Bisphenol A controversy centers on concerns and debates about the biomedical significance of bisphenol A (BPA), which is a precursor to polymers that are used in some consumer products, including some food containers. The concerns began with the hypothesis that BPA is an endocrine disruptor; it mimics endocrine hormones and thus has the unintended and possibly far-reaching effects on humans in physical contact with the chemical. Since 2008, several governments have investigated its safety, which prompted some retailers to withdraw polycarbonate products. The U.S. Food and Drug Administration (FDA) ended its authorization of the use of BPA in baby bottles and infant formula packaging, based on market abandonment, not safety. The European Union and Canada have banned BPA use in baby bottles. The U.S. FDA states "BPA is safe at the current levels occurring in foods" based on extensive research, including two more studies issued by the agency in early 2014. The European Food Safety Authority (EFSA) reviewed new scientific information on BPA in 2008, 2009, 2010, 2011 and 2015: EFSA's experts concluded on each occasion that they could not identify any new evidence which would lead them to revise their opinion that the known level of exposure to BPA is safe; however, the EFSA does recognize some uncertainties, and will continue to investigate them. In February 2016, France announced that it intends to propose BPA as a REACH Regulation candidate substance of very high concern (SVHC). The European Chemicals Agency agreed to the proposal in June 2017.
Production The BPA controversy has gained momentum because of the quantity of BPA produced by the chemical industry. World production capacity of BPA was 1 million tons in the 1980s, and more than 2.2 million tons in 2009. It is a high production volume chemical. In 2003, U.S. consumption was 856,000 tons, 72% of which used to make polycarbonate plastic and 21% going into epoxy resins. In the U.S., less than 5% of the BPA produced is used in food contact applications, but remains in the canned food industry and printing applications such as sales receipts. On 20 February 2018, Packaging Digest reported that "At least 90%" of food cans no longer contained BPA.
Occurrence BPA is rarely encountered in industrial products: it is invariably bound in a polymeric structure. Concerns therefore about exposure focus on the degradation, mainly by hydrolysis, of these polymers and the plastic objects derived therefrom. Polycarbonate plastic, which is formed from BPA, is used to make a variety of common products including baby and water bottles, sports equipment, medical and dental devices, dental fillings sealants, CDs and DVDs, household electronics, eyeglass lenses, foundry castings, and the lining of water pipes. BPA is also used in the synthesis of polysulfones and polyether ketones, as an antioxidant in some plasticizers, and as a polymerization inhibitor in PVC. Epoxy resins derived from bisphenol A are used as coatings on the inside of almost all food and beverage cans; however, due to BPA health concerns, in Japan epoxy coating was mostly replaced by PET film. Bisphenol A is a preferred color developer in carbonless copy paper and thermal point of sale receipt paper. When used in thermal paper, BPA is present as "free" (i.e., discrete, non-polymerized) BPA, which is likely to be more available for exposure than BPA polymerized into a resin or plastic. Upon handling, BPA in thermal paper can be transferred to skin, and there is some concern that residues on hands could be ingested through incidental hand-to-mouth contact. Furthermore, some studies suggest that dermal absorption may contribute some small fraction to the overall human exposure. European data indicate that the use of BPA in paper may also contribute to the presence of BPA in the stream of recycled paper and in landfills. Although there are no estimates for the amount of BPA used in thermal paper in the United States, in Western Europe, the volume of BPA reported to be used in thermal paper in 2005/2006 was 1,890 tonnes per year, while total production was estimated at 1,150,000 tonnes per year. (Figures taken from 2012 EPA draft paper.) Studies document potential spreading and accumulation of BPA in paper recycling, suggesting its presence for decades in paper recycling loop even after a hypothetical ban. Epoxy resin may or may not contain BPA, and is employed to bind gutta percha in some root canal procedures.
