FRAMING HEALTH MATTERS
`
`The Politics of Plastics: The Making and Unmaking
`of Bisphenol A ‘‘Safety’’
`
`Sarah A. Vogel, PhD, MPH, MEM
`
`Bisphenol A (BPA), a synthetic chemical used in the production of plastics
`since the 1950s and a known endocrine disruptor, is a ubiquitous component of
`the material environment and human body. New research on very-low-dose
`exposure to BPA suggests an association with adverse health effects, including
`breast and prostate cancer, obesity, neurobehavioral problems, and reproduc-
`tive abnormalities. These findings challenge the long-standing scientific and
`legal presumption of BPA’s safety. The history of how BPA’s safety was defined
`and defended provides critical insight into the questions now facing lawmakers
`and regulators: is BPA safe, and if not, what steps must be taken to protect the
`public’s health? Answers to both questions involve reforms in chemical policy,
`with implications beyond BPA. (Am J Public Health. 2009;99:S559–S566. doi:10.
`2105/AJPH.2008.159228)
`
`‘‘US cites fears on chemical in plastics’’ was the
`headline of an April14, 2008, front-page article in
`the Washington Post.1 The chemical of concern
`was BPA, used in the production of plastics found
`in numerous commercial products, including
`laptops, cell phones, baby bottles, water main
`pipes, laboratory and hospital equipment, and
`food containers.
`BPA made national headline news because
`of high economic, scientific, and political stakes
`involved in the debate about its safety. With
`over 6 billion pounds of BPA produced
`globally every year and continued growth
`expected in the coming years, the market for
`BPA is large and extensive.2 Recent biomoni-
`toring studies indicate that exposure to BPA is
`widespread,3,4 and this ubiquity has raised
`concerns—or, as the April 2008 article noted,
`‘‘fears’’—regarding the health effects of exposure.
`A growing body of laboratory research on very
`low doses of BPA—levels that fall below the
`regulatory safety standard—reports associations
`with increased rates of breast and prostate
`cancer, chromosomal abnormalities, brain and
`behavioral abnormalities, and metabolic disor-
`ders.5 In response to this new research on
`exposure to BPA and its health effects, state and
`federal lawmakers in the United States and
`around the world are faced with the critical
`question of whether BPA is safe.
`In April 2008, the Canadian government took
`a precautionary approach, classifying BPA as
`
`‘‘toxic’’ under the Canadian Environment Pro-
`tection Act and is considering a limited ban.6,7 By
`contrast, the European Food Safety Authority
`and the US Food and Drug Administration (FDA)
`declared BPA safe at estimated levels of human
`exposure.8,9 Retailers, however, chose not to wait
`for a regulatory decision and began pulling
`plastic water and baby bottles made with BPA
`from the shelves in 2008. In early 2009, a bill
`banning BPA in children’s food containers was
`introduced in Congress.10 The safety and future
`of BPA remain resolutely uncertain.
`There are two issues to be resolved in this
`current debate about BPA safety. First, what is
`the best available science for assessing the safety
`of BPA? And second, if BPA is unsafe, why was it
`presumed to be safe for the past 50 years and
`how did this understanding change? To answer
`these questions demands a critical examination of
`the historical process by which BPA’s safety was
`defined and the ways this assumption was
`ultimately challenged by new scientific research.
`
`Plastics and Estrogenicity
`
`Although BPA was first synthesized in 1891,
`exploration of its commercial possibilities did not
`occur until the period between the two world
`wars. While in pursuit of a synthetic estrogen,
`Edward Charles Dodds, a British medical re-
`searcher at the University of London, identified
`the estrogenic properties of BPA in the
`
`mid-1930s.11 For the next several years, Dodds
`continued testing chemical compounds in search
`of what he later referred to as the ‘‘mother
`substance,’’ a powerful estrogenic substance that
`he identified as diethylstilbestrol (DES).12
`DES was commercialized in the 1940s for the
`purported therapeutic treatment of numerous
`female ‘‘problems’’ related to menstruation,
`menopause, nausea during pregnancy, and for
`the prevention of miscarriages.13 Meat producers
`injected animals with the synthetic estrogen to
`increase meat production. For 30 years, DES was
`prescribed to millions of pregnant women and
`injected into millions of animals despite persis-
`tent concerns about its carcinogenicity.14 In 1971,
`the drug was finally banned for use in pregnant
`women after the first epidemiological studies
`reported rare vaginal cancers in young women
`exposed to DES while in their mothers’ wombs.15
`After considerable debate and controversy, the
`FDA finally banned all forms of DES use in meat
`production in 1979.14,16
`BPA never found use as a drug; its future was
`in plastics. Several years after Dodds published
`his research on synthetic estrogens, chemists in
`the United States and Switzerland synthesized
`the first epoxy resins using BPA, and commercial
`production began in the early 1950s.17 Epoxy
`resins quickly found extensive use throughout
`industrial production as protective coatings on
`metal equipment, piping, steel drums, and the
`interior of food cans, as well as adhesives used to
`lay flooring and seal teeth. As a manager of Shell
`Chemical Company, one of the first producers of
`BPA and epoxy resins, noted in the mid-1970s,
`epoxy resins ‘‘now serve virtually every major US
`industry, either directly or indirectly.’’18(p27)
`In 1957, chemists at Bayer and General
`Electric discovered another use for BPA—when
`polymerized (linked together in long chains)
`it forms a hard plastic called polycarbonate.
`This plastic is strong enough to replace steel
`and clear enough to replace glass. It found new
`uses in electronics, safety equipment, automo-
`biles, and food containers. With markets for
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`FRAMING HEALTH MATTERS
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`diminished levels, the FDA has long considered
`BPA in food to be safe. However, the agency
`established no regulatory standard for the
`chemical until1988. (No regulatory standard was
`ever set for workplace exposure.)
`But the 1958 law also included a separate
`standard for the safety of carcinogenic
`chemicals, the Delaney Clause, which stated that
`carcinogens were hazards per se regardless of
`dose.24 The scientific principle at the time used
`to support dual standards for chemical safety—
`for carcinogens (hazards per se) and noncarcin-
`ogens (hazards defined by dose)—was the con-
`tention that carcinogens functioned differently
`than toxic compounds; a carcinogen, for exam-
`ple, could have low toxicity.25 Although BPA’s
`general toxicity was low, no examination of its
`carcinogenicity occurred until the late 1970s.
`
`The Regulatory Toxicology of
`Bisphenol A
`
`By the mid-1970s, the high-volume produc-
`tion of BPA and the large number of workers
`possibly exposed to the chemical captured the
`attention of researchers at the National Cancer
`Institute (NCI) responsible for coordinating
`the National Carcinogenesis Bioassay Program.
`In 1977, the NCI initiated the first carcinogen-
`esis study of BPA. The carcinogenesis study
`followed the standard procedures for assessing
`cancer risk: it was a 2-year, adult rodent model
`experiment that exposed animals daily to
`high doses at and just below the toxic threshold
`on the assumption that if a carcinogenic effect
`was present it would more likely be seen at
`high doses.26 The assumption that high-dose
`testing and adult animals could provide sufficient
`data for interpreting safety for a diverse popula-
`tion was a fundamental presumption of regula-
`tory toxicity testing. Such a study design was not
`designed to investigate the transplacental effects
`(exposure effects on the offspring whose mother’s
`had been exposed) of estrogenic compounds
`or hormonal carcinogenesis, areas of
`expanding research—particularly regarding DES
`carcinogenicity—in the 1970s.27–29
`During the course of the BPA study, from
`1977 to 1979, responsibility for the Carcino-
`genesis Bioassay Program passed from the NCI
`to the newly established National Toxicology
`Program (NTP), created to coordinate federal
`toxicological research. During this transfer,
`
`both plastics booming over the subsequent two
`decades, the production of BPA in the United
`States reached half a billion pounds by the late
`1970s.2
`As BPA found more markets and major US
`producers (General Electric, Shell Chemical,
`Dow Chemicals, and Union Carbide in the first
`20 years of production) added capacity, the
`chemical remade the material as well as the
`molecular environment. The ubiquity of BPA
`products meant there were more and more
`potential sources of exposure to this synthetic
`estrogen. And yet, although BPA’s estrogenlike
`properties (or estrogenicity) were never com-
`pletely forgotten, its safety was defined by its
`commercial use in plastics and, accordingly, by
`its toxic rather than hormonelike properties.
`
`Defining Chemical Safety
`
`How, then, was BPA’s safety defined, scien-
`tifically and legally? For the past 50 years,
`BPA’s safety, along with that of most chemicals,
`has been defined according to the scientific
`presumption that the dose–response relation-
`ship is monotonic—that is, with increasing dose
`the effect increases and vice versa. Thus, at
`some diminished level of dose, the effect is
`marginal. Legally, this is called the de minimis
`standard.
`This legal interpretation of chemical safety
`as related to dose was included in the 1958
`Federal Food, Drug and Cosmetics Act,19 which
`directed the FDA to regulate chemicals in food.
`Prior to this law, hazards were prohibited
`from the food supply as dangerous per se,
`regardless of dose.20 The 1958 law changed this
`by requiring that companies obtain FDA
`approval for the use of chemicals that directly
`or indirectly contaminated food during its pro-
`duction, processing, packaging, and distribution.
`This included thousands of chemicals, from pre-
`servatives and pesticide residues to chemicals
`used in packaging.
`Because BPA migrates from epoxy resins
`and polycarbonates used in food packaging and
`production, the FDA considered the chemical
`to be an indirect food additive.21 Early research
`demonstrating BPA’s low general toxicity22 and
`rapid metabolism in animals,23 combined with
`the low levels at which it contaminates food,
`provided support for its approved use in food
`packaging. In other words, at very low or
`
`Congress asked the General Accounting Office
`(GAO) to investigate the quality of the private
`laboratories conducting research for the Car-
`cinogenesis Bioassay Program. At the time, the
`quality of research and federal oversight of
`private laboratories were under considerable
`scrutiny; in 1976, the federal government
`conducted an extensive investigation of
`Industrial Bio-Test, one of the largest private
`research laboratories conducting chemical
`safety tests in the United States, and found
`extensive fraudulent practices.30,31 Several
`years later, in 1979, the GAO’s investigation
`found problems with several facilities working
`under contract for the NCI. The worst conditions
`were reported at Litton Biotechnics, where the
`investigators found maintenance problems, poor
`quality-control measures, and poor pathology
`practices, all of which, they concluded, could
`have affected the outcome of any research.32
`Litton Biotechnics was the laboratory hired to
`conduct the carcinogenesis bioassay of BPA in
`1977.26
`Despite the GAO’s findings, neither the NCI
`nor the NTP required a reassessment of BPA’s
`carcinogenicity, and in 1982, the NTP released
`the final report on the carcinogenesis study.
`With only 2 categories of evidence—‘‘convincing
`evidence’’ or ‘‘no convincing evidence’’—used
`to describe data at the time,33 the report found
`‘‘no convincing evidence’’ of carcinogenicity, with
`the following conditions added:
`
`[T]hat ‘‘bisphenol A is not carcinogenic’’ should
`be qualified to reflect the facts that leukemia in
`male rats showed a significant positive trend, that
`leukemia incidence in high-dose male rats was
`considered not significant only on the basis of the
`Bonferroni criteria, that leukemia incidence was
`also elevated in female rats and male mice, and
`that the significance of interstitial-cell tumors of
`the testes in rats was dismissed on the basis of
`historical control data.26(ix)
`
`This study provided the basis for the first
`regulatory safety standard for BPA set by the
`Environmental Protection Agency (EPA) in
`1988 and adopted by the FDA as a reference
`dose. Considering BPA to be a noncarcinogen,
`the EPA used the lowest dose from the carci-
`nogenesis study as the ‘‘lowest observed ad-
`verse effect level’’ and divided this number by
`an uncertainty factor of 1000 to determine
`a reference dose of 50 lg/kg of body weight
`per day.34 (The 1000-fold uncertainty factor was
`the safety margin between the lowest observed
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`physiologists, and toxicologists—was a scientific
`consensus statement, ‘‘Chemically-Induced
`Alterations in Sexual Development,’’ or the
`Wingspread Consensus Statement of 1991, that
`declared ‘‘with certainty’’ that some chemicals in
`the environment had the potential to disrupt the
`endocrine system of humans and wildlife.40
`Although the term ‘‘endocrine disruption’’
`was new at the time, the hypothesis built on
`decades of wildlife and laboratory research on
`synthetic and environmental estrogens.
`Beginning in 1979, researchers interested in
`the study of synthetic estrogenic compounds
`found in the environment, or ‘‘xenoestrogens,’’
`gathered every several years at the ‘‘Estrogens
`in the Environment’’ meeting, organized by
`John McLachlan at the National Institute of
`Environmental Health Sciences.41 In the early
`1980s, McLachlan published the first studies of
`transplacental effects of DES exposure that
`reproduced the carcinogenic and reproductive
`effects reported in epidemiological studies from
`the 1970s.42,43
`McLachlan, along with Howard Bern,
`a comparative endocrinologist at the Univer-
`sity of California, Berkeley, who studied in
`utero and neonatal exposure to DES in
`humans and animals in the early to mid-
`1970s, attended the 1991 Wingspread meet-
`ing. Many of the participants at that meeting,
`among them McLachlan, wildlife biologist
`Louis Guillette, molecular biologists Ana Soto
`and Carlos Sonnenschein, and biologist
`Frederick vom Saal, went on to become
`prominent leaders of the controversial and
`paradigm-shifting field of environmental en-
`docrine disruption.41
`Struck by the research presented at the
`meeting, vom Saal, who for years had studied
`the effects of in utero exposure to natural
`hormones on the developing organism, decided
`to test a number of synthetic estrogens. He
`chose BPA and octylphenol, also a chemical
`used in plastics and a synthetic estrogen. Unlike
`regulatory toxicity tests, this research exposed
`pregnant mice to levels of BPA determined
`to be physiologically active as synthetic estro-
`gens. These were not toxic levels, and indeed
`fell below the safety standard of 50 lg/kg/day.
`In the first published studies on BPA from his
`laboratory in 1997, vom Saal’s team reported
`increased prostate weights in the exposed
`mice and a higher than expected estrogenic
`
`response from BPA.44 Other researchers pub-
`lished two additional papers on the low-dose
`effects of BPA: a 1997 report on the mammary
`gland45 and a 1998 study of the female re-
`productive system.46 Collectively, these new low-
`dose studies challenged the long-held presump-
`tion that BPA was a weak estrogen.
`
`Low-Dose Safety of Bisphenol A
`
`This new research on BPA fueled a heated
`debate about the safety of endocrine disruptors
`at a time when the EPA was struggling to
`establish a testing and screening program for
`such compounds. In 1996, Congress passed the
`Food Quality Protection Act, which amended
`the Federal Insecticide, Fungicide and Roden-
`ticide Act,47 and an amendment to the Safe
`Drinking Water Act.48 Both amendments in-
`cluded language directing the EPA to establish
`a testing and screening program for endocrine
`disruptors.41The challenge faced by the EPA was
`to reach an agreement among a number of
`stakeholders, including representatives from in-
`dustry and from environmental nongovernmen-
`tal organizations, on a testing program. This
`meant agreeing on the definition of an endocrine
`disruptor and adverse health effects—for
`example, was a change in prostate size an
`adverse effect? Did binding to the estrogen
`receptor define a chemical as an endocrine
`disruptor? Should the agency change the testing
`protocol to include low doses and exposure
`during fetal and neonatal development, or were
`high-dose toxicity tests relevant for evaluating
`risks of endocrine disruptors? These all proved to
`be controversial topics, particularly the issue of
`testing at very low doses.49
`In 2000, the EPA turned to the NTP and
`requested that the institute review the research
`on the effects of low doses of estrogenic
`compounds, including DES and BPA. The
`NTP’s Report of the Endocrine Disruptors Low
`Dose Peer Review,50 released in 2001, concluded
`that there was credible evidence for effects from
`BPA exposure at or below the safety standard,
`including vom Saal’s studies and a replication
`of his findings by another laboratory.51 The NTP
`report also included credible evidence of no
`effects reported by two studies52,53 funded by
`the chemical industry. Further research on BPA
`was needed, the report concluded. As for low-
`dose effects generally, the NTP found
`
`adverse effect level in the carcinogenesis study
`and permitted daily exposure limits.) This re-
`mains the current safety standard. As for its long-
`overlooked estrogenic properties, the EPA noted
`that BPA’s estrogenicity, more potent than that of
`o,p’-DDT, could explain evidence of impaired
`fertility in a small study in 198135; however, the
`agency concluded that because of BPA’s lack of
`bioaccumulation and short half-life, it did not
`present a likely threat or hazard.36
`
`Bisphenol A as an Endocrine
`Disruptor
`
`By the late 1980s, production of BPA in
`the United States soared to close to a billion
`pounds per year as polycarbonates found new
`markets in compact discs, digital versatile
`discs (DVDs), water and baby bottles, and
`laboratory and hospital equipment. Only a few
`years after the reference dose was set, the
`safety of BPA’s estrogenicity, which was long
`presumed to be weak, came under the investi-
`gative lens of an expanding interdisciplinary
`field: the study of the hormonelike effects of
`synthetic chemicals.
`In 1993, endocrinologists at Stanford Uni-
`versity determined that BPA was leaching
`from polycarbonate flasks in their laboratory.37
`The researchers made this discovery while
`searching for an endogenous estrogen in yeast.
`What they originally thought was an endogenous
`estrogen, however, turned out to be BPA when
`tested with estrogen-responsive breast cancer
`cells. Their published findings brought BPA’s
`estrogenicity to the attention of a number of
`researchers interested not only in synthetic
`estrogens but, more broadly, in what were re-
`ferred to as endocrine disruptors.38
`Endocrine disruption, the hypothesis that
`some chemicals could interfere with the
`production, processing, and transmission of
`hormones in the body and disrupt the normal
`functioning of the endocrine system, was a
`phrase coined at a meeting in 1991. The meet-
`ing, held at the Wingspread Conference Center
`in Racine, Wisconsin, was organized by Theo
`Colborn, then with the World Wildlife Fund,
`and J. P. ‘‘Pete’’ Myers, then director of an
`environmental grant-making foundation.39
`The outcome of the meeting, which brought
`together a diverse collection of researchers—
`wildlife biologists, endocrinologists, reproductive
