Bisphenol A

Bisphenol A

Names
IUPAC name 4,4'-(propane-2,2-diyl)diphenol
Other names BPA, p,p'-isopropylidenebisphenol, 2,2-bis(4-hydroxyphenyl)propane.
Identifiers
CAS Number	80-05-7 Y
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:33216 Y
ChEMBL	ChEMBL418971 Y
ChemSpider	6371 Y
DrugBank	DB06973 Y
ECHA InfoCard	100.001.133
EC Number	201-245-8
KEGG	C13624 Y
PubChem CID	6623
RTECS number	SL6300000
UNII	MLT3645I99 Y
UN number	2430
CompTox Dashboard (EPA)	DTXSID7020182
InChI InChI=1S/C15H16O2/c1-15(2,11-3-7-13(16)8-4-11)12-5-9-14(17)10-6-12/h3-10,16-17H,1-2H3 Y Key: IISBACLAFKSPIT-UHFFFAOYSA-N Y InChI=1/C15H16O2/c1-15(2,11-3-7-13(16)8-4-11)12-5-9-14(17)10-6-12/h3-10,16-17H,1-2H3 Key: IISBACLAFKSPIT-UHFFFAOYAI
SMILES Oc1ccc(cc1)C(c2ccc(O)cc2)(C)C CC(C)(c1ccc(cc1)O)c2ccc(cc2)O
Properties
Chemical formula	C15H16O2
Molar mass	228.291 g·mol−1
Appearance	White solid
Density	1.20 g/cm³
Boiling point	220 °C (428 °F; 493 K)
Solubility in water	120–300 ppm (21.5 °C)
Hazards
NFPA 704 (fire diamond)	3 0 0
Flash point	227 °C (441 °F)
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

Bisphenol A (BPA) is an organic compound with the chemical formula (CH₃)₂C(C₆H₄OH)₂ belonging to the group of diphenylmethane derivatives and bisphenols.

BPA is used to make certain plastics and epoxy resins; it has been in commercial use since 1957. BPA-based plastic is clear and tough, and is used to make a variety of common consumer goods (such as baby and water bottles, sports equipment, and CDs and DVDs) and for industrial purposes, like lining water pipes. Epoxy resins containing BPA are used as coatings on the inside of many food and beverage cans. It is also used in making thermal paper such as that used in sales receipts.

It is part of the bisphenols group of chemical compounds with two hydroxyphenyl functionalities. It is a colorless solid that is soluble in organic solvents, but poorly soluble in water. Bisphenol A has a vapor pressure of 5×10⁻⁶ Pa.

BPA exhibits hormone-like properties that raise concern about its suitability in consumer products and food containers. Since 2008, several governments have questioned its safety, which prompted some retailers to withdraw polycarbonate products. A 2010 report from the United States Food and Drug Administration (FDA) warned of possible hazards to fetuses, infants, and young children. In September 2010, Canada became the first country to declare BPA a toxic substance. The European Union, Canada, and recently the United States have banned BPA use in baby bottles.

Production

World production capacity of this compound was 1 million tons in the 80s, and more than 2.2 million tons in 2009. In 2003, U.S. consumption was 856,000 tons, 72% of which was 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.

Bisphenol A was first synthesized by the Russian chemist A.P. Dianin in 1891. This compound is synthesized by the condensation of acetone (hence the suffix A in the name) with two equivalents of phenol. The reaction is catalyzed by a strong acid, such as hydrochloric acid (HCl) or a sulfonated polystyrene resin. Industrially, a large excess of phenol is used to ensure full condensation; the product mixture of the cumene process (acetone and phenol) may also be used as starting material:

A large number of ketones undergo analogous condensation reactions. Commercial production of BPA requires distillation – either extraction of BPA from many resinous byproducts under high vacuum, or solvent-based extraction using additional phenol followed by distillation.

Use

Further information: Polycarbonate

Bisphenol A is primarily used to make plastics, such as this polycarbonate water bottle.

Bisphenol A is used primarily to make plastics, and products using bisphenol A-based plastics have been in commercial use since 1957. At least 3.6 million tonnes (8 billion pounds) of BPA are used by manufacturers yearly. It is a key monomer in production of epoxy resins and in the most common form of polycarbonate plastic. Bisphenol A and phosgene react to give polycarbonate under biphasic conditions; the hydrochloric acid is scavenged with aqueous base:

Diphenyl carbonate may be used in place of phosgene. Phenol is eliminated instead of hydrochloric acid. This transesterification process avoids the toxicity and handling of phosgene.

Polycarbonate plastic, which is clear and nearly shatter-proof, 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 for lining 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 containing 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 also a precursor to the flame retardant tetrabromobisphenol A, and formerly was used as a fungicide.

Bisphenol A is a preferred color developer in carbonless copy paper and thermal paper, with the most common public exposure coming from some 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 currently 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.)

Epoxy resin, which may or may not contain BPA, is employed to bind gutta percha in some root canal procedures. The prohibition of BPA in consumer products and food containers by the Canadian government (see above) may or may not have affected the dentistry industry.

Identification in plastics

Some type 7 plastics may contain bisphenol A

Main article: Resin identification code

There are seven classes of plastics used in packaging applications. Currently there are no BPA labeling requirements for plastics.

"In general, plastics that are marked with Resin Identification Codes 1, 2, 3, 4, 5, and 6 are very unlikely to contain BPA. Some, but not all, plastics that are marked with the Resin Identification Code 7 may be made with BPA."

Type 7 is the catch-all "other" class, and some type 7 plastics, such as polycarbonate (sometimes identified with the letters "PC" near the recycling symbol) and epoxy resins, are made from bisphenol A monomer.

Type 3 (PVC) also may contain bisphenol A as an antioxidant in plasticizers. This refers to "flexible PVC", but not for rigids such as pipe, windows, and siding.

History

BPA's ability to mimic the effects of natural estrogen derive from the similarity of phenol groups on both BPA and estradiol (structure shown above), which enable this synthetic molecule to trigger estrogenic pathways in the body.

Bisphenol A was discovered in 1891 by Russian chemist Aleksandr Dianin and it first appeared in a scientific publication in 1905 by Thomas Zincke of the University of Marburg, Germany.

Based on research by chemists at Bayer and General Electric, BPA has been used since the 1950s to harden polycarbonate plastics and make epoxy resin, and in the lining of food and beverage containers.

In the early 1930s the British chemist Charles Edward Dodds recognized BPA as an artificial estrogen. Dodds eventually developed 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 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 derive from the similarity of phenol groups on both BPA and estradiol, which enable this synthetic molecule to trigger estrogenic pathways in the body.

In 1997 adverse effects of low-dose exposure of BPA on laboratory animals were first proposed (hormesis). Modern studies began finding possible connections to health issues caused by exposure to BPA during pregnancy and during development. See Government and industry response. Research is ongoing and the debate continues as to whether BPA should be banned or not, and to what extent, all over the world. In 2010 Canada's department of the environment declared BPA to be a "toxic substance".

Health effects

The largest exposure humans have to BPA is by mouth from such sources as food packaging, the epoxy lining of metal food and beverage cans, and plastic bottles.

