Bisphenol A (BPA) is a synthetic chemical compound produced in the United States in large quantities, approximately 2.3 billion pounds annually. BPA is not found in nature. Two notable uses are in manufacturing certain forms of plastic: relatively hard, clear polycarbonate (PC), and epoxy resins that are used to line food cans. Under certain conditions, BPA may migrate or leach (i.e., be released) from PC containers and plastic-lined cans into the food or liquids they contain. The widespread use of BPA and the potential for human exposure, together with accumulating scientific evidence about possible BPA toxicity, led the National Toxicology Program (NTP) at the National Institutes of Health (NIH) to select BPA for a comprehensive review. NTP released a draft "brief" on BPA in April 2008, and a final monograph in September 2008. NTP's conclusions prompted some to call for federal restrictions on certain BPA uses, and sparked congressional and media interest in the past and current positions of the Food and Drug Administration (FDA). FDA regulates BPA and other chemicals used in food containers, and until recently maintained that current uses of BPA are safe. In August 2008, FDA reiterated this finding in a published risk assessment. The finding prompted criticism from an agency advisory committee and others. FDA is now reviewing its BPA risk assessment for food exposures, and considering exposures from other products it regulates (such as drugs and medical devices), in response to the committee's critique. In January 2010, FDA announced that it is evaluating recent scientific evidence and conducting additional studies. FDA has announced no further subsequent action. Exposure to large amounts of BPA is acutely toxic to humans and animals, but typical levels of BPA exposure from plastics are low. The possibility of human health effects from exposure to low doses of BPA is controversial, although animal evidence of possible harmful effects has been mounting for about 10 years. It is clear that BPA is capable of interfering with the action of estrogen, an important regulator of reproduction and development. (Interference with hormonal action is often referred to as endocrine disruption .) Therefore, many recent studies have focused on the potential effects of low levels of BPA exposure on fetal or newborn rats or mice. Some of the developmental effects seen among rodents exposed to low doses of BPA include changes in brains and behaviors; precancerous lesions in the prostate and mammary glands; altered prostate and urinary tract development; and early onset of puberty. These low-dose experiments are difficult to conduct, in part because BPA is ubiquitous in the environment. Thus, different studies have produced different results. Scientists employed by BPA manufacturers and some independent contractors argue that the hundreds of studies conducted so far have produced inconsistent results and are insufficient justification for more stringent BPA regulation. Other scientists maintain that well-designed and executed studies of sufficient statistical power on sensitive strains of laboratory rodents have clearly demonstrated the toxicity of low doses of BPA in mammals, and justify actions to reduce exposure for potentially vulnerable human populations. In 2001, an expert workshop to evaluate the data on low-dose effects of endocrine disruptors concluded that biological effects have been shown to occur in rodents following exposure to some estrogenic compounds at very low levels. The question remains whether those effects would adversely affect rodent health and are a useful predictor of human health impacts. Some researchers have proposed that low levels of BPA exposure may interfere with functions other than reproduction and development, potentially causing additional types of health effects. The body of research in this area is less extensive than that into BPA's potential effects on reproductive hormones, but this appears to be an active field of investigation. Recent studies using animal models, human cells, or epidemiological data on humans have demonstrated effects on the regulation of insulin or other metabolic hormones, leading authors to posit that environmental BPA exposure may increase susceptibility to obesity and diabetes. Some investigators have called for long-term studies to determine whether high BPA levels are associated with specific health effects later on. Such long-term, prospective studies would provide stronger evidence, one way or the other, regarding a possible causal role of BPA on adverse health effects. The so-called "low-dose hypothesis" is controversial because it appears to challenge a tenet of toxicology, that "the dose makes the poison." That is, at some low level of exposure, any potentially toxic chemical is innocuous, and conversely, above some other level of exposure, any substance may be toxic. The low-dose hypothesis does not necessarily contradict the traditional tenet, but it states that some chemicals that are known to be toxic at high levels of exposure, and that may have no observable health effect (using traditional toxicological methods), may nonetheless harm health at a still lower level of exposure. In other words, endocrinologists argue, the relationship between the dose and effect is not always in the direction that more exposure