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 Registry Number	80-05-7 Y
ChEBI	CHEBI:33216 Y
ChEMBL	ChEMBL418971 Y
ChemSpider	6371 Y
DrugBank	DB06973 Y
EC number	201-245-8
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
Jmol-3D images	Image Image
KEGG	C13624 Y
PubChem	6623
RTECS number	SL6300000
SMILES Oc1ccc(cc1)C(c2ccc(O)cc2)(C)C CC(C)(c1ccc(cc1)O)c2ccc(cc2)O
UNII	MLT3645I99 Y
UN number	2430
Properties
Molecular formula	C15H16O2
Molar mass	228.29 g·mol−1
Appearance	White solid
Density	1.20 g/cm³
Melting point	158 °C (316 °F; 431 K)
Boiling point	220 °C (428 °F; 493 K) 4 mmHg
Solubility in water	120–300 ppm (21.5 °C)
Vapor pressure	5×10−6 Pa (25 °C)[1]
Hazards
R-phrases	R36 R37 R38 R43
S-phrases	S24 S26 S37
NFPA 704	0 3 0
Flash point	227 °C (441 °F; 500 K)
Autoignition temperature	600 °C (1,112 °F; 873 K)
Related compounds
Related compounds	phenols Bisphenol S
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Bisphenol A (BPA) is a carbon-based synthetic compound with the chemical formula (CH₃)₂C(C₆H₄OH)₂ belonging to the group of diphenylmethane derivatives and bisphenols, with two hydroxyphenyl groups. It is a colorless solid that is soluble in organic solvents, but poorly soluble in water and has been in commercial use since 1957.

BPA is employed to make certain plastics and epoxy resins. BPA-based plastic is clear and tough, and is made into a variety of common consumer goods, such as water bottles, sports equipment, CDs, and DVDs. Epoxy resins containing BPA are used to line water pipes, as coatings on the inside of many food and beverage cans and in making thermal paper such as that used in sales receipts.

BPA exhibits hormone-like properties that raise concern about its suitability in some consumer products and food containers. Since 2008, several governments have investigated its safety, which prompted some retailers to withdraw polycarbonate products. The FDA has ended its authorization of the use of BPA in baby bottles and infant formula packaging, based on market abandonment, not safety.^[2] The European Union and Canada have banned BPA use in baby bottles.

A 2010 report from the US Food and Drug Administration (FDA) identified possible hazards to fetuses, infants, and young children.^[3] However, an FDA assessment released in March 2013 said that BPA is safe at the very low levels that occur in some foods.^[4] In July 2014, the FDA updated its perspective on the use of BPA in food contact applications, confirming that "BPA is safe at the current levels occurring in foods" based on extensive research, including two more studies issued by the agency in early 2014.^[5] The European Food Safety Authority (EFSA) reviewed new scientific information on BPA in 2008, 2009, 2010, 2011 and 2015: EFSA’s experts concluded on each occasion that they could not identify any new evidence which would lead them to revise their opinion that the presently known levels of exposure to BPA is safe; however, EFSA does recognize some uncertainties, and will continue to investigate them.^[6]

Production

World production capacity of this compound was 1 million tons in the 1980s,^[7] and more than 2.2 million tons in 2009.^[8] and thus belongs to the high production volume chemicals. In 2003, U.S. consumption was 856,000 tons, 72% of which used to make polycarbonate plastic and 21% going into epoxy resins.^[9] In the U.S., less than 5% of the BPA produced is used in food contact applications,^[10] but remains in the canned food industry and printing applications such as sales receipts.^[11][12]

Bisphenol A was first synthesized by the Russian chemist A.P. Dianin in 1891.^[13][14] This compound is synthesized by the condensation of acetone (hence the suffix A in the name)^[15] 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:^[7]

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.^[7]

Use

Bisphenol A is used primarily to make plastics, and products using bisphenol A-based plastics have been in commercial use since 1957.^[16] At least 3.6 million tonnes (8 billion pounds) of BPA are used by manufacturers yearly.^[17] It is a key monomer in production of epoxy resins^[18][19] and in the most common form of polycarbonate plastic.^[7][20][21] 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.^[22]

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,^[7] foundry castings, and the lining of water pipes.^[10] 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;^[23] however, due to BPA health concerns, in Japan epoxy coating was mostly replaced by PET film.^[24] Bisphenol A is also a precursor to the flame retardant tetrabromobisphenol A, and formerly was used as a fungicide.^[25]

Bisphenol A is a preferred color developer in carbonless copy paper and thermal point of sale receipt paper.^[26][27] 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.)^[28][29] Epoxy resin may or may not contain BPA, and is employed to bind gutta percha in some root canal procedures.^[30]

Identification in plastics

Plastic packaging is split into seven broad classes for recycling purposes by a Plastic identification code. As of 2014 there are no BPA labeling requirements for plastics in the US. "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."^[31] 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.^[7][32] Type 3 (PVC) may contain bisphenol A as an antioxidant in "flexible PVC" softened by plasticizers,^[7] but not rigid PVC such as pipe, windows, and siding.

History

Bisphenol A was discovered in 1891 by Russian chemist Aleksandr Dianin.^[33]

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, which is contained in the lining of food and beverage containers.^[34][35]

In the early 1930s, the British biochemist Edward Charles Dodds tested BPA as an artificial estrogen, but found it to be 37,000 times less effective than estradiol.^[36][37][38] 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 in humans came in 1971 and in animals, in 1979.^[36] BPA was never used as a drug.^[36] 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.^[39]

In 1997, adverse effects of low-dose BPA exposure in laboratory animals were first proposed.^[23] Modern studies began finding possible connections to health issues caused by exposure to BPA during pregnancy and during development. See US public health regulatory history and Chemical manufacturers reactions to bans. As of 2014, research and debates are ongoing as to whether BPA should be banned or not.

