Bisphenol A

Bisphenol A (BPA) is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications.

As it has been known to be estrogenic since the mid 1930s, concerns about the use of bisphenol A in consumer products were regularly reported in the news media in 2008, after several governments issued reports questioning its safety, prompting some retailers to remove products containing it from their shelves. A 2010 report from the United States Food and Drug Administration (FDA) raised further concerns regarding exposure of fetuses, infants and young children. In September 2010, Canada became the first country to declare BPA as a toxic substance. In the European Union and Canada, BPA use is banned in baby bottles.

Production
World production capacity of this compound was 1 million tons in the 1980s, 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 US, less than 5% of the BPA produced is used in food contact applications.

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:


 * Synthesis Bisphenol A.svg

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
Bisphenol A is used primarily to make plastics, and products containing bisphenol A-based plastics have been in commerce use since 1957. At least 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. The overall reaction to give polycarbonate can be written:


 * Polycarbonatsynthese.svg

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 and sealants, eyeglass lenses, CDs and DVDs, and household electronics. 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 was formerly 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. BPA-based products are also used in foundry castings and for lining water pipes.

Identification in plastics


"In general, plastics that are marked with recycle codes 1, 2, 4, 5, and 6 are very unlikely to contain BPA. Some, but not all, plastics that are marked with recycle codes 3 or 7 may be made with BPA."

There are seven classes of plastics used in packaging applications. 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) can also contain bisphenol A as an antioxidant in plasticizers. This is particularly true for "flexible PVC", but not true for PVC pipes.

Health effects
Bisphenol A is an endocrine disruptor, which can mimic the body's own hormones and may lead to negative health effects. Early development appears to be the period of greatest sensitivity to its effects, and some studies have linked prenatal exposure to later neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or under review as a result of new scientific studies. A 2011 study that investigated the number of chemicals to which pregnant women in the U.S. are exposed found BPA in 96% of women.

In 2009, The Endocrine Society released a statement expressing concern over current human exposure to BPA.

In 2011, the Food Standards Agency's chief scientist said "the evidence [is] that BPA is rapidly absorbed, detoxified, and eliminated from humans – therefore is not a health concern."

Expert panel conclusions
In 2007, a consensus statement by 38 experts on bisphenol A concluded that average levels in people are above those that cause harm to many animals in laboratory experiments. However, they noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous, 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 that either BPA intake is much higher than accounted for, or that BPA can bioaccumulate in some conditions such as pregnancy, or both. A 2011 study, the first to examine BPA in a continuous low level exposure throughout the day, did find an increased absorption and accumulation of BPA in the blood of mice.

In 2007 it was reported that among government-funded BPA experiments on lab animals and tissues, 153 found adverse effects and 14 did not, whereas all 13 studies funded by chemical corporations reported no harm. The studies indicating harm reported a variety of deleterious effects in rodent offspring exposed in the womb: abnormal weight gain, insulin resistance, prostate cancer, and excessive mammary gland development.

A panel convened by the U.S. National Institutes of Health in 2007 determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior. The concern over the effect of BPA on infants was also heightened by the fact that infants and children are estimated to have the highest daily intake of BPA. A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A," and "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." The NTP had "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."

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 "perinatal BPA exposure acts to exert persistent effects on body weight and adiposity". 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. A later study on rats has suggested that perinatal exposure to drinking water containing 1 mg/L of BPA increased adipogenesis in females at weaning. Other study suggested that larger size-for-age was due to a faster growth rate rather than obesity

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 has concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar 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 microg/kg bw BPA has concluded that corticosterone and its actions in the brain are sensitive to the programming effects of BPA.

Disruption of the dopaminergic system
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 impacts 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
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, "animal studies have not provided convincing evidence of risk of cancer from BPA exposure."

Neither the U.S. Environmental Protection Agency nor the International Agency for Research on Cancer has evaluated bisphenol A for possible carcinogenic activity.

A 2010 review at Tufts University Medical School concluded that Bisphenol A may increase cancer risk.

