Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA.
To reduce uncertainties about the metabolism and excretion of ...BPA in humans following oral administration.
We exposed six men and eight women to 100μg/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.
Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711nM (390ng/ml) was observed at Tmax of 1.1±0.50h. Unconjugated d6-BPA appeared in serum within 5–20min of dosing with a mean Cmax of 6.5nM (1.5ng/ml) observed at Tmax of 1.3±0.52h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48h in some subjects at concentrations near the LOD (0.001–0.002ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4±2.0h 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.
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.
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•Findings are consistent with data from animal and other human studies.•Maximum total serum levels are 3.9ng/ml for each μg ingested per kg.•Maximum unconjugated serum levels are 0.015ng/ml for each μg ingested per kg.•Unconjugated BPA in blood following oral administration is <1% of the total.•Most subjects excreted >90% as conjugated metabolites within 24h.
By virtue of its binding to steroid hormone receptors, bisphenol A (BPA, the unconjugated bioactive monomer) is hypothesized to be estrogenic when present in sufficient quantities in the body, ...raising concerns that widespread exposure to BPA may impact human health. To better understand the internal exposure of adult humans to BPA and the relationship between the serum and urinary pharmacokinetics of BPA, a clinical exposure study was conducted. Blood and urine samples were collected approximately hourly over a 24-h period from 20 adult volunteers who ingested 100% of one of three specified meals comprising standard grocery store food items for breakfast, lunch, and dinner. The volunteers' average consumption of BPA, estimated from the urinary excretion of total BPA ((TOT)BPA = conjugated BPA + BPA), was 0.27 μg/kg body weight (range, 0.03-0.86), 21% greater than the 95th percentile of aggregate exposure in the adult U.S. population. A serum time course of (TOT)BPA was observable only in individuals with exposures 1.3-3.9 times higher than the 95th percentile of aggregate U.S. exposure. The (TOT)BPA urine concentration T(max) was 2.75 h (range, 0.75-5.75 h) post-meal, lagging the serum concentration T(max) by ∼1 h. Serum (TOT)BPA area under the curve per unit BPA exposure was between 21.5 and 79.0 nM•h•kg/μg BPA. Serum (TOT)BPA concentrations ranged from less than or equal to limit of detection (LOD, 1.3 nM) to 5.7 nM and were, on average, 42 times lower than urine concentrations. During these high dietary exposures, (TOT)BPA concentrations in serum were undetectable in 83% of the 320 samples collected and BPA concentrations were determined to be less than or equal to LOD in all samples.
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•Reaction kinetics for glutathione (GSH) with inorganic and methylated arsenic species are reported.•GSH reactions include reduction of pentavalent and complexation with trivalent As ...species.•The GSH complex of arsenite is also the substrate for enzymatic methylation.•GSH is likely to participate in metabolic activation to and tissue transport of trivalent As species.
Arsenic (As) is a common contaminant in the earth’s crust and widely distributed in food and drinking water. As exposures have been associated with human disease, including cancer, diabetes, lung and cardiovascular disorders, and there is accumulating evidence that early life exposures are important in the etiology. Mode-of-action analysis includes a critical role for metabolic activation of As species to reactive trivalent intermediates that disrupt cellular regulatory systems by covalent binding to thiol groups. The central role of glutathione (GSH) in the chemical reactions of metabolism and disposition of arsenic species was investigated here. The chemical kinetics were measured for reactions in which GSH is a ligand for trivalent As complex formation, a reductant for pentavalent As species, and a participant in ligand exchange reactions with other biological As-thiol complexes. The diverse reactions of GSH with As species demonstrate prominent roles in: (1) metabolic activation via reduction; (2) transport from tissues that are the primary sources of reactive trivalent As intermediates following ingestion (intestine and liver) to downstream target organs (e.g., lung, kidney, and bladder); and (3) oxidation to the terminal metabolite, dimethylarsinic acid (DMAV), which is excreted. Studies of As metabolism and disposition emphasize the link between metabolic activation vs. excretion of As (i.e., internal dosimetry of reactive species) and the disruption of critical cellular thiol-based regulatory processes that define the dose-response characteristics of disease in human epidemiological studies and animal models and underpin risk assessment.