A 2007 study investigated the interaction between bisphenol A's and estrogen-related receptor γ (ERR-γ). This orphan receptor (endogenous ligand unknown) behaves as a constitutive activator of transcription. BPA seems to bind strongly to ERR-γ (dissociation constant = 5.5 nM), but not to the estrogen receptor (ER).^[41] BPA binding to ERR-γ preserves its basal constitutive activity.^[41] It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen.^[41] This may be the mechanism by BpA acts as a xenoestrogen.^[41] 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.^[40]

Pharmacokinetics

The area of the pharmacokinetics of BPA has expanded greatly since 2010. In the US, the National Institute of Environmental Health Sciences (NIEHS) and the Food and Drug Administration have been working collaboratively to understand the internal exposure to humans. In a 2013 editorial in Environmental Health Perspectives, the authors Linda Birnbaum, Director of NIEHS, Jason Aungst of FDA, Thaddeus Schug of NIEHS and Jesse Goodman, then Chief Scientist at FDA stated, "The results of our collaborations to date have been [..] important in [..] understanding of how BPA is [..] handled once in the body. This has [..] reduced key uncertainties concerning [..] levels of internal exposure in humans. For example, we have learned that newborn and young rodents have significant age-dependent differences in metabolic capabilities, resulting in their not being able to metabolize BPA as well as adult rodents do and thus being exposed to higher levels internally; this is not the case for non-human primates. Multiple pharmacokinetic studies in monkeys supported by preliminary results in humans, have now demonstrated, that newborn and young primates metabolize BPA at or very near the level of adult metabolism. [..] potential fetal exposure is significantly reduced by the mother's metabolic capabilities, and that the fetus can effectively metabolize BPA."^[42]

Human exposure sources

The major human exposure route to BPA is diet, including ingestion of contaminated food and water.^[43] 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.^[44] It is especially likely to leach from plastics when they are 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.^[45] 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.^[46]

In 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 FDA "Cumulative Exposure Daily Intake" limit.^[11][47]

The CDC had found bisphenol A in the urine of 95% of adults sampled in 1988–1994^[48] and in 93% of children and adults tested in 2003–04.^[49] 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,^[50][51] and several studies of children, who tend to have the highest levels, have found levels over the EPA's suggested safe limit figure.^[52]

“	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[53]

A 2009 Health Canada study found that the majority of canned soft drinks it tested had low, but measurable levels of bisphenol A.^[54] 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.^[55] 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.^[56] 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.^[52]

A 2011 experiment by researchers at the Harvard School of Public Health indicated that BPA used in the lining of food cans is absorbed by the food and then ingested by consumers. Of 75 participants, half ate a lunch of canned vegetable soup for five days, followed by five days of fresh soup, while 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."^[57] A 2009 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.^[58] 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.^[59] 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.^[60]

Besides diet, exposure can also occur through air and through skin absorption.^[61] 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.^[62][63][64] 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.^[65] 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.^[66] Also, other paper products, such as toilet paper, newspapers and napkins, become contaminated with BPA during the recycling process.^[67] Free BPA can readily be transferred to skin, and residues on hands can be ingested.^[10] 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)^[67] 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).^[9]

A study from 2011 found that Americans of all age groups had twice as much BPA in their bodies as Canadians; the reasons for the disparity were unknown, as there was no evidence to suggest higher amounts of BPA in U.S. foods, or that consumer products available in the U.S. containing BPA were BPA-free in Canada. According to another study it may have been due to differences in how and when the surveys were done,^[68] because "although comparisons of measured concentrations can be made across populations, this must be done with caution owing to differences in sampling, in the analytical methods used and in the sensitivity of the assays."^[69]

Fetal and early-childhood exposures

A 2009 study found higher urinary concentrations in young children than in adults under typical exposure scenarios.^[70][71] 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.^[52]

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).^[72] In the US and Canada, BPA has been found in infant liquid formula in concentrations varying from 0.48 to 11 ng/g.^[73][74] BPA has been rarely found in infant powder formula (only 1 of 14).^[73] 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.".^[75]

Children may be more susceptible to BPA exposure than adults (see health effects). 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.^[76] 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.^[77] 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.^[78] 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.^[79] After the baby is born, maternal exposure can continue to affect the infant through transfer of BPA to the infant via breast milk.^[80][81] 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.^[82] 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 body wt/day. Table adapted from the National Toxicology Program Expert Panel Report.[9]
Infant (0–6 months) formula-fed	1–11
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 (general population)	0.008–1.5
Adult (occupational)	0.043–100

Health effects

The first evidence of the estrogenicity of bisphenol A came from experiments on rats conducted in the 1930s,^[38][83] but it was not until 1997 that adverse effects of low-dose exposure on laboratory animals were first reported.^[23] Bisphenol A is an endocrine disruptor that can mimic estrogen and has been shown to cause negative health effects in animal studies. To be specific, 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.^{[84][85][86][87][88]} Early developmental stages appear to be the period of greatest sensitivity to its effects,^[89] 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.^[90][91] A 2011 study that investigated the number of chemicals pregnant women are exposed to in the U.S. found BPA in 96% of women.^[92]

