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Bisphenol A

Bisphenol A, commonly abbreviated as BPA, is an organic compound with two phenol functional groups. It is a difunctional building block of several important polymers and polymer additives. With an annual production of 2–3 million tonnes, it is an important monomer in the production of polycarbonate.

Suspected of being hazardous to humans since the 1930s, concerns about the use of Bisphenol A in consumer products grabbed headlines in 2008 when several governments issued reports questioning its safety, and some retailers pulled products made from it off their shelves.

Synthesis

Bisphenol A was first reported by A.P. Dianin in 1891. It is prepared by the condensation of acetone (hence the suffix A in the name) with two equivalents of phenol. The reaction is catalyzed by an acid, such as hydrochloric acid (HCl) or a sulfonated polystyrene resin. Typically, a large excess of phenol is used to ensure full condensation:

(CH₃)₂CO + 2 C₆H₅OH → (CH₃)₂C(C₆H₄OH)₂ + H₂O

A large number of ketones undergo analogous condensation reactions. The method is efficient and the only by-product is water.

Use

Products containing or made from Bisphenol A have been in commerce for more than 50 years, and its current uses are numerous. It is used in the synthesis of polyesters, polysulfones, and polyether ketones, as an antioxidant in some plasticizers, and as a polymerization inhibitor in PVC. It is a key monomer in production of polycarbonate plastic and epoxy resins. 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, lenses, and household electronics. Polycarbonate is used in the manufacture of all CDs and DVDs. Epoxy resins are used as coatings on the inside of almost all food and beverage cans. It is also a precursor to the flame retardant, tetrabromobisphenol A, and was formerly used as a fungicide.

Global production of bisphenol A in 2003 was estimated to be over 2 million metric tonnes (t). In the U.S., it is manufactured by Bayer MaterialScience, Dow Chemical Company, General Electric, Hexion Specialty Chemicals, and Sunoco Chemicals. In 2004, these companies produced just over 1 million t of bisphenol A, up from just 7,260 t in 1991. In 2003, annual U.S. consumption was 856,000 t, 72% of which was used to make polycarbonate plastic and 21% going into epoxy resins.

Health effects

Bisphenol A has low acute toxicity, with an oral LD₅₀ of 3250 mg/kg in rats, but it is an endocrine disruptor. Low doses of Bisphenol A can mimic the body's own hormones, possibly causing negative health effects. There is thus concern that long term low dose exposure to bisphenol A may induce chronic toxicity in humans.

Animal Studies

The first evidence of the estrogenicity of bisphenol A came from experiments in the 1930s in which it was fed to ovariectomized rats, but it was not until 1997 that adverse effects of low-dose exposure on laboratory animals were first reported. Since then, its endocrine disrupting properties have been extensively investigated, and more than 100 studies have been published "rais[ing] health concerns" about the chemical.

Early development appears to be the period of greatest sensitivity to its effects, and studies have demonstrated developmental toxicity, carcinogenic effects, and possible neurotoxicity at low doses in animal models (see table below). Recent studies suggest it may also be linked to obesity by triggering fat-cell activity and have confirmed that bisphenol A exposure during development has carcinogenic effects and produce precursors of breast cancer. However, neither the U.S. Environmental Protection Agency nor the International Agency for Research on Cancer have evaluated Bisphenol A for possible carcinogenic activity. Most recently, a 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 the United States Environmental Protection Agency's (EPA) maximum safe dose of 50 µg/kg/day. This research found a connection between BPA and interferance with brain cell connections vital to memory, learning and mood. In 2007, a consensus statement by 38 experts on bisphenol A concluded that average levels in people are above those that cause harm to animals in laboratory experiments, and 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) 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."

In April 2008, Health Canada released its Draft Screening Assessment for bisphenol A, which concluded that the chemical may pose some risk to infants and proposed classifying the chemical as "'toxic' to human health and the environment. This action follows Canadian regulators selection of bisphenol A in 2006 as one of 200 substances deserving of thorough safety assessments because preliminary studies had found it to be "inherently toxic"; the chemical had not previously been studied by them in depth, having been accepted under grandfather clauses when stricter regulations were passed in the 1980s.

In contrast to the recent actions in North America, earlier assessment by governments in other regions found no cause for concern. In January 2006 the German regulators announced that polycarbonate baby bottles are safe and stated that published research on the health effects of Bisphenol A is "difficult to interpret and [is] occasionally contradictory". Also that year by the European Union’s Food Safety Authority reached a similar conclusion, expressing "considerable reservations" about the biological significance and robustness of the low-dose exposure studies on rodents. In 2007 Japan also concluded that for individuals in that country, "the current exposure levels of BPA will not pose any unacceptable risk to human health [and] that a ban is not needed.