Biomedical history In the early 1930s, the British biochemist Edward Charles Dodds tested BPA as an artificial estrogen, but found it to be 37,000 times less effective than estradiol. Dodds eventually developed a structurally similar compound, diethylstilbestrol (DES), which was used as a synthetic estrogen drug in women and animals until it was banned due to its risk of causing cancer; the ban on use of DES in humans came in 1971 and in animals, in 1979. BPA was never used as a drug. BPA's ability to mimic the effects of natural estrogen derives from the similarity of phenol groups on both BPA and estradiol, which enable this synthetic molecule to trigger estrogenic pathways in the body. Typically phenol-containing molecules similar to BPA are known to exert weak estrogenic activities, thus it is also considered an endocrine disruptor (ED) and estrogenic chemical. Xenoestrogens is another category the chemical BPA fits under because of its capability to interrupt the network that regulates the signals which control the reproductive development in humans and animals. In 1997, adverse effects of low-dose BPA exposure in laboratory animals were first proposed. Modern studies began finding possible connections to health issues caused by exposure to BPA during pregnancy and during development. See Public health regulatory history in the United States and Chemical manufacturers' reactions to bans. As of 2014, research and debates are ongoing as to whether BPA should be banned or not.
A 2007 study investigated the interaction between bisphenol A's and estrogen-related receptor γ (ERR-γ). This orphan receptor (endogenous ligand unknown) behaves as a constitutive activator of transcription. BPA seems to bind strongly to ERR-γ (dissociation constant = 5.5 nM), but only weakly to the ER. BPA binding to ERR-γ preserves its basal constitutive activity. It can also protect it from deactivation from the SERM 4-hydroxytamoxifen (afimoxifene). This may be the mechanism by which BPA acts as a xenoestrogen. Different expression of ERR-γ in different parts of the body may account for variations in bisphenol A effects. For instance, ERR-γ has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue. BPA has also been found to act as an agonist of the GPER (GPR30).
Safety
Health effects
In 2017 the European Chemicals Agency concluded that BPA should be listed as a substance of very high concern due to its properties as an endocrine disruptor. In 2023, the European Food Safety Authority re-evaluated the safety of BFA and significantly reduced tolerable daily intake (TDI) to 0.2 nanograms (0.2 billionths of a gram), 20,000 times lower than the previous TDI from 2015. The European Food Safety Authority concluded that consumers with both average and high exposure to BPA in all age groups exceeded the new TDI, indicating health concerns. In 2012, the United States' Food and Drug Administration (FDA) banned the use of BPA in baby bottles intended for children under 12 months. The Natural Resources Defense Council called the move inadequate, saying the FDA needed to ban BPA from all food packaging. The FDA maintains that the agency continues to support the safety of BPA for use in products that hold food. In 2011, Andrew Wadge, the chief scientist of the United Kingdom's Food Standards Agency, commented on a 2011 U.S. study on dietary exposure of adult humans to BPA, saying, "This corroborates other independent studies and adds to the evidence that BPA is rapidly absorbed, detoxified, and eliminated from humans – therefore is not a health concern." The Endocrine Society said in 2015 that the results of ongoing laboratory research gave grounds for concern about the potential hazards of endocrine-disrupting chemicals – including BPA – in the environment, and that on the basis of the precautionary principle these substances should continue to be assessed and tightly regulated. A 2016 review of the literature said that the potential harms caused by BPA were a topic of scientific debate and that further investigation was a priority because of the association between BPA exposure and adverse human health effects including reproductive and developmental effects and metabolic disease.