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`evidence in the courtroom.) The Harvard
`Center’s review,56 as well as an updated review
`released in 2006 by Gradient Corporation,61
`a private consulting firm specializing in risk
`science, concluded that two large multigenera-
`tional studies provided the most relevant and
`reliable data. These studies were funded by the
`American Plastics Council and the Society of the
`Plastics Industry.62,63
`Both reports cited the same reasons for
`determining the relevance and reliability of
`these two studies: they used large number of
`animals, included a wide distribution of doses,
`measured a number of endpoints, and followed
`‘‘Good Laboratory Practices’’ (regulatory stan-
`dards for conducting research adopted in the
`mid-1970s64 after the laboratory scandal dis-
`cussed earlier in ‘‘The Regulatory Toxicology of
`Bisphenol A.’’) These larger studies, the Harvard
`Center’s review concluded, ‘‘cast doubt on sug-
`gestions of significant physical or functional
`impairment.’’56(p875) Further, the report con-
`tended that inconsistent effects among different
`strains of animals, lack of a ‘‘single, biologically
`plausible explanation’’56(p877) of effects due to
`differences in responses of BPA compared with
`estradiol or DES, and differences in the route of
`administered dose all reduced the reliability and
`relevance of low-dose studies.56 These conclu-
`sions discounted evidence of significant effects
`presented in many of the low-dose studies,
`notably reports of nonlinear dose–response re-
`lationships, BPA binding to 2 estrogen receptors
`(a and b, as well as estrogen receptors on the cell
`membrane), the insensitivity of certain rodent
`strains to estrogen (specifically, those used in one
`of the multigenerational studies), and the critical
`significance of timing of exposure for determin-
`ing endpoint.65
`In 2005, after the release of the Harvard
`Center review, vom Saal, together with one of the
`original participants of the Harvard panel, pub-
`lished a response66 to the Harvard Center’s
`report that roundly criticized the work. They
`argued that the assessment failed to evaluate the
`body of research, given the current knowledge in
`endocrinology, developmental biology, and es-
`trogen receptor research. Most alarmingly, they
`highlighted an apparent funding effect in the BPA
`research. Between 1997 and 2005, there were
`115 studies on the effects of BPA at or below the
`safety standard, conducted by dozens of labora-
`tories in the United States, Japan, and Europe. The
`
`reported effects of BPA included changes in fetal
`prostate and mammary gland development, dis-
`ruption of chromosomal alignment in developing
`eggs in females, altered immune function, meta-
`bolic abnormalities, and changes in the brain and
`behavior. Of these 115 studies, 90% of those that
`were government funded reported some effects
`from exposures at or below the reference dose,
`whereas none of the11studies funded by industry
`reported any effects.66
`This expanding field of research, the long list
`of reported effects at concentrations orders of
`magnitude below the safety standard, and
`charges of a funding effect drew the attention
`of the federal government in 2006.
`
`Politics of Bisphenol A Safety
`Since 2005
`
`Since the NTP’s first assessment of BPA’s low
`dose effects in 2001, five different reviews of
`the scientific literature have been conducted
`(Table 1). In 2006, the first of two government-
`sponsored assessments of the BPA literature
`was coordinated by the Division of Extramural
`Research and Training at the National Institute
`of Environmental Health Sciences. The meet-
`ing brought together 38 experts on endocrine
`disruptors and BPA in Chapel Hill, North
`Carolina. The meeting’s final product, the
`Chapel Hill Consensus Statement, concluded
`with certainty, on the basis of several hundred
`studies, that BPA at concentrations found in
`the human body is associated with ‘‘organiza-
`tional changes in the prostate, breast, testis,
`mammary glands, body size, brain structure
`and chemistry, and behavior of laboratory
`animals.’’67(p134)
`On the heels of the Chapel Hill Statement,
`a second major government assessment was
`released. The Center for the Evaluation of