Recent technological advances have made available reverse phase chromatographic media with a 1.7
μm particle size along with a liquid handling system that can operate such columns at much higher ...pressures. This technology, termed ultra performance liquid chromatography (UPLC), offers significant theoretical advantages in resolution, speed, and sensitivity for analytical determinations, particularly when coupled with mass spectrometers capable of high-speed acquisitions. This paper explores the differences in LC–MS performance by conducting a side-by-side comparison of UPLC for several methods previously optimized for HPLC-based separation and quantification of multiple analytes with maximum throughput. In general, UPLC produced significant improvements in method sensitivity, speed, and resolution. Sensitivity increases with UPLC, which were found to be analyte-dependent, were as large as 10-fold and improvements in method speed were as large as 5-fold under conditions of comparable peak separations. Improvements in chromatographic resolution with UPLC were apparent from generally narrower peak widths and from a separation of diastereomers not possible using HPLC. Overall, the improvements in LC–MS method sensitivity, speed, and resolution provided by UPLC show that further advances can be made in analytical methodology to add significant value to hypothesis-driven research.
Urine and serum biomonitoring was used to measure internal exposure to selected dietary estrogens in a cohort of 30 pregnant women. Exposure was measured over a period comprising one-half day in the ...field (6 h) and one day in a clinic (24 h). Biomonitoring of the dietary phytoestrogens genistein (GEN), daidzein (DDZ) and equol (EQ), as well as the mycoestrogen, zearalenone (ZEN) and its congeners, was conducted using UPLC-MS/MS. Biomonitoring revealed evidence of internal exposure to naturally occurring dietary estrogens during pregnancy. Urinary concentrations of total GEN, DDZ and EQ were similar to levels reported for general adult U.S. population. Measurable concentrations of total (parent and metabolites) GEN, DDZ and EQ were present in 240, 207 and 2 of 270 serum samples, respectively. Six out of 30 subjects had measurable concentrations of unconjugated GEN and/or DDZ in serum between 0.6 and 7.1 nM. Urine to serum total isoflavone ratios for GEN, DDZ and EQ were 13, 47, and 180, respectively. ZEN and its reductive metabolite, α-zearalenol (α-ZEL), were present in pregnant women (11 out of 30 subjects) as conjugates at levels near the limit of quantification. The average total urinary concentration was 0.10 μg/L for ZEN and 0.11 μg/L for α-ZEL.
•Concurrent urine and serum biomonitoring demonstrate pregnant women are exposed to multiple dietary estrogens.•Urinary concentrations of genistein, daidzein and equol in pregnant women reflect the exposure of the general adult U.S. population.•Aglycone levels of genistein and/or daidzein in serum were measured in 6 out of 30 subjects and ranged between 0.6 and 7.1 nM.•Zearalenone and its reductive metabolite α-zearalenol were measured in 11 out of 30 subjects’ urine with levels ranging between 0.03 and 0.29 μg/L.
Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to <1% of total BPA in humans and non-human ...primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24hour period in 10 adult male volunteers following ingestion of 30μg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t1/2=0.45h) and elimination of the administered dose was complete 24h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43nM at 1.6h after administration and represented <0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29h vs 0.45h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (<1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies.