United States expert panel conclusions In 2007, the U.S. federal government invited experts to Chapel Hill, North Carolina to perform a scientific assessment of literature on BPA. Thirty-eight experts in fields involved with bisphenol A gathered in Chapel Hill, North Carolina to review several hundred studies on BPA, many conducted by members of the group. At the end of the meeting, the group issued the Chapel Hill Consensus Statement, which stated "BPA at concentrations found in the human body is associated with organizational changes in the prostate, breast, testis, mammary glands, body size, brain structure and chemistry, and behavior of laboratory animals." The Chapel Hill Consensus Statement stated that average BPA levels in humans were above those that cause harm to many animals in laboratory experiments. It noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous. This is problematic because acute animal exposure studies are used to estimate daily human exposure to BPA, and no studies that had examined BPA pharmacokinetics in animal models had followed continuous low-level exposures. The authors added that measurement of BPA levels in serum and other body fluids suggests the possibilities that BPA intake is much higher than accounted for or that BPA can bioaccumulate in some conditions (such as pregnancy). Following the Chapel Hill Statement, the US National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction (NTP – CERHR), sponsored another literature assessment. The report, released in 2008, noted that "the possibility that bisphenol A may alter human development cannot be dismissed". Despite this report, the US Food and Drug Administration (FDA) BPA Task Force (formed in April 2008), concluded that products containing BPA were safe. In 2009, the FDA Science Board Subcommittee on Bisphenol A, an external committee assigned to review the FDA's report "concluded that the FDA failed to conduct a rigorous or extensive exposure assessment", leading the US Environmental Protection Agency (EPA) to conduct their own assessment. The United States Federal Interagency Working Group (FIW) included a goal to reduce BPA exposure in the 2 December 2010 release of their 2020 Healthy People national objectives for improving the health of all Americans.
Metabolic disease
Numerous animal studies have demonstrated an association between endocrine disrupting chemicals (including BPA) and obesity. However, the relationship between bisphenol A exposure and obesity in humans is unclear. Cohort studies have shown there has been an association of prenatal BPA exposure and increased body fat percentage at age 7 and increased BMI by age 9. Not all studies have shown a positive relationship between BPA exposure and obesity, further studies on the effects of BPA on metabolic diseases need to take diet into consideration to remove any influence it might have on the outcome. Proposed mechanisms for BPA exposure to increase the risk of obesity include BPA-induced thyroid dysfunction, activation of the PPAR-gamma receptor, and disruption of neural circuits that regulate feeding behavior. BPA works by imitating the natural hormone 17B-estradiol. In the past BPA has been considered a weak mimicker of estrogen but newer evidence indicates that it is a potent mimicker. When it binds to estrogen receptors it triggers alternative estrogenic effects that begin outside of the nucleus. This different path induced by BPA has been shown to alter glucose and lipid metabolism in animal studies. There are different effects of BPA exposure during different stages of development. During adulthood, BPA exposure modifies insulin sensitivity and insulin release without affecting weight.
Thyroid function
A 2007 review concluded that bisphenol-A has been shown to bind to thyroid hormone receptor and perhaps has selective effects on its functions. A 2009 review about environmental chemicals and thyroid function raised concerns about BPA effects on triiodothyronine and concluded that "available evidence suggests that governing agencies need to regulate the use of thyroid-disrupting chemicals, particularly as such uses relate exposures of pregnant women, neonates and small children to the agents". A 2009 review summarized BPA adverse effects on thyroid hormone action. A 2016 case control study found that there was a significant association between urinary BPA levels and increased TSH levels (Thyroid- stimulating hormone) in a group of adult women.
Neurological effects Limited epidemiological evidence suggests that exposure to BPA in the uterus and during childhood is associated with poor behavioral outcomes in humans. Exposure may be associated with higher levels of anxiety, depression, hyperactivity, and aggression in children. A panel convened by the National Toxicology Program (NTP) of the U.S. National Institutes of Health determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior. In January 2010, based on the NTP report, the FDA expressed the same level of concern. A 2007 literature review concluded that BPA, like other chemicals that mimic estrogen (xenoestrogens), should be considered as a player within the nervous system that can regulate or alter its functions through multiple pathways. A 2008 review of animal research found that low-dose BPA maternal exposure can cause long-term consequences for the neurobehavioral development in mice.
A 2009 review raised concerns about a BPA effect on the anteroventral periventricular nucleus.
Disruption of the dopaminergic system
A 2008 review of human participants has concluded that BPA mimics estrogenic activity and affects various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse.
Cancer According to the WHO's INFOSAN, carcinogenicity studies conducted under the U.S. National Toxicology Program have shown increases in leukemia and testicular interstitial cell tumors in male rats. However, according to the note, "these studies have not been considered as convincing evidence of a potential cancer risk because of the doubtful statistical significance of the small differences in incidences from controls." A 2010 review concluded that bisphenol A may increase cancer risk. Several studies show evidence that the formation of prostate cancer in men is directly proportional to BPA exposure. Male subject diagnosed with prostate cancer were found to have higher urine concentration of BPA as opposed to the concentrations found in the control group's. This correlation may be due to BPA's ability to induce cell proliferation of the prostate cancer cells.
