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Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption

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Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption
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  Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption Laura N. Vandenberg, Maricel V. Maffini, Carlos Sonnenschein, Beverly S. Rubin, and Ana M. Soto Tufts University School of Medicine, Department of Anatomy and Cellular Biology, Boston, Massachusetts 02111 In 1991, a group of 21 scientists gathered at the WingspreadConference Center to discuss evidence of developmental al-terations observed in wildlife populations after chemical ex-posures. There, the term “endocrine disruptor” was agreedupon to describe a class of chemicals including those that actas agonists and antagonists of the estrogen receptors (ERs),androgen receptor, thyroid hormone receptor, and others.This definition has since evolved, and the field has grown toencompass hundreds of chemicals. Despite significant ad-vances in the study of endocrine disruptors, several contro-versies have sprung up and continue, including the debateovertheexistenceofnonmonotonicdoseresponsecurves,themechanisms of low-dose effects, and the importance of con-sidering critical periods of exposure in experimental design.Onechemicalfoundubiquitouslyinourenvironment,bisphe-nol-A (BPA), has received a tremendous amount of attentionfromresearchscientists,governmentpanels,andthepopularpress. In this review, we have covered the above-mentionedcontroversiesplussixadditionalissuesthathavedividedsci-entistsinthefieldofBPAresearch,namely:1)mechanismsof BPA action; 2) levels of human exposure; 3) routes of humanexposure; 4) pharmacokinetic models of BPA metabolism; 5)effects of BPA on exposed animals; and 6) links between BPA and cancer. Understanding these topics is essential for edu-cating the public and medical professionals about potentialrisks associated with developmental exposure to BPA andother endocrine disruptors, the design of rigorously re-searched programs using both epidemiological and animalstudies, and ultimately the development of a sound publichealth policy. (  Endocrine Reviews  30: 75–95, 2009) I.  IntroductionII. The Synthetic Estrogen (Xenoestrogen), Bisphenol-AA. Biochemical properties of BPAB. Estrogenic activities of BPAC. Other activities of BPAIII. The Controversy about Nonmonotonic Dose ResponseCurvesIV. Physiological Conditions Support Low-Dose EffectsA. Intrauterine positional effects in rodentsB. Uterine environments in other animal models andhumansV. Critical Periods of Exposure during DevelopmentVI. Controversies Specific to BPAA. Controversy 1: What is the mechanism for low-doseBPA action?B. Controversy 2: Are humans exposed to truly signifi-cant levels of BPA?C. Controversy 3: Does human exposure occur exclu-sively through the oral route?D. Controversy 4: Is BPA inactivated by conjugation inthe digestive system? Are animal studies using othermodes of exposure relevant?E. Controversy5:Arethereanydefinitivepatternstotheeffects seen in BPA-exposed animals?F. Controversy 6: Could low doses of BPA affect cancerincidence?VII. Expert Opinions and Government DecisionsVIII. Conclusions I. Introduction I MAGINE A WORLD WHERE both livestock and wildanimals become weak, sicken, and then die; where in-sects do not roam, pollination cannot occur effectively, andso there are no fruits; where vegetation withers and brownsalong the roadsides; where silence falls across the land be-cause there are no birds left to sing. This is the world thatRachel Carson asked readers to picture in her 1962 book,“Silent Spring” (1), which detailed countless examples of poisonings by pesticides, insecticides, and herbicides. Thisanalysis was the first of its kind, and it brought attention tothe danger inherent in the ubiquitous release of man-madechemicals into the environment. The observations made byCarson are still valid today. Over 80,000 chemicals are in usein the United States, and approximately 1000–2000 newchemicals are introduced into commerce each year, but theU.S. Environmental Protection