Bisphenol A is thought to be an endocrine disruptor which can mimic estrogen and may lead to negative health effects. More specifically, bisphenol A closely mimics the structure and function of the hormone estradiol with the ability to bind to and activate the same estrogen receptor as the natural hormone. Early developmental stages appear to be the period of greatest sensitivity to its effects, and some studies have linked prenatal exposure to later physical and neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or are under review as a result of new scientific studies. A 2011 study that investigated the number of chemicals pregnant women are exposed to in the U.S. found BPA in 96% of women.

Overall, empirical evidence supporting the negative health effects of BPA varies significantly across studies. Opinions vary greatly about the health effects of BPA. Some studies conclude that BPA poses no health risks while others state that BPA causes a number of adverse health effects. In general, the European Commission's Scientific Committee on Food, the EU's European Chemicals Bureau, the European Food Safety Authority, and the US Food and Drug Administration have concluded that current levels of BPA present no risk to the general population. However, experts in the field of endocrine disruptors have stated that the entire population may suffer adverse health effects from current BPA levels. In 2009, The Endocrine Society released a statement citing the adverse effects of endocrine-disrupting chemicals, and the controversy surrounding BPA. In 2012 the FDA did ban the use of BPA in baby bottles, however the Environmental Working Group called the ban "purely cosmetic". In a statement they said,"If the agency truly wants to prevent people from being exposed to this toxic chemical associated with a variety of serious and chronic conditions it should ban its use in cans of infant formula, food and beverages." The Natural Resources Defense Council called the move inadequate, saying the FDA needs to ban BPA from all food packaging. In a statement a FDA spokesman said the agency's action was not based on safety concerns and that "the agency continues to support the safety of BPA for use in products that hold food."

The Environmental Protection Agency (EPA) also holds the position that BPA is not a health concern. In 2011, Andrew Wadge, the chief scientist of the United Kingdom's Food Standards Agency, commented on a 2011 US 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." In the 2011 US study 20 subjects were tested for BPA every hour for twenty-four hours while consuming three meals consisting of canned food. This study has been criticized, however, as lacking data and having flawed assumptions.

Expert panel conclusions

In 2006, the US Government sponsored an assessment of the scientific literature on BPA. 38 opponents of 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 claimed that average levels in people are above those that cause harm to many animals in laboratory experiments. They noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous, however, which 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. They added that measurement of BPA levels in serum and other body fluids suggests the possibilities that BPA intake is much higher than accounted for, and/or that BPA can bioaccumulate in some conditions (such as pregnancy).

A panel convened by the U.S. National Institutes of Health in 2007 produced a 384 review of the literature and found that many of the studies referenced by the Chapel Hill group had methodological problems. Its conclusions. "expressed relative to current estimates of general population exposure levels in the U.S." were:

1. For pregnant women and fetuses the Expert Panel has different levels of concern for the different

developmental endpoints that may be susceptible to bisphenol A disruption, as follows:
• For neural and behavioral effects, the Expert Panel has some concern
• For prostate effects, the Expert Panel has minimal concern
• For the potential effect of accelerated puberty, the Expert Panel has minimal concern
• For birth defects and malformations, the Expert Panel has negligible concern
2. For infants and children the Expert Panel has the following levels of concern for biological processes that might be altered by Bisphenol A, as follows:
• some concern for neural and behavioral effects
• minimal concern for the effect of accelerated puberty

3. For adults, the Expert Panel has negligible concern for adverse reproductive effects following exposures in the general population to Bisphenol A. For highly exposed subgroups, such as occupationally exposed populations, the level of concern is elevated to minimal.

A 2008 report by the U.S. National Toxicology Program (NTP) found "some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A"; "minimal concern for effects on the mammary gland and an earlier age for puberty for females in fetuses, infants, and children at current human exposures to bisphenol A", and "negligible concern that exposure of pregnant women to bisphenol A will result in fetal or neonatal mortality, birth defects, or reduced birth weight and growth in their offspring" and "that exposure to bisphenol A will cause reproductive effects in non-occupationally exposed adults and minimal concern for workers exposed to higher levels in occupational settings."

Obesity

Bisphenol A may increase the risk for obesity.

Main article: Obesity

A 2008 review has concluded that obesity may be increased as a function of BPA exposure, which "...merits concern among scientists and public health officials." A 2009 review of available studies has concluded that "Given the potential of BPA to exert pleiotropic effects, it is likely that early BPA exposure can influence several mechanisms important for body weight regulation, including adipocyte deposition, glucose uptake and homeostasis, and the development and maturation of pathways and circuits important for energy homeostasis." Another 2009 review has concluded that "Eliminating exposures to (BPA) and improving nutrition during development offer the potential for reducing obesity and associated diseases". Other reviews have come with similar conclusions.

Neurological issues

A panel convened by 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. A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain". In January 2010 the FDA expressed the same level of concern.

A 2007 review has concluded that BPA, like other xenoestrogens, should be considered as a player within the nervous system that can regulate or alter its functions through multiple pathways. A 2007 review has concluded that low doses of BPA during development have persistent effects on brain structure, function and behavior in rats and mice. A 2008 review concluded that low-dose BPA maternal exposure causes long-term consequences at the level of neurobehavioral development in mice. A 2008 review has concluded that neonatal exposure to bisphenol-A (BPA) can affect sexually dimorphic brain morphology and neuronal adult phenotypes in mice. A 2008 review concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar (10^-9 Mol)dosage could induce significant effects on memory processes.

A 2008 review of studies concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar (10^-9 Mol) dosage could induce significant effects on memory processes.

A 2009 review raised concerns about BPA effect on anteroventral periventricular nucleus.

A 2008 study by the Yale School of Medicine demonstrated that adverse neurological effects occur in non-human primates regularly exposed to bisphenol A at levels equal to the United States Environmental Protection Agency's (EPA) maximum safe dose of 50 µg/kg/day. This research found a connection between BPA and interference with brain cell connections vital to memory, learning, and mood.

A 2010 study with rats prenatally exposed to 40 µg/kg bw BPA has concluded that corticosterone and its actions in the brain are sensitive to the programming effects of BPA.

A 2012 study found that the neurological effects of BPA are trans-generational in mice. Genetic expression was found to extend into the fourth generation. The authors stated that they believe that their study is the first to have demonstrated that BPA has trans-generational actions on social behavior and neural expression.

Disruption of the dopaminergic system

Main article: Dopaminergic system

A 2008 review 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.

A 2005 review concluded that prenatal and neonatal exposure to BPA in mice can potentiate the central dopaminergic systems, resulting in the supersensitivity to the drugs-of-abuse-induced reward effects and hyperlocomotion.

A 2008 review 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.

A 2009 study on rats has concluded that prenatal and neonatal exposure to low-dose BPA causes deficits in development at dorsolateral striatum via altering the function of dopaminergic receptors. Another 2009 study has found associated changes in the dopaminergic system.

Thyroid function

Main article: Thyroid

BPA is a thyroid-disrupting chemical, that may especially affect pregnant women, neonates and small children.

A 2007 review has concluded that bisphenol-A has been shown to bind to thyroid hormone receptor and perhaps have 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.

Cancer research

According to the WHO's INFOSAN, carcinogenicity studies conducted under the US National Toxicology Program, have shown increases in leukaemia and testicular interstitial cell tumours 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.

Breast cancer

Further information: Risk factors of breast cancer § Bisphenol A

Evidence from animal models is accumulating that perinatal exposure to BPA alters breast development and increases breast cancer risk.

A 2008 review stated that "evidence from animal models is accumulating that perinatal exposure to (...) low doses of (..) BPA, alters breast development and increases breast cancer risk". Another 2008 review concluded that "animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the last 50 years".

A 2009 in vitro study has concluded that BPA is able to induce neoplastic transformation in human breast epithelial cells. Another 2009 study concluded that maternal oral exposure to low concentrations of BPA during lactation increases mammary carcinogenesis in a rodent model.

A 2010 study with the mammary glands of the offspring of pregnant rats treated orally with 0, 25 or 250 µg BPA/kg body weight has found that key proteins involved in signaling pathways such as cellular proliferation were regulated at the protein level by BPA.

A 2010 study has found that BPA may reduce sensitivity to chemotherapy treatment of specific tumors.

Neuroblastoma

BPA promotes the growth, invasiveness and metastasis of cells from a laboratory neuroblastoma cancer cell line, SK-N-SH.

In vitro and in vivo mouse studies have suggested that BPA can promote the growth of cells from a laboratory neuroblastoma cancer cell line, SK-N-SH. A 2010 in vitro study of SK-N-SH cells has concluded that BPA potently promotes invasion and metastasis of SK-N-SH cells through overexpression of MMP-2 and MMP-9 as well as downregulation of TIMP2.

Prostate development and cancer

A 1997 study in mice has found that neonatal BPA exposure of 2 μg/kg increased adult prostate weight. A 2005 study in mice has found that neonatal BPA exposure at 10 μg/kg disrupted the development of the fetal mouse prostate. A 2006 study in rats has shown that neonatal bisphenol A exposure at 10 μg/kg levels increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. A 2007 in vitro study has found that BPA within the range of concentrations currently measured in human serum is associated with permanent increases in prostate size. A 2009 study has found that newborn rats exposed to a low-dose of BPA (10 µg/kg) showed increased prostate cancer susceptibility when adults.

DNA methylation

At least one study has suggested that bisphenol A suppresses DNA methylation which is involved in epigenetic changes.

Reproductive system and sexual behavior research

A study released in 2013 demonstrated that BPA in weak concentrations is sufficient to produce a negative reaction on the human testicle. The researchers found that a concentration equal to 2 micrograms per litre of bisphenol A in the culture medium, a concentration equal to the average concentration generally found in the blood, urine and amniotic fluid of the population, was sufficient to produce the effects. The researchers believe that exposure of pregnant women to bisphenol A may be one of the causes of congenital masculinisation defects of the hypospadia and cryptorchidism types the frequency of which has doubled overall in the past 40 years. They also suggested that "it is also possible that bisphenol A contributes to a reduction in the production of sperm and the increase in the incidence of testicular cancer in adults that have been observed in recent decades."

A 2007 study using pregnant mice showed that BPA changes the expression of key developmental genes that form the uterus, which may impact female reproductive tract development and future fertility of female fetuses.

A series of studies made in 2009 found:

• Mouse ovary anomalies from exposure as low as 1 µg/kg, concluded that BPA exposure causes long-term adverse reproductive and carcinogenic effects if exposure occurs during prenatal critical periods of differentiation.
• Neonatal exposure of as low as 50 µg/kg disrupts ovarian development in mice.
• Neonatal BPA exposition of as low as 50 µg/kg permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat.
• Prenatal exposure to BPA at levels of (10 μg/kg/day) affects behavioral sexual differentiation in male monkeys.
• In placental JEG3 cells in vitro BPA may reduce estrogen synthesis.
• BPA exposure disrupted the blood-testis barrier when administered to immature, but not to adult, rats.
• Exposure to BPA in the workplace was associated with self-reported adult male sexual dysfunction.

A 2009 rodent study, funded by EPA and conducted by some of its scientists, concluded that, compared with ethinyl estradiol, low-dose exposures of bisphenol A (BPA) showed no effects on several reproductive functions and behavioral activities measured in female rats. That study was criticized as flawed for using polycarbonate cages in the experiment (since polycarbonate contains BPA) and the claimed resistance of the rats to estradiol, but that claim was contested by the authors and others. Another 2009 rodent study found that BPA exposure during pregnancy has a lasting effect on one of the genes that are responsible for uterine development and subsequent fertility in both mice and humans (HOXA10). The authors concluded, "We don't know what a safe level of BPA is, so pregnant women should avoid BPA exposure."

In a 2010 study, mice were given BPA at doses thought to be equivalent to levels currently being experienced by humans. The research showed that BPA exposure affects the earliest stages of egg production in the ovaries of the developing mouse fetuses, thus suggesting that the next generation may suffer genetic defects in such biological processes as mitosis and DNA replication. In addition, the research team noted that their study "revealed a striking down-regulation of mitotic/cell cycle genes, raising the possibility that BPA exposure immediately before meiotic entry might act to shorten the reproductive lifespan of the female" by reducing the total pool of fetal oocytes. Another 2010 study with mice concluded that BPA exposure in utero leads to permanent DNA alterations in sensitivity to estrogen. Also in 2010, a rodent study found that by exposing fetal mice to BPA during pregnancy and examining gene expression and DNA in the uteruses of female fetuses, BPA exposure permanently affected the uterus by decreasing regulation of gene expression. The changes caused the mice to over-respond to estrogen throughout adulthood, long after the BPA exposure, thus suggesting that early exposure to BPA genetically "programmed" the uterus to be hyper-responsive to estrogen. Extreme estrogen sensitivity can lead to fertility problems, advanced puberty, altered mammary development and reproductive function, as well as a variety of hormone-related cancers. One of the authors concluded that BPA may be similar to diethylstilbestrol that caused birth defects and cancers in young women whose mothers were given the drug during pregnancy.

A 2011 study using the rhesus monkey – a species that is very similar to humans in regard to pregnancy and fetal development – found that prenatal exposure to BPA causes changes in female primates' uterus development. A 2011 rodent study found that male rats exposed to BPA had lower sperm counts and testosterone levels than those of unexposed males. A 2011 mice study found that male mice exposed to BPA became demasculinized and behaved more like females in their spatial navigational abilities. They were also less desirable to female mice.

General research

At an Endocrine Society meeting in 2009, new research reported data from animals experimentally treated with BPA. Studies presented at the group's annual meeting show BPA can affect the hearts of women, can permanently damage the DNA of mice, and appears to be entering the human body from a variety of unknown sources.

A 2009 in vitro study on cytotrophoblast cells has found cytotoxic effects in exposure of BPA doses from 0.0002 to 0.2 µg/ml and concluded this finding "suggests that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss".

A 2009 study in rats concluded that BPA, at the reference safe limit for human exposure, was found to impact intestinal permeability and may represent a risk factor in female offspring for developing severe colonic inflammation in adulthood.

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, and a 2011 study found that higher BPA concentrations in the urine of the pregnant women at 16 weeks were associated with wheezing, a symptom of asthma, in their babies.

