FDA draft decision on BPA deeply flawed

Oct 30, 2008

Myers, JP, FS vom Saal, BT Akingbemi, K Arizono, S Belcher, T Colborn, I Chahoud, DA Crain, F Farabollini, LGuillette, Jr., T Hassold, S Ho, PA Hunt, T Iguchi, S Jobling, J Kanno, H Laufer, M Marcus, JA McLachlan, A Nadal, J Oehlmann, N Olea, P Palanza, S Parmigiani, BS Rubin, G Schoenfelder, Carlos Sonnenschein, AM Soto, CE Talsness, JA Taylor, LN Vandenberg, JG Vandenbergh, S Vogel, CS Watson, WV Welshons, and RT Zoeller 2008. Why public health agencies cannot depend upon 'Good Laboratory Practices' as a criterion for selecting data: The case of bisphenol A. Environmental Health Perspectives