Agency (EPA) does not rou-tinely assess the safety and risks associated with all existingor new chemicals (2). Carson outlined several importantpoints in “Silent Spring” that are especially relevant to thecurrent situation, namely: 1) very low doses of chemicals canhave profound effects on exposed animals; 2) mixtures of chemicals can lead to compounded effects; and 3) timing of exposures is critical.After the publication of “Silent Spring”, researchers con-tinuedtomakeconnectionsbetweenchemicalexposuresandadverseoutcomesinwildlifeandhumans.Inthe1980s,Theo First Published Online December 12, 2009 Abbreviations: AhR, Aryl hydrocarbon receptor; BPA, bisphenol-A;BW, body weight; DES, diethylstilbestrol; ER, estrogen receptor; ERR-   ,estrogen-related receptor-   ; GLP, good laboratory practices; GPR30, Gprotein-coupled receptor 30; mER, membrane-bound ER  ; NMDR,nonmonotonic dose response; PND, postnatal day. Endocrine Reviews  is published by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving theendocrine community. 0163-769X/09/$20.00/0 Endocrine Reviews 30(1):75–95  Printed in U.S.A.  Copyright © 2009 by The Endocrine Societydoi: 10.1210/er.2008-0021 75   Endocrine Reviews. First published ahead of print January 22, 2009 as doi:10.1210/er.2008-0021 Copyright (C) 2009 by The Endocrine Society  Colborn, then at the World Wildlife Fund, was researchingthe health of vertebrates living in the Great Lakes (3). Heranalysis of the body of the literature revealed that adversehealth outcomes had been measured repeatedly in birds andfish.Colborncreatedaspreadsheettotallytheeffectssheandothers were observing across dozens of species. She con-cluded that animals were being affected in a variety of ways:diminished reproduction, thyroid problems, altered behav-ior, and metabolism changes including wasting. Each of these outcomes suggested that the endocrine system wasperturbed. Perhaps the most important observation made byColborn was that these problems were observed in the off-spring of exposed animals, and not the adult animalsthemselves.InJulyof1991,Colbornsummonedagroupof21scientiststo Racine, Wisconsin, at the Wingspread Conference Center(3). These scientists came from diverse backgrounds includ-ing ecology, endocrinology, medicine, law, reproductivephysiology, toxicology, wildlife management, and cancer biology and presented their work relevant to the topic“Chemically-Induced Alterations in Sexual Development:The Wildlife/Human Connection.” Reports covered the ef-fects of endocrine disruptors on gene imprinting, sexual dif-ferentiation,andreproductivefunctioninmammalsandfish,neurobehavioral development, and autoimmune diseases.About this meeting, Colborn later said: “The reason thesepeoplewerebroughttogetherwasbecausewehadseensuchvery blatant, open evidence among various wildlife speciesand populations concerning this problem of transgenera-tional exposure . . . by the third morning, these people wereso moved by what they heard that they decided they wantedto produce what was called a consensus statement. Theywanted the rest of the world to know what they had dis-covered that weekend” (4).The following consensus statement was composed by theconference attendees: “We are certain of the following: alarge number of man-made chemicals that have been re-leased into the environment, as well as a few natural ones,have the potential to disrupt the endocrine system of ani-mals, including humans” (5).From this 1991 Wingspread meeting, the term “endocrinedisruptor” became widely accepted in the scientific commu-nity. Additionally, the conference attendees noted similari-tiesbetweenexposuretoendocrinedisruptorsandthepotentestrogen diethylstilbestrol (DES), a pharmacological agentadministered to pregnant women from 1948–71 (Fig. 1). DESproduced striking effects in exposed offspring but much lessserious effects in exposed mothers (6). Hence, there wasparticularly strong concern about exposure during criticalperiods of development.In 1995, the EPA sponsored a workshop to assess researchneeds for the risk assessment of the effects of endocrinedisruptors on wildlife and human populations. At that time,an endocrine disruptor was defined as “an exogenous agentthat interferes with the synthesis, secretion, transport, bind-ing, action, or elimination of natural hormones in the bodythat are responsible for the maintenance of homeostasis, re-production, development and/or behavior” (7). In severalother meetings held since 1995, scientists have examinedevidence of the effects of endocrine disruptors on wildlifeand humans. In particular, the National Toxicology Pro-gram’s report of the Endocrine Disruptors Low-Dose PeerReview in 2000 confirmed that there was sufficient evidenceto support the claim that many of these chemicals had effectsat low, environmentally relevant doses (8). Pointedly, “Low-dose effects . . . were demonstrated in laboratory animals ex-posed to certain endocrine active agents. The effects aredependent on the compound studied and the endpoint mea-sured . . . The toxicological significance of many of these ef-fects has not been determined.” II. The Synthetic Estrogen(Xenoestrogen), Bisphenol-A  Bisphenol-A (BPA) is one of the highest volume chemicalsproduced worldwide, with over 6 billion pounds producedeach year and over 100 tons released into the atmosphere byyearly production. BPA is the building block of polycarbon-ate plastic. Numerous studies found that BPA leaches frompolycarbonate baby bottles (see Ref. 9) and reusable water bottles (10). Other polycarbonate containers intended to beused as reusable food containers, food-contact items such aspolyvinyl chloride stretch films, and some paper and card- board used as food containers have been examined for theirBPA content (reviewed in Ref. 9). Metallic food cans areprotected from rusting and corrosion by the application of epoxy resins as inner coatings. Many of these resins aresynthesizedbythecondensationofBPAwithepichlorhydrinto create BPA diglycidyl ether. When incomplete polymer-izationoccurs,residualBPAleachesfromtheepoxyresinandhasthepotentialtocontaminatestoredfoods.Severalstudieshave documented conditions that support or enhance BPA F IG . 1. Chemical structures of BPA, DES, and estradiol. The struc-tures of BPA and DES are more similar to one another than they areto the endogenous estradiol, indicating that chemicals with variablestructures are capable of binding to the ER. 76  Endocrine Reviews, February 2009, 30(1):75–95 Vandenberg   et al . • BPA and the Great Divide  migration from the coating of cans (9). Others have alsoexamined BPA levels leaching from epoxy resins lining cansto specific foods including canned pet foods, vegetables, andfish, whereas still others have found BPA contamination incanned infant formula (9).Toxicology studies have determined that the maximumtolerated dose for BPA is 1000 mg/kg body weight (BW)    d(11). The EPA calculated a reference dose of 50   g/kg    dusing a safety factor of 1000. [Three safety factors of 10-foldwere applied to account for the following: human risk esti-mated from animal studies; variability within the humanpopulation; and extrapolation for subchronic to chronic ex-posures (12).] A reference dose is typically calculated usingthe NOAEL (no-observed-adverse-effect level), but the ref-erence dose for BPA was calculated using the LOAEL(lowest-observable-adverse-effectlevel)becauseaNOAELhadnotbeendeterminedandadverseresponsesweredetectedevenat the lowest dose administered (12).  A. Biochemical properties of BPA BPA contains two phenol functional groups (Fig. 1), andit is prepared by the combination of two equivalents of phe-nolwithoneequivalentofacetone.BPAwasfirstsynthesized byA.P.Dianinin1891andwaslaterinvestigatedinthe1930sduring the search for synthetic estrogens. It was tested for itsestrogenic properties at that time but abandoned for phar-maceutical use when DES was determined to be much morepotent (13).BPA, with its two benzene rings and two (4, 4  )-OH sub-stituents, fits in the ER binding pocket. Biochemical assayshave examined the kinetics of BPA binding to ER and havedetermined that BPA binds both ER   and ER  , with ap-proximately 10-fold higher affinity to ER   (14, 15).AstudyofBPAand19relatedcompoundsdeterminedtheminimum structural requirements for estrogenic activity: a4-OH group on the A-phenyl ring and a hydrophobic moietyat the 2-position of the propane (16). However, the affinity of BPA for the ERs is approximately 10,000-fold weaker thanthat of estradiol (15). Extensive biochemical studies of ER  have identified two distinct gene transactivating regions,termed AF1 (found in the amino terminus) and AF2 (locatedin the carboxyl terminus) (14). ER agonists are subdivided based on their ability to activate these regions. Binding of xenoestrogens to the ERs alters their ability to recruit coac-tivators that may be important for differences in tissue-dependent responses. For instance, biochemical analysesindicate that BPA is able to induce greater changes in down-stream gene expression in cells containing ER   where TIF2is the main coactivator, but may be equally effective in cellsexpressing either ER   or ER   if the steroid receptor coacti-vator-1a is present (17). Based on these biochemical studies,it has been proposed that differences in the ability of ER   orER   to recruit coactivators when BPA is bound may con-tribute to the complex tissue-specific responses to BPA ex-posure (18).  B. Estrogenic activities of BPA Several  in vitro  assays are available for measuring theestrogenic activity of possible endocrine disruptors includ-ing BPA (reviewed in Ref. 19). The E-SCREEN assay uses theestrogensensitiveMCF7breastepithelialcelllinetomeasurecell proliferation after treatment with a range of concentra-tions of the chemical to be tested, as well as estradiol for apositive control (20). The E-SCREEN is the most sensitiveassay for estrogenicity; it can discriminate between partialandfullagonists,canaccuratelyidentifyantagonists,andhasverifiedtheestrogenicpropertiesofBPA.Untilrecently,BPAwasconsideredaweakenvironmentalestrogenbecauseofitsrelatively low affinity for the nuclear ERs compared withestradiol [EC 50  2–7  10  7 m compared with 1–6  10  13 m forestradiol(21,22)].However,resultsfromrecentstudieshave revealed a variety of pathways through which BPA canstimulate cellular responses at very low concentrations, be-low the levels where BPA is expected to bind to the classicalnuclear ERs (reviewed in Ref. 23).Several membrane steroid receptors have been described,including a membrane-bound form of ER   (mER) that issimilar but not identical to the nuclear ER   (24, 25) and atransmembrane ER called G protein-coupled receptor 30(GPR30)(thefirstmembraneERidentifiedthatisstructurallydissimilar to the nuclear ERs) (26). BPA has been shown to bind to both mER and GPR30, and studies have determinedthat these membrane-bound receptors are capable of non-genomic steroid actions (25–27) (also reviewed in Ref. 18).GH3/B6 pituitary cells, which naturally express mER, re-spond to low level BPA exposure (in the picomolar to nano-molar range) by producing a calcium flux which leads toprolactin release (25). However, examination of other non-genomic signaling pathways in these same cells ( i . e ., ERKactivation)revealednoeffectofBPAexposure.Thissuggeststhat BPA, like other xenoestrogens, differentially utilizes sig-naling pathways downstream of mER activation. Pancreatic  -cells treated with BPA also demonstrate nongenomic sig-nals occurring via mER, suggesting that the affected non-genomic signaling pathways are not specific to a single celltype (28, 29). A third example indicates that BPA can signalthrough a nongenomic pathway in cultured mouse endo-thelial cells to increase nitric oxide production, although itwas not specifically demonstrated that these effects weremediated via mER (30). In fact, most studies of nongenomicactions of BPA and other xenoestrogens do not specifywhether they are due to actions via ER in the plasma mem- brane, the cytosol, or elsewhere (31). However, based on theresults of these studies, it is now widely accepted that BPAnotonlyhastheefficacyofestradiolbutisalsoequallypotentregarding several of its effects (12, 18, 27). In vivo  assays have also been used to determine the es-trogenicity of BPA. When prepubescent CD-1 mice weretreated with doses of BPA ranging from 0.1 to 100 mg/kgBW, estrogenic responses including increased uterine wetweight, luminal epithelial height, and increased expressionof the estrogen-inducible protein lactoferrin were observed(32). Additionally, single, high doses of BPA (up to 150mg/kg BW) induced proliferation of the uterine and vaginalepithelial cells of ovariectomized rats (33). Other organs in-cluding the mammary and pituitary glands displayed estro-genic responses to BPA exposure as well, but at lower dosesthan those needed to generate a significant response in theuterotrophic assay (34). Thus, the characterization of BPA as  Vandenberg   et al . • BPA and the Great Divide Endocrine Reviews, February 2009, 30(1):75–95  77  a weak estrogen is likely to underestimate the impact of BPAexposure on different target organs. C. Other activities of BPA Inadditiontoitsestrogenicactivity,thereissomeevidencethat BPA binds to thyroid hormone receptor, acting as athyroid hormone antagonist by preventing the binding of T 3 .One study found the affinity of BPA for this receptor sev-eralfold lower than its affinity for the ERs (35). However,other studies have been unable to duplicate these results,finding that BPA does not competitively inhibit the bindingof labeled T 3  to the thyroid hormone receptor or inducethyroid hormone-dependent production of GH in GH3 cells(16, 36). Halogenated BPA (tetrachlorobisphenol A and tet-rabromobisphenol A) used as flame retardants were alsoshown to inhibit the binding of T 3  to the thyroid hormonereceptor (36).  In vivo  studies examining the effects of BPA onthyroid hormone signaling have been conducted in rats ex-posed to 1, 10, or 50 mg/kg BW starting on embryonic d 6(37). Perinatally exposed rats had elevated T 4  levels on post-natal day (PND) 15 and up-regulation of a thyroid hormone-responsive gene in the brain. It was also observed in medakafishthattheaccelerationinembryonicdevelopmentandtimetohatchinducedbyBPAwereblockedbyathyroidhormonereceptor antagonist, suggesting that BPA is acting through athyroid hormone pathway (38).The antiandrogenic properties of BPA are still somewhatin dispute. Using a competitive binding assay with labeleddihydroxytestosterone and a yeast reporter assay, antian-drogenic activity of BPA was detected in the 10  5 to 10  7 m range (39). However, other studies have shown a half-maximal response of approximately 50 n m BPA, suggestinga dose response curve shifted to the left (40). There have also been mixed results with mammalian cell reporter assays,  i . e .,some groups measured antiandrogenic activity of BPA witha half-maximal response at 2.14–3.2   m  (41, 42), whereasothers were unable to demonstrate any antagonist activity(43).Addressingthesediscrepanciesinananimalmodelmay be difficult because distinguishing estrogenic effects and an-tiandrogenic effects  in vivo  is not easy (39). For instance,evidence that BPA inhibits testicular steroidogenesis at lowexposure levels has been suggested to occur via the ER andis likely due to its estrogenicity (44).Additional studies indicate that BPA also binds to an or-phan nuclear receptor called estrogen-related receptor-   (ERR-   ) (45). Although the endogenous ligand for ERR-   remains unknown, the human receptor behaves as a consti-tutive activator of transcription and may play a role in dif-ferentiation and maturation of the fetal brain. When BPA is boundtoERR-   ,itpreservesthisreceptor’sbasalactivityandcan prevent its deactivation by antiestrogens (46).BPA also binds the aryl hydrocarbon receptor (AhR) (42),a ligand-dependent transcription factor present in almostevery tissue. AhR is thought to be activated by many chem-icals with diverse structures and may mediate the toxicand/or biological effects of these chemicals. Although AhRhas been implicated in several signal transduction path-ways, the effects of BPA binding to AhR remain unknownat this time. Because AhR can cross-talk with other recep-tors including ERs and the androgen receptor, endocrine-related endpoints may be affected by its activation (re-viewed in Ref. 47). III. The Controversy about Nonmonotonic DoseResponse Curves For many years, when assessing the effects of possibleendocrine disruptors, toxicologists have relied on the prin-ciple that “the dose makes the poison,” implying that higherdoseswereexpectedtocausegreaterharm.Thus,effectsthatare not seen at high doses are not expected at low doses. Thisthreshold model is used most often for risk assessment of noncarcinogens (Fig. 2A) (12, 48). This model identifies a“safe” dose by assessing different doses of a chemical untilthe NOEL (no observable effect level) is determined. Addi-tionally, toxicologists depend on the linear nonthresholdmodel (Fig. 2B) to assess the danger of different doses of  F IG . 2. Hypothetical curves to illustrate the threshold (A), linearnonthreshold (B), and nonmonotonic (C) model dose response curves.Inthethresholdmodel,treatmentwithincreasingdosesofadrughasno effect until the “threshold” dose is reached, at which point anincrease in response is observed. In the linear nonthreshold model, aresponse occurs even at the lowest treatment dose, and thereforeeffects at high doses can be used to predict responses at low doses.With a NMDR curve, an increase in dose does not necessarily corre-spond to an increase in response, such that, in this example, dosesfrom 10  12 -10  3 M  result in an increase in response, and doses from10  3 -10 7 M resultinadecreaseinresponse.Thesecurvesarecommonfor endocrine endpoints. D, Examples of NMDR curves observed inmammary gland morphological parameters after administration of estradiol to ovariectomized females. The  left y-axis  is the number of terminal end buds (TEBs), and the  right y-axis  is total area of allTEBs; the TEB is an estrogen-dependent structure. [Panel D is re-produced from L. N. Vandenberg,  et al .:  J. Steroid Biochem Mol Biol 101:263–274 (49). Copyright 2006, with permission from Elsevier.] 78  Endocrine Reviews, February 2009, 30(1):75–95 Vandenberg   et al . • BPA and the Great Divide  carcinogens and extrapolate these findings to very low dosesof the chemical. In contrast to the above-mentioned dogmain toxicology, multiple studies have found that neither thethreshold nor the linear nonthreshold models are applicableto the responses of hormones in which biphasic dose re-sponses have been observed for many different endpoints atmanylevelsoforganization(reviewedinRefs.12,48,and49).These U-shaped and inverted U-shaped dose responsecurves are considered “nonmonotonic” (Fig. 2C) and areusedasevidencethatverylowdosesofnaturalandsynthetichormones can affect endpoints such as cell proliferation andorgan size (12).In some nonmonotonic dose responses (NMDRs), thedose response curve may be shaped like a U with highresponses at low and at high levels of exposure, whereasothers are shaped like an inverted U, with the greatestresponses at intermediate doses (50). Calabrese and Bald-win (51) described the importance of experimental designto detect the presence of a NMDR curve. In particular,studies of dose response curves must use a wide range of doses, including doses below the established LOAEL. Ameta-analysis of 20,285 toxicology studies conducted be-tween 1962 and 1998 found that only 1% of the publishedstudies met the criteria set  a priori  to determine whether astudy was designed properly to detect a NMDR curve (51).Almost 40% of these studies satisfied the requirements fora NMDR, supporting the idea that the occurrence of NMDRs is nonrandom and may even be more commonthan monotonic dose response curves.A curious criticism of NMDR curves has been the lack of a definitive mechanism to explain these nonmonotonic re-sponses. Several studies have suggested that the shape of these curves can be explained by the down-regulation of receptors at higher hormone levels (52, 53). There is alsoevidencethatNMDRcurvesaregeneratedbytheintegrationof two or more monotonic dose response curves that occurthrough different pathways affecting a common end pointwith opposing effects (54). For instance,  in vitro  studies haveshown that low doses of androgens can mediate a prolifer-ative response in androgen-target cells, whereas at a higherdose they inhibit cell proliferation (55). When the end pointis cell number, the resulting curve has the shape of an in-verted U. The two arms of this curve are induced indepen-dently of each other; they can be segregated, generating twodifferently behaving cell types,  i . e ., one that shows a mono-tonic proliferative response (the cell number increases as theandrogen dose increases), and another that shows a mono-tonic inhibitory response (the cell number decreases as thehormone concentration increases) (54). The biochemicalevents underlying these effects are distinct (56). Additionalstudies have indicated that NMDRs occur at various levelsof organization (Fig. 2D and Ref. 49).NMDR curves have been observed after exposure of cul-tured cells to BPA. For instance, the response of GH3/B6pituitary cells to BPA followed a U-shaped NMDR curve,where doses of 10  12 , 10  11 , and 10  8 m  elicited significantresponsesanddosesof10  10 and10  9 m didnot(57).LNCaPprostate cancer cells responded to BPA in a similar mannerwith maximal proliferation induced by 10  9 m  (58). Fewercells proliferated at lower (10  10 m ) and higher (10  8 and10  7 m )dosesofBPA.Additionally,BPAinhibitedadiponec-tin secretion from human adipose explants with a U-shapedNMDR curve; concentrations of 10  10 and 10  9 m inhibitedrelease, whereas doses of 10  8 and 10  7 m  were indistin-guishable from unexposed controls (59). Finally, pancreaticislet cells exposed to BPA release insulin, displaying an in-verted U-shaped NMDR curve where only doses of 10  9 and10  10 m  significantly increase insulin release (29).Typically, only a few doses are tested in animal studies, soit is more difficult to determine whether the observed re-sponses are truly nonmonotonic. However, many studiesconducted with a low and a high dose of BPA show effectsat the low dose that are not apparent after exposure to thehigh dose (60). For instance, one of the first  in vivo  studies of BPA demonstrated that female offspring born to pregnantdams exposed to 0.1 mg BPA/kg BW    d from d 5 gestationthrough the period of lactation were significantly heavierthan controls when weighed as adults, but the body weightof females exposed to a higher dose (1.2 mg BPA/kg BW    d)were not different from controls (61). Low-dose perinatalBPA exposure (2   g BPA/kg BW    d) increased anogenitaldistance in female offspring, but a higher dose (20   gBPA/kg BW    d) had no effect (62). The low dose examinedinthisstudyalsoaffectedthenumberofdayswhencornifiedcells appeared in vaginal smears, whereas the high doseagainhadnoeffect.NMDRsarenotobservedinallendpointsexamined after BPA exposure, but they have been observedin behaviors, protein expression, development of embryos,and organ size (60).It has been suggested that the linear nonthreshold modeland the threshold model routinely used for risk assessmentpurposes by government agencies, including the EPA,should be rejected and replaced entirely (12, 48). Addition-ally, typical high-dose toxicology studies used for risk as-sessment purposes are designed to detect gross changes inmorphologyordevelopment,withendpointsincludingmor-tality,bodyweight,andtumorincidence(48).Unfortunately,these studies are not designed to detect more subtle devel-opmentaleffectsthatimpactthehealthoftheindividualsuchas the presence and hormonal responsiveness of prostatelesions, tissue organization of the mammary gland, expres-sion of sexually dimorphic behaviors,  etc . Many of thesestudiesexamineonlyanimalsexposedduringadulthoodandthus lack information about offspring of animals treatedduring pregnancy. Making predictions about the safety of low doses by testing higher doses is not appropriate whenvery low doses of endocrine disruptors can alter biochemicaland morphological endpoints in a manner that is not nec-essarily predicted by exposures at much higher doses (12). IV. Physiological Conditions SupportLow-Dose Effects Evidence for the ability of low doses of hormone to induceand/ormodifyphenotypescomesfromstudiesoftheuniquehormonal microenvironment of the rodent uterus. Each ro-dent fetus is fixed in position with respect to its neighbors inthe bicornate uterus (Fig. 3); thus, delivery by cesarean sec-tionallowsforthedeterminationofthepositionofeachfetus  Vandenberg   et al . • BPA and the Great Divide Endocrine Reviews, February 2009, 30(1):75–95  79
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