`Risks to Human Reproduction (CERHR),68
`located within the NTP, sponsored an assessment
`of the literature, the original draft of which was
`conducted by the private firm Sciences Interna-
`tional. After a number of public meetings, an
`internal audit69 to assess possible conflicts of
`interest by Sciences International, and a review
`by NTP staff, the CERHR released its final report
`on BPA in 2008. The report found ‘‘some
`concern for effects on the brain, behavior and
`prostate gland in fetuses, infants and children
`at current human exposures to BPA.’’68(vii)
`
`that the current testing paradigm used for as-
`sessments of reproductive and developmental
`toxicity should be revisited to see if changes are
`needed regarding dose selection, animal model
`selection, age when animals are evaluated, and
`the end points being measured following expo-
`sure to endocrine-active agents.50(vii)
`
`The call for a new testing paradigm recog-
`nized a growing consensus that low doses of
`endocrine-disrupting chemicals may not follow
`a monotonic dose–response relationship, an
`issue discussed in a National Academy of
`Sciences report, Hormonally Active Agents in the
`Environment,54 published in 1999. In its discus-
`sion of dosing, the committee concluded:
`
`[I]f an underlying monotonic dose–response
`function (i.e., a function where response in-
`creases as dose increases or at least does not
`decrease) and a dose below which there is no
`effect (a threshold dose) are assumed when
`designing a toxicologic study, there is a risk of
`failing to understand or properly test a contami-
`nant that does not display a monotonic dose-
`response function or threshold dose.54(p82)
`
`The NTP’s recommendation to reconsider
`the current testing paradigm and its failure to
`declare BPA safe set off alarm bells for the
`major industry trade groups. In a letter to the
`NTP in 2001, Steven Hentges, director of the
`Polycarbonate Business Unit of the American
`Plastics Council, wrote that the NTP’s BPA
`panel ‘‘did not complete a weight-of-evidence
`assessment, which would have concluded that
`low-dose effects from BPA have not been
`demonstrated.’’50(pC-52) The American Plastics
`Council subsequently contracted with the
`Harvard Center for Risk Analysis—an organiza-
`tion that received financial support from the
`American Chemistry Council, the Society of the
`Plastics Industry, Dow Chemical Company, the
`Business Roundtable, Phillip Morris, and General
`Electric—to conduct a review.55
`The Harvard Center report on BPA,56 pub-
`lished in 2004, used a ‘‘weight of the evidence’’
`assessment framework developed at a 2001
`meeting sponsored by the Annapolis Center for
`Science and Policy,57 an organization founded
`by the former vice president of the National
`Association of Manufacturers and funded by
`tobacco giant Phillip Morris58,59 and ExxonMobil
`Foundation.60 The framework assessed the
`published literature on BPA according to 7
`categories used to evaluate the ‘‘relevance’’ and
`‘‘reliability’’ of the data. (‘‘Relevance’’ and ‘‘re-
`liability’’ are also legal standards for assessing
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`TABLE 1—Reviews of Bisphenol A (BPA) Conducted in the United States
`
`Sponsor
`
`Title
`
`Research Institution
`
`Date Released
`
`Key Findings
`
`National Toxicology
`
`NTP Technical Report on the
`
`Litton Biotechnics
`
`1982
`
`‘‘[N]o convincing evidence of carcinogenicity’’; ‘‘that ‘bisphenol
`
`Program
`
`Carcinogenesis Bioassay of
`
`Bisphenol A (CAS No. 80–0507)
`
`in F344 Rats and B6c3fl
`
`Mice (Feed Study)
`
`National Institute
`
`National Toxicology Program’s
`
`National Toxicology Program
`
`2001
`
`of Environmental
`
`Report of the Endocrine Disruptor’s
`
`Health Sciences,
`
`Low Dose Peer Review
`
`Environmental
`
`Protection Agency
`
`American Plastics
`
`‘‘Weight of the evidence evaluation
`
`Harvard Center for
`
`2004
`
`A is not carcinogenic’ should be qualified to reflect the facts that
`
`leukemia in male rats showed a significant positive trend, that
`
`leukemia in high-dose male rats was considered not significant only
`
`on the basis on the Bonferroni criteria, that leukemia incidence was also
`
`elevated in female rats and male mice, and that the significance of
`
`interstitial-cell tumors of the testes in rats was dismissed on the basis
