Corresponding with the absorbed dose and subsequent distribution were the appearance of metabolite biomarkers in urine.

Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.

Record Details: