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EWG Letter to CERHR, Re: Interim Draft Report on Bisphenol A

EWG Letter to CERHR, Re: Interim Draft Report on Bisphenol A

Monday, July 2, 2007

Download a PDF of this letter. June 20, 2007 Dr. Michael D. Shelby Director Center for the Evaluation of Risks to Human Reproduction National Institute of Environmental Health Services Department of Health and Human Services P.O. Box 12233MD EC-32 Research Triangle Park, NC 27709 Re: Comments on the Interim Draft NTP-CERHR Report on the Reproductive andDevelopmental Toxicity of Bisphenol A Dear Dr. Shelby: As you know, in March of 2007, the National Institutes of Health, citing potentialconflicts of interest, fired the contractor you hired to prepare the Bisphenol A (BPA)review document for the panel evaluating the chemical for your center, the federalCenter for the Evaluation of Risks to Human Reproduction (CERHR). Environmental andpublic health advocates supported that decision by NIH but expressed serious concernsabout the integrity and objectivity of the BPA review document itself and endorsed fora process that would allow for an objective review of the science with significantrevision to the document. In response, NIH pledged to review the entire document toensure that it accurately represented the state of the science on the reproductivetoxicity of BPA. Presumably, the new interim draft report your expert panel has released should reflectthe results of the review that NIH pledged to conduct. But we find no public record ofsuch a review having been conducted. Instead, we understand that what may have beena closed-door session in North Carolina was convened, not of independent experts, butof members of the expert panel already vested in the draft document. And instead ofthe open and transparent process needed to ensure a quality BPA review, this meetingwas announced only 72 hours in advance, severely limiting opportunities for publiccomment, if the public was indeed allowed to attend. And our thorough evaluation of the interim draft document produced through thisprocess shows that significant and systematic revisions have been made to the BPAreview document that magnify the scientifically unsupportable bias towards industryfundedstudies that was inherent in the previous draft prepared by your now-firedsubcontractor. Our findings raise questions about the ability of this expert panel toproduce unbiased conclusions. If this BPA review document is to stand as ascientifically valid assessment of the risks that BPA poses to human reproduction anddevelopment, it must undergo the review promised by NIH, and this review much bethorough, open, transparent, and independent. Environmental Working Group has analyzed the latest version of the BPA reviewdocument and come to the following conclusions. 1. The current document is less objective, more biased, and based on an even moreinconsistent and arbitrarily applied set of criteria than the document preparedby the fired contractor, Sciences International. 2. The arbitrary and inconsistent application of scientific criteria used inevaluating the quality of studies of BPA toxicity leaves the panel with anunbalanced and incomplete science base to determine BPA’s reproductive risksto humans. 3. An objective and fair review of the science of BPA’s reproductive toxicity is notpossible based on this review document. The NIH must follow through on thecommitment it made and place the evaluation of the science of BPA’sreproductive toxicity in unbiased hands, which in this case means halting thecurrent review and starting over. The following describe some of the most serious inconsistencies and arbitrary criticismsfrom the panel: Inconsistent and arbitrary findings on studies using DMSO: In some studies, thepanel critiques the use of dimethyl sulfoxide (DMSO) as a vehicle for BPAadministration. In other studies, the panel finds no fault with the use of DMSO. Thisinconsistency appears to be arbitrary. In addition, of all the BPA administrationvehicles used in the dozens of studies reviewed by the panel, the panel targets onlyDMSO as being of concern in its potential to influence study findings, and only in selectstudies, even though other administration vehicles should raise similar concerns.In the draft, the panel states “Dimethyl sulfoxide (DMSO) has significant biologicalactivities of its own and its use as a vehicle for in vivo studies raises significantconcern about the relevance of those results for the human oral exposure situation.Those studies which used DMSO to solubilize BPA and injected or implanted thatmixture were deemed of little or no utility because of this double limitation (injection+ DMSO).” The following points illustrate how this critique by the panel was used arbitrarily tojustify elimination of some very high quality studies that found BPA toxicity at lowdoses: 1) Several studies from the Soto lab at Tufts University were disregarded,purportedly due to the panel’s concern about the potential confounding effectsthat might arise from the use of DMSO as a vehicle to deliver BPA to testanimals. Other studies using DMSO were treated differently. For example, onpage 194 of the document, there is a study from Fukumori et al (translated toEnglish by the American Plastics Council, suggesting that it is industry funded)in which BPA is injected into rats with DMSO as the vehicle; this study wasfound to be “suitable for inclusion” by the panel. There is no critique aboutthe use of DMSO as a vehicle in this study. 2) What makes the exclusion of Soto’s studies more suspect is that many of themhave negative controls that consist of DMSO alone. If these low doses of DMSOhad some sort of biological effect on the endpoints that are being investigatedin these studies, the negative controls would show these effects; however, noeffects were seen in the control animals. Only the animals that wereadministered BPA and DMSO had relevant changes in the endpoints that werebeing examined, but the studies were still thrown out by the panel. 3) While the panel isolates DMSO as a vehicle that may have biological properties,they do not comment on the use of oil as a vehicle. Other types of oil,especially corn oil, have been found to be contaminated with estrogens; this issummarized in a recent commentary in Environmental Health Perspectives(Schettler 2003). Corn oil is used as a vehicle in many studies that are includedin the draft and the panel does not bring this potential source of contaminationup at all. Inconsistent and arbitrary critique on the route of administration: In this case, thepanel criticizes one form of administration of BPA to test animals, while ignoring, withno explanation or scientific justification, the well-known issues with other methods ofdosing animals. The panel criticizes subcutaneous dosing of BPA in studies while ignoring the inherentweaknesses of other forms of administration, especially oral gavage. They focus on themerits of BPA administration via food or gavage, stating “the panel carefully consideredthe value of studies where Bisphenol A was administered anywhere other than to themouth or stomach of the experimental animal,” and concluded that all of these studiesshould receive minimal consideration. Several studies using subcutaneous dosing foundreproductive effects at very low levels of exposure but were considered inadequate bythe panel. While the panel is quick to point out the weaknesses in subcutaneous and intravenousadministration, they fail to note that oral gavage is also a traumatizing process andmay have its own effects on an animal’s reaction to a compound. In 2006, scientistsfound that animals that were administered estradiol (an estrogenic compound) viagavage had completely different responses than when they were exposed via implantedcapsules (Garza-Meilandt et al, Behavioral Neuroscience, 2006 August: 120(4): 905-16,Estradiol’s effects on learning and neuronal morphology vary with route ofadministration). If the panel is intent on drawing conclusions on study relevancebased on routes of administration, they should assess the limitations of all routes,including gavage. This inconsistency could inject a dramatic and biologically inaccurate bias into thepanel’s deliberations. It is generally accepted that human exposure to BPA tends tooccur in small, steady doses, best replicated by subcutaneous pump, as opposed toboluses of high doses that occur via gavage. By systematically excluding thesestudies, the panel introduces a bias into the process that is not supported by thescience. Inconsistent conclusions on the use and response of positive controls: The panelrecognizes the inherent value of positive controls, stating at the beginning of section3.0 Developmental Toxicity “A positive control is valuable to show that anexperimental model is capable of responding to a certain stimulus. This is of even morevalue when there is no response to a main exposure under study”. However, whenfaced with several industry funded studies in which the positive controls fail to showthe expected response, indicating a failed experiment, the panel downplays thesignificance. Several industry funded studies included in this evaluation show minimal or noresponse to the positive control. In the evaluation of the study by Cagen (Cagen, 1999pg 156), the panel notes “the lack of much effect with diethylstilbestrol treatment is aweakness” but goes on to state “this study is adequate for the evaluation process”.This is repeated in another evaluation of a study by Cagen (Cagen, 1999 pg 211) whereit is stated “lack of response of the positive control DES group is problematic…” butthe study is still deemed “marginally useful for the evaluation”. Another study byAshby et al (Ashby, 1999, pg 212) was also accepted as “marginally useful for theevaluation process due to absence of response of the positive control group and smallsample sizes”. It is unclear why the panel would consider these studies adequate in any way, marginalor otherwise, when the positive control fails. The panel also states that they are unclear why the dose of DES (0.2 ug/kg/day) usedas a positive control would work since “only 1 study has shown effects at this dose” (pg212) and again on pg 213 “the lack of effect of the positive control is a weakness, butit is unclear why this dose (0.2 ug/kg/day) of diethylstilbestrol was expected to give apositive response”. Yet, the panel must be aware that a number of examples in the literature show that thesame or smaller dose of DES administered prenatally to mice has produced changes inthe reproductive system of male and female offspring (Gupta, Timms et al, Nikaido etal, and Honma et al), so the panel is incorrect in stating that the dose of DES that isused as a positive control is too low to be effective. Instead of recognizing that thestudies in which the positive controls fail to elicit the expected response may haveflaws in study design, the panel simply criticizes the dose of the positive control,despite evidence in the literature that this dose is adequate.Inconsistent treatment of studies that do not use positive controls: In thebeginning of section 3.0 Developmental Toxicity, the panel outlines the importance ofpositive controls, “A positive control is valuable to show that an experimental model iscapable of responding to a certain stimulus. This is of even more value when there isno response to a main exposure under study”. In fact, they go on to criticize several6/20/07, page 5 of 7EWG: THE POWER OF INFORMAT IONstudies throughout the draft for not including positive controls (Zoeller et al. pg 169,Negishi et al. pg 178, Golubkova et al. pg 322). All of these studies were considered“inadequate”, partly because they did not include positive controls. In contrast, two industry funded studies that were included in the evaluation from Emaet al. (pg 