Breast cancer
A 2008 review has concluded 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
In vitro studies have suggested that BPA can promote the growth of neuroblastoma cells. A 2010 in vitro study has concluded that BPA potently promote invasion and metastasis of neuroblastoma 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) increased prostate cancer susceptibility when adults.

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

Reproductive system and sexual behavior research
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 the future fertility of female fetuses the mother is carrying.

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 is 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 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 appear to be entering the human body from a variety of unknown sources.

A 2009 in vitro study on cytotrophoblasts cells has found cytoxic effects in exposure of BPA doses from 0.0002 to 0.2 micrograms per millilitre 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 micrograms/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.

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.

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

Xenoestrogen
There is evidence that bisphenol A functions as a xenoestrogen by binding strongly to 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.

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
Bisphenol A has been known to be leached from the plastic lining of canned foods and polycarbonate plastics, especially those that are cleaned with harsh detergents or those which contain acidic or high-temperature liquids. BPA is an ingredient in the internal coating of metal food and beverage cans used to protect the food from direct contact with the can. A recent Health Canada study found that the majority of canned soft drinks it tested had low, but measurable levels of bisphenol A. Furthermore, 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, foods sold in plastic packaging, and in cat and dog foods in cans and plastic packaging. This included fresh turkey, canned green beans, and canned infant formula. While most human exposure is through diet, exposure can also occur through air and through skin absorption.

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.

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. While there is little concern for dermal absorption of BPA, free BPA can readily be transferred to skin and residues on hands can be ingested.

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.

In 2009, a study found that drinking from polycarbonate bottles increased urinary bisphenol A levels by two thirds, from 1.2 micrograms/gram creatinine to 2 micrograms/gram 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. In order 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 the U.S., consumption of soda, school lunches, and meals prepared outside the home was statistically significantly associated with higher urinary BPA.

BPA is also used to form epoxy resin coating of water pipes. In older buildings, such resin coatings are used to avoid replacement of deteriorating hot and cold water pipes.

Fetal and early-childhood exposures
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. This increased susceptibility is most likely based on their reduced capacity to eliminate xenobiotics and also their estimated higher daily exposure to BPA, adjusted for weight, compared to adults. 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 lead 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. After the baby is born, maternal exposure can continue to effect 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.

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 reverted by arylsulfatase C. A 2010 vitro study has shown that placenta P-glycoprotein may efflux BPA from placenta.

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

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).

A 2009 research has found that some drugs, like naproxen, salicylic acid, carbamazepine and mefenamic acid can, in vitro, significantly inhibit BPA glucuronidation.

A 2010 study on rats embryos has found that genistein may enhance developmental toxicity of BPA.

Environmental risk
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.

BPA can contaminate the environment either directly or through degradation of products containing BPA, such as ocean-borne plastic trash.

As an environmental contaminant this compound 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."

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 have 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.

World Health Organization
Arguing uncertainty of possible adverse health effects of low dose BPA exposure, especially on the nervous system and on behaviour, and also the differences of exposure of very young children, the WHO announced in November 2009 that it would organize an expert consultation in 2010 to assess BPA safety.

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.

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, Canadian Health Minister Tony Clement 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 to be 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. Health officials wrote in Canada Gazette that "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." The federal ministries of health and the environment announced they would seek to restrict imports, sales and advertising of polycarbonate baby bottles containing BPA.

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”.

Environment Canada listed bisphenol A as a "toxic substance" in September 2010.

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

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 will no longer go to buy them in stores.

UK
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 their BPA-containing epoxy resin can liners with BPA-free polyethylene terephthalate (PET) in many of their products. For other products, they 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 people have declined dramatically (50% in one study).

