Development of a PBPK Model for 2,2′,4,4′-Tetrabromodiphenyl Ether in Rats and its Extrapolation to Humans for Measurement of In Utero Exposures

Abstract

SM1-PD-17 Introduction: Exposures to environmental contaminants in utero and during childhood create the potential for a variety of adverse health effects, including abnormal or disturbed development of organ systems. Work at RTI is focused on the development of a PBPK model for 2,2'4,4'-tetrabromodiphenyl ether (BDE-47) to permit the prediction of exposure both in utero and during the neonatal period. The model was developed for rats, extrapolated to humans, and evaluated using maternal blood, cord blood, meconium, and breast milk. In addition, PBDE content in house dust collected from the residences of the mothers was analyzed for PBDEs. Methods: Sprague-Dawley rats were dosed either with a single dose or 10-day repeated (iv or PO) at a total dose of 0, 1, or 10 mg/kg. Samples of blood, urine, and feces were collected at various times post-dose. Liver, kidney, adipose, muscle, skin, and brain were collected 10 days post-dosing in pregnant and nonpregnant animals. Tissues and fluids from near-term fetuses were also acquired including amniotic fluid, placentae, fetal brain, liver, and the remainder of the fetus. The extraction method involved the addition of a surrogate standard followed by homogenization/extraction with hexane, SPE cleanup using Florisil, and analysis by GC/ECD. Berkeley Madonna (v 8.0) software was used for modeling. A total of 25 women were recruited into the study. Maternal blood, cord blood, and meconium were collected. Baseline data were acquired by hospital staff. At least 4 weeks following delivery, a visit was made to the participants’ homes and samples of breast milk and floor dust were collected. Results: Recoveries of BDE-47 from blood and tissues ranged from 90% to 110%. Concentrations of BDE-47 were measured in all human samples and ranged from 0.9 to 2.9 pg/mL and from 0.3 to 2.6 pg/mL in maternal and cord blood, respectively, not adjusted for lipid. Other PBDEs also appeared to be in the samples. Discussion and Conclusions: BDE-47 concentrations in cord blood were similar to those in maternal blood and show in utero exposure. Additional data to be available include breast milk concentrations; lipd adjustments will allow for more consistent evaluations. Analysis of the meconium data will provide insight into this medium for cumulative exposure estimations. Supported by Grant No. R830756-01-0 from the U.S. Environmental Protections Agency's STAR program.