Grantee Research Project Results
2009 Progress Report: Development of a PBPK Model for Interpreting Biomonitoring Data on Carbaryl and Other N-methyl-carbamates
EPA Grant Number: R833452Title: Development of a PBPK Model for Interpreting Biomonitoring Data on Carbaryl and Other N-methyl-carbamates
Investigators: Yoon, Miyoung , Allen, Bruce , Kedderis, Gregory , Clewell, Harvey , Tan, Yu-Mei
Current 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 Period Covered by this Report: September 1, 2008 through August 31,2009
Project Amount: $750,000
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2006) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The primary objective of this study is to develop the first human physiologically based pharmacokinetic (PBPK) model for N-methyl-carbamate pesticides, using the recently developed model for carbaryl in the rat as the starting point (Nong et al., 2008). 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 and the extent of acethylcholinesterase inhibition in red blood cells. With a reverse dosimetry approach, this model will be able to estimate aggregate carbaryl exposures consistent with the measured biomarker concentrations. The developed carbaryl model will also be extended to other N-methyl carbarmates to demonstrate the use of the model in assessing cumulative risks from the combined exposure to the common mechanism pesticide mixtures.Progress Summary:
In phase 2 of the project, parameters for metabolism and ChE inhibition of carbaryl were determined in vitro to refine the previously developed rat physiologically based pharmacokinetic (PBPK) model. Metabolism was determined in freshly isolated hepatocytes from adult male Sprague-Dawley rats. Carbaryl disappearance followed Michaelis-Menten kinetics with Vmax of 1.3 nmol/min/106 cells and apparent KM 50 - 80μM. 1-naphthol metabolism was also determined to better describe the kinetics of this biomarker in the body. Interactions between carbaryl and ChEs were determined in brain, red blood cells (RBCs), and plasma. Bimolecular inhibition rate constants (Ki) were from 2 to 12μM-1h-1 for acetylcholinesterase (AchE) suggesting differing degrees of sensitivity of AChEs in RBCs, brain, and plasma. The Ki for butyrylcholinesterase (BChE) in plasma was lower than AChE. The rates of regeneration of the carbamylated ChEs ranged from 0.5 to 2h-1 indicating similar rates of recovery for AchE and BChE. These in vitro PK and pharmacodynamic data were extrapolated to the whole animal to refine the description of the metabolism and ChE inhibition dynamics of carbaryl in the model. Predicted tissue carbaryl concentrations and ChE inhibition profiles in brain and blood were in better agreement with the observed data compared to the previous modeling, in which the metabolic and ChE inhibition parameters were all estimated from in vivo kinetic data. For future modeling efforts, we started to build a platform using the acslX program for Bayesian analysis of the rat and human PBPK models using the MCMC technique. The aggregate exposure to carbaryl from dietary and drinking water events was simulated using an exposure software CARES, which will be used to generate input data for human PBPK model for carbaryl. The rat model will be further refined with additional in vitro studies in the rat. Predictions from the refined model together with in vitro kinetic studies of carbaryl with human hepatocytes will be used to develop a human PBPK model to assess risks from carbaryl in humans and to interpret human biomonitoring data.Future Activities:
In vitro studies in the rat, including carbaryl metabolism study in blood, 1-naphthol metabolism in hepatocytes, and measurement of carbaryl partition in rat tissues, will be finished next year. The resulting data will be utilized to refine the current rat model by extrapolating in vitro findings to in vivo. After this refinement, the rat model will be analyzed by applying a sequential Bayesian approach (Markov Chain Monte Carlo estimation) and generate posterior parameter values for developing human PBPK model in conjunction with in vitro biochemical data from human tissues. The resulting human model will be used to conduct reverse dosimetry to interpret biomonitoring data.Journal Articles:
No journal articles submitted with this report: View all 4 publications for this projectSupplemental Keywords:
Carbaryl, Freshly isolated hepatocytes, cholinesterase inhibition, 1-naphtol, PBPK model, RFA, Scientific Discipline, Health, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, Risk Assessments, endocrine disruptors, Biochemistry, Biology, Endocrine Disruptors - Human Health, neurotoxic, bioindicator, thyroid toxicants, exposure studies, developmental biology, human growth and development, toxicity, hormone production, assessment technology, ecological risk assessment model, human health riskProgress 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.