Pharmacokinetics of bisphenol A in humans following a single oral administration.

BACKGROUND: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. OBJECTIVE: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. METHODS: We exposed six men and eight women to 100 µg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. RESULTS: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h. CONCLUSIONS: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h.

Application of Sholl analysis to quantify changes in growth and development in rat mammary gland whole mounts.

Studies that utilize the rodent mammary gland (MG) as an endpoint for assessing the developmental toxicity of chemical exposures typically employ either basic dimensional measurements or developmental scoring of morphological characteristics as a means to quantify MG development. There are numerous means by which to report these developmental changes, leading to inconsistent translation across laboratories. The Sholl analysis is a method historically used for quantifying neuronal dendritic patterns. The present study describes the use of the Sholl analysis to quantify MG branching characteristics. Using this method, we were able to detect significant differences in branching density in MG of peripubertal female Sprague Dawley rats that had been exposed to vehicle or a potent estrogen. These data suggest the Sholl analysis can be an effective tool for quantitatively measuring an important characteristic of MG development and for examining associations between MG growth and density and adverse effects in the breast.

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats.

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite alpha-halocarboxymethylglutathione (alphaH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.

Pharmacokinetic modeling of arsenite uptake and metabolism in hepatocytes--mechanistic insights and implications for further experiments.

Arsenic (iAs) is a known human carcinogen and widespread contaminant in drinking water. To provide a quantitative framework for experimental design and hypothesis testing, we developed a pharmacokinetic model describing the uptake and methylation of arsenite (AsIII) in primary rat hepatocytes. Measured metabolites were inorganic As (iAs), mono-methylated As (MMA), and di-methylated As (DMA) concentration in cells and media. Transport and methylation parameters were estimated from time course data for iAs, MMA, and DMA at three initial media As(III) concentrations (0.1, 0.4, 1.0 microM). Inhibition of the formation DMA from MMA by As(III) was necessary to adequately describe the data. The data were consistent with multiple types of inhibition, although uncompetitive inhibition provided a slightly better fit. Model simulations indicate that cellular MMA (cMMA) is a key arsenical to measure; measurement of cMMA in the 4-6 hr time range using an initial concentration of 1.4 microM AsIII would provide the best experimental conditions to distinguish uncompetitive from other types of inhibition. Due to the large number of model parameters estimated from the data, we used sensitivity analysis to determine the influential parameters. Use of sensitivity surfaces facilitated the comparison of parameters over time and across doses. Predicted model responses were most sensitive to influx and efflux parameters, suggesting that transport processes are critical in determining cellular arsenical concentrations. These high sensitivities imply that independent experiments to estimate these parameters with greater certainty may be crucialfor refinement of this model and to extend this model to describe methylation and transport in human hepatocytes.