Experts in the field of endocrine disruptors have stated the opposite in 2010 that the general population may suffer adverse health effects from current BPA levels.^[93] In 2009, The Endocrine Society released a statement citing the adverse effects of endocrine-disrupting chemicals, and the controversy surrounding BPA.^[94]

In 2012 the FDA banned the use of BPA in baby bottles, however the Environmental Working Group called the ban "purely cosmetic" and "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 needed to ban BPA from all food packaging.^[95] In a statement an 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."^[96]

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,^[97] 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."^[98] 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.^[97] This study has been criticized, however, as lacking data and having flawed assumptions.^[99]

United States expert panel conclusions

In 2006, the US Government sponsored an assessment of the scientific literature on BPA. Thirty-eight experts in fields involved with bisphenol A gathered in Chapel Hill, North Carolina to review several hundred studies on BPA, many conducted by members of the group. At the end of the meeting, the group issued the Chapel Hill Consensus Statement,^[100] 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."^[101] The Chapel Hill Consensus Statement stated that average BPA levels in people were above those that cause harm to many animals in laboratory experiments. It noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous. This is problematic because acute animal exposure studies are used to estimate daily human exposure to BPA, and no studies that had examined BPA pharmacokinetics in animal models had followed continuous low-level exposures. The authors added that measurement of BPA levels in serum and other body fluids suggests the possibilities that BPA intake is much higher than accounted for or that BPA can bioaccumulate in some conditions (such as pregnancy).^[100]

A 2008 report by the Center for the Evaluation of Risks to Human Reproduction within the U.S. National Toxicology Program, which is part of the National Institute of Environmental Health Sciences, reported its review of the literature, finding "some concern", midpoint of a five-level scale, that infants were at risk from exposure to the chemical.^[102] It concluded, "expressed relative to current estimates of general population exposure levels in the U.S." the following:

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.^{[9]:382–3[102]}

Obesity

Endocrine disruptors, like bisphenol A (a monomer of polycarbonate plastic), can distress neural circuits that regulate feeding behavior, which has been proposed to increase the risk of obesity.^[103]

BPA works by imitating the natural hormone 17B-estradiol. In the past BPA has been considered a weak mimicker of estrogen but newer evidence indicates that it is a potent mimicker.^[104] When it binds to estrogen receptors it triggers alternative estrogenic effects that begin outside of the nucleus. This different path induced by BPA has been shown to alter glucose and lipid metabolism in animal studies.^[105]

A 2013 study found an association between urinary concentrations of BPA and body mass indexes of children and adults aged 6–19 years.^[106] Interestingly, obesity was not correlated with exposure to any other environmental phenols such as those found in soaps or sunscreens. This finding strengthens the association between BPA and obesity. Although several associations have been discovered, the molecular mechanisms linking BPA exposure and obesity are not yet known; however, cell-based in vitro studies have been performed to develop a better understanding.

In developing organisms, effects can occur at concentrations of the chemical that are much lower than those that would cause harmful effects in the adult. Studies have indicated that perinatal exposure to BPA at very low concentration feminizes activity and spatial memory of male offspring. This tendency toward feminization has led to a gender difference in sweet and salty taste preference. One study discovered that mature female rats prefer sweeter tastes compared to mature males.^[107] Tan and colleagues (2011) built upon this finding as they conducted a similar study but incorporated BPA exposure. They exposed rats perinatally to BPA and tested their sweet preference for varying levels of saccharin and sucrose. They found that the correlation discovered previously where mature female rats tend to prefer sweeter tastes compared to mature males was reversed by perinatal exposure to 0.1 mg/L BPA. This finding implies the feminization of males (increased preference for sweet tastes) and masculinization of females upon exposure to BPA.

There are different effects of BPA exposure during different stages of development: During adulthood, BPA exposure modifies insulin sensitivity and insulin release without affecting weight.^[108] Exposure during pregnancy has effects on both mother and offspring later in life. During pregnancy and lactation (perinatally) BPA exposure induces metabolic alterations, including weight gain. Effects of exposure during infancy and puberty have not been studied yet and will most likely be the subject of future research.

The effect on pancreatic B-cells is significant because its function is to store and release insulin, the main hormone involved in maintaining blood sugar levels. A 2006 animal study demonstrated a link between environmental estrogens and insulin resistance.^[109] Mice were injected with BPA to replicate plasma concentrations found in late pregnancy. The authors concluded that BPA imitates the sex hormone 17B-estradiol, which leads to a rise in insulin and eventually resistance which can lead to type 2 diabetes and hypertension.^[110]

Neurological effects

A panel convened by the National Toxicology Program (NTP) of the U.S. National Institutes of Health determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior.^[9][102] In January 2010, based on the NTP report, the FDA expressed the same level of concern.^[111][112]

A 2007 literature review 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.^[113] A 2007 animal study found that low doses of BPA during development have persistent effects on brain structure, function and behavior in rats and mice.^[114] A 2008 review of animal research found that low-dose BPA maternal exposure can cause long-term consequences for the neurobehavioral development in mice.^[115] A 2008 animal study showed that neonatal exposure to bisphenol-A (BPA) can affect sexually dimorphic brain morphology and neuronal adult phenotypes in mice.^[116] A 2008 rat study concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar (10⁻⁹ mol)dosage could induce significant effects on memory processes.^[117]

A 2009 review raised concerns about a BPA effect on the anteroventral periventricular nucleus.^[118]

A 2008 study 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.^[119][120] This research found a connection between BPA interference with brain cell connections vital to memory, learning, and mood.