In 2013, research from scientists at the Columbia Center for Children's Environmental Health found a link between the compound and an increased risk for asthma.

ERR-γ (modeled here) has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue.

The Shimohigashi lab at Kyushu University has been studying 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 not to the estrogen receptor (ER). BPA binding to ERR-γ preserves its basal constitutive activity. It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen. This may be the mechanism by 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.

Studies on humans

Lang study and heart disease

The first large study of health effects on humans associated with bisphenol A exposure was published in September 2008 by Iain Lang and colleagues in the Journal of the American Medical Association. The cross-sectional study of almost 1,500 people assessed exposure to bisphenol A by looking at levels of the chemical in urine. The authors found that higher bisphenol A levels were significantly associated with heart disease, diabetes, and abnormally high levels of certain liver enzymes. An editorial in the same issue concludes:

"Based on this background information, the study by Lang et al,1 while preliminary with regard to these diseases in humans, should spur US regulatory agencies to follow the recent action taken by Canadian regulatory agencies, which have declared BPA a "toxic chemical" requiring aggressive action to limit human and environmental exposures.4 Alternatively, Congressional action could follow the precedent set with the recent passage of federal legislation designed to limit exposures to another family of compounds, phthalates, also used in plastic. Like BPA,5 phthalates are detectable in virtually everyone in the United States.6 This bill moves US policy closer to the European model, in which industry must provide data on the safety of a chemical before it can be used in products."

A later similar study performed by the same group of scientists, published in January 2010, confirmed, despite of lower concentrations of BPA in the second study sample, an associated increased risk for heart disease but not for diabetes or liver enzymes. Patients with the highest levels of BPA in their urine carried a 33% increased risk of coronary heart disease. In 2012, David Melzer and colleagues also published a correlation between BPA levels in urine and heart disease. BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease.

Effects on human oocytes

In 2011, studies performed in human fetal oocytes demonstrated: BPA concentrations of 1 µM or higher decrease the survival of human fetal oocytes in vitro, and concentrations of 10 µM or higher increase MLH1 foci number. MLH1 is considered a crossing-over marker (meiotic recombination)(Brieño-Enríquez et al., 2011). An increment in the recombination points, and an alteration in the number (or localization) of the recombination pattern could affect the segregation of the homologs, leading to an increase in the possibility of generating oocytes with numerical alterations such as monosomy or trisomy (Orr-Weaver et al., 1996; Bugge et al., 1998, 2007; Hassold et al., 2007; Oliver et al., 2008; Chowdhury et al., 2009; Cheng et al., 2009; Allard and Colaiacovo, 2010; Brieño-Enriquez et al., 2011. BPA-exposed oocytes. These data suggest that BPA can act as a toxic substance, which has particular implications for human females and the critical events of meiotic prophase, such as pairing-synapsis and recombination processes, as well as oocyte survival The effects of Bisphenol A not only were observed at cytogenetic level. BPA also induces the over-expression of Spo11, H2ax, Rpa and Blm in human fetal ovarian cultures. All of these genes are involved in the DSB generation, signaling and repair during meiosis, but some of them are shared with mitosis (H2ax, Rpa and Blm). The up-regulation caused by BPA could disrupt the cell cycle and, in consequence, cell survival and differentiation. Ovarian pieces exposed to BPA also showed an up-regulation of ERs, Erα, Erβ and Errγ, which was also observed in ovarian fibroblasts, suggesting that these receptors could be related to the effects of BPA on the ovary

Brain tumors

A Chinese human study conducted from May 15, 2009 to May 15, 2010 links BPA to noncancerous brain tumors. Those with higher urine BPA levels were about 1.6 times more likely to have meningioma compared to those with lower concentrations.

Other studies

Studies have associated recurrent miscarriage with BPA serum concentrations, oxidative stress and inflammation in postmenopausal women with urinary concentrations, externalizing behaviors in two-year old children, especially among female children, with mother's urinary concentrations, altered hormone levels in men and declining male sexual function with urinary concentrations. The Canadian Health Measures Survey, 2007 to 2009 published in 2010 found that teenagers carry 30 percent more BPA in their bodies than older adults. The reason for this is not known. A 2010 study that analyzed BPA urinary concentrations has concluded that for people under 18 years of age BPA may negatively impact human immune function. A study done in 2010 reported the daily excretion levels of BPA among European adults in a large-scale and high-quality population-based sample, and it was shown that higher BPA daily excretion was associated with an increase in serum total testosterone concentration in men. A 2011 study found higher BPA levels in women with polycystic ovary syndrome compared to controls. Furthermore, researchers found a statistically significant positive association between male sex hormones and BPA in these women, suggesting a potential role of BPA in ovarian dysfunction. A 2010 study found that people over age 18 with higher levels of BPA exposure had higher CMV antibody levels, which suggests their cell-mediated immune system may not be functioning properly.

Sexual difficulties

A 2009 study on Chinese workers in BPA factories found that workers were four times more likely to report erectile dysfunction, reduced sexual desire and overall dissatisfaction with their sex life than workers with no heightened BPA exposure. BPA workers were also seven times more likely to have ejaculation difficulties. They were also more likely to report reduced sexual function within one year of beginning employment at the factory, and the higher the exposure, the more likely they were to have sexual difficulties.

Historical studies

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.

Low-dose exposure in animals

Dose (µg/kg/day)	Effects (measured in studies of mice or rats, descriptions (in quotes) are from Environmental Working Group)	Study Year
0.025	"Permanent changes to genital tract"	2005
0.025	"Changes in breast tissue that predispose cells to hormones and carcinogens"	2005
1	long-term adverse reproductive and carcinogenic effects	2009
2	"increased prostate weight 30%"	1997
2	"lower bodyweight, increase of anogenital distance in both genders, signs of early puberty and longer estrus."	2002
2.4	"Decline in testicular testosterone"	2004
2.5	"Breast cells predisposed to cancer"	2007
10	"Prostate cells more sensitive to hormones and cancer"	2006
10	"Decreased maternal behaviors"	2002
30	"Reversed the normal sex differences in brain structure and behavior"	2003
50	Adverse neurological effects occur in non-human primates	2008
50	Disrupts ovarian development	2009

The current U.S. human exposure limit set by the EPA is 50 µg/kg/day. 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.

Human exposure sources

The major human exposure route to BPA is diet, including ingestion of contaminated food and water. Bisphenol A is leached from the lining of food and beverage cans where it is used as an ingredient in the plastic used to protect the food from direct contact with the can. It is especially likely to leech from plastics when they are a cleaned with harsh detergents or when they contain acidic or high-temperature liquids. BPA is used to form epoxy resin coating of water pipes; in older buildings, such resin coatings are used to avoid replacement of deteriorating pipes. There is limited evidence on inhalation exposure but the body of research on dermal absorption continues to grow. There are many uses of BPA for which related potential exposures have not been fully assessed including digital media, electrical and electronic equipment, automobiles, sports safety equipment, electrical laminates for printed circuit boards, composites, paints, and adhesives.

Studies conducted by the CDC found bisphenol A in the urine of 95% of adults sampled in 1988–1994 and in 93% of children and adults tested in 2003–04. While the EPA considers exposures up to 50 µg/kg/day to be safe, the most sensitive animal studies show effects at much lower doses, and several studies of children, who tend to have the highest levels, have found levels over the EPAs suggested safe limit figure.