Intestinal microbiota composition and gut-associated immune response can contribute to the toxicity of arsenic. We investigated the potential toxicity of short-term arsenic exposure on gut microbiome ...composition, intestinal immune status, microbial arsenic resistance gene, and arsenic metabolic profiles in adult and developmental stages of CD-1 mice. The potential toxicity of arsenite As(III) was determined for two life stages: (i) adult animals at 24 or 48 h after single gavage (0.05 mg/kg body weight b.w. low dose, 0.1 mg/kg b.w. medium dose, and 0.2 mg/kg b.w. high dose) and repeated exposure at 1 mg/liter for 8 days and (ii) postnatal day 10 (PND10) and PND21 after single gavage (0.05 mg/kg b.w.). Dose- and time-dependent responses in bacterial recovery/microbial composition were observed in adults after a single gavage. Repeated exposure caused a transient decrease in the recovery of intestinal bacteria, a shift in the bacterial population with abundance of arsenic resistance genes, and evidence for host metabolism of arsenite into less-reactive trivalent methylated species. Arsenic exposure in adult animals induced high levels of CC chemokines and of proinflammatory and anti-inflammatory cytokine secretion in intestine. Arsenic exposure at PND21 resulted in the development of distinct bacterial populations. Results of this study highlight significant changes in the intestinal microbiome and gut-associated immune status during a single or repeated exposure to arsenic in juvenile and adult animals. The data warrant investigation of the long-term effects of oral arsenic exposure on the microbiome and of immune system development and responses.
Transformation of organic arsenic to toxic inorganic arsenic (iAs) is likely carried out by intestinal bacteria, and iAs may alter the viability of certain microbial populations. This study addressed the impact of arsenic exposure on intestinal microbiota diversity and host gut-associated immune mediators during early development or adulthood using scenarios of acute or repeated doses. During acute arsenic exposure, animals developed defense functions characterized by higher abundances of bacteria that are involved in arsenic resistance or detoxification mechanisms. Arsenite had a negative effect on the abundance of bacterial species that are involved in the conversion of protein to butyrate, which is an alternative energy source in the intestine. The intestinal mucosal immune cytokine profile reflected a mechanism of protection from arsenic toxicity.
A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II ...conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species.
•A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans.•Serum concentrations of aglycone BPA are available for model calibration.•Model predicted peak BPA serum levels for adult humans were in the range of pM.•Model predicted 95% of human variability fell within an order of magnitude.
Arsenic species contaminate food and water, with typical dietary intake below 1 μg/kg bw/d. Exposure to arsenic in heavily contaminated drinking water is associated with human diseases, including ...cardiovascular and respiratory disorders, diabetes, and cancer. Dietary intake assessments show that rice and seafood are the primary contributors to intake of both inorganic arsenic and dimethylarsinic acid (DMAV) and at similar magnitudes. DMAV plays a central role in the toxicology of arsenic because enzymatic methylation of arsenite produces DMAV as the predominant metabolite, which may promote urinary clearance but also generates reactive intermediates, predominantly DMAIII, that bind extensively to cellular thiols. Both inorganic arsenic and DMAV are carcinogenic in chronically exposed rodents. This study measured pentavalent and trivalent arsenic species in blood and tissues after oral and intravenous administration of DMAV (50 μg As/kg bw). DMAV underwent extensive first-pass metabolism in the intestine and liver, exclusively by reduction to DMAIII, which bound extensively to blood and tissues. The results confirm a role for methylation-independent reductive metabolism in producing fluxes of DMAIII that presumably underlie arsenic toxicity and indicate the need to include all dietary intake of inorganic arsenic and DMAV in risk assessments.
•Extensive first-pass metabolism of ingested DMAV occurs in the intestine and liver.•Bound DMAIII was observed in all tissues analyzed, but was lowest in muscle and brain.•Methylation-independent reductive metabolism of DMAV produces reactive trivalent species.•Dietary intake of both inorganic arsenic and DMAV should be included in risk assessments.
Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to ...determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death. Rhesus monkeys (N = 3 for each treatment and control group) at three stages of development (122 days of gestation and 5 and 35 postnatal days PNDs) were administered ketamine intravenously for 24 h to maintain a surgical anesthetic plane, followed by a 6-h withdrawal period. Similar studies were performed in PND 5 animals with 3 h of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-h infusion) produced a significant increase in the number of caspase 3–, Fluoro-Jade C– and silver stain–positive cells in the cortex of gestational and PND 5 animals but not in PND 35 animals. Electron microscopy indicated typical nuclear condensation and fragmentation in some neuronal cells, and cell body swelling was observed in others indicating that ketamine-induced neuronal cell death is most likely both apoptotic and necrotic in nature. Ketamine increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit messenger RNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 PNDs) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 PNDs). However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey.
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