364) and Tyl et al. (pg 366) didn’t include positive controls; yet, they werehighly praised by the panel with the following statements “this thorough multiplegeneration rat study is highly valuable for human risk assessment of low dose exposurefor bisphenol A…and this study is adequate and useful for the evaluation process” forthe Ema study and “this study is highly valuable for human risk assessment for oralexposure to bishpenol A…this study is adequate and useful for the evaluation process”for the Tyl study. Nowhere in the evaluation of these studies is there any comment onthe lack of use of positive controls. Inconsistent conclusions on diet: The panel was inconsistent in expressing concernsabout phytoestrogen content of feed by bringing it up as a relevant issue inassessments of some studies while pointedly ignoring it in other studies. The paneltakes care to criticize certain studies based on the high phytoestrogen content of thediet that was fed to lab animals, noting in a study by Nagel “the Purina 5001 chow hashigh and variable levels of soy phytoestrogens” (pg 210). However, on the next page,the panel evaluates an industry funded study conducted by Cagen in which animalswere given certified rodent chow 5002, which is also considered to have highphytoestrogen content (Thigpen et al. 2004); however, there is no mention of the highphytoestrogen diet in the evaluation of this industry funded study. In a study by Ashby (also industry funded), the pregnant animals are fed a diet thatcontains 18.5% soy, but there is no mention by the panel of how this may affect theoutcome. Replication of prior studies: In general, when a lab attempts to replicate a priorstudy, it is prudent to follow the prior study protocol as closely as possible in order toduplicate the conditions in the original study. The panel notes that two industryfunded studies (from Cagen et al and Ashby et al, pg 210-212) “attempted to duplicatethe findings reported by vom Saal et al and Nagel et al”; however, the panel notes inboth cases that there are differences from the original studies with respect to the strainof animal that was used and the type of feed, as well as other environmentalconditions. It has been well established in the literature that these factors cancompletely change the outcome in studies that investigate endocrine disruption. Ifthese studies were truly designed as replicate studies, they would necessarily have usedthe same animal strain and the same feed, two critical components of study design thatcan influence findings. The panel never brings up this issue. Summary: These examples illustrate how the CERHR panel has applied arbitrary and inconsistentstandards throughout this evaluation of the developmental and reproductive toxicitiesof BPA. They bring up, in many cases, valid concerns regarding the use of appropriatevehicles, type of feed, and need for positive controls but express concernsinconsistently and in every case described above, in a manner that appears to besystematically biased towards industry-funded science. The results of this lack of consistency are revealed in a general analysis of section 3.0of the two drafts of this document. In the first draft (prepared by SciencesInternational), almost 90% of industry-funded studies and 70% of non-industry fundedstudies were found to be adequate. In the next draft (prepared by the CERHR panel),70% of industry-funded studies and only 30% of non-industry funded studies werefound to be adequate. The panel quadrupled the number of studies considered"inadequate" compared to the previous draft, but in doing so, they rejectedindependent studies (academic or government) at three times the rate of industryfunded studies. This illustrates that the inconsistent application of standards across allevaluated studies throughout this draft appears to systematically reject independentstudies and favor industry funded studies being categorized as “ adequate” for thepanel’s final evaluation. As you know from our testimony at the March 2007 expert panel meeting, our own testsof 100 name-brand canned foods confirmed widespread exposures of the public withthis ubiquitous reproductive and developmental toxin (EWG 2007). The need for anobjective evaluation of the literature concerning BPA is absolutely vital, since thefindings of this panel may influence decisions that affect the public health of millions. Sincerely, Anila Jacob, M.D., M.P.H. Senior Scientist Environmental Working Group References Environmental Working Group (EWG). 2007. A Survey of Bisphenol A in Canned Foods.Available at http://ewg.org/reports/bisphenola. Garza-Meilandt A, Cantu RE, Claiborne BJ. 2006. Estradiol’s effects on learning andneuronal morphology vary with route of administration. Behavioral Neuroscience120(4): 905-916. Gupta C. 2000. Reproductive malformation of the male offspring following maternalexposure to estrogenic chemicals. Proc Soc Exp Biol Med 224(2): 61-8. Honma S, Suzuki A, Buchanan DL, Katsu Y, Watanabe H, Iguchi T. 2002. Low dose effectof in utero exposure to bisphenol A and diethylstilbestrol on female mousereproduction. Reproductive Toxicology16(2): 117-22. Nikaido Y, Yoshizawa K, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, Tsubura A.2004. Effects of maternal xenoestrogen exposure on development of the reproductivetract and mammary gland CD-1 mouse offspring. Reproductive Toxicology 18(6): 803-11. Schettler T. 2003. Corn and corn-derived products: sources of endocrine disruptors.Correspondence in Environmental Health Perspectives 111(13). Thigpen JE, Setchell KD, Saunders HE, Haseman JK, Grant MG, Forsythe DB. 2004.Selecting the appropriate rodent diet for endocrine disruptor research and testingstudies. ILAR Journal 45(4): 401-416. Timms BG, Howdeshell KL, Barton L, Bradley S, Richter CA, vom Saal FS. 2005.Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetalmouse prostate and urethra. Proc Natl Acad Sci USA 102(19):7014-9.