The problem is, BPA is also a synthetic estrogen, and plastics with BPA can break down, especially when they're washed, heated or stressed, allowing the chemical to leach into food and water and then enter the human body. That happens to nearly all of us; the CDC has found BPA in the urine of 93% of surveyed Americans over the age of 6. If you don't have BPA in your body, you're not living in the modern world.

— The Perils of Plastic, TIME Magazine

A recent Health Canada study found that the majority of canned soft drinks it tested had low, but measurable levels of bisphenol A. A study conducted by the University of Texas School of Public Health in 2010, found BPA in 63 of 105 samples of fresh and canned foods, including fresh turkey sold in plastic packaging and canned infant formula. A 2011 study published in Environmental Health Perspectives, "Food Packaging and Bisphenol A and Bis(2-Ethyhexyl) Phthalate Exposure: Findings from a Dietary Intervention," selected 20 participants based on their self-reported use of canned and packaged foods to study BPA. Participants ate their usual diets, followed by three days of consuming foods that were not canned or packaged. The study's findings include: 1) evidence of BPA in participants' urine decreased by 50% to 70% during the period of eating fresh foods; and 2), participants' reports of their food practices suggested that consumption of canned foods and beverages and restaurant meals were the most likely sources of exposure to BPA in their usual diets. The researchers note that, even beyond these 20 participants, BPA exposure is widespread, with detectable levels in urine samples in more than an estimated 90% of the U.S. population. Another U.S. study found that consumption of soda, school lunches, and meals prepared outside the home were statistically significantly associated with higher urinary BPA.

While most human exposure is through diet, exposure can also occur through air and through skin absorption. Free BPA is found in high concentration in thermal paper and carbonless copy paper, which would be expected to be more available for exposure than BPA bound into resin or plastic. Popular uses of thermal paper include receipts, event and cinema tickets, labels, and airline tickets. A Swiss study found that 11 of 13 thermal printing papers contained 8 – 17 g/kg Bisphenol A (BPA). Upon dry finger contact with a thermal paper receipt, roughly 1 μg BPA (0.2 – 6 μg) was transferred to the forefinger and the middle finger. For wet or greasy fingers approximately 10 times more was transferred. Extraction of BPA from the fingers was possible up to 2 hours after exposure. Further, it has been demonstrated that thermal receipts placed in contact with paper currency in a wallet for 24 hours cause a dramatic increase in the concentration of BPA in paper currency, making paper money a secondary source of exposure. Also, other paper products, such as toilet paper, newspapers and napkins, become contaminated with BPA during the recycling process. Free BPA can readily be transferred to skin, and residues on hands can be ingested. Bodily intake through dermal absorption (99% of which comes from handling receipts) has been shown for the general population to be 0.219 ng/kg bw/day (occupationally exposed persons absorb higher amounts at 16.3 ng/kg bw/day) whereas aggregate intake (food/beverage/environment) for adults is estimated at 0.36–0.43 μg/kg bw/day (estimated intake for occupationally exposed adults is 0.043–100 μg/kg bw/day).

In 2009, a study found that drinking from polycarbonate bottles increased urinary bisphenol A levels by two thirds, from 1.2 μg/g creatinine to 2 μg/g creatinine. Consumer groups recommend that people wishing to lower their exposure to bisphenol A avoid canned food and polycarbonate plastic containers (which shares resin identification code 7 with many other plastics) unless the packaging indicates the plastic is bisphenol A-free. To avoid the possibility of BPA leaching into food or drink, the National Toxicology Panel recommends avoiding microwaving food in plastic containers, putting plastics in the dishwasher, or using harsh detergents.

In 2011 it was found that Americans of all age groups have twice as much BPA in their bodies as do Canadians, but the reasons for the disparity was unknown. According to the researcher, there is no evidence to suggest that there are higher amounts of BPA in U.S. foods, or that other consumer products available in the U.S. containing BPA are BPA-free in Canada. According to Laura Vandenberg, a post-doctoral fellow at Tufts Universitymay be due to differences in how and when the surveys were done.

Fetal and early-childhood exposures

Studies have found that fetuses and young children exposed to BPA are at risk for secondary sexual developmental changes, brain and behavior changes and immune disorders. Children may be more susceptible to BPA exposure than adults. A recent study found higher urinary concentrations in young children than in adults under typical exposure scenarios. In adults, BPA is eliminated from the body through a detoxification process in the liver. In infants and children, this pathway is not fully developed so they have a decreased ability to clear BPA from their systems. Several recent studies of children have found levels that exceed the EPAs suggested safe limit figure.

Infants fed with liquid formula are among the most exposed, and those fed formula from polycarbonate bottles can consume up to 13 micrograms of bisphenol A per kg of body weight per day (μg/kg/day; see table below). In the US and Canada, BPA has been found in infant liquid formula in concentrations varying from 0.48 to 11 ng/g. BPA has been rarely found in infant powder formula (only 1 of 14). While breast milk is the optimal source of nutrition for infants, it is not always an option. The U.S. Department of Health & Human Services (HHS) states that "the benefit of a stable source of good nutrition from infant formula and food outweighs the potential risk of BPA exposure.".

A 2010 study of people in Austria, Switzerland, and Germany has suggested polycarbonate (PC) baby bottles as the most prominent role of exposure for infants, and canned food for adults and teenagers. In the United States, the growing concern over BPA exposure in infants in recent years has led the manufacturers of plastic baby bottles to stop using BPA in their bottles. However, babies may still be exposed if they are fed with old or hand-me-down bottles bought before the companies stopped using BPA.

One often overlooked source of exposure occurs when a pregnant woman is exposed, thereby exposing the fetus. Animal studies have shown that BPA can be found in both the placenta and the amniotic fluid of pregnant mice. A small US study in 2009, funded by the EWG, detected an average of 2.8 ng/mL BPA in the blood of 9 out of the 10 umbilical cords tested. A study of 244 mothers indicated that exposure to BPA before birth could affect the behavior of girls' at age 3. Girls whose mother's urine contained high levels of BPA during pregnancy scored worse on tests of anxiety and hyperactivity. Although these girls still scored within a normal range, for every 10-fold increase in the BPA of the mother, the girls scored at least six points lower on the tests. Boys did not seem to be affected by their mother's BPA levels during pregnancy. After the baby is born, maternal exposure can continue to affect the infant through transfer of BPA to the infant via breast milk. Because of these exposures that can occur both during and after pregnancy, mothers wishing to limit their child's exposure to BPA should attempt to limit their own exposures during that time period.

While the majority of exposures have been shown to come through the diet, accidental ingestion can also be considered a source of exposure. One study conducted in Japan tested plastic baby books to look for possible leaching into saliva when babies chew on them. While the results of this study have yet to be replicated, it gives reason to question whether exposure can also occur in infants through ingestion by chewing on certain books or toys.