United States
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April 2008
As of the release of NTP and Health Canada reports in April, 10 U.S. states, including California, Maryland, and New Jersey, already had legislation pending that would affect the use of BPA. In the wake of these reports, U.S. Senator Charles Schumer (D–N.Y.) introduced legislation that would ban bisphenol A nationally from products for infants. In addition, the U.S. Congress is investigating the Weinberg Group, a chemical industry consulting firm, for its role in downplaying the health effects of bisphenol A and other chemicals, and the Energy and Commerce Committee in the House of Representatives is investigating the use of BPA in baby products as well as the FDA's approval of the chemical. In asking the FDA to reassess its approval of bisphenol A, committee chairman Bart Stupak (D–Mich.) said "We would expect the FDA to make decisions based on the best available science…Yet the FDA relied on only two industry-funded studies, while other respected authorities used all available data to reach vastly different conclusions." The FDA maintained that bisphenol A is safe and did not recommend that people avoid using products made from it. The Consumer Product Safety Commission agreed, and its deputy director stressed that use of bisphenol A based plastics has many practical benefits and that "a ban could result in less effective protection of children from head, eye, or bodily injury." FDA then announced it would set up a task force to address these concerns, and in August it released a draft finding concurring with its initial position that the chemical is safe. The agency will make its final decision after an advisory panel on the issues is convened in September.

In response to these events, an American Chemistry Council (ACC)/BPA Global Group (an industry trade association) spokesman said, “The weight of scientific evidence, as assessed by Health Canada and other agencies around the world, provides reassurance that consumers can continue to safely use products made from bisphenol A." The Grocery Manufacturers Association also insisted that bisphenol A is safe, and argues that "Data purporting to demonstrate 'low' dose effects on the male reproductive system by BPA have not been successfully replicated and, therefore, are not credible to estimate human health risks and safety in light of the weight of a large body of evidence to the contrary." A spokesman for the tin can industry said that without lining cans with bisphenol A based resins, E. coli and botulism poisoning would be "rampant."

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September 2008
In September, the National Toxicology Program finalized their report on bisphenol A, finding "some concern", mid-point 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."

March 2009
Sunoco, a producer of gasoline and chemicals, is now refusing to sell the chemical to companies for use in food and water containers for children younger than 3, saying it can't be certain of the compound's safety. Sunoco plans to require its customers to guarantee that the chemical will not be used in children's food products.

The six largest US companies which commercialize baby bottles decided to stop using bisphenol A in their products. Suffolk County, New York banned baby beverage containers made with bisphenol A.

On 13 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.

May 2009
The first US jurisdictions to pass regulations limiting or banning BPA were Minnesota and Chicago. Minnesota's regulation takes effect in 2010, "manufacturers of ... children's products containing BPA may not sell them in the state after 1 Jan. 2010. The ban extends to all retailers in the state a year later." The products impacted are known as sippy cups and baby bottles. The City of Chicago adopted a similar ban shortly thereafter. Coverage of Chicago's ban in the news showed a relentless opposition by the industry. A Chicago Tribune article noted an up-hill battle while passing legislation, "[industry officials] used FDA’s position on the issue when they tried to block the city’s measure."

In May 2009, 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".

June 2009
In June 2009, the FDA announced the decision to reconsider the BPA safety levels.

Connecticut was the first US state to ban bisphenol A from infant formula and baby food containers, as well from any reusable food or beverage container.

July 2009
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.

August 2009
On 3 August, Massachusetts' Department of Public Health advised mothers to take certain actions to prevent possible health impact in children. Mothers with children up to two years old were advised to limit exposure by avoiding products that might contain BPA, such as plastic drinking bottles and other plastic materials with recycling codes of 7 or 3.

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.

September 2009
On 29 September, the U.S. Environmental Protection Agency announced that it is evaluating BPA, and another five chemicals, for action plan development.

October 2009
On 28 October, the NIH announced $30,000,000 in stimulus grants to study the health effects of BPA. This money is expected to result in many peer-reviewed publications.

November 2009
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 current FDA Cumulative Exposure Daily Intake.

January 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.

February 2010
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.

March 2010
On 29 March, the EPA declared BPA a "chemical of concern".

April 2010
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,, 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.

February 2011
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 January 1, 2012. Governor LePage refused to sign the bill.