A 2010 study with rats prenatally exposed to 40 µg/kg bw BPA found corticosterone in the brain was sensitive to programming effects of BPA.^[121]

A 2012 study in mice found the neurological effects of BPA are trans-generational, extending into the fourth generation. The authors believe their study to be the first to have demonstrated BPA's trans-generational actions on social behavior and neural expression.^[122]

Disruption of the dopaminergic system

A 2005 study found prenatal and neonatal exposure of mice to BPA can potentiate the central dopaminergic systems, resulting in the supersensitivity to the drugs-of-abuse-induced reward effects and hyperlocomotion.^[124]

A 2008 review of human participants has concluded that BPA mimics estrogenic activity and affects various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse.^[123]

A 2009 study on rats found prenatal and neonatal exposure to low-dose BPA causing deficits in development at the dorsolateral striatum by altering the function of dopaminergic receptors.^[125] Another 2009 study has found associated changes in the dopaminergic system.^[126]

Thyroid function

A 2007 review concluded that bisphenol-A has been shown to bind to thyroid hormone receptor and perhaps has selective effects on its functions.^[127]

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".^[128]

A 2009 review summarized BPA adverse effects on thyroid hormone action.^[129]

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."^[130]

A 2010 review concluded that bisphenol A may increase cancer risk.^[131]

At least one study suggested that bisphenol A suppresses DNA methylation,^[132] which is involved in epigenetic changes.^[133]

Breast cancer

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".^[134] 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".^[135]

A 2009 in vitro study has concluded that BPA is able to induce neoplastic transformation in human breast epithelial cells.^[136] Another 2009 study concluded that maternal oral exposure to low concentrations of BPA during lactation increases mammary carcinogenesis in a rodent model.^[137]

A 2010 rat 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.^[138]

A 2010 study found that BPA may reduce sensitivity to chemotherapy treatment of breast cancer cells.^[139]

Neuroblastoma

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.^[141][142] 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.^[140]

Brain tumors

A Chinese human study linked 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.^[143]

Prostate development and cancer

A 1997 study in mice has found that neonatal BPA exposure of 2 μg/kg increased adult prostate weight.^[144] A 2005 study in mice has found that neonatal BPA exposure at 10 μg/kg disrupted the development of the fetal mouse prostate.^[145] 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.^[146] 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.^[147] 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.^[148]

Reproductive system and sexual behavior

A 2009 study had shown exposure to BPA in the workplace was associated with self-reported adult male sexual dysfunction.^[149]

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.^[149] 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.^[150] A 2010 study found that fetuses and young children exposed to BPA were at risk for secondary sexual developmental changes, brain and behavior changes and immune disorders.^[151]

A study released in 2013 demonstrated that BPA in weak concentrations is sufficient to have a negative effect 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 stated 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."^[152]

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.^[153]

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^[154] 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^[155] Animal studies 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.^[156]
• Neonatal exposure of mice as low as 50 µg/kg disrupts their ovarian development.^[157][158]
• Neonatal rat 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.^[159]
• Prenatal exposure to BPA at levels of (10 μg/kg/day) affects behavioral sexual differentiation in male monkeys.^[160]
• In placental JEG3 cells in vitro BPA may reduce estrogen synthesis.^[161]
• BPA exposure in rats disrupted the blood-testis barrier when administered to immature, but not to adult, rats.^[162]
• 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.^[163] 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,^[164] but that claim was contested by the authors and others.^[165]
• 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."^[166]

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.^[167] Another 2010 study with mice concluded that BPA exposure in utero leads to permanent DNA alterations in sensitivity to estrogen.^[168] 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.^[168]

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.^[169] A 2011 rodent study found that male rats exposed to BPA had lower sperm counts and testosterone levels than those of unexposed males.^[170] 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.^[171]

Asthma

Asthma rates have shown a dramatic increase since the 1970s; in 2011 the CDC reported the rate of childhood asthma to be about 1 in 10.^[172] Some experts believe that the cause may be related to early-life exposures and changes in immune systems.^[173] Studies in mice have found a link between BPA exposure and asthma; a 2010 study on mice has concluded that perinatal exposure to 10 µg/ml of BPA in drinking water enhances allergic sensitization and bronchial inflammation and responsiveness in an animal model of asthma.^[173][174] 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,^[175] and in 2013, research from scientists at the Columbia Center for Children's Environmental Health also found a link between the compound and an increased risk for asthma. The research team reported that children with higher levels of BPA at ages 3, 5 and 7 had increased odds of developing asthma when they were between the ages of 5 and 12.^[176] Kim Harley, who studies environmental chemicals and children's health, commented in the Scientific American journal saying while the study does not show that BPA causes asthma or wheezing, "it's an important study because we don't know a lot right now about how BPA affects immune response and asthma".^[173]

Heart disease

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.^[177][178] 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.^[179][180] 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."^[88][181]

A similar study performed by the same group in 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.^[182] 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.^[183]

A 2014 Korean study pointed to a strong correlation between hypertension and the BPA used in the plastic lining of canned drinks.^[184]