Breast cancer
Higher susceptibility to breast cancer has been found in many studies of rodents and primates exposed to BPA. However, it is the impact BPA has on breast cancer development in humans is unclear, as it is difficult to quantify an individual's BPA exposure over their lifetime. BPA, which includes a phenolic structure, has shown an association with agonist and antagonistic endocrine receptors that facilitate endocrine disorders such as breast and prostate cancer. Other endocrine disorders include infertility, polycystic ovary syndrome, and precocious puberty. More oxidative stress in breast cancer cells were found to be directly proportional to BPA exposure as per the findings in several in vitro studies. Additionally, work related exposure to BPA, and women who are postmenopausal have suggested an increase in breast cancer incidence.
Mechanism of action BPA is an endocrine disruptor, meaning BPA has a similar structure to oestrogen (ligand) and can bind to the oestrogen receptor ERα and ERβ and activate it. Oestrogen is hydrophobic and is able to diffuse through the plasma membrane and into the target cell. Oestradiol binding to the oestrogen receptor releases the heat shock protein from the ligand binding domain of the receptor causing dimerization. The nuclear localisation signal targets the ligand-receptor complex to the nucleus where it can bind oestrogen response elements within the promoter of target genes on DNA. Subsequently, various cofactors are recruited allowing transcription of genes including those involved in cell proliferation. When BPA is exposed to high temperatures or changes in pH, the ester bond linking BPA monomers is hydrolysed. Free BPA then competes with oestrogen for ERα and ERβ binding sites. When BPA successfully binds the receptor, it interacts with ERE and increases expression of target genes like WNT-4 and RANKL; two key players in stem cell proliferation and carcinogenesis. BPA was also shown to inactivate p53 which prevents tumour formation as it triggers apoptosis.
Fertility As of 2022, current evidence shows a possible positive correlation between BPA levels, lower sperm quality, decreased motility and an increase in sperm immaturity. There is tentative evidence to support the idea that BPA exposure has negative effects on human fertility. Few studies have investigated whether recurrent miscarriage is associated with BPA levels. Exposure to BPA does not appear to be linked with higher rates of endometrial hyperplasia. A 2009 cohort study linked urinary BPA concentration of women undergoing IVF egg retrieval, with an inverse correlation to oocyte release. The study found that for each unit increase in day 3 FSH (IU/L), there was an average decrease of 9% in the number of oocytes retrieved. The positive correlations found in animal studies warrants the continued research of BPA for couple fecundity. Ubiquitous in environment through consumer products such as reusable plastics, food and beverage container liners, baby bottles, water resistant clothing. It has been identified as an EDC and found in urine, blood, amniotic fluid, breast milk and cord blood. Comparing blood BPA and phthalate levels between fertile and infertile women between the ages of 20–40, using gas chromatographic-mass spectrometry to analyze the amount of BPA, phthalate and their metabolites in peripheral venous blood, showed significantly elevated serum BPA level in infertile women, as well as women with PCOS (polycystic ovarian syndrome) and women with endometriosis BPA is shown to have transgenerational effect by targeting ovarian function by changes in the structural integrity of microtubules that constitute meiotic spindles. BPA contaminants pass through amniotic fluid can alter steroidogenesis in fetal development. This will result if oocyte maturation failure as well as fertility This in turn will result in transgenerational effect and affect the third generation of offspring
Sexual function Higher BPA exposure has been associated with increased self-reporting of decreased male sexual function, but few studies examining this relationship have been conducted.
