By Jennifer Sass and Sarah Janssen
As described in earlier posts (here and here), the NIHâs National Institute of Environmental Health Sciences (NIEHS) has contracted the work of the Center for the Evaluation of Risks to Human Reproduction (CERHR) out to the consulting company Sciences International. This issue received public attention just as CERHRâs scheduled review of the chemical Bisphenol A (BPA) was taking place.
We submitted comments to CERHR detailing concerns about the content and the process of the BPA review. Our concerns include:
The NIEHS NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) outsourced responsibility for developing the first draft scientific review, while failing to provide adequate oversight.
It is our understanding that the current process of reviewing chemicals for the CERHR program relies on an outside contractor, Sciences International, to conduct a literature review and write up. This includes selecting and evaluating/ranking the literature to be included in the review, and is therefore very influential and vulnerable to abuse. The contractor then submits the review to the NTP. The NTP staff select an expert panel. This is also a very influential step. The expert panel develops a final expert panel report for the NTP. This final panel report is used by the NTP in the development of an âNTP-briefâ, which is an official government opinion. The final NTP-CERHR monograph contains the NTP brief along with the expert panel report and other supplementary material (public comments, etc.). The Monograph is considered to be an authoritative body and, for example, can trigger listings under California Prop65.
NTP has failed to include some important studies in their draft report of Bisphenol A (BPA):
There are a few studies which were not included in the draft BPA report that should be evaluated by the expert committee. These include studies previously published that highlight the potential of BPA to mimic estrogen at extremely low doses. (For details, see Sarah Janssenâs comments (PDF).)
NTP should consider the choice of experimental animal when evaluating studies.
Several of the studies under consideration in the CERHR were done using inappropriate animal models and this information was left out of the evaluation process. It has been noted by other investigators that the Charles-River Sprague-Dawley (CD-SD) rat is relatively insensitive to exogenously administered estrogen, including potent estrogenic drugs.  Several of the studies under consideration by NTPâs CERHR used this animal strain in their experimental design and found either no effect of BPA or effects only at high doses.
It is critical that use of an appropriate animal model is determined when evaluating the strength of a study. There was no discussion by the committee of the relative insensitivity of the CD-SD strain to exogenous estrogen treatment in their reviews of these studies.Â
NTP should consider whether an adequate positive control was included when evaluating the strength of studies.
Several of the studies under consideration in the CERHR did not have the expected results using positive controls, indicating problems in the study design. Establishment of a positive control is essential for determining the quality of a research study and its ability to predict differences in treatment outcomes. In addition to the studies described previously [NTP references (#293 Tyl et al.); (#297 Kwon et al.); (#411 Tyl et al.); and (#438 Ashby et al.)] that did not have adequate positive controls, there were other studies determined to be adequate for analysis by the committee that did not have positive controls (#294 Cagen et al., #342 Cagen et al.).
In their evaluation, the CERHR review did not justify how studies lacking adequate positive controls are determined to be appropriate for evaluation by the CERHR.
NTP should consider the impact of bias in industry-funded research.
A recently published study demonstrated that the source of funding had significant impact on whether or not adverse effects were found with low-dose BPA treatment.2 Of a total 130 studies, 119 were done by government funded entities and 11 were done by chemical corporations. Ninety-two percent (109/130) of the government funded studies found evidence of adverse effects after low dose BPA treatment while only 8% found no adverse outcome. Some of the government funded studies finding no effect used the previously described estrogen insensitive strain of CD-SD rats. In contrast, 100% (11/11) industry funded studies found no evidence of harm from low dose BPA treatment.Â
The bias of industry-funded research has been well documented for many products such as tobacco, pharmaceuticals, and pesticides. NTP should carefully consider the source of funding when evaluating the adequacy of studies. A bias towards no-effect has already been demonstrated for low dose effects of BPA and several of those studies reviewed by the NTP CERHR committee have been determined to be adequate for evaluation.
Based on the existing data and comments made above, we strongly feel that BPA should be considered a hazard to human development and reproduction. BPA has been demonstrated to have multiple developmental and reproductive toxicities at low and environmentally relevant doses in a number of well designed government funded studies. In addition, significant new data indicates that in utero exposure to BPA causes aneuploidy in developing oocytes, which could contribute to miscarriage and birth defects.