Oxidative Stress

Clinical biomarkers of oxidative stress such as malondialdehyde, 8-Oxo-2'-deoxyguanosine and 3-nitrotyrosine correlate positively with high urinary BPA levels in pregnant ^[185] and postmenopausal women.^[186] Higher incidence of cardiovascular diseases are also associated with high urinary BPA levels. Similarly, laboratory animals rats^[187] and mice.^[188] exposed to bisphenol A shown to have oxidative stress markers. Redox enzymes including catalase, peroxidase and other antioxidant compounds such as phenolic acids, alkyresorcinols, and aminophenols are shown to alternate with BPA expossure.It is generally observed with increase levels of BPA, there is a depletion of endogenic anti-oxidant molecules and increased generation of reactive oxygen species. Since BPA is a phenolic compound, it can act as pro-oxidant.^[189] BPA phenoxyl radicals oxidize cellular co-factors such as NADPH and antibiotic drug molecule such as Rifampicin. On the contrary, co-administration of Vitamin C reversed the effects of bisphenol A-induced oxidative stress in male rats. Similarly, wheat sprout (Triticum aestivum) juice shown to reduce the levels oxidative stress markers malondialdehyde, 8-Oxo-2'-deoxyguanosine in young women.

Miscellaneous effects

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".^[190]

A 2009 study in rats found 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.^[191]

Studies have associated recurrent miscarriage with BPA serum concentrations,^[192] oxidative stress and inflammation in postmenopausal women with urinary concentrations,^[186] externalizing behaviors in two-year-old children, especially among female children, with mother's urinary concentrations,^[193] altered hormone levels in men^[194][195] and declining male sexual function^[196] 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.^[197] 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.^[198] 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.^[199] 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.^[200] 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.^[201] A recently published review found evidence that BPA alters immune responses.^[202]

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)[50][203]	Study Year
0.025	"Permanent changes to genital tract"	2005[204]
0.025	"Changes in breast tissue that predispose cells to hormones and carcinogens"	2005[205]
1	long-term adverse reproductive and carcinogenic effects	2009[156]
2	"increased prostate weight 30%"	1997[206]
2	"lower bodyweight, increase of anogenital distance in both genders, signs of early puberty and longer estrus."	2002[207]
2.4	"Decline in testicular testosterone"	2004[208]
2.5	"Breast cells predisposed to cancer"	2007[209]
10	"Prostate cells more sensitive to hormones and cancer"	2006[210]
10	"Decreased maternal behaviors"	2002[211]
30	"Reversed the normal sex differences in brain structure and behavior"	2003[212]
50	Adverse neurological effects occur in non-human primates	2008[119]
50	Disrupts ovarian development	2009[157]

The current U.S. human exposure limit set by the EPA is 50 µg/kg/day.^[51] 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.^[40]

Environmental issues

Environmental risk

In 2010, the U.S. Environmental Protection Agency reported that over one million pounds of BPA are released into the environment annually.^[151] BPA can enter the environment either directly from chemical, plastics. coat and staining manufacturers, from paper or material recycling companies, foundries who use BPA in casting sand, or indirectly leaching from plastic, paper and metal waste in landfills.^[213] or ocean-borne plastic trash.^[214] Despite a soil half-life of only 1–10 days, BPA's ubiquity makes it an important pollutant; It was shown to interfere with nitrogen fixation at the roots of leguminous plants associated with the bacterial symbiont Sinorhizobium meliloti.^[215]

A 2005 study conducted in the US had found that 91–98% of BPA may be removed from water during treatment at municipal water treatment plants.^[216] Nevertheless, a 2009 meta-analysis of BPA in the surface water system showed BPA present in surface water and sediment in the US and Europe.^[217] According to Environment Canada in 2011, "BPA can currently be found in municipal wastewater. [...]initial assessment shows that at low levels, bisphenol A can harm fish and organisms over time.^[218]

BPA affects growth, reproduction, and development in aquatic organisms. Among freshwater organisms, fish appear to be the most sensitive species. Evidence of endocrine-related effects in fish, aquatic invertebrates, amphibians, and reptiles has been reported at environmentally relevant exposure levels lower than those required for acute toxicity. There is a widespread variation in reported values for endocrine-related effects, but many fall in the range of 1μg/L to 1 mg/L.^[10] A large 2010 study of two rivers in Canada had found that areas contaminated with bisphenol A and other hormone-like chemicals showed females made up 85 percent of the population of a certain fish, while in uncontaminated areas only 55 percent of fish were female.^[219]

A 2009 review of the biological impacts of plasticizers on wildlife published by the Royal Society with a focus on aquatic and terrestrial annelids, molluscs, crustaceans, insects, fish and amphibians concluded that BPA affects reproduction in all studied animal groups, impairs development in crustaceans and amphibians and induces genetic aberrations.^[220]