Asthma Studies in mice have found a link between BPA exposure and asthma; a 2010 study on mice has concluded that perinatal exposure to 10 μg/mL of BPA in drinking water enhances allergic sensitization and bronchial inflammation and responsiveness in an animal model of asthma. A study published in JAMA Pediatrics has found that prenatal exposure to BPA is also linked to lower lung capacity in some young children. This study had 398 mother-infant pairs and looked at their urine samples to detect concentrations of BPA. They study found that every 10-fold increase in BPA was tied to a 55% increase in the odds of wheezing. The higher the concentration of BPA during pregnancy were linked to decrease lung capacity in children under four years old but the link disappeared at age 5. Associate professor of pediatrics at the University of Maryland School of Medicine said, "Exposure during pregnancy, not after, appears to be the critical time for BPA, possibly because it's affecting important pathways that help the lung develop." In 2013, research from scientists at the Columbia Center for Children's Environmental Health also found a link between the compound and an increased risk for asthma. The research team reported that children with higher levels of BPA at ages 3, 5 and 7 had increased odds of developing asthma when they were between the ages of 5 and 12. The children in this study had about the same concentration of BPA exposure as the average U.S. child. Dr. Kathleen Donohue, an instructor at Columbia University Medical Center said, "they saw an increased risk of asthma at fairly routine, low doses of BPA." Kim Harley, who studies environmental chemicals and children's health, commented in the Scientific American journal saying while the study does not show that BPA causes asthma or wheezing, "it's an important study because we don't know a lot right now about how BPA affects immune response and asthma...They measured BPA at different ages, measured asthma and wheeze at multiple points, and still found consistent associations."
Animal research The first evidence of the estrogenicity of bisphenol A came from experiments on rats conducted in the 1930s, but it was not until 1997 that adverse effects of low-dose exposure on laboratory animals were first reported. Bisphenol A is an endocrine disruptor that can mimic estrogen and has been shown to cause negative health effects in animal studies. Bisphenol A closely mimics the structure and function of the hormone estradiol by binding to and activating the same estrogen receptor as the natural hormone. Early developmental stages appear to be the period of greatest sensitivity to its effects, A study from 2008 concluded that blood levels of bisphenol A in neonatal mice are the same whether it is injected or ingested. The current U.S. human exposure limit set by the EPA is 50 μg/kg/day. In a 2010 commentary a group of scientists criticized a study designed to test low dose BPA exposure published in "Toxicological Sciences" and a later editorial by the same journal, which claimed the rats used in the study were insensitive to estrogen and that had other problems like the use of BPA-containing polycabonate cages while the authors disagreed. Different expression of ERR-γ in different parts of the body may account for variations in bisphenol A effects. For instance, ERR-γ has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue.
Environmental effects In 2010, the U.S. Environmental Protection Agency reported that over one million pounds of BPA are released into the environment annually. BPA can be released into the environment by both pre-consumer and post-consumer leaching. Common routes of introduction from the pre-consumer perspective into the environment are directly from chemical plastics, coat and staining manufacturers, foundries who use BPA in casting sand, or transport of BPA and BPA-containing products . Post-consumer BPA waste comes from effluent discharge from municipal wastewater treatment plants, irrigation pipes used in agriculture, ocean-borne plastic trash, indirect leaching from plastic, paper, and metal waste in landfills, and paper or material recycling companies. Despite a rapid soil and water half-life of 4.5 days, and an air half-life of less than one day, BPA's ubiquity makes it an important pollutant. BPA has a low rate of evaporation from water and soil, which presents issues, despite its biodegradability and low concern for bio-accumulation. BPA has low volatility in the atmosphere and a low vapor pressure between 5.00 and 5.32 Pascals. BPA has a high water solubility of about 120 mg/L and most of its reactions in the environment are aqueous. An interesting fact is that BPA dust is flammable if