health effects of bisphenol a health effects of bisphenol a bisphenol a controversy centers on concerns and debates about the biomedical significance of bisphenol a (bpa), which is a precursor to polymers that are used in some consumer products, including some food containers. the concerns began with the hypothesis that bpa is an endocrine disruptor, i.e. it mimics endocrine hormones and thus has the unintended and possibly far-reaching effects on people in physical contact with the chemical. chemical structure of bisphenol a(bpa). since 2008, several governments have investigated its safety, which prompted some retailers to withdraw polycarbonate products. the u.s. food and drug administration (fda) ended its authorization of the use of bpa in baby bottles and infant formula packaging, based on market abandonment, not safety. the european union and canada have banned bpa use in baby bottles. the u.s. fda states "bpa is safe at the current levels occurring in foods" based on extensive research, including two more studies issued by the agency in early 2014. the european food safety authority (efsa) reviewed new scientific information on bpa in 2008, 2009, 2010, 2011 and 2015: efsa's experts concluded on each occasion that they could not identify any new evidence which would lead them to revise their opinion that the known level of exposure to bpa is safe; however, the efsa does recognize some uncertainties, and will continue to investigate them. in february 2016, france stated that it intends to propose bpa as a reach regulation candidate substance of very high concern (svhc). the european chemicals agency agreed to the proposal in june 2017. production the bpa controversy has gained momentum because of the quantity of bpa produced by the chemical industry. world production capacity of bpa was 1 million tons in the 1980s, and more than 2.2 million tons in 2009. it is a high production volume chemical. in 2003, u.s. consumption was 856,000 tons, 72% of which used to make polycarbonate plastic and 21% going into epoxy resins. in the u.s., less than 5% of the bpa produced is used in food contact applications, but remains in the canned food industry and printing applications such as sales receipts. on 20 february 2018, packaging digest reported that "at least 90%" of food cans no longer contained bpa. some type 7 plastics may contain bisphenol a occurrence bpa is rarely encountered in industrial products: it is invariably bound in a polymeric structure. concerns therefore about exposure focus on the degradation, mainly by hydrolysis, of these polymers and the plastic objects derived therefrom. polycarbonate plastic, which is formed from bpa, is used to make a variety of common products including baby and water bottles, sports equipment, medical and dental devices, dental fillings sealants, cds and dvds, household electronics, eyeglass lenses, foundry castings, and the lining of water pipes. bpa is also used in the synthesis of polysulfones and polyether ketones, as an antioxidant in some plasticizers, and as a polymerization inhibitor in pvc. epoxy resins derived from bisphenol a are used as coatings on the inside of almost all food and beverage cans; however, due to bpa health concerns, in japan epoxy coating was mostly replaced by pet film. bisphenol a is a preferred color developer in carbonless copy paper and thermal point of sale receipt paper. when used in thermal paper, bpa is present as "free" (i.e., discrete, non-polymerized) bpa, which is likely to be more available for exposure than bpa polymerized into a resin or plastic. upon handling, bpa in thermal paper can be transferred to skin, and there is some concern that residues on hands could be ingested through incidental hand-to-mouth contact. furthermore, some studies suggest that dermal absorption may contribute some small fraction to the overall human exposure. european data indicate that the use of bpa in paper may also contribute to the presence of bpa in the stream of recycled paper and in landfills. although there are no estimates for the amount of bpa used in thermal paper in the united states, in western europe, the volume of bpa reported to be used in thermal paper in 2005/2006 was 1,890 tonnes per year, while total production was estimated at 1,150,000 tonnes per year. (figures taken from 2012 epa draft paper.) studies document potential spreading and accumulation of bpa in paper recycling, suggesting its presence for decades in paper recycling loop even after a hypothetical ban. epoxy resin may or may not contain bpa, and is employed to bind gutta percha in some root canal procedures. biomedical history in the early 1930s, the british biochemist edward charles dodds tested bpa as an artificial estrogen, but found it to be 37,000 times less effective than estradiol. dodds eventually developed a structurally similar compound, diethylstilbestrol (des), which was used as a synthetic estrogen drug in women and animals until it was banned due to its risk of causing cancer; the ban on use of des in humans came in 1971 and in animals, in 1979. bpa was never used as a drug. bpa's ability to mimic the effects of natural estrogen derives from the similarity of phenol groups on both bpa and estradiol, which enable this synthetic molecule to trigger estrogenic pathways in the body. typically phenol-containing molecules similar to bpa are known to exert weak estrogenic activities, thus it is also considered an endocrine disrupter (ed) and estrogenic chemical. xenoestrogens is another category the chemical bpa fits under because of its capability to interrupt the network that regulates the signals which control the reproductive development in humans and animals. in 1997, adverse effects of low-dose bpa exposure in laboratory animals were first proposed. modern studies began finding possible connections to health issues caused by exposure to bpa during pregnancy and during development. see public health regulatory history in the united states and chemical manufacturers' reactions to bans. as