Environmental regulation in the United States

On 30 December 2009 EPA released a so called action plan for four chemicals, including BPA, which would have added it to the list of "chemicals of concern" regulated under the Toxic Substances Control Act. In February 2010, after lobbyists for the chemical industry had met with administration officials, the EPA delayed BPA regulation by not including the chemical.^[221][222] On 29 March 2010, EPA published a revised action plan for BPA as "chemical of concern".^[223] In October 2010 an advanced Notice of Proposed Rulemaking for BPA testing was published in the Federal Register July 2011.^[224] After more than 3 years at the Office of Information and Regulatory Affairs (OIRA), part of the Office of Management and Budget (OMB), which has to review draft proposals within 3 months, OIRA had not done so. In September 2013 EPA withdrew its 2010 draft BPA rule.^[225] saying the rule was “no longer necessary”, because EPA was taking a different track at looking at chemicals, a so-called "Work Plan" of more than 80 chemicals for risk assessment and risk reduction. Another proposed rule that EPA withdrew would have limited industry's claims of confidential business information (CBI) for the health and safety studies needed, when new chemicals are submitted for review under TSCA. The EPA said it continued "to try to reduce unwarranted claims of confidentiality and has taken a number of significant steps that have had dramatic results... tightening policies for CBI claims and declassifying unwarranted confidentiality claims, challenging companies to review existing CBI claims to ensure that they are still valid and providing easier and enhanced access to a wider array of information.” The chemical industry group American Chemistry Council commended EPA for "choosing a course of action that will ultimately strengthen the performance of the nation’s primary chemical management law.” Richard Denison, senior scientist with the Environmental Defense Fund, commented “both rules were subject to intense opposition and lobbying from the chemical industry” and “Faced presumably with the reality that [the Office of Information and Regulatory Affairs] was never going to let EPA even propose the rules for public comment, EPA decided to withdraw them.”^[226]

On 29 January 2014 EPA released a final alternatives assessment for BPA in thermal paper as part of its Design for the Environment program.^[227]

Bioremediation

Microbial degradation

Two enzymes participate in bisphenol degradation:

• The enzyme 2,4'-dihydroxyacetophenone dioxygenase, which can be found in Alcaligenes sp, transforms 2,4'-dihydroxyacetophenone and O₂ into 4-hydroxybenzoate and formate.
• The enzyme 4-hydroxyacetophenone monooxygenase, which can be found in Pseudomonas fluorescens, uses (4-hydroxyphenyl)ethan-1-one, NADPH, H⁺ and O₂ to produce 4-hydroxyphenyl acetate, NADP⁺, and H₂O.

The fungus Cunninghamella elegans is also able to degrade synthetic phenolic compounds like bisphenol A.^[228]

Plant degradation

Portulaca oleracea efficiently removes bisphenol A from a hydroponic solution. How this happens is unclear.^[229]

Government positions on safety

World Health Organization

In November 2009, the WHO announced to organize an expert consultation in 2010 to assess low-dose BPA exposure health effects, focusing on the nervous and behavioral system and exposure to young children.^[130] The 2010 WHO expert panel recommended no new regulations limiting or banning the use of Bisphenol-A, stating that "initiation of public health measures would be premature."^[230]

United States

In 2013, the FDA posted on its web site: "Is BPA safe? Yes. Based on FDA's ongoing safety review of scientific evidence, the available information continues to support the safety of BPA for the currently approved uses in food containers and packaging. People are exposed to low levels of BPA because, like many packaging components, very small amounts of BPA may migrate from the food packaging into foods or beverages."^[231] FDA issued a statement on the basis of three previous reviews by a group of assembled Agency experts in 2014 in its "Final report for the review of literature and data on BPA" that said in part, "The results of these new toxicity data and studies do not affect the dose-effect level and the existing NOAEL (5 mg/kg bw/day; oral exposure)."^[232]

Australia and New Zealand

In 2009 the Australia and New Zealand Food Safety Authority (Food Standards Australia New Zealand) did not see any health risk with bisphenol A baby bottles if the manufacturer's instructions were followed, as levels of exposure were very low and would not pose a significant health risk. It added that "the move by overseas manufacturers to stop using BPA in baby bottles is a voluntary action and not the result of a specific action by regulators."^[233] In 2008 it had suggested the use of glass baby bottles if parents had concerns.^[234]

In 2012 the Australian Government introduced a voluntary phase out of BPA use in polycarbonate baby bottles.^[235]

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^[236] and proposed classifying the chemical as "'toxic' to human health and the environment."^[237] 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.^[89] Subsequent news reports from April 2008 showed many retailers removing polycarbonate drinking products from their shelves.^[238] 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".^[239] In 2010, Canada's department of the environment declared BPA to be a "toxic substance"and added it to schedule 1 of the Canadian Environmental Protection Act, 1999.^[240]

European Union

The 2008 European Union Risk Assessment Report on bisphenol A, published by the European Commission and European Food Safety Authority (EFSA), concluded that bisphenol A-based products, such as polycarbonate plastic and epoxy resins, are safe for consumers and the environment when used as intended.^[241] 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.^[242]

On 22 December 2009, the EU Environment ministers released a statement expressing concerns over recent studies showing adverse effects of exposure to endocrine disruptors.^[243]

In September 2010, the European Food Safety Authority (EFSA) concluded after a "comprehensive evaluation of recent toxicity data [...] that no new study could be identified, which would call for a revision of the current TDI".^[244] 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.^[244]

On 25 November 2010, the European Union executive commission said it planned to ban the manufacturing by 1 March 2011 and ban the marketing and market placement of polycarbonate baby bottles containing the organic compound bisphenol A (BPA) by 1 June 2011, according to John Dalli, commissioner in charge of health and consumer policy. This was backed by a majority of EU governments.^[245][246] 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.^[247]

In January 2011 use of bisphenol A in baby bottles was forbidden in all EU-countries.^[248]

After reviewing more recent research, in 2012 EFSA made a decision to re-evaluate the human risks associated with exposure to BPA. They completed a draft assessment of consumer exposure to BPA in July 2013 and at that time asked for public input from all stakeholders to assist in forming a final report, which is expected to be completed in 2014.^[249]

