Development of a PBPK Model for Interpreting Biomonitoring Data on Carbaryl and Other N-methyl-carbamatesEPA Grant Number: R833452
Title: Development of a PBPK Model for Interpreting Biomonitoring Data on Carbaryl and Other N-methyl-carbamates
Investigators: Clewell, Harvey , Allen, Bruce , Kedderis, Gregory , Tan, Yu-Mei
Institution: The Hamner Institutes
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2007 through August 31, 2010
Project Amount: $750,000
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2006) RFA Text | Recipients Lists
Research Category: Health Effects , Health
This project will develop a human physiologically based pharmacokinetic (PBPK) model for carbaryl. This model will represent the first demonstration of a PBPK model for an N-methyl-carbamate (NMC) in the human. The model will be designed to support the interpretation of human biomarker data, including blood or urine concentrations of carbaryl or its metabolite, 1-naphthol, as well as measurements of acetylcholinesterase inhibition in red blood cells. We will then demonstrate the application of the model in a reverse dosimetry approach to estimate aggregate carbaryl exposures consistent with measured biomarker concentrations, using open-access exposure software such as CARES. We will also demonstrate the extendability of the model to other NMCs, using aldicarb as an example, and will demonstrate the use of the model to conduct an aggregate, cumulative risk assessment for NMCs, using the example of carbaryl and aldicarb.
The primary objective of this study is to develop the first human PBPK model for an NMC, using our recently developed model for carbaryl in the rat as the starting point. The model will be capable of supporting the interpretation of human biomarker data using reverse dosimetry. A secondary objective is to demonstrate the extendability of the model to other NMCs, using aldicarb as the example, to support aggregate, cumulative risk assessments for the NMC common mechanism group.
The development of the human model will be based on a model of carbaryl in the rat that we have recently developed, together with in vitro studies to identify the differences in carbaryl metabolism and esterase binding between the rat and human. The development of the human model will also make use of a novel sequential Bayesian approach that will provide a completely transparent calibration of all model parameters, characterize the uncertainty and variability in model predictions, document the propagation of error from the animal model and in vitro studies to the final human model, and minimize the need for in vivo human validation data.
The successful completion of this project is expected to provide the first demonstration of a PBPK model for an NMC in the human. The documented development of this model, including the in vitro assays, will provide a basis for the more efficient development of models for other carbamates, similar to the seminal impact of the PBPK model for diisopropylfluorophosphate on the development of models for other organophosphates. The project will also demonstrate a novel sequential Bayesian approach for examining the propagation of error from data collection and modeling to the uncertainty associated with the application of the final model. This approach will be applicable to the characterization of PBPK and Biologically Based Dose-Response models for other compounds in the future.