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INTERPRETATION OF BIOMONITORING DATA FOR ORTHO-PHTHALATES USING PHYSIOLOGICALLY BASED PARMACOKINETIC MODELING: ESTIMATION OF FETAL EXPOSURE AND RISK
Impact/Purpose:
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).
Description:
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.