Risk assessment of predicted serum concentrations of bisphenol A in children and adults following treatment with dental composite restoratives, dental sealants, or orthodontic adhesives using physiologically based pharmacokinetic modeling.

Bisphenol A (BPA) is a chemical used to manufacture bisphenol A glycidyl methacrylate (BisGMA). BisGMA has been used for decades in dental composite restoratives, sealants, and adhesives. Based on published studies, exposure to low concentrations of BPA are possible from dental and orthodontic devices. The serum BPA concentrations arising from such devices and oral doses were predicted using a PBPK model in children and adult females based on 1) published extraction data for cured and uncured 3M ESPE Filtek Supreme Ultra Flowable, 3M ESPE Filtek Bulk Fill Restorative, and 3M ESPE Clinpro Sealant and 2) published 20% ethanol/water and water rinsate data following orthodontic application with 3M ESPE Transbond MIP Primer and 3M ESPE Transbond XT Adhesive. Predicted oral exposure to BPA arising from these dental and orthodontic devices is low (median <10 ng/treatment) and predicted serum BPA concentrations were also low (<10-4 nM). Even the maximum predicted exposure in this study (533.2 ng/treatment) yields a margin of exposure of 7.5 relative to the EFSA t-TDI (4 µg/kg-day) and is only 2.8% of the daily BPA exposure for the US population in a 58-kg woman (15,660 ng/day). Therefore, the exposure to BPA arising from the 3M ESPE dental and orthodontic devices evaluated in this study is negligible relative to daily BPA exposure in the general population and these potential BPA sources do not constitute a risk to patients.

Processing 'Ataulfo' Mango into Juice Preserves the Bioavailability and Antioxidant Capacity of Its Phenolic Compounds.

The health-promoting effects of phenolic compounds depend on their bioaccessibility from the food matrix and their consequent bioavailability. We carried out a randomized crossover pilot clinical trial to evaluate the matrix effect (raw flesh and juice) of 'Ataulfo' mango on the bioavailability of its phenolic compounds. Twelve healthy male subjects consumed a dose of mango flesh or juice. Blood was collected for six hours after consumption, and urine for 24 h. Plasma and urine phenolics were analyzed by electrochemical detection coupled to high performance liquid chromatography (HPLC-ECD). Five compounds were identified and quantified in plasma. Six phenolic compounds, plus a microbial metabolite (pyrogallol) were quantified in urine, suggesting colonic metabolism. The maximum plasma concentration (Cmax) occurred 2-4 h after consumption; excretion rates were maximum at 8-24 h. Mango flesh contributed to greater protocatechuic acid absorption (49%), mango juice contributed to higher chlorogenic acid absorption (62%). Our data suggests that the bioavailability and antioxidant capacity of mango phenolics is preserved, and may be increased when the flesh is processed into juice.

Absorption, Metabolism and Excretion of Cranberry (Poly)phenols in Humans: A Dose Response Study and Assessment of Inter-Individual Variability.

The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r² = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone-4'-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r² ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

Rapid and sensitive detection of bisphenol a from serum matrix.

Bisphenol A (BPA) is an endocrine disrupting compound that may have adverse developmental, reproductive, neurological, and immune system effects. Low-level exposure to BPA is ubiquitous in human populations due to its widespread use in consumer products. Therefore, highly sensitive methods are needed to quantify BPA in various matrices including water, serum, and food products. In this study, we developed a simple, rapid, highly sensitive and specific sensor based on an aptamer probe and AC electrokinetics capacitive sensing method that successfully detected BPA at femto molar (fM) levels, which is an improvement over prior work by a factor of 10. We were able to detect BPA spiked in human serum as well as in maternal and cord blood within 30s. The sensor is responsive to BPA down to femto molar levels, but not to structurally similar compounds including bisphenol F (BPF) or bisphenol S (BPS) even at much higher concentration. Further development of this platform may prove useful in monitoring exposure to BPA and other small molecules in various matrices.

Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A.

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.

Bisphenol A and child and youth behaviour: Canadian Health Measures Survey 2007 to 2011.

BACKGROUND: Bisphenol A (BPA) is a synthetic industrial chemical commonly used in consumer products. Results from the Canadian Heath Measures Survey (CHMS) indicate that more than 90% of children and youth aged 6 to 19 have detectable levels of urinary BPA. Childhood concentration levels of BPA have been linked with negative behavioural outcomes. DATA AND METHODS: The data are from the first two cycles (2007 to 2009 and 2009 to 2011) of the CHMS, which collected biomonitoring indicators via spot blood and urine samples. Behavioural outcomes--hyperactivity/inattention, emotional symptoms, conduct problems, peer problems, and prosocial behavior--were assessed with Goodman's Strengths and Difficulties Questionnaire. Geometric mean urinary BPA concentration was examined overall and by demographic and socioeconomic correlates. Six multiple logistic regression analyses were conducted to investigate associations between childhood BPA concentrations and risk status for each outcome. RESULTS: Children aged 6 to 8 had higher BPA concentrations than did older children and youth. Concentrations were significantly higher among children and youth exposed to second-hand smoke every day or almost every day and those in low or lower-middle income households. Higher BPA concentrations were associated with increased odds of hyperactivity among girls and lower prosocial behaviour among boys. INTERPRETATION: These findings suggest an association between urinary BPA concentration and children's behavioural outcomes.

Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010.

Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol A and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society.

Occurrence of bisphenol A in surface water, drinking water and plasma from Malaysia with exposure assessment from consumption of drinking water.

This study investigated the level of bisphenol A (BPA) in surface water used as potable water, drinking water (tap and bottled mineral water) and human plasma in the Langat River basin, Malaysia. BPA was present in 93% of the surface water samples at levels ranging from below limit of quantification (LOQ; 1.3 ng/L) to 215 ng/L while six fold higher levels were detected in samples collected near industrial and municipal sewage treatment plant outlets. Low levels of BPA were detected in most of the drinking water samples. BPA in tap water ranged from 3.5 to 59.8 ng/L with the highest levels detected in samples collected from taps connected to PVC pipes and water filter devices. Bottled mineral water had lower levels of BPA (3.3±2.6 ng/L) although samples stored in poor storage condition had significantly higher levels (11.3±5.3 ng/L). Meanwhile, only 17% of the plasma samples had detectable levels of BPA ranging from 0.81 to 3.65 ng/mL. The study shows that BPA is a ubiquitous contaminant in surface, tap and bottled mineral water. However, exposure to BPA from drinking water is very low and is less than 0.01% of the tolerable daily intake (TDI).

Serum unconjugated bisphenol A concentrations in men may influence embryo quality indicators during in vitro fertilization.

Here we assess bisphenol A (BPA) in couples undergoing in vitro fertilization (IVF) and indicators of embryo quality; embryo cell number (ECN) and embryo fragmentation score (EFS). Twenty-seven couples provided serum on the day of oocyte retrieval. Unconjugated BPA was measured by HPLC with Coularray detection. Odds ratios (OR) were generated using ordinal logistic regression including female and male BPA concentrations, age and race, and day of embryo transfer for ECN. Inverse associations are suggested for male BPA with ECN (OR=0.70, P=0.069), and EFS (OR=0.54, P=0.009), but not for women. Male BPA exposure may affect embryo quality during IVF.

Development of a radioimmunoassay for the measurement of Bisphenol A in biological samples.

Bisphenol A (BPA) is widely used in the manufacturing of polycarbonate plastic food and drink packaging. Possessing a weak estrogenic activity, BPA is listed among a growing list of endocrine disrupting compounds. In this study, a polyclonal anti-BPA antibody was obtained by immunization with BPA-monocarboxymethylether covalently linked to BSA. The antibody demonstrates negligible cross-reactivity with most analogous BPA phenolic structures, and no cross-reactivity with endogenous steroids. An extraction step with ethyl acetate minimized matrix effects and allowed the BPA measurement in plasma and other biological samples. Recovery after loading test was 96 +/- 4% and dilution tests had a linear profile (r2 > 0.93). The limit of detection of the BPA RIA was 0.08 microg L(-1) with an IC50 of 1.25 microg L(-1). The intra- and inter-assay coefficients of variation were 5.6 and 8.6%, respectively at a BPA concentration of 0.7 microg L(-1) and 6.9 and 5.7% at a BPA concentration of 1.3 microg L(-1). A significant correlation was found between the values obtained by the RIA and HPLC-MS (r2 = 0.92) or HPLC coupled to a fluorescence detector (r2 = 0.80). In conclusion, we described a BPA-RIA that is a suitable tool for evaluating human exposure to BPA.

Assessment of human contamination of estrogenic endocrine-disrupting chemicals and their risk for human reproduction.

There is broad human exposure to estrogenic endocrine-disrupting chemicals (EDCs), but the data sets that exist are primarily for various environmental media such as food and water rather than the most relevant internal exposure. We have detected various kind of EDC contamination in humans including dioxin and bisphenol A (BPA) widely used for the production of plastic products. BPA was present in serum and follicular fluid at approximately 1-2 ng/ml, as well as in fetal serum and full-term amniotic fluid, confirming passage through the placenta. An approximately five-fold higher concentration, 8.3+/-8.7 ng/ml, was revealed in amniotic fluid at 15-18 weeks of gestation, compared to other fluids showing increased exposure at the critical developmental period in humans. Interestingly, serum BPA concentrations were significantly higher in normal men and in women with polycystic ovary syndrome (PCOS) compared with normal women possibly due to differences in the androgen-related metabolism of BPA. These findings may provide some insight into the metabolism of EDCs in human and the pathophysiology of endocrine disorders such as PCOS. Dioxin contamination in relationship to development of endometriosis is also discussed.

In-vitro assessment of the removal of phenols by ACAC hemoperfusion.

The in-vitro removal of free phenols by means of perfusion over albumin coated cellulose nitrate microencapsulated activated charcoal (ACAC) was studied. The phenols tested were in the form of a standard solution comprised of phenol, p-cresol, and p-hydroxyphenylacetic acid in a ratio of 1:5:14. Four different activated charcoals were tested for their adsorption capacity. Further studies were conducted to determine; the effect of microencapsulation and albumin coating of the activated charcoal on the adsorption of phenols; the adsorption isotherm of phenols; the capacity; and the clearance values. The results obtained suggest that ACAC used in the management of patients with uremia or hepatic coma is extremely efficient in removing phenols in aqueous solution in the in-vitro situation.