ignited, but it has a minimal explosive concentration in air. Also, in aqueous solutions, BPA has shown absorption of wavelengths greater than 250 nm. The ubiquitous nature of BPA makes the compound an important pollutant to study as it has been shown to interfere with nitrogen fixation at the roots of leguminous plants associated with the bacterial symbiont Sinorhizobium meliloti. A 2013 study also observed changes in plant health due to BPA exposure. The study exposed soybean seedlings to various concentrations of BPA and saw changes in root growth, nitrate production, ammonium production, and changes in the activities of nitrate reductase and nitrite reductase. At low doses of BPA, the growth of roots were improved, the amount of nitrate in roots increased, the amount of ammonium in roots decreased, and the nitrate and nitrite reductase activities remained unchanged. However, at considerably higher concentrations of BPA, the opposite effects were seen for all but an increase in nitrate concentration and a decrease in nitrite and nitrate reductase activities. Nitrogen is both a plant nutritional substance, but also the basis of growth and development in plants. Changing concentrations of BPA can be harmful to the ecology of an ecosystem, as well as to humans if the plants are produced to be consumed. The amount of absorbed BPA on sediment was also seen to decrease with increases in temperature, as demonstrated by a study in 2006 with various plants from the XiangJiang River in Central-South China. In general, as temperature increases, the water solubility of a compound increases. Therefore, the amount of sorbate that enters the solid phase will lower at the equilibrium point. It was also observed that the adsorption process of BPA on sediment is exothermic, the molar formation enthalpy, ΔH°, was negative, the free energy ΔG°, was negative, and the molar entropy, ΔS°, was positive. This indicates that the adsorption of BPA is driven by enthalpy. The adsorption of BPA has also been observed to decrease with increasing pH. A 2005 study conducted in the United States had found that 91–98% of BPA may be removed from water during treatment at municipal water treatment plants. A more detailed explanation of aqueous reactions of BPA can be observed in the Degradation of BPA section below. Nevertheless, a 2009 meta-analysis of BPA in the surface water system showed BPA present in surface water and sediment in the United States and Europe. According to Environment Canada in 2011, "BPA can currently be found in municipal wastewater. […]initial assessment shows that at low levels, bisphenol A can harm fish and organisms over time." BPA affects growth, reproduction, and development in aquatic organisms. Among freshwater organisms, fish appear to be the most sensitive species. Evidence of endocrine-related effects in fish, aquatic invertebrates, amphibians, and reptiles has been reported at environmentally relevant exposure levels lower than those required for acute toxicity. There is a widespread variation in reported values for endocrine-related effects, but many fall in the range of 1μg/L to 1 mg/L. A 2009 review of the biological impacts of plasticizers on wildlife published by the Royal Society with a focus on aquatic and terrestrial annelids, molluscs, crustaceans, insects, fish and amphibians concluded that BPA affects reproduction in all studied animal groups, impairs development in crustaceans and amphibians and induces genetic aberrations.
Vertebrates BPA is known as an endocrine disruptor compound (EDC) and has major neurological effects on vertebrates. Depending on the vertebrate species studied, the documented effects of ingestion and exposure to BPA may differ. In species such as Zebrafish, BPA affects the lateral line which is crucial for sensory perception and may affect the expression of genes that are controlling heart and skeletal muscle metabolism, as well as insulin secretion control. Aquatic vertebrates are especially impacted by BPA in reproduction. In the broad- snouted caiman, Caiman latirostris, gender is normally determined by the temperature at which the egg is incubated at. A study was conducted where their eggs were exposed to BPA. The first set was exposed at about 1000 μg/egg and all of the offspring were female. When the eggs were exposed at a lower concentration at about 90 μg/egg, the offspring produced were males. These male offspring exhibited disrupted seminiferous tubules. In mice, maternal diet has been studied and found to have a major effect on the offspring that were exposed to BPA during certain developmental stages. There are no direct studies on humans, however, studies on the vertebrates suggest the potential harm it may have.