The problem of outsourcing at NTP
To the extent that NTP farms out critical task, such as scientific reviews and assessments, in some cases to contractors that are also working for regulated industries, without adequate transparency, oversight, or accountability, it seriously compromises both the public trust and the NTPs ability to ensure that it is meeting its obligation to the American public.
The Center for the Evaluation of Risks to Human Reproduction (CERHR) contracts with Sciences International (SI), a private consulting firm, to provide scientific and administrative support. According to a recent news report, âthe company also oversees the nomination of chemicals for review and of panel members who evaluate the chemicalsâ.   The same report also revealed that, âsince the late 1990s, SI has helped the tobacco company RJ Reynolds fight stricter regulations on toxic pesticides.” The report also noted that, scientists who serve on CERHR panels to assess chemicals are required to sign conflict-of-interest forms, but that according to a letter to Environmental Working Group from CERHR director Michael Shelby, “no specific [conflict of interest] restrictions are placed on [SI].” Public reports such as these represent a potential disastrous failure of public trust in the NTP program.
Congress has also raised its hackles on this issue. In a letter sent to Dr. David Schwartz, the Director of NIEHS, Senator Boxer (Chair, Senate Environment and Public Works Committee) and Representative Waxman (Chair, House Oversight and Government Reform Committee) expressed concern at potential conflicts of interest with Sciences International regarding the review of Bisphenol-A (PDF). Congressmen stated they were concerned that, âextensive use of contractors at CERHR may undermineâ the ability of NIEHS to appropriately review the health impacts of toxic chemicals.
In fact, NTP is spending millions of dollars on contractors that also serve industries impacted by NTP reports and assessments. These contractual arrangements are not subject to âsunshineâ laws include the Federal Advisory Committee Act (FACA) and the Freedom of Information Act (FOIA), that play a critical role in ensuring government accountability. When NTP outsources tasks without ensuring transparency, without adequate oversight, and without demanding public accountability, it has compromised public trust and the credibility of its products. To erode public trust, it matters not whether the conflicts are perceived or actual, and whether the product is scientifically sound or flawed.
Process RecommendationsÂ
 We recommend the following:
â¢Â If NIEHS intends to continue to contract out the task of developing a literature review and write up, then it is essential that:
* the review be conducted by experts in the field, and be as inclusive as possible of relevant literature
*the review be conducted by experts that have no financial conflicts
*Â the review be subjected to rigorous scrutiny for errors by NIEHS scientific experts, prior to review by the Expert Panel.
â¢Â Following internal review and approval by NIEHS experts, the scientific review should be available for public comment, and comments forwarded with the review to the Expert Panel.
â¢Â The Expert Panel must be comprised of independent scientific experts without financial conflicts. The experts must be familiar with the relevant literature, and with the relevant experts in the field. This is critical to provide rigorous scientific review and overall credibility to the document. Experts will be sufficiently familiar with the cutting edge research to identify misstatements, mis-interpretations, and missing literature in the review document. The use of experts will enable the Panel and NTP to identify where other experts or public commentors may have conflicts that may be undisclosed. These should be disclosed and, if appropriate, experts removed from the Panel.
The use of public funds to support poor-quality or poor-credibility science is of tremendous concern. Congress adopted strong sunshine laws in part to prevent clandestine manipulation of the government process, and that objective is in serious jeopardy to the extent NTP is permitted to outsource critical responsibilities. NIEHS must ensure that the public funding it is entrusted with is used in a manner that preserves the scientific integrity of the regulatory process and that any important science activities that the NTP funds are conducted with adequate transparency and direct lines of accountability.
Jennifer Sass, Ph.D is a senior scientist in the Health and Environment program at Natural Resources Defense Council.
Sarah Janssen, MD, PhD, MPH is a science fellow in the Health and Environment program at Natural Resources Defense Council.
“We submitted comments to CERHR detailing concerns about the content and the process of the BPA review.”
________
This is extremely well written. I am someone concerned about this issue and the outcome, and appreciate you taking these actions to do something about the flawed regulatory process.
What was the response?
I had a lengthy meeting with NTP staff, and their response was very receptive and concerned. I feel confident that they will take steps to ensure that the final BPA report reflects the best science, and not propaganda. Moreover, they will doubtless improve their process, including some of my recommendations, so that they are not caught in a similar situation in the future. NTP and NIEHS have been very responsive to the concerns that we’ve raised, from the staff level right up to the NIEHS Director’s Office. However, as we all know, the proof will be in the pudding. NRDC plans to continue to track this issue closely (both the science and the process).
Thanks for replying. I’m glad there is still room for positive thinking on this particular issue. It’s great to hear that NRDC is on top of this.
Update on NTP Activities on BPA and SI COI
Over the past few months, the National Toxicology Program (NTP) has undertaken a number of activities to address issues related to conflicts of interest (COI) and to ensure continued public confidence in its work. These included an independent review of its contracts for potential COI, development of a strong clause about COI for adding to NTP contracts, and an audit to assess the objectivity of information in draft reports prepared on the reproductive and developmental toxicity of bisphenol A (BPA). NTP would like to update you on these activities.
Review of NTP contracts
A working group of the NTP Board of Scientific Counselors conducted a review of NTP contracts to (1) assess potential COI, (2) develop recommendations appropriate for reducing the potential for conflicts to occur, and (3) address mechanisms for mitigating any current or future COI. The working group reviewed NTP contracts, information on contract performance provided by NTP staff, and information on policies and practices concerning COI provided by selected NTP contractors. The working group report was presented to the NTP Board of Scientific Counselors at its meeting on June 22, 2007, and following discussion, accepted unanimously without revision. The working group found no evidence of actual or apparent COI in its review of NTP contracts; however, it did recommend a number of best practices and areas where improvements could be made. The working group report is posted on the NTP web site
( http://ntp.niehs.nih.gov under âLatest Newsâ).
COI clause for NTP contracts
A clause that specifically addresses contractor COI was developed and is being added to all NTP contracts. This action complements the review of NTP contracts by the NTP Board of Scientific Counselors Working Group, as noted above (see BSC Working Group report, Attachment 9, available
at http://ntp.niehs.nih.gov under âLatest Newsâ).
Audit of draft BPA reports
The NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) conducts rigorous independent scientific evaluations to assess risk to human reproduction and development caused by environmental agents, such as bisphenol A, a chemical currently under review. In response to concerns raised about Sciences International, Inc. (SI), the former CERHR contractor (see March 2007 and April 2007 statements available at http://cerhr.niehs.nih.gov under âCERHR Newsâ), NTP committed to a review of the contractorâs services to CERHR. As part of this review, NTP conducted an audit of two key activities carried out by SI: (1) selection of literature relevant for review by the expert panel on BPA and (2) incorporation of input from expert panel members into draft reports.
NTP found that SI made available to the expert panel members for their consideration appropriate references relevant to the BPA evaluation. NTP also found that SI reliably made changes to the draft reports requested by the expert panel. Based upon this audit, NTP concluded that the draft expert panel reports are useful for the BPA evaluation. The audit report is posted on the NTP
( http://ntp.niehs.nih.gov under âLatest Newsâ) and CERHR
( http://cerhr.niehs.nih.gov under âCERHR Newsâ) web sites.
Second BPA Expert Panel Meeting
The second BPA expert panel meeting is scheduled for August 6-8, 2007, at the Hilton Alexandria Old Town in Alexandria, Virginia. Details about the meeting are available on the CERHR web site for BPA ( http://cerhr.niehs.nih.gov/chemicals/bisphenol/bisphenol-mtg.html ).
DRAFT MEETING SUMMARY
NATIONAL TOXICOLOGY PROGRAM CENTER FOR THE EVALUATION OF RISKS TO HUMAN REPRODUCTION
EXPERT PANEL EVALUATION OF BISPHENOL A AUGUST 6-8, 2007
The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) convened an expert panel on August 6-8, 2007, in Alexandria, Virginia to evaluate bisphenol A. This was the second public meeting of the expert panel, a group of 12 independent scientists convened to review and assess scientific studies on the potential reproductive and developmental hazards of Bisphenol A.
Expert Panel Conclusions For pregnant women and fetuses:
The Expert Panel expressed some concern that exposure to Bisphenol A in utero causes neural and behavioral effects.
The Expert Panel expressed minimal concern that exposure to Bisphenol A in utero causes effects on the prostate.
The Expert Panel expressed minimal concern that exposure to Bisphenol A in utero potentially causes accelerations in puberty.
The Expert Panel expressed negligible concern that exposure to Bisphenol A in utero produces birth defects and malformations.
For infants and children:
The Expert Panel expressed some concern that exposure to Bisphenol A causes neural and behavioral effects.