In January 2014, EFSA presented a second part of the draft opinion which discussed the human health risks posed by BPA. The draft opinion was accompanied by an eight-week public consultation and also included adverse effects on the liver and kidney as related to BPA. From this it was recommended that the current TDI to be revised.^[250] In January 2015 EFSA indicated that the TDI was reduced from 50 to 4 µg/kg body weight/day - a recommendation, as national legislatures make the laws.^[248]

Denmark

In May 2009, the Danish parliament passed a resolution to ban the use of BPA in baby bottles, which had not been enacted by April 2010. In March 2010, a temporary ban was declared by the Health Minister.^[251]

Belgium

On March 2010, senator Philippe Mahoux proposed legislation to ban BPA in food contact plastics.^[252] On May 2011, senators Dominique Tilmans and Jacques Brotchi proposed legislation to ban BPA from thermal paper.^[253]

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.^[254][255] In April 2010, the AFFSA suggested the adoption of better labels for food products containing BPA.^[256]

On 24 March 2010, the French Senate unanimously approved a proposition of law to ban BPA from baby bottles.^[257] The National Assembly (Lower House) approved the text on 23 June 2010, which has been applicable law since 2 July 2010.^[258] 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.^[259]

On 9 October 2012, the French Senate adopted unanimously the law proposition to suspend manufacture, import, export and marketing of all food containers that include bisphenol A for 2015. The ban of bisphenol A in 2013 for food products designed for children less than 3-years-old was maintained.^[260]

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.^[261]

In October 2009, the German environmental organization Bund für Umwelt und Naturschutz Deutschland requested a ban on BPA for children's products, especially pacifiers,^[262] and products that make contact with food.^[263] In response, some manufacturers voluntarily removed the problematic pacifiers from the market.^[264]

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.^[265]

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.^[266]

Sweden

By May 26, 1995, 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.^[267][268] 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 BPA in cans containing food for children under the age of three.^[269]

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",^[270] 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".^[271]

Turkey

As of 10 June 2011, Turkey banned the use of BPA in baby bottles and other PC items produced for babies.^[272]

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 up to 50% in one study.^[273]

US public health regulatory history

Charles Schumer introduced a 'BPA-Free Kids Act of 2008' to the U.S. Senate seeking to ban BPA in any product designed for use by children and require the Center for Disease Control to conduct a study about the health effects of BPA exposure.^[274] It was reintroduced in 2009 in both Senate and House, but died in committee each time.^[151]

In 2008, the FDA reassured consumers that current limits were safe, but convened an outside panel of experts to review the issue. The Lang study was released, and co-author David Melzer presented the results of the study before the FDA panel.^[275] An editorial accompanying the Lang study's publication 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."^[88] The FDA was criticized that it was "basing its conclusion on two studies while downplaying the results of hundreds of other studies."^[275] Diana Zuckerman, president of the National Research Center for Women and Families, criticized the FDA in her testimony at the FDA's public meeting on the draft assessment of bisphenol A for use in food contact applications, that "At the very least, the FDA should require a prominent warning on products made with BPA".^[276][277] -->

In March 2009 Suffolk County, New York became the first county to pass legislation to ban baby beverage containers made with bisphenol A.^[278] By March 2009, legislation to ban bisphenol A had been proposed in both House and Senate.^[279] In the same month, Rochelle Tyl, author of two studies used by FDA to assert BPA safety in August 2008, said those studies did not claim that BPA is safe, because they were not designed to cover all aspects of the chemical's effects.^[280] In May 2009, Minnesota and Chicago were the first US jurisdictions to pass regulations limiting or banning BPA.^[281][282] In June 2009, the FDA announced its decision to reconsider the BPA safety levels.^[283] Grassroots political action led Connecticut to become the first US state to ban bisphenol A not only from infant formula and baby food containers, but also from any reusable food or beverage container.^[284] In July 2009, the California Environmental Protection Agency's Developmental and Reproductive Toxicity Identification Committee in the California Office of Environmental Health Hazard Assessment unanimously voted against placing Bisphenol A on the state's list of chemicals that are believed to cause reproductive harm. The panel was concerned over the growing scientific evidence showing BPA's reproductive harm in animals, found that there was insufficient data of the effects in humans.^[285] Critics pointed 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.^[286] In September, the US Environmental Protection Agency announced that it was evaluating BPA for an action plan development.^[287] 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.^[288]

On 15 January 2010, the FDA expressed "some concern", the middle level in its scale of concerns, about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children, and announced that it was taking reasonable steps to reduce human exposure to BPA in the food supply. However, the FDA was not recommending that families change the use of infant formula or foods, as it saw the benefit of a stable source of good nutrition as outweighing the potential risk from BPA exposure.^[3] On the same date, the Department of Health and Human Services released information to help parents to reduce children's BPA exposure.^[289] As of 2010 many US states were considering some sort of BPA ban.^[290]

In June 2010 the 2008–2009 Annual Report of the President's Cancer Panel was released and recommended: "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".^[291] 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.^[292] 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."^[293][294] In April 2011, 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.^[295]

In October 2011, California banned BPA from baby bottles and toddlers' drinking cups, effective 1 July 2013.^[296] By 2011, 26 states had proposed legislation that would ban certain uses of BPA. Many bills died in committee.^[297] In July 2011, the American Medical Association (AMA) declared feeding products for babies and infants that contain BPA should be banned. It recommended better federal oversight of BPA and clear labeling of products containing it. It stressed the importance of the FDA to "actively incorporate current science into the regulation of food and beverage BPA-containing products."^[298]