Population	Estimated daily bisphenol A intake, μg/kg/day. Table adapted from the National Toxicology Program Expert Panel Report.
Infant (0–6 months) formula-fed	1–24
Infant (0–6 months) breast-fed	0.2–1
Infant (6–12 months)	1.65–13
Child (1.5–6 years)	0.043–14.7
Adult	0.008–1.5

Pharmacokinetics

There is no agreement between scientists of a physiologically based pharmacokinetic (PBPK) BPA model for humans. The effects of BPA on an organism depend on how much free BPA is available and for how long cells are exposed to it. Glucuronidation in the liver, by conjugation with glucuronic acid to form the metabolite BPA-glucuronide (BPAG), reduces the amount of free BPA, however BPAG can be deconjugated by beta-glucuronidase, an enzyme present in high concentration in placenta and other tissues. Free BPA can also be inactivated by sulfation, a process that can also be reversed by arylsulfatase C.

A 2009 research study found that many drugs, including naproxen, salicylic acid, carbamazepine and mefenamic acid can, in vitro, significantly inhibit BPA glucuronidation (detoxification). The authors suggested that a health risk assessment should address this issue.

A 2010 study on rat embryos found that genistein may enhance developmental toxicity of BPA, and another 2010 vitro study has shown that placenta P-glycoprotein may efflux BPA from placenta.

A 2010 review of 80+ biomonitoring studies concluded that the general population is internally exposed to significant amounts of unconjugated BPA (in the ng/ml blood range). Using GC/MS on 20 samples, BPA was detected in 100% of urine samples with a median of 1.25 ng/ml, and 10% of blood samples (LOD 0.5 ng/ml). In a 2011 study, researchers found that after a 5-day consumption of 1 serving of canned vegetarian soup, subjects exhibited a 1200% increase in urinary BPA concentrations compared to controls, suggesting that such a diet induces a peak of BPA elevation of unknown duration and of unknown biological safety.

The best test methods for studying BPA effects are currently under discussion with scientists sharing different opinions.

Environmental risk

In 2010 the EPA reported that over one million pounds of BPA are released into the environment annually. BPA can enter the environment either directly or through degradation of products, such as ocean-borne plastic trash. Leaching of BPA from plastic and metal waste in landfills is one potential source of environmental contamination. A 2009 meta-analysis of BPA in the surface water system reported that BPA is found in surface water and sediment in the United States and Europe.

In general, studies have shown that BPA can affect 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.

As an environmental contaminant, BPA interferes with nitrogen fixation at the roots of leguminous plants associated with the bacterial symbiont Sinorhizobium meliloti. Despite a half-life in the soil of only 1–10 days, its ubiquity makes it an important pollutant. According to Environment Canada, "initial assessment shows that at low levels, bisphenol A can harm fish and organisms over time. Studies also indicate that it can currently be found in municipal wastewater." However, a study conducted in the United States in 2005 found that 91–98% of BPA may be removed from water during treatment at municipal water treatment plants.

A 2009 review of the biological impacts of plasticizers on wildlife published by the Royal Society with a focus on annelids (both aquatic and terrestrial), molluscs, crustaceans, insects, fish and amphibians concluded that BPA has been shown to affect reproduction in all studied animal groups, to impair development in crustaceans and amphibians and to induce genetic aberrations.

A large 2010 study of two rivers in Canada found that areas contaminated with hormone-like chemicals including bisphenol A showed females made up 85 per cent of the population of a certain fish, while females made up only 55 per cent in uncontaminated areas.

Government and industry response

World Health Organization

In November 2009, the WHO announced it would 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 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."

Australia and New Zealand

The Australia and New Zealand Food Safety Authority (Food Standards Australia New Zealand) does not see any health risk with bisphenol A baby bottles if the manufacturer's instructions are followed. Levels of exposure are very low and do 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." It suggests the use of glass baby bottles if parents have any concerns.

The Australian Government has 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."

After the release of that assessment, Health Canadian Minister 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. While the agency concluded that human exposures were less than levels believed unsafe, the margin of safety was not high enough for formula-fed infants. Around the same time, Wal-Mart announced that it was immediately ceasing sales in all its Canadian stores of food containers, water and baby bottles, sippy cups, and pacifiers containing bisphenol A, and that it would phase out baby bottles made with it in U.S. stores by early 2009. Nalgene also announced it will stop using the chemical in its products, and Toys-R-Us said it too will cease selling baby bottles made from it. Subsequent news reports showed many retailers removing polycarbonate drinking products from their shelves.

The federal government proposed declaring Bisphenol A a hazardous substance in October 2008 and has since placed it on its list of toxic substances (October, 2010). Health Canada and Environment Canada officials declared in Canada Gazette that bisphenol A is entering or may be entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity. It is concluded that bisphenol A be considered as a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health. It is therefore concluded that bisphenol A does meet the criteria in paragraphs 64(a) and 64(c) of CEPA 1999. http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=3C756383-1. The federal ministries of Health Canada and the Environment Canada announced they would seek to restrict imports, sales and advertising of polycarbonate baby bottles containing BPA. and would develop a risk management instrument to control the release of BPA from industrial effluent. Environment Canada published a Pollution Prevention Planning Notice in the Canada Gazette, Part 1 in April 2012. |http://www.ec.gc.ca/planp2-p2plan/default.asp?lang=En&n=6A389B0B-1 |accessdate=16 April 2012

In its statement released 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".

Europe

European Union

The updated 2008 European Union Risk Assessment Report on bisphenol A, published in June 2008, 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.

A 2009 scientific study criticized the European risk assessment processes of endocrine disruptors, including BPA.

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) published its latest scientific opinion, based on a "comprehensive evaluation of recent toxicity data [...] concluded 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 will ban the manufacturing by 1 March 2011 and ban the marketing and market placement of polycarbonate baby bottles containing the organic compound bisphenol A (BPA) by 1 June 2011, according to John Dalli, commissioner in charge of health and consumer policy. This is 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.

Denmark

In May 2009, the Danish parliament passed a resolution to ban the use of BPA in baby bottles, which has not been enacted by April 2010. In March 2010, a temporary ban was declared by the Health Minister.

Belgium

On March 2010, senator Philippe Mahoux proposed legislation to ban BPA in food contact plastics.

France

On 5 February 2010, the French Food Safety Agency (AFSSA) questioned the previous assessments of the health risks of BPA, especially in regard to behavioral effects observed in rat pups following exposure in utero and during the first months of life. In April 2010, the AFFSA suggested the adoption of better labels for food products containing BPA.

On 24 March 2010, French Senate unanimously approved a proposition of law to ban BPA from baby bottles. The National Assembly (Lower House) approved the text on 23 June 2010, which has been applicable law since 2 July 2010. On 12 October 2011, the French National Assembly voted a law forbidding the use of Bisphenol A in products aimed at less than 3-year-old children for 2013, and 2014 for all food containers.

On 9 October 2012, the French Senate adopted unanimously the law proposition to suspend manufacture, import, export and marketing of all food containers which include bisphenol A for 2015. The ban of bisphenol A in 2013 for food products designed for children less than 3-ears-old was maintained.

Germany

On 19 September 2008, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) stated that there was no reason to change the current risk assessment for bisphenol A on the basis of the Lang Study.

In October 2009, the German environmental organization Bund für Umwelt und Naturschutz Deutschland requested a ban on BPA for children's products, especially pacifiers, and products that make contact with food. In response, some manufacturers voluntarily removed the problematic pacifiers from the market.