The Expert Panel had expressed minimal concern that exposure to Bisphenol A potentially causes accelerations in puberty.
For adults:
The Expert Panel expressed negligible concern for adverse reproductive effects following exposures in the general population to Bisphenol A. For highly exposed subgroups, such as occupationally exposed populations, the level of concern is elevated to minimal.
[The conclusions noted above are those of the Bisphenol A Expert Panel and should not be construed to represent the views of the NTP.]
Background on Bisphenol A
Bisphenol A is a high production volume chemical used primarily in the production of polycarbonate plastics and epoxy resins. Polycarbonate plastics are used in food and drink packaging; resins are used as lacquers to coat metal products such as food cans, bottle tops, and water supply pipes. Some polymers used in dental sealants and tooth coatings contain bisphenol A. Exposure to the general population can occur through direct contact with bisphenol A or by exposure to food or drink that has been in contact with a material containing bisphenol A. CERHR selected this chemical for evaluation because of (1) high production volume, (2) widespread human exposure, (3) evidence of reproductive toxicity in laboratory animal studies, and (4) public concern.
The expert panel reviewed and evaluated the available scientific data on bisphenol A in three primary areas: human exposure, reproductive toxicity, and developmental toxicity. In their deliberations, the expert panel considered the quality, quantity, and strength of the scientific evidence that exposure to bisphenol A might cause adverse effects on human reproduction and/or development of the fetus or infant. The expert panel identified gaps in the available scientific data on the possible effects of bisphenol A and suggested areas where additional research is needed.
Next Steps
The final expert panel report on bisphenol A will be posted on the CERHR web site (http://cerhr.niehs.nih.gov) and available in printed text from CERHR in fall 2007. CERHR will solicit public comments on this report through an announcement in the Federal Register. Following this comment period, CERHR will prepare the NTP-CERHR monograph on bisphenol A consisting of an NTP brief, the expert panel report, and all public comments on that report. The NTP brief contains the NTPâs opinion regarding whether current human exposures to bisphenol A are a risk for human development and reproduction. CERHR will solicit public comment on the NTP brief, after which it will undergo independent peer review. NTP will consider the public and peer review comments before finalizing the brief. The monographs will be available to the public in PDF format on the CERHR web site and in hardcopy by contacting CERHR and will be distributed to appropriate federal health and regulatory agencies.
Background on CERHR
The NTP established CERHR in 1998 as an environmental health resource to the public and to regulatory and health agencies. CERHR provides scientifically based, uniform assessments of the potential for adverse effects on reproduction and/or development caused to man-made or naturally occurring chemicals or chemical mixtures to which humans are exposed. CERHR convenes independent panels of scientific experts to conduct its evaluations. Expert panel meetings are open to the public and the public is invited to nominate scientists to serve on these panels. Following completion of the evaluation of a chemical, the NTP prepares an a NTP-CERHR monograph that contains its opinion on the potential for the chemical to be a reproductive and/or developmental hazard, the expert panel report, and public comments received on the final expert panel report. NTP-CERHR monographs on other chemicals evaluated by CERHR include seven phthalates, methanol, 1-bromopropane, 2-bromopropane, ethylene glycol, propylene glycol, fluoxetine, acrylamide, amphetamines, methylphenidate, and styrene. These monographs are available on the CERHR website and in hardcopy or CD from CERHR.
Questions about the expert panel review of bisphenol A or about CERHR can be directed to Dr. Michael Shelby, CERHR Director, at 919-541-3455 or shelby@niehs.nih.gov.
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Update on bisphenol A.
The scientific community has not reached consensus on the potential health effects of BPA to humans, but they are getting closer.
This week, an independent panel of scientists, the BSC reviewed the National Toxicology Program’s Draft Brief on BPA. The NTP’s highest levels of concern in the Draft did not reach “concern” or “serious concern” for any effect. Furthermore, the BSC peer review of this Draft recommended lowering the levels of concern about the effects of BPA on puberty in females and effects on the mammary gland from “some concern” to “minimal concern”.
This means that all but two effects are rated as of “negligible” or “minimal” concern and two (neural and behavioral and prostate) are of “some concern”. These levels of concern differ from those recommended by the NTP CERHR BPA Expert Panel in only 1 area (the prostate). http://ntp.niehs.nih.gov/files/BSCactionsBPA_508.pdf