In 2012, the FDA concluded an assessment of scientific research on the effects of BPA and stated in the March 2012 Consumer Update 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" although recognizing "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."^[299] Yet on 17 July 2012, the FDA banned BPA from baby bottles and sippy cups. 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."^[96] Since manufacturers had already stopped using the chemical in baby bottles and sippy cups, the decision was a response to a request by the American Chemistry Council, the chemical industry's main trade association, who believed that a ban would boost consumer confidence.^[300] The ban was criticized as "purely cosmetic" by the Environmental Working Group, which stated that "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.^[95]

As of 2014, 12 states have banned BPA from children's bottles and feeding containers.^[301]

Chemical manufacturers reactions to bans

In March 2009 the six largest US producers of baby bottles decided to stop using bisphenol A in their products.^[302] The same month Sunoco, a producer of gasoline and chemicals, refused to sell BPA to companies for use in food and water containers for children younger than 3, saying it could not be certain of the compound's safety.^[303] In May 2009, Lyndsey Layton from the Washington Post accused manufacturers of food and beverage containers and some of their biggest customers of the public relations and lobbying strategy to block government BPA bans. She noted 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".^[304] In August 2009 the Milwaukee Journal Sentinel investigative series into BPA and its effects showed the Society of the Plastics Industry plans of a major public relations blitz to promote BPA, including plans to attack and discredit those who report or comment negatively on BPA and its effects.^[305][306]

BPA free, unknown substitute

The chemical industry over time responded to criticism of BPA by promoting "BPA-free" products. For example, in 2010, General Mills announced it had found a "BPA-free alternative" can liner that works with tomatoes. It said it would begin using the BPA-free alternative in tomato products sold by its organic foods subsidiary Muir Glen with that year's tomato harvest.^[307] As of 2014, General Mills has refused to state which alternative chemical it uses, and whether it uses it on any of its other canned products.^[308]

BPA free, epoxyfree

A minority of companies have stated what alternative compound(s) they use. Following an inquiry by Representative Edward Markey(D-Mass)^[308] seventeen companies replied, xxx said they were going BPA-free. None of the companies said they are or were going to use BPS; only four stated the alternative to BPA that they will be using; : ConAgra stated in 2013 "alternate liners for tomatoes are vinyl...New aerosol cans are lined with polyester resin", Eden Foods stated that only their "beans are canned with a liner of an "oleoresinous c-enamel that does not contain the endocrine disrupter BPA. Oleoresin is a mixture of oil and resin extracted from plants such as pine or balsam fir", Hain Celestial Group will use "modified polyester and/ or acrylic ... by June 2014 for our canned soups, beans, and vegetables", Heinz stated in 2011 it "intend[s] to replace epoxy linings in all our food containers…. We have prioritized baby foods", and in 2012 "no BPA in any plastic containers we use".^[308]

BPA substitute BPS

Some "BPA free" plastics are made from epoxy containing a compound called bisphenol S (BPS). BPS shares a similar structure and versatility to BPA and has been used in numerous products from currency to thermal receipt paper. Widespread human exposure to BPS was confirmed in an analysis of urine samples taken in the U.S., Japan, China, and five other Asian countries.^[309][310] Researchers found BPS in all the receipt paper, 87 percent of the paper currency and 52 percent of recycled paper they tested. 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.^[311] In a 2011 study 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."^[311] According to a 2013 study, BPS like BPA has been found to be an estrogen hormone disruptor even at extremely low levels of exposure.^[312][313]

References

Further reading

External links

Look up bisphenol a in Wiktionary, the free dictionary.

Wikimedia Commons has media related to: Bisphenol A

• International Chemical Safety Cards – Bisphenol A NIOSH, partly updated in October 2005, retrieved 8 April 2015
• Bisphenol A (BPA) in food FDA, November 2014, retrieved 8 April 2015
• BPA Data Gap Analysis FDA, undated, retrieved 8 April 2015
• Bisphenol A website Polycarbonate/BPA Global Group, American Chemistry Council, retrieved 8 April 2015
• Bisphenol A articles Environmental Health Perspectives by NIEHS, retrieved 8 April 2015 (200 articles)(open access)
• Bisphenol A ChemSub Online, retrieved 8 April 2015
• How to Protect Your Baby from BPA (Bisphenol A) Brochure, 2 pages, 2009, Massachusetts Department of Public Health, retrieved 8 April 2015
• Plastic Not Fantastic with Bisphenol A February 19, 2008 By David Biello, www.scientificamerican.com, retrieved 8 April 2015
• Report on BPA Endocrine/Estrogen Letter Vol. 9, No. 2&3 (174&175) 2003, 31 pages, retrieved 8 April 2015
• Hazard in a bottle. The plastics industry’s Pyrrhic victory Attempt to regulate BPA in California defeated, The Economist, 22 August 2008
• Alternatives to BPA containers not easy for U.S. foodmakers to find Lyndsey Layton. Washington Post, 23 February 2010. retrieved 8 April 2015
• Is It Time to End Concerns over the Estrogenic Effects of Bisphenol A? Richard Sharpe, Toxicological Sciences (2010) 114 (1): 1-4. doi: 10.1093/toxsci/kfp299 (open access)retrieved 8 April 2015
• Hand sanitizer may increase BPA absorption in Science Friday, October 24, 2014.
• Bisphenol-A News & Products News commentary on BPA Containing Products
• bisphenol A US FDA statement, 2008
• News Story about Canadian Study on BPA Free Marketed Bottles not being BPA Free gforceproducts.com, July 30 2009

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