Human exposure to bisphenol A (BPA).

Of the more than 2,000 high-production volume chemicals that are manufactured in or imported into the United States in amounts of one million pounds or more per year (U.S. Environmental Protection Agency 2004), many are widely used in consumer products. Among these chemicals are bisphenol A [BPA; 2,2-bis(4-hydroxyphenyl)propane; CAS no. 80-05-7] and 4-tertiary-octylphenol [tOP; 4-(1,1,3,3-tetramethylbutyl)phenol; CAS no. 140-66-9]. BPA is used in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry [Center for the Evaluation of Risks to Human Reproduction (CERHR) 2007; European Union 2003]. Exposure to BPA is thought to result primarily from ingestion of food containing BPA (Kang et al. 2006; Vandenberg et al. 2007). tOP is both a degradation product of and an intermediate in the manufacture of octylphenol ethoxylates, which are nonionic surfactants used in detergents, pesticide formulations, and other applications (Ying et al. 2002). Exposure to tOP may occur from contact with personal care products, detergents, water, and food containing tOP.

Exposures to tOP can result in developmental and reproductive alterations in aquatic species (Segner et al. 2003) and in laboratory animals (Aydogan and Barlas 2006; Bian et al. 2006; Blake et al. 2004; Nagao et al. 2001; Willoughby et al. 2005). At high doses, BPA demonstrates estrogen-like effects on uterine and prostate organ weights in experimental animals. At doses below the putative lowest observed adverse effect level, exposure to BPA has reportedly resulted in decreased sperm production, increased prostate gland volume, altered development and tissue organization of the mammary gland, altered vaginal morphology and estrous cycles, disruption of sexual differentiation in the brain, and accelerated growth and puberty (Durando et al. 2007; Howdeshell et al. 1999; Kubo et al. 2003; Richter et al. 2007; Rubin et al. 2006; Schonfelder et al. 2002; Timms et al. 2005; vom Saal et al. 1998). At present, the interpretation of the evidence related to the low-dose effects of BPA is a subject of scientific debate (European Union 2003; Goodman et al. 2006; Gray et al. 2004; National Toxicology Program 2001; vom Saal and Hughes 2005).

BPA and tOP are of concern to environmental public health because of the high potential for exposure of humans to these phenols and their demonstrated animal toxicity. Information about the concentrations of these compounds in the general population is important for understanding human exposure to BPA and tOP. The National Health and Nutrition Examination Survey (NHANES), conducted continuously since 1999 by the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC), is designed to measure the health and nutritional status of the civilian noninstitutionalized U.S. population ≥ 2 months of age (CDC 2003). The surveys include household interviews; collection of medical histories; standardized physical examinations; and collection of biologic specimens (e.g., blood and urine from participants ≥ 1 and ≥ 6 years of age, respectively) for clinical chemistry testing, nutritional indicators assessments, and assessment of exposure to environmental chemicals (CDC 2005, 2006).

Previously, we analyzed 394 urine samples collected from adult participants of NHANES III, conducted during 1988–1994, to estimate urinary concentrations of total BPA (free plus conjugated species) in selected demographic groups (Calafat et al. 2005). We now report the first estimate of urinary concentrations of total BPA and tOP in NHANES 2003–2004 participants, a representative sample of the noninstitutionalized U.S. population ≥ 6 years of age.

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Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004

https://www.healthandenvironment.org/docs/RochesterBPAstudy2013.pdf

Bisphenol A and human health: a review of the literature.

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

In 1991, a group of 21 scientists gathered at the Wingspread Conference Center to discuss evidence of developmental alterations observed in wildlife populations after chemical exposures. There, the term "endocrine disruptor" was agreed upon to describe a class of chemicals including those that act as agonists and antagonists of the estrogen receptors (ERs), androgen receptor, thyroid hormone receptor, and others. This definition has since evolved, and the field has grown to encompass hundreds of chemicals. Despite significant advances in the study of endocrine disruptors, several controversies have sprung up and continue, including the debate over the existence of nonmonotonic dose response curves, the mechanisms of low-dose effects, and the importance of considering critical periods of exposure in experimental design. One chemical found ubiquitously in our environment, bisphenol-A (BPA), has received a tremendous amount of attention from research scientists, government panels, and the popular press. In this review, we have covered the above-mentioned controversies plus six additional issues that have divided scientists in the field of BPA research, namely: 1) mechanisms of BPA action; 2) levels of human exposure; 3) routes of human exposure; 4) pharmacokinetic models of BPA metabolism; 5) effects of BPA on exposed animals; and 6) links between BPA and cancer. Understanding these topics is essential for educating the public and medical professionals about potential risks associated with developmental exposure to BPA and other endocrine disruptors, the design of rigorously researched programs using both epidemiological and animal studies, and ultimately the development of a sound public health policy.

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Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption

Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an "endocrine disruptor". This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d(16)-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (approximately 800 nM) were measured 80 min after oral administration of d(16)-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses.

Johannes G Filser

Papers

Metabolism and kinetics of bisphenol a in humans at low doses following oral administration.