`on historical control data.’’26(ix)
`‘‘There is credible evidence that low doses of BPA [bisphenol A] can
`
`cause effects on specific endpoints. However, due to the inability of other
`
`credible studies in several different laboratories to observe low dose effects
`
`of BPA, and the consistency of these negative studies, the Subpanel is not
`
`persuaded that a low dose effect of BPA has been conclusively established
`as a general or reproducible finding.’’50(vii)
`‘‘The panel found no consistent affirmative evidence of low-dose BPA effects for
`
`Council
`
`of low-dose reproductive and
`
`Risk Analysis
`
`any endpoint. Inconsistent responses across rodent species and strain made
`
`developmental effects of
`
`bisphenol A’’
`
`American Plastics
`
`‘‘An updated weight of the
`
`Gradient Corporation
`
`2006
`
`generalizability of low-dose BPA effects questionable. Lack of adverse effects
`
`in two multiple generation reproductive and developmental studies casts doubt
`on suggestions of significant physiological or functional impairment.’’56(p875)
`‘‘No effect is marked or consistent across species, doses and time points. Some
`
`Council
`
`evidence evaluation of reproductive
`
`mouse studies report morphological changes in testes and sperm and some
`
`and developmental effects of low
`
`doses of bisphenol A’’
`
`National Institute of
`
`‘‘Chapel Hill bisphenol A expert
`
`National Institute of
`
`2007
`
`Environmental Health
`
`panel consensus statement:
`
`Sciences, National
`
`integration of mechanisms,
`
`Environmental Health
`
`Sciences and invited
`
`Institutes of Health
`
`effects in animals and potential to
`
`BPA experts
`
`impact human health at current
`
`levels of exposure’’
`
`National Toxicology
`
`‘‘NTP-CERHR monograph on the
`
`Sciences International,
`
`2008
`
`Program (NTP)
`
`potential human reproductive and
`
`Center for the Evaluation
`
`developmental effects of bisphenol A’’
`
`of Risks to Human
`
`Reproduction (CERHR)
`
`non-oral mouse studies report morphological changes in the female reproductive
`
`organ. Owing to lack of first pass metabolism, results from non-oral studies
`are of limited relevance to oral human exposure.’’61(p1)
`‘‘We are confident that . . . human exposure to BPA is variable, and exposure levels
`cover a broad range [central tendency for unconjugated [active] BPA:
`
`0.3-4.4 ng ml-1 (ppb)] in tissues and fluids in fetuses, children and
`
`adults. . . . Sensitivity to endocrine disruptors, including BPA, varies extensively
`with life stage, indicating that there are specific windows of increased sensitivity
`
`at multiple life stages. . . . BPA alters ’epigenetic programming’ of genes in
`experimental animals and wildlife that results in persistent effects that are
`
`expressed later in life. . . . Specifically, prenatal and/or neonatal exposure to low
`doses of BPA results in organizational changes in the prostate, breast, testis,
`
`mammary gland, body size, brain structure and chemistry and behavior of
`laboratory animals.’’67(p134)
`‘‘[S]ome concern for effects on brain, behavior and prostate gland in fetuses,
`infants and children at current human exposures to bisphenol A.’’68(vii)
`‘‘[T]he possibility that bisphenol A may alter human development cannot be
`dismissed.’’68(p7)
`
`Because these conclusions drew on laboratory
`studies at levels ‘‘similar to those experienced
`by humans,’’ the NTP–CERHR report declared
`that ‘‘the possibility that bisphenol A may
`alter human development cannot be dis-
`missed.’’68(p7)
`
`By the spring of 2008, BPA was making
`headlines in major national newspapers.1,70
`Within days of the NTP–CERHR report, the
`Canadian government announced its decision to
`declare BPA toxic, and retailers began scram-
`bling to meet growing consumer demands for
`
`alternatives to BPA-based polycarbonate baby
`and water bottles. Environmental health advo-
`cates and researchers came before state legisla-
`tures in California, Maryland, Massachusetts,
`and Maine in support of a number of bills
`restricting BPA in children’s products. Members
`
`Supplement 3, 2009, Vol 99, No. S3 | American Journal of Public Health
`
`Vogel
`
`| Peer Reviewed | Framing Health Matters | S563
`
`ClearCorrect Exhibit 1069, Page 5 of 8
`
`

`

`FRA