Urinary Biomarker Kinetics to Quantify Human Bisphenol A Exposure and Endocrine System Target Tissue DosimetryEPA Grant Number: R833868
Title: Urinary Biomarker Kinetics to Quantify Human Bisphenol A Exposure and Endocrine System Target Tissue Dosimetry
Investigators: Teeguarden, Justin , Hattis, Dale , Hinderliter, Paul
Institution: Battelle Memorial Institute , Clark University
EPA Project Officer: Pascual, Pasky
Project Period: July 1, 2009 through June 30, 2012
Project Amount: $749,967
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2007) RFA Text | Recipients Lists
Research Category: Health Effects , Health
Humans are widely exposed to the estrogenic/anti-androgenic compound bisphenol A (BPA) through the food supply. Conventional biomarker-based methods of estimating human exposure to this important estrogen (ER) /androgen (AR) receptor binding endocrine disruptor are inaccurate because they ignore the kinetics of uptake, metabolism, and elimination. Our working hypothesis is that high accuracy estimates of individual and population-level human BPA exposure and estrogen/androgen responsive target tissue (pituitary, prostate, uterus) dose can be made by utilizing a human BPA PBPK model to interpret a common biomarker of BPA exposure: total urinary BPA. The overall goal is to develop a computational framework for calculating exposure and target tissue dose for ER/AR binding endocrine disruptors using BPA as an example. Project objectives are to: A) Develop, calibrate and validate a human PBPK model-based method for estimating human oral exposure to BPA from urinary biomarker data and experimentally demonstrate its accuracy; B) Calculate distributions of human oral BPA exposures from a 2600 person NHANES urine BPA data set using a reverse dosimetry enabled human BPA PBPK model and Monte-Carlo simulations; C) Calculate distributions of BPA concentration and ER and AR occupancy in estrogen/androgen-responsive target tissues to determine if exposures reach levels likely to cause endocrine disruption; and D) Produce and disseminate a BPA urine biomarker-based BPA exposure calculator.
The existing human BPA PBPK model will be revised to conduct Monte-Carlo based reverse dosimetry to calculate human BPA exposures from urine biomarker data. This model’s ability to determine exact BPA exposure given the ingestion pattern, urination pattern and urine sampling time will be tested against new urine biomarker data collected in a clinical setting. Monte-Carlo methods will be used to determine distributions of human BPA exposure from the NHANES data based on distributions of important physiological and biomonitoring study parameters. Exposures and target tissue ER/AR binding will then be estimated for potentially sensitive populations using the reverse dosimetry enabled human PBPK model revised to include three estrogen/androgen responsive target tissues.
This research will produce high accuracy estimates of human BPA exposure from NHANES urine BPA spot sampling data by applying human BPA uptake, metabolism and urinary BPA elimination kinetics represented in a PBPK model to urine spot sampling data. The method will be made available in the form of a simplified BPA exposure calculator. Improving the accuracy of exposure estimates made from NHANES biomonitoring data increases the value of the NHANES program and improves the scientific basis for assessing the risks of exposure to BPA. A novel extension of the typical exposure assessment is proposed that will permit evaluation of the potential impact of calculated human BPA exposures on three estrogen/androgen responsive tissues in sensitive populations, enabling future linkages to pharmacodynamic models of the hypothalamic-pituitary-gonadal (HPG) axis. Most importantly, this work will demonstrate and articulateboth a refined urine biomonitoring protocol and a PBPK-model based exposure assessment method that together greatly improve the accuracy of all exposure estimates made from urine biomonitoring data.