is worse. Moreover, health effects from a low exposure may differ in type from effects observed at a higher dose. For example, some scientists who specialize in the study of hormones say that endocrine-disrupting chemicals like BPA have been shown to cause adverse developmental effects at a level of exposure lower than that at which no adverse effects have been identified using traditional high-dose test methods, particularly when the lower-level exposure occurred at a critical point during fetal development. Such effects are plausible, these scientists argue, because hormones work by regulating or modulating (i.e., by stimulating or dampening) responses of organs so as to maintain optimal physiological conditions that will vary depending on the tissue, dose, and timing in development. Normal responses of endocrine systems sometimes are regulated by very slight changes in hormone levels, and changes in these hormonal systems could be caused by low-dose exposure to external agents such as BPA. Bisphenol A exposure in the general population comes primarily from consumption of food and beverages. The latest national survey by the Centers for Disease Control and Prevention (CDC) found BPA in the urine of more than 90% of the people studied, which included children six years of age and older and adults. Among these people, the highest average concentrations were found in children. The NTP monograph estimates that the highest daily intakes of BPA occur in infants and children. BPA has been found in human breast milk; however, the NTP monograph estimates that infants who are formula-fed have higher daily BPA intake levels than those who are breast-fed, because there is more BPA in infant formula than in breast milk, and because BPA may increase when PC baby bottles are used for formula feeding, especially if the bottles are heated. These BPA exposure levels in humans "are similar to levels of [BPA] associated with several 'low' dose laboratory animal findings of effects on the brain and behavior, prostate and mammary gland development, and early onset of puberty in females," according to the NTP monograph. More recently, some scientists have concluded that sources of exposure other than food may be important. For example, there have been calls for assessments of human exposure from other FDA-regulated products such as drugs and medical devices. Some are especially concerned about medical devices, such as feeding and breathing tubes, that could leach the chemical into tissues, and, in particular, the possible health effects of such exposures in premature or critically ill infants, in whom such products may be used for long periods of time. Other potential sources of exposure are regulated by the Environmental Protection Agency (EPA). For example, in July 2010, several studies indicated that skin contact with BPA in thermal paper coatings (for example, the paper used for cash register receipts) may contribute significantly to human exposure. Depending on its use, BPA is potentially regulated by various regulatory agencies, including the Consumer Product Safety Commission (CPSC), the Occupational Safety and Health Administration (OSHA), EPA, and FDA. EPA is responsible for protecting public health and the environment from unreasonable risks associated with production, interstate commerce, and use of industrial chemicals, including BPA, when they are not specifically regulated under other federal laws, such as those covering alcohol, food, drugs, or consumer products. EPA has made BPA the focus of a "chemical action plan" to gather information and possibly to regulate the chemical. The plan was released in March 2010. It proposes to include BPA on a list of chemicals of concern, a list created under the authority of the Toxic Substances Control Act (TSCA), section 5(b)(4), "on the basis of its potential for long-term adverse effects on growth, reproduction and development in aquatic species at concentrations similar to those found in the environment." A chemical of concern is "a substance that may present an unreasonable risk of injury to the environment." Listed chemicals may be subject to additional rulemaking. In addition, EPA sent an advance notice of proposed rulemaking to the White House Office of Management and Budget in December 2010. The notice requests comment on whether it should initiate rulemaking under section 4(a) of TSCA to develop data with respect to effects on the environment. Specifically, EPA intends to request comment on requiring toxicity testing to determine the potential for BPA to cause endocrine-related adverse effects in environmental organisms at low concentrations. The ANPRM will also seek comment on requiring sampling and monitoring of surface water, ground water, drinking water, soil, sediment, sludge, and landfill leachate in the vicinity of expected BPA releases to determine whether potentially sensitive organisms may currently be exposed to concentrations of BPA in the environment that are at or above levels of concern for adverse effects, including endocrine-related effects. Finally, EPA has initiated "collaborative alternatives assessment activities" under its Design for the Environment (DfE) program. These activities aim to reduce BPA releases and environmental exposures. The first partnership is searching for alternatives to BPA in thermal paper.