Soon-Young Han

PHYSIOLOGICALLY BASED PHARMACOKINETICS OF BISPHENOL A

A physiologically based pharmacokinetic (PBPK) model consisting of vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, stomach, and small intestine was developed to predict the tissue distribution and blood pharmacokinetics of bisphenol A in rats and humans. To demonstrate the validity of the developed PBPK model, bisphenol A was administered to rats by multiple iv injections to steady state. The PBPK model predicted the steady-state levels of bisphenol A in blood and various tissues observed in rats after multiple iv injections. The PBPK model was further applied to predict blood and various tissue levels of bisphenol A in a 70 kg-human after single iv injection (5-mg dose) and multiple oral administrations to steady state (100-mg doses every 24 h). The simulated steady-state human blood levels (0.9–1.6 ng/ml) were comparable to basal blood levels of bisphenol A reported in literature (1.49 ng/ml). Furthermore, pharmacokinectic parameters of CL (116.6 L/h), V ss (141.8 L), and t 1/2 (76.8 min) predicted for humans were comparable to those previously predicted by simple allometric scaling. This PBPK model may provide insights into the tissue distribution characteristics as a result of human exposure to bisphenol A.

Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration

This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4?8.2 min and 38.6?62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1?123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6?6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration?time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0? 5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4-8.2 min and 38.6-62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1-123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6-6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration-time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0-5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.

Bioavailability and mammary excretion of bisphenol A in Sprague-Dawley rats

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 - 1.3 min and 52.5 - 2.4 min, respectively. The systemic clearance (Cl s ) and the steady-state volume of distribution ( V ss ) averaged 107.9 - 28.7 ml/min/kg and 5.6 - 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration ( C max ) and the time to reach the maximum concentration ( T max ) were 14.7 - 10.9 ng/ml and 0.2 - 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 - 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 - 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.

Maternal-fetal disposition of bisphenol a in pregnant Sprague-Dawley rats.

This study describes the maternal-fetal disposition of bisphenol A and its distribution into the placenta and amniotic fluid after iv injection (2 mg/kg) to pregnant Sprague-Dawley rats. Bisphenol A was distributed extensively to the placenta and fetus, with their respective AUC values 4.4- and 2.2-fold greater than AUC for the maternal serum. In contrast, the distribution of bisphenol A into the amniotic fluid was low, with the mean amniotic fluid-to-maternal serum AUC ratio of 0.2. The decay curves of bisphenol A in the placenta, fetus, and amniotic fluid paralleled that of the maternal serum during the terminal elimination phase. A five-compartment open model consisting of the maternal central, maternal peripheral, placental, fetal, and amniotic fluid compartments was used to describe the disposition of bisphenol A in pregnant rats, with the elimination occurring from the maternal central and fetal compartments. Based on this model, bisphenol A delivered to the placenta was transferred primarily to the fetus [ k pf /( k pf + k pc + k pa ) = 65.4%], with the remaining fraction transported to the maternal central (33.2%) and amniotic fluid (1.4%) compartments. Bisphenol A was eliminated from the amniotic fluid by the fetal (63.9%) and placental (36.1%) routes. On the other hand, bisphenol A was eliminated from the fetus primarily by the placental route back to mother [ k fp /( k fp + k fa + k fo ) = 100%], with the amniotic route playing an insignificant role in fetal elimination. The percent contribution of the fetal elimination to the total elimination in the maternal-fetal unit was 0.05% [CL fo AUC fetus /(CL co AUC maternal serum + CL fo AUC fetus )]. The pharmacokinetic model used in this study provides insights into the routes of elimination of bisphenol A in the maternal-fetal rat upon maternal administration.

Validation Study of OECD Rodent Uterotrophic Assay for The Assessment of Estrogenic Activity in Sprague-Dawley Immature Female Rats

The Organization for Economic Cooperation and Development (OECD) is developing a screening and testing method to identify estrogenic/antiestrogenic compounds. Based on these demands, phase 1 study for OECD uterotrophic assay was undertaken. The OECD is in the process of validating the assay results from international participating laboratories, which carried out this study with established environmental estrogenic compounds using designed protocols. The aim of this study was to provide data for validating the OECD uterotrophic assay using Sprague-Dawley immature female rats when testing with weak or partial estrogenic compounds. Ethinyl estradiol (EE) at 0.3 or 1μg/kg/d, a positive control used in the present study, significantly increased both uterine wet and blotted weights. In the case of weak estrogenic compounds, the uterine wet weights were significantly increased by bisphenol A (BPA) at 300 mg/kg/d, nonylphenol (NP) at 80 mg/kg/d, genistein (GN) at 35 mg/kg/d, and methoxychlor (MXC) at 500 mg/kg/d. In addition, the increase in uterine blotted weights also showed a similar pattern to that of uterine wet weights. However, both 1,1,1-trichloro-2,2-bis(p-chlorphenyl)ethane (o,p-DDT) and dibutyl phthalate (DBP) did not affect uterus (wet and blotted) weights at doses of 100 and 500 mg/kg/d. These results suggest that the increase in uterine weights should be considered useful as a sensitive endpoint for detecting weak estrogenic compounds in 3-d rodent uterotrophic assay. However, further combination studies using surrogate biomarkers may be needed to improve the sensitivity of this assay for the detection of weak estrogenic compounds, such as o,p-DDT.

Pharmacokinetic scaling of bisphenol A by species-invariant time methods

1. The study was performed to predict the pharmacokinetic disposition of bisphenol A in humans using simple allometry and several species-invariant time methods based on animal data. Bisphenol A was injected intravenously to mouse, rat, rabbit and dog (1-2 mg kg−1 doses). 2. The obtained serum concentration-time profiles were best described by bi-exponential equations in all these animal species, with the mean Cl, Vss and t1/2 of 0.3 l h−1, 0.1 litres and 39.9 min in mouse, 1.9 l h−1, 1.3 litres and 37.6 min in rat, 12.6 l h−1, 7.1 litres and 40.8 min in rabbit, and 27.1 l h−1, 20.0 litres and 43.7 min in dog, respectively. 3. The human pharmacokinetic parameters of Cl, Vss and t1/2 were predicted by simple allometry as well as by normalization according to species-invariant times of kallynochrons, apolysichrons and dienetichrons. 4. The simple allometric scaling and different time transformation methods predicted the human Cl, Vss and t1/2 ranging from 46.0 to 127.1 l h−1, 125.3 to 229.7 litres and 43.6 to 196.2 min, respectively. Species-invariant time transformations showed that all animal data from the four species were superimposable. These preliminary parameter values may be useful in interpreting toxicity data in humans on environmental exposure to bisphenol A.