Grantee Research Project Results
Final 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: 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: 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.
Summary/Accomplishments (Outputs/Outcomes):
In the third year of the project, biokinetic parameters for plasma metabolism and tissue partition of carbaryl were determined in vitro to refine the previously developed rat physiologically based pharmacokinetic (PBPK) model. Carbaryl hydrolysis in plasma followed a first order process under the current experimental conditions with up to 75 µM carbaryl concentration. Carbaryl tissue partition coefficients were determined using an equilibrium dialysis method for liver, brain, fat, muscle and red blood cells. The in vitro PK and PD data collected in our rat experiments were appropriately extrapolated to in vivo to refine the description of the metabolism and ChE inhibition dynamics of carbaryl in the previously developed rat model. Predicted target 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. As a first step for the proposed multi-step Bayesian analysis of the carbaryl PBPK/PD model both for the rat and human, we have initiated the MCMC analysis of the collected in vitro metabolism data. For future modeling efforts in the coming year, we have built a platform to link the simulated outputs from the exposure model CARES to the human PBPK model for characterizing the aggregate human exposure to carbaryl from dietary and drinking water events. The human carbaryl model will be developed by extrapolation from the rat model and by incorporating in vitro results in the human tissues. Predictions from the human PBPK/PD model will be valuable in assessing risks from carbaryl in humans and in interpreting human biomonitoring data.
Conclusions:
The sequential Bayesian approach (Markov Chain Monte Carlo estimation) for the rat model will be completed, which will generate posterior parameter values for developing a human PBPK model in conjunction with in vitro biochemical data from human tissues. In vitro studies in the human tissues, including carbaryl metabolism study in blood and hepatocytes, will be finished in the coming year. The resulting data will be extrapolated to in vivo for the human PBPK/PD model for carbaryl. The resulting human model will be used to conduct reverse dosimetry to interpret biomonitoring data.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
| Other project views: | All 4 publications | 1 publications in selected types | All 1 journal articles |
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Yoon M, Kedderis GL, Yan GZ, Clewell III HJ. Use of in vitro data in developing a physiologically based pharmacokinetic model: Carbaryl as a case study. Toxicology 2015;332:52-66. |
R833452 (Final) |
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Supplemental Keywords:
Carbaryl, in vitro to in vivo extrapolation, MCMC analysis, 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.