Some toxicologists and regulatory agencies have criticized low-dose toxicity studies, especially those that involved injecting bisphenol A directly into animals, since human exposures typically involve ingestion and subsequent metabolism in the liver, and the experimental design of a few of these early studies has also been questioned. On the other hand, studies have also appeared pointing out flaws in chemical-industry-funded studies that found no evidence of adverse effects from low dose exposure, and a study from 2008 concluded that blood levels of bisphenol A in neonatal mice are the same whether it is injected or ingested.

Selected studies on low dose bisphenol A exposure in animals

Dose (µg/kg/day)	Effects (measured in studies of mice or rats, descriptions are from Environmental Working Group)	Study Year
0.025	Permanent changes to genital tract	2005
0.025	Changes in breast tissue that predispose cells to hormones and carcinogens	2005
2	increased prostate weight 30%	1997
2	lower bodyweight, increase of anogenital distance in both genders, signs of early puberty and longer estrus.	2002
2.4	Decline in testicular testosterone	2004
2.5	Breast cells predisposed to cancer	2007
10	Prostate cells more sensitive to hormones and cancer	2006
10	Decreased maternal behaviors	2002
30	Reversed the normal sex differences in brain structure and behavior	2003
50	U.S. human exposure limit (not a result from an animal study, but a guideline set by EPA)	1998

The Lang Study

The first study of bisphenol A's effects on humans 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 high bisphenol A levels were significantly associated with heart disease, diabetes, and abnormally high levels of certain liver enzymes. An editorial in the same issue notes that while this preliminary study needs to be confirmed and cannot prove causality, there is precedent for analogous effects in animal studies, which "add[s] biological plausibility to the results reported by Lang et al."

Human exposure to bisphenol A

Bisphenol A has been known to leach from the plastic lining of canned foods and, to a lesser degree, polycarbonate plastics that are cleaned with harsh detergents or used to contain acidic or high-temperature liquids. While most exposure is through diet, exposure can also occur through air and through skin absorption.

Studies 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. 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). The most sensitive animal studies show effects at much lower doses, while the EPA considers exposures up to 50 µg/kg/day to be safe.

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. The National Toxicology Panel recommends avoiding microwaving food in plastic containers, putting plastics in the dishwasher, or using harsh detergents, to avoid leaching.

Population	Estimated daily bisphenol A intake, μg/kg/day. Table adapted from the National Toxicology Program Expert Panel Report.
Infant (0–6 months) formula-fed	1–11
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	0.008–1.5

Government and industry response

Canada

After the release of the Health Canada assessment in April 2008, 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. 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.

United States

April 2008

As of the release of NTP and Health Canada reports in April, 10 U.S. states, including California, Maryland, Connecticut 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 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 ACC said that bisphenol A does not pose a risk to consumers and called on the Food and Drug Administration to review the chemical. The ACC also called the media coverage of the controversy "unnecessarily confusing and frightening the public." 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."

September 2008

In September, the NTP finalized their report on Bisphenol A, finding "some concern" that infants were at risk from exposure to the chemical. At the same time, the FDA reassured consumers that it was 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." The Union of Concerned Scientists similarly criticized the agency saying, "We're concerned that the FDA is basing its conclusion on two studies while downplaying the results of hundreds of other studies...This appears to be a case of cherry-picking data with potentially high cost to human health." The chemical industry had earlier been criticized by Democrats and their allies. David Michaels, who served in the Clinton Administration, told the Washington Post that "Tobacco figured this out, and essentially it's the same model … If you fight the science, you're able to postpone regulation and victim compensation, as well. As in this case, eventually the science becomes overwhelming. But if you can get five or 10 years of avoiding pollution control or production of chemicals, you've greatly increased your product."

In contrast, the American Chemistry Council was skeptical of the latest study: "Due to inherent limitations in study design, this new study cannot support a conclusion that bisphenol A causes any disease...The weight of scientific evidence continues to support the conclusion of governments worldwide that bisphenol A is not a significant health concern at the trace levels present in some consumer products."

Environmental risk

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.

Identification in plastics

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. When such plastics are exposed to hot liquids, bisphenol A leaches out 55 times faster than it does under normal conditions, at up to 32 ng/hour. Type 3 (PVC) can also contain bisphenol A as antioxidant in plasticizers. Types 1 (PET), 2 (HDPE), 4 (LDPE), 5 (polypropylene), and 6 (polystyrene) do not use bisphenol A during polymerization or package forming.