Netherlands

On 6 November 2008, the Dutch Food and Consumer Product Safety Authority (VWA) stated in a newsletter that baby bottles made from polycarbonate plastic do not release measurable concentrations of bisphenol A and therefore are safe to use.

Switzerland

In February 2009, the Swiss Federal Office for Public Health, based on reports of other health agencies, stated that the intake of bisphenol A from food represents no risk to the consumer, including newborns and infants. However, in the same statement, it advised for proper use of polycarbonate baby bottles and listed alternatives.

Sweden

By May 2010, the Swedish Chemicals Agency asked for a BPA ban in baby bottles, but the Swedish Food Safety Authority prefers to await the expected European Food Safety Authority's updated review. The Minister of Environment said to wait for the EFSA review but not for too long. From March 2011 it is prohibited to manufacture babybottles containing bisphenol A and from July 2011 they can not be bought in stores. On 12 April 2012, the Swedish government announced that Sweden will ban the endocrine disruptor Bisphenol A (BPA) in cans containing food for children under the age of three.

United Kingdom

In December 2009, responding to a letter from a group of seven scientists that urged the UK Government to "adopt a standpoint consistent with the approach taken by other Governments who have ended the use of BPA in food contact products marketed at children", the UK Food Standards Agency reaffirmed, in January 2009, its view that "exposure of UK consumers to BPA from all sources, including food contact materials, was well below levels considered harmful".

Turkey

As of 10 June 2011, Turkey banned the use of BPA in baby bottles and other PC items produced for babies.

Japan

Between 1998 and 2003, the canning industry voluntarily replaced its BPA-containing epoxy resin can liners with BPA-free polyethylene terephthalate (PET) in many of its products. For other products, it switched to a different epoxy lining that yielded much less migration of BPA into food than the previously used resin. In addition, polycarbonate tableware for school lunches was replaced by BPA-free plastics. As a result of these changes, Japanese risk assessors have found that virtually no BPA is detectable in canned foods or drinks, and blood levels of BPA in the Japanese people have declined dramatically (50% in one study).

United States

Organizations such as the American Chemistry Council (ACC) have lobbied to make BPA federally recognized as a safe product. The ACC is composed of companies that represent 85% of chemical manufacturing capacity in the United States. The ACC position states that BPA is safe for use in products. "Government and scientific bodies around the globe have extensively evaluated the weight of scientific evidence on bisphenol A (BPA) and have declared that BPA is safe as used, including in materials that come into contact with food, such as reusable foodstorage containers and linings in metal cans."

Due to consumer pressure, by 2011 BPA was no longer being used in sippy cups and baby bottles. In October 2011, the ACC said that it had petitioned the FDA to make it clear to consumers that BPA is no longer present in those products. Steven Hentges of ACC's Polycarbonate/BPA Global Group said, "What we are trying to do is cut through the confusion and provide some clarity about sippy cups and baby bottles. We want that to be very clear, these products are not on the market. There is no need for parents or consumers to worry about them. They aren't there and they won't be in the future." In July 2012, the FDA moved to ban BPA in baby bottles and sippy cups to satisfy a request by the ACC, stating that the measure was intended to "boost consumer confidence" and not due to safety concerns. (See 2012 below)

2008

In April, the Federal BPA-Free Kids Act of 2008 was introduced to the U.S. Senate. The bill sought to ban BPA in any product designed for use by children and require the Center for Disease Control conduct a study about the health effects of BPA exposure. No action was taken.

In September, the National Toxicology Program finalized its report on bisphenol A, finding "some concern", midpoint of a five-level scale, that infants were at risk from exposure to the chemical.

At that time, the FDA reassured consumers that current limits were safe, but convened an outside panel of experts to review the issue. The Lang study was also released that month, and David Melzer, a co-author of the study, presented the results of the study before the FDA panel.

The editorial accompanying the Lang study's publication in JAMA criticized the FDA's assessment of bisphenol A: "A fundamental problem is that the current ADI [acceptable daily intake] for BPA is based on experiments conducted in the early 1980s using outdated methods (only very high doses were tested) and insensitive assays. More recent findings from independent scientists were rejected by the FDA, apparently because those investigators did not follow the outdated testing guidelines for environmental chemicals, whereas studies using the outdated, insensitive assays (predominantly involving studies funded by the chemical industry) are given more weight in arriving at the conclusion that BPA is not harmful at current exposure levels."

2009

Sunoco, a producer of gasoline and chemicals, refused to sell the chemical to companies for use in food and water containers for children younger than 3, saying it couldn't be certain of the compound's safety. The six largest US companies that produce baby bottles decided to stop using bisphenol A in their products.

Suffolk County, New York became the first county to pass legislation to ban baby beverage containers made with bisphenol A.

In March, leaders from the House and Senate proposed legislation to ban bisphenol A. In the same month, Rochelle Tyl, author of two studies used by FDA to assert BPA safety in August 2008, said those studies didn't claim that BPA is safe because they weren't designed to cover all aspects of the chemical's effects.

In May, the first US jurisdictions to pass regulations limiting or banning BPA were Minnesota and Chicago. Grassroots political action led Connecticut to become the first US state to ban bisphenol A from infant formula and baby food containers, as well from any reusable food or beverage container.

In May, the Washington Post accused the manufacturers of food and beverage containers and some of their biggest customers of trying to devise a public relations and lobbying strategy to block government BPA bans. Lyndsey Layton, from the Washington Post, criticized the FDA noting that, "Despite more than 100 published studies by government scientists and university laboratories that have raised health concerns about the chemical, the Food and Drug Administration has deemed it safe largely because of two studies, both funded by a chemical industry trade group".

In June, the FDA announced the decision to reconsider the BPA safety levels. In July, the California Environmental Protection Agency's Developmental and Reproductive Toxicant Identification Committee unanimously voted against placing Bisphenol A on the state's list of chemicals that are believed to cause reproductive harm. The panel, although concerned over the growing scientific research showing BPA's reproductive harm in animals, found that there was insufficient data of the effects in humans. Critics point out that the same panel failed to add second-hand smoke to the list until 2006, and only one chemical was added to the list in the last three years. In September, the United States Environmental Protection Agency announced that it was evaluating BPA for an action plan development. IN October, the NIH announced $30,000,000 in stimulus grants to study the health effects of BPA. This money was supposed to result in many peer-reviewed publications.

The Milwaukee Journal Sentinel, as part of an ongoing investigative series into BPA and its effects, revealed plans by the Society of the Plastics Industry to execute a major public relations blitz to promote BPA, including plans to attack and discredit those who report or comment negatively on the monomer and its effects.

In November, the Consumer Reports magazine published an analysis of BPA content in some canned foods and beverages, where in specific cases the content of a single can of food could exceed the FDA "Cumulative Exposure Daily Intake" limit.

2010

On 15 January, the FDA expressed "some concern", the middle level in the scale of concerns, about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children, and announced it was taking reasonable steps to reduce human exposure to BPA in the food supply. However, the FDA is not recommending that families change the use of infant formula or foods, as it sees the benefit of a stable source of good nutrition as outweighing the potential risk from BPA exposure.

On the same date, the U.S. Department of Health & Human Services released information to help parents to reduce children's BPA exposure.

