Interpretation of Biomonitoring Data for Ortho-Phthalates Using Physiologically Based Parmacokinetic Modeling: Estimation of Fetal Exposure and RiskEPA Grant Number: R833867
Title: Interpretation of Biomonitoring Data for Ortho-Phthalates Using Physiologically Based Parmacokinetic Modeling: Estimation of Fetal Exposure and Risk
Investigators: Clewell, Harvey , Andersen, Melvin E. , Campbell, Jerry L. , Tan, Yu-Mei
Institution: The Hamner Institutes
EPA Project Officer: Pascual, Pasky
Project Period: November 1, 2008 through October 31, 2011
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2007) RFA Text | Recipients Lists
Research Category: Health Effects , Health
This project will develop human pregnancy PBPK models for several ortho-phthalates including di-ethyl (DEP), di-n-octyl (DOP), butylbenzyl (BBP), di-n-butyl (DBP) and di-(2-ethylhexyl) (DEHP) phthalates. The models will be designed to support the interpretation of human biomarker data, including blood or urine concentrations of the monoester metabolites and/or the oxidative and glucuronide conjugated metabolites. We will then demonstrate the application of the model in a reverse dosimetry approach to estimate aggregate phthalate exposures consistent with measured biomarker concentrations. We will also assess the cumulative risk from phthalate exposure on the developing male fetus based on in vitro determined DBP toxic equivalents (TEQ) of the individual phthalate monoesters based on their ability to inhibit testosterone production in vivo.
The primary objective of this study is to develop a phthalate mixture PBPK model for human pregnancy using our recently developed models for DBP and DEHP in the pregnant 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 develop DBP TEQs for the remaining phthalates in the mixture model and use this information to support aggregate, cumulative risk assessments for the common mechanism group (i.e., inhibition of testosterone production).
We will develop human pregnancy PBPK models for phthalates based on the rodent models recently developed for the rodent at The Hamner. These models will be extrapolated using in vitro measurement and quantitative structureproperty relationships. TEQs for the monoester metabolites will be estimated using an in vitro assay for progesterone inhibition that has previously been shown to reasonably estimate inhibition of testosterone production in vivo.
Successful completion of this project will provide a phthalate mixtures PBPK model for human pregnancy that can be used to assess the published biomonitoring data as well as for assessment of risks posed to the developing fetus based on the cumulative exposure to phthalates in the environment. This approach will be applicable to the characterization of PBPK and Biologically Based Dose-Response models for other compounds in the future.