Reproductive effects Bisphenol A (BPA) is an environmental contaminant that disrupts the ecosystem, with the most profound effects observed in vertebrates. BPA infiltrates the environment by running off of landfills so because of this, it is mostly found in water. Aquatic vertebrates are thus the most affected by this form of pollution. After the aquatic vertebrates inhale BPA through their gills or skin, they are mainly affected by BPA at the cellular level, affecting their estrogen levels. BPA binds to the estrogen receptors and has an antagonist effect, which means that it decreases the amount of estrogen produced. To regulate reproductive functions, Gonadotropin releasing hormone (GnRH) is released. This helps with maturation of the sex organs in both males and females. Another study found that Barbus sp., immature barbels, in a river with traces of BPA expressed intersex characteristics. They had gonads with oogonia, spermatogonia and spermatocytes. Researchers concluded that BPA did not induce but did contribute to these intersex morphological expressions. After being exposed to 1μg/L BPA, Salmo trutta, brown trout, had reduced sperm density and mobility. In Pimephales promelas, fathead minnows, there was a reduction of sperm production. Both species were also exposed to 2 μg/L and 5 μg/L of BPA and it resulted in delayed ovulation or no ovulation for the fish. A study was conducted using adult female Gobiocypris rarus, a rare minnow. The fish were exposed to 5 μg/L, 15μg/L and 50 μg/L of BPA for 14 days and 35 days. The results showed the group exposed to the highest amount of BPA (50 μg/L) for 35 days showed suppressed effects on oocyte development. It also showed that all groups had a stimulatory effect on the hepatic vitellogenin transcription (VTG). VTG is an indicator that the vertebrate has become exposed to environmental estrogens. The groups exposed to a lower concentration of BPA (5 μg/L & 15μg/L) showed an increase in expressed ovarian steroidogenic genes. Meanwhile, the group exposed to a higher concentration of BPA (50 μg/L) showed a decrease in expressed ovarian steroidogenic genes. Although aquatic vertebrates are most commonly affected by BPA exposure in natural settings, researchers often learn how BPA effects other vertebrates using experimental mice models. In a study conducted twenty years ago, there was an accidental BPA exposure. This resulted in an increase in chromosomally abnormal eggs. This led researchers to question what other effects this has on mammals. It showed that BPA leads to meiotic changes such as fertility and maturation of sex organs. Scientists started to realize that this type of exposure could lead to mutations and affect multiple generations. Because of this, "BPA free" products started to be made but to do this, BPS was being used. A study was conducted showing that exposure to BPS increased mutations before zygotic development showing that it is just as dangerous as BPA.
Behavioral effects BPA has major effects on the behavior of vertebrates, especially in their sensory processing systems. In zebrafish BPA can disrupt the signaling in the endocrine system and affect auditory development and function. Similar to a human ear, the zebrafish have a sensory organ called the lateral line that detects different forms of vibration. The hair cells within the lateral line are very sensitive to the toxic effects of BPA and are most commonly killed from BPA; fish are able to regrow hair cells but BPA has decreased their ability to reproduce them as efficiently. Fish without a fully functioning lateral line have behavioral changes such as: higher risk of predation, lowered prey detection and possible reproduction abilities. Unlike fish, mammals have a threat to go deaf if exposed directly. As well as an endocrine disruptor compound (EDC), BPA has been found to inhibit nerve conduction. In the sciatic nerve of a frog (Rana tigrina), BPA inhibits the fast-conducting compound action potential (CAP). Estrogen receptors found in the plasma membrane of the sciatic nerve are affected by the BPA and inhibit CAP. However, estrogen receptors are not the only reason for inhibition, BPA is able to inhibit nerve functions without affecting estrogen. A study in mice shows that BPA as an EDC acts as an agonist/antagonist for behavioral effects. BPA caused a decrease in exploratory and spatial behaviors in male mice who were exposed in the developmental state. In order to expose the males, pregnant females were fed with BPA in food the mice were compared to males whose mothers were fed with a phytoestrogen-free CTL diet. Males with the BPA exposure in developmental stages were less likely to be territorial when the other male mice were present. BPA exposure changed the behavior of sex and species-dependent behavior. These conclusions are suggestions to support the idea that BPA can cause sexually selected traits. Furthermore, maternal diet and exposing the developmental mice to BPA, may cause harm and lead to sexually dimorphic responses.
Positions of national and international bodies
World Health Organization In November 2009, the WHO announced to organize an expert consultation in 2010 to assess low-dose BPA exposure health effects, focusing on the nervous and behavioral system and exposure to young children. The 2010 WHO expert panel recommended no new regulations limiting or banning the use of bisphenol-A, stating that "initiation of public health measures would be premature."
