AUDIT OF LITERATURE CITED AND FIDELITY OF

REQUESTED CHANGES TO DRAFT BISPHENOL A

          EXPERT PANEL REPORTS









                   National Toxicology Program



           Department of Health and Human Services









                           July 24, 2007









      (This report is available at http://cerhr.niehs.nih.gov/)

  AUDIT OF LITERATURE CITED AND FIDELITY OF REQUESTED CHANGES TO

              DRAFT BISPHENOL A EXPERT PANEL REPORTS



BACKGROUND



In a letter dated March 26, 2007 from Dr. David Schwartz, Director of the National Institute of

Environmental Health Sciences (NIEHS) and National Toxicology Program (NTP), to

Representative Henry Waxman and Senator Barbara Boxer, Dr. Schwartz pledged to carry out a

review of the Sciences International, Inc. (SI) contract and the nature of the services provided by

SI to the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). As part of

this review, there was an audit of two key activities carried out by SI: (1) selection of literature

relevant for review by the expert panel on bisphenol A (BPA) and (2) incorporation of input

from expert panel members into draft reports. The first task of the audit was to conduct an

independent survey of the literature on BPA to identify references and compare them with the

list selected by SI to summarize in the initial August 2006 draft expert panel report and with the

total bibliography considered by SI and the expert panel during development of the first three

drafts (August 2006, December 2006, March 2007) of the expert panel report. The second task

was to audit the fidelity with which changes requested by expert panel members were

incorporated into the December 2006 and March 2007 draft expert panel reports by SI staff.



PART 1. LITERATURE REVIEW



Strategy

The literature review was designed to identify references that were not included in the draft

reports, but might have been considered important for the BPA evaluation. Two sets of

references were screened for this purpose.



First, staff from the NIEHS library carried out a search of PubMed using the search terms

bisphenol and the Chemical Abstract Service number for BPA (80-05-7). This all-inclusive

search identified 4900 references. NTP staff screened the titles of all 4900 citations to identify

ones seemingly relevant to the deliberations of the expert panel for carrying out its specific

charge of determining whether BPA is a hazard to human reproduction and/or development.

References (set 1) related to the following topics were selected:



                Reproduction and development (in vivo and in vitro), animal and human studies

        �

                In vivo measures of estrogenicity in relevant species

        �

                Absorption, disposition in the body, and metabolism during pregnancy

        �

                Body burden when related to pregnancy/children

        �

                General toxicity

        �

                Studies of BADGE, BISGMA, BIS-DMA (chemicals with a BPA core structure)

        �

                included if related to reproduction/developmental toxicity

                Immunological or neurological measures not resulting from exposure during

        �

                development

                Studies in non-traditional species that included (1) developmental exposure and/or (2)

        �

                endpoint(s) related to reproductive organs or function









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                In vitro assays of estrogenicity (excluding estrogen receptor binding/transcriptional

        �

                activation/cell proliferation/yeast variants)

                In vitro estrogen response genes in cells from reproductive organs

        �

                Comparisons of batteries of in vitro screens for estrogenicity

        �

                Vitellogenin (protein produced in oviparous vertebrates in response to estrogens)

        �



NTP staff identified a second set of references from a web site that lists literature citations

pertaining to BPA with specific emphasis on studies that demonstrate biological activity at doses

lower than those used in traditional toxicology studies. This web site

(http://endocrinedisruptors.missouri.edu/vomsaal/vomsaal.html) is maintained by Dr. Fred vom

Saal, a researcher active in the field at the University of Missouri. NTP staff reviewed the titles

and abstracts of these references and identified ones of potential relevance to the BPA

evaluation.



NTP staff compared the collective, unique citations from these two sets against the bibliography

of 447 references in the August 2006 draft of the expert panel report and against the larger list of

742 references (includes the 447) made available by SI for the panel’s consideration at all stages

during development of the 3 draft reports (August 2006, December 2006, and March 2007).



Findings

The comparison of citations against the bibliography in the August 2006 draft identified fewer

than 100 references considered of potential relevance, but not included in the August 2006 draft

report. Approximately 50 citations were for papers published in 2005 or before and the

remaining was for papers published in 2006 and 2007 presumably after the initial SI literature

search. The expert panel added 9 of these references to subsequent drafts of the report

(December 2006 and March 2007).



The second comparison of citations against the list of 742 references identified fewer than 50

papers not cited in the August, December, or March draft reports. NTP staff reviewed these

references for their potential relevance to the BPA evaluation. Eliminating abstracts, papers not

in English, and papers dated 2007 that may have been published subsequent to the final literature

search done for the March 2007 draft, left 5 papers considered of potential relevance.1 CERHR







1

 Ashby J, Lefevre P (2000) The peripubertal male rat assay as an alternative to the Hershberger castrated male rat

assay for the detection of anti-androgens, oestrogens, and metabolic modulators. Journal of Applied Toxicology

20:35-47.



Nakamura K, Itoh K, Yaoi T, Fujiwara Y, Sugimoto T, Fushiki S (2006) Murine neocortical histogenesis is

perturbed by prenatal exposure to low doses of bisphenol A. Journal of Neuroscience Research 84:11197-1205.



Schmidt S, Degen G, Seibel J, Hertrampf T, Vollmer G, Diel P (2006) Hormonal activity of combinations of

genistein, bisphenol A and 17beta-estradiol. Archives of Toxicology 80:839-845.



Shin B, Kim C, Jun Y, Kim D, Lee B, Yoon C, Park E, Lee K, Han S-Y, Park K, Kim H, Yoo S (2004)

Physiologically based pharmacokinetics of bisphenol A. Journal of Toxicology and Environmental Health, Part A

67:1971-1985.







July 24, 2007                                                                                                        2

has now provided these 5 papers to the expert panel members for their consideration and

discussion at the second BPA expert panel meeting on August 6-8, 2007.



PART 2. RECORD OF REQUESTED CHANGES TO THE DRAFT EXPERT PANEL REPORTS DATED

        DECEMBER 2006 AND MARCH 2007



Strategy

The second part of the audit was carried out by an independent company working under an

existing contract to the NIEHS for the purpose of performing data audits. Dynamac Corporation

audited e-mail records that pertained to requests from expert panel members for changes to the

August 2006 and December 2006 expert panel reports. SI furnished paper copies of the e-mails,

separated into received and sent, and in chronological order. Dynamac staff then compared the

requests for changes with the changes made. NTP staff then reviewed the Dynamac audit

findings.



Findings

This phase of the audit found that all but 6 of the multiple changes requested in over 300 e-mails

from the expert panel members were in fact recorded in the draft expert panel reports. These 6

changes have now been made to the expert panel report.



The audit also identified changes in the draft reports that did not appear to track to an e-mail

request from an expert panel member. NTP staff reviewed all of the changes. Upon inspection,

NTP staff determined that these changes consisted of: (1) formatting errors, (2) addition of

literature summaries and tabular entries for new references added to the draft reports as a result

of updated literature searches, and (3) corrections to text or tables resulting from the contractor’s

fact-checking procedures and information received in public comments. These changes were

part of the normal editing process for draft reports.



DISCUSSION



Part 1. Literature Review

NTP carried out a review of the literature, independently of SI, to identify references relevant to

the expert panel evaluation of BPA. NTP found that SI made available to the expert panel

members for their consideration references relevant to the BPA evaluation. NTP identified only

5 additional papers out of the 4900 eligible for consideration that were not included in any of the

3 draft expert panel reports or in the list of 742 references provided by SI to the expert panel for

their consideration in development of the December 2006 and March 2007 drafts. These papers

have been provided to the panel and will be included in their discussions at the August 6-8

meeting.



NTP also found no evidence for the exclusion of relevant citations by SI in the August 2006 draft

expert panel report (the working draft of literature summaries prepared by SI prior to expert

panel input). NTP identified nearly 50 papers that were possibly relevant for the deliberations on



Thomas P, Dong J (2006) Binding and activation of the seven-membrane estrogen receptor GPR30 by

environmental estrogens: A potential novel mechanism of endocrine disruption. Journal of Steroid Biochemistry &

Molecular Biology 102:175-179.





July 24, 2007                                                                                                     3

BPA and were published in 2005 or before, but were not represented in the initial August draft

report’s bibliography. These papers were included in the list of 742 references provided by SI

for development of subsequent drafts and the expert panel members chose to add 9 to the

December or March drafts.



Part 2. Audit of Expert Panel Changes to Draft Reports

NTP found that SI reliably made changes to the draft reports requested by the expert panel

members. The Dynamac audit and response to the audit findings by NTP documented nearly

complete fidelity between changes requested by the expert panel and changes appearing in the

draft expert panel reports.



CONCLUSION



The audit provides assurance that the draft BPA expert panel reports include consideration of all

relevant references and reliably include changes requested by the expert panel members. NTP

concludes that the draft expert panel reports are useful for the CERHR evaluation of BPA.









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