In February, according to The Milwaukee Journal Sentinel, which supports a BPA ban, after lobbyists for the chemical industry met with administration officials, the EPA delayed BPA regulation and did not include the chemical in an action plan released 30 December 2009.

Many US states are considering some sort of BPA ban.

On 29 March, the EPA declared BPA a "chemical of concern".

The 2008–2009 Annual Report of the President's Cancer Panel declared: "because of the long latency period of many cancers, the available evidence argues for a precautionary approach to these diverse chemicals, which include (...) bisphenol A".

Meanwhile, as of April 2011, General Mills has announced that it has found a BPA-free alternative can liner that apparently works even with tomatoes, a highly acidic product that has long baffled the industry in terms of finding a suitable substitute. General Mills says that with the next tomato harvest, it will begin using the BPA-free alternative in tomato products sold by its organic foods subsidiary Muir Glen. Thus far, there has been no word on whether General Mills will use BPA-free alternatives on any of its other canned products.

2011

In 2011, 26 states proposed legislation that would ban certain uses of BPA. Many bills died in committee however, some are moving forward. In August 2010, the Maine Board of Environmental Protection voted unanimously to ban the sale of baby bottles and other reusable food and beverage containers made with bisphenol A as of January 2012. In February 2011, the newly elected governor of Maine, Paul LePage, gained national attention when he spoke on a local TV news show saying he hoped to repeal the ban because, "There hasn't been any science that identifies that there is a problem" and added: "The only thing that I've heard is if you take a plastic bottle and put it in the microwave and you heat it up, it gives off a chemical similar to estrogen. So the worst case is some women may have little beards." In April, the Maine legislature passed a bill to ban the use of BPA in baby bottles, sippy cups, and other reusable food and beverage containers, effective 1 January 2012. Governor LePage refused to sign the bill.

A study by researchers at the Harvard School of Public Health indicates that BPA used in the lining of food cans is absorbed by the food and then ingested by consumers. The experiment involved 75 participants, half of whom ate a lunch of canned vegetable soup for five days, followed by five days of fresh soup; the other half did the same experiment in reverse order. "The analysis revealed that when participants ate the canned soup they experienced more than a 1,000 percent increase in their urinary concentrations of BPA, compared to when they dined on fresh soup."

In October 2011, California banned BPA from baby bottles and toddlers' drinking cups. The ban will take effect 1 July 2013.

In a July report, the American Medical Association (AMA) declared that they believe that feeding products for babies and infants that contain BPA should be banned. In the report AMA said they would also like to see better federal oversight of BPA and the clear labeling of products containing it. It stressed the importance of the Food and Drug Administration to "actively incorporate current science into the regulation of food and beverage BPA-containing products."

2012

The FDA recently concluded an assessment of scientific research on the effects of BPA. In the March 2012 Consumer Update, the FDA concluded that "the scientific evidence at this time does not suggest that the very low levels of human exposure to BPA through the diet are unsafe." However, the FDA recognizes potential uncertainties in the overall interpretation of these studies including route of exposure used in the studies and the relevance of animal models to human health. The FDA is continuing to pursue additional research to resolve these uncertainties.

On 17 July, the FDA banned BPA from baby bottles and sippy cups. Since manufacturers have already stopped using the chemical in baby bottles and sippy cups, the decision was not over concerns about the safety of BPA but a response to a request by the American Chemistry Council, the chemical industry's main trade association, who believe that a ban would boost consumer confidence. The Environmental Working Group called the ban "purely cosmetic". In a statement they said,"If the agency truly wants to prevent people from being exposed to this toxic chemical associated with a variety of serious and chronic conditions it should ban its use in cans of infant formula, food and beverages." The Natural Resources Defense Council called the move inadequate saying, the FDA needs to ban BPA from all food packaging. In a statement a FDA spokesman said the agency's action was not based on safety concerns and that "the agency continues to support the safety of BPA for use in products that hold food."

Substitute chemicals

The industry has responded to criticism of BPA by promoting "BPA-free" products, which are made from plastic containing a compound called bisphenol S (BPS). BPS, which shares a similar structure and versatility to BPA, is now being used in everything from currency to thermal receipt paper, and widespread human exposure to BPS was confirmed in a 2012 analysis of urine samples taken in the U.S., Japan, China and five other Asian countries.

Recent research suggests that endocrine -disrupting chemicals may in fact be much more common to many or most plastics than was previously realized. In 2011 researchers looked at 455 common plastic products and found that 70% tested positive for estrogenic activity. After the products had been washed or microwaved the proportion rose to 95%. The study concluded:

"Almost all commercially available plastic products we sampled, independent of the type of resin, product, or retail source, leached chemicals having reliably-detectable EA [endocrine activity], including those advertised as BPA-free. In some cases, BPA-free products released chemicals having more EA than BPA-containing products."

A 2011 study found that people are being exposed to high levels of BPS in cash register thermal paper receipts and many of the other products that engendered concerns about the health effects of BPA. The researchers found BPS in all the receipt paper they tested, 87 percent of the samples of paper currency and 52 percent of recycled paper. The study found that people may be absorbing 19 times more BPS through their skin than the amount of BPA they absorbed when it was more widely used.

According to a 2013 study, BPS shares similar problems to BPA in that it has been found to be an estrogen hormone disruptor even at extremely low levels of exposure.

Further reading

• Kabiersch G, Rajasärkkä J, Ullrich R, Tuomela M, Hofrichter M, Virta M, Hatakka A, Steffen K (2011). "Fate of bisphenol A during treatment with the litter-decomposing fungi Stropharia rugosoannulata and Stropharia coronilla". Chemosphere. 83 (3): 226–32. doi:10.1016/j.chemosphere.2010.12.094. PMID 21295326. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
• Myers JP, vom Saal FS, Akingbemi BT, Arizono K, Belcher S, Colborn T, Chahoud I, Crain DA, Farabollini F, Guillette LJ, Hassold T, Ho SM, Hunt PA, Iguchi T, Jobling S, Kanno J, Laufer H, Marcus M, McLachlan JA, Nadal A, Oehlmann J, Olea N, Palanza P, Parmigiani S, Rubin BS, Schoenfelder G, Sonnenschein C, Soto AM, Talsness CE, Taylor JA, Vandenberg LN, Vandenbergh JG, Vogel S, Watson CS, Welshons WV, Zoeller RT (2009). "Why public health agencies cannot depend on good laboratory practices as a criterion for selecting data: the case of bisphenol A". Environ. Health Perspect. 117 (3): 309–15. doi:10.1289/ehp.0800173. PMC 2661896. PMID 19337501. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

• Plastic Not Fantastic with Bisphenol A (www.scientificamerican.com)
• US FDA statement on bisphenol A from 2008
• EHP Collection: Bisphenol A
• Hazard in a bottle Attempt to regulate BPA in California defeated (from The Economist)
• How to Protect Your Baby from BPA (Bisphenol A)
• Alternatives to BPA containers not easy for U.S. foodmakers to find Layton, Lyndsey. 23 February 2010. Washington Post
• ChemSub Online : Bisphenol A.
• Is It Time to End Concerns over the Estrogenic Effects of Bisphenol A?