United States In 2013, the FDA posted on its web site: "Is BPA safe? Yes. Based on FDA's ongoing safety review of scientific evidence, the available information continues to support the safety of BPA for the approved uses in food containers and packaging. People are exposed to low levels of BPA because, like many packaging components, very small amounts of BPA may migrate from the food packaging into foods or beverages." FDA issued a statement on the basis of three previous reviews by a group of assembled Agency experts in 2014 in its "Final report for the review of literature and data on BPA" that said in part, "The results of these new toxicity data and studies do not affect the dose-effect level and the existing NOAEL (5 mg/kg bw/day; oral exposure)."
Australia and New Zealand In 2009 the Australia and New Zealand Food Safety Authority (Food Standards Australia New Zealand) did not see any health risk with bisphenol A baby bottles if the manufacturer's instructions were followed, as levels of exposure were very low and would not pose a significant health risk. It added that "the move by overseas manufacturers to stop using BPA in baby bottles is a voluntary action and not the result of a specific action by regulators." In 2008 it had suggested the use of glass baby bottles if parents had concerns. In 2012 the Australian Government introduced a voluntary phase out of BPA use in polycarbonate baby bottles.
Canada In April 2008, Health Canada concluded that, while adverse health effects were not expected, the margin of safety was too small for formula-fed infants and proposed classifying the chemical as "'toxic' to human health and the environment." The Canadian Minister of Health announced Canada's intent to ban the import, sale, and advertisement of polycarbonate baby bottles containing bisphenol A due to safety concerns, and investigate ways to reduce BPA contamination of baby formula packaged in metal cans. Subsequent news reports from April 2008 showed many retailers removing polycarbonate drinking products from their shelves. On 18 October 2008, Health Canada noted that "bisphenol A exposure to newborns and infants is below levels that cause effects" and that the "general public need not be concerned". In 2010, Canada's department of the environment declared BPA to be a "toxic substance" and added it to schedule 1 of the Canadian Environmental Protection Act, 1999.
European Union The 2008 European Union Risk Assessment Report on bisphenol A, published by the European Commission and European Food Safety Authority (EFSA), concluded that bisphenol A-based products, such as polycarbonate plastic and epoxy resins, are safe for consumers and the environment when used as intended. By October 2008, after the Lang Study was published, the EFSA issued a statement concluding that the study provided no grounds to revise the current Tolerable Daily Intake (TDI) level for BPA of 0.05 mg/kg bodyweight. On 22 December 2009, the EU Environment ministers released a statement expressing concerns over recent studies showing adverse effects of exposure to endocrine disruptors. In September 2010, the European Food Safety Authority (EFSA) concluded after a "comprehensive evaluation of recent toxicity data […] that no new study could be identified, which would call for a revision of the current TDI". The Panel noted that some studies conducted on developing animals have suggested BPA-related effects of possible toxicological relevance, in particular biochemical changes in brain, immune-modulatory effects and enhanced susceptibility to breast tumours but considered that those studies had several shortcomings so the relevance of these findings for human health could not be assessed. On 25 November 2010, the European Union executive commission said it planned to ban the manufacturing by 1 March 2011 and ban the marketing and market placement of polycarbonate baby bottles containing the organic compound bisphenol A by 1 June 2011, according to John Dalli, commissioner in charge of health and consumer policy. This was backed by a majority of EU governments. The ban was called an over-reaction by Richard Sharpe, of the Medical Research Council's Human Reproductive Sciences Unit, who said to be unaware of any convincing evidence justifying the measure and criticized it as being done on political, rather than scientific grounds. In January 2011 use of bisphenol A in baby bottles was forbidden in all EU-countries. After reviewing more recent research, in 2012 EFSA made a decision to re-evaluate the human risks associated with exposure to BPA. They completed a draft assessment of consumer exposure to BPA in July 2013 and at that time asked for public input from all stakeholders to assist in forming a final report, which is expected to be completed in 2014. In January 2014, EFSA presented a second part of the draft opinion which discussed the human health risks posed by BPA. The draft opinion was accompanied by an eight-week public consultation and also included adverse effects on the liver and kidney as related to BPA. From this it was r