of 2014, research and debates are ongoing as to whether bpa should be banned or not. err-γ (modeled here) has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue. a 2007 study investigated the interaction between bisphenol a's and estrogen-related receptor γ (err-γ). this orphan receptor (endogenous ligand unknown) behaves as a constitutive activator of transcription. bpa seems to bind strongly to err-γ (dissociation constant = 5.5 nm), but only weakly to the er. bpa binding to err-γ preserves its basal constitutive activity. it can also protect it from deactivation from the serm 4-hydroxytamoxifen (afimoxifene). this may be the mechanism by which bpa acts as a xenoestrogen. different expression of err-γ in different parts of the body may account for variations in bisphenol a effects. for instance, err-γ has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue. bpa has also been found to act as an agonist of the gper (gpr30). safety health effects the largest exposure humans have to bpa is by mouth from such sources as food packaging, the epoxy lining of metal food and beverage cans, and plastic bottles. according to the european food safety authority "bpa poses no health risk to consumers of any age group (including unborn children, infants and adolescents) at current exposure levels". but in 2017 the european chemicals agency concluded that bpa should be listed as a substance of very high concern due to its properties as an endocrine disruptor. in 2012, the united states' food and drug administration (fda) banned the use of bpa in baby bottles intended for children under 12 months. the natural resources defense council called the move inadequate, saying the fda needed to ban bpa from all food packaging. the fda maintains that the agency continues to support the safety of bpa for use in products that hold food. the u.s. 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 u.s. study on dietary exposure of adult humans to bpa, saying, "this corroborates other independent studies and adds to the evidence that bpa is rapidly absorbed, detoxified, and eliminated from humans – therefore is not a health concern." the endocrine society said in 2015 that the results of ongoing laboratory research gave grounds for concern about the potential hazards of endocrine-disrupting chemicals – including bpa – in the environment, and that on the basis of the precautionary principle these substances should continue to be assessed and tightly regulated. a 2016 review of the literature said that the potential harms caused by bpa were a topic of scientific debate and that further investigation was a priority because of the association between bpa exposure and adverse human health effects including reproductive and developmental effects and metabolic disease. united states expert panel conclusions in 2007, the u.s. federal government invited experts to chapel hill, north carolina to perform a scientific assessment of literature on bpa. thirty-eight experts in fields involved with bisphenol a gathered in chapel hill, north carolina to review several hundred studies on bpa, many conducted by members of the group. at the end of the meeting, the group issued the chapel hill consensus statement, which stated "bpa at concentrations found in the human body is associated with organizational changes in the prostate, breast, testis, mammary glands, body size, brain structure and chemistry, and behavior of laboratory animals." the chapel hill consensus statement stated that average bpa levels in 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). following the chapel hill statement, the us national toxicology program – center for the evaluation of risks to human reproduction (ntp – cerhr), sponsored another literature assessment. the report, released in 2008, noted that "the possibility that bisphenol a may alter human development cannot be dismissed". despite this report, the us food and drug administration (fda) bpa task force (formed in april 2008), concluded that products containing bpa were safe. in 2009, the fda science board subcommittee on bisphenol a, an external committee assigned to review the fda's report "concluded that the fda failed to conduct a rigorous or extensive exposure assessment", leading the us environmental protection agency (epa) to conduct their own assessment. the united states federal interagency working group (fiw) included a goal to reduce bpa exposure in the 2 december 2010 release of their 2020 healthy people national objectives for improving the health of all americans. metabolic disease main article: obesity numerous animal studies have demonstrated an association between endocrine disrupting chemicals (including bpa) and obesity. however, the relationship between bisphenol a exposure and obesity in humans is unclear. cohort studies have shown there has been an association of prenatal bpa exposure and increased body fat percentage at age 7 and increased bmi by age 9. not all studies have shown a positive relationship between bpa exposure and obesity, further studies on the effects of bpa on metabolic diseases need to take diet into consideration to remove any influence it might have on the outcome. proposed mechanisms for bpa exposure to increase the risk of obesity include bpa-induced thyroid dysfunction, activation of the ppar-gamma receptor, and disruption of neural circuits that regulate feeding behavior. bpa works by imitating the natural hormone 17b-estradiol. in the past bpa has been considered a weak mimicker of estrogen but newer evidence indicates that it is a potent mimicker. when it binds to estrogen receptors it triggers alternative estrogenic effects that begin outside of the nucleus. this different path induced by bpa has been shown to alter glucose and lipid metabolism in animal studies. there are different effects of bpa exposure during different stages of development. during adulthood, bpa exposure modifies insulin sensitivity and insulin release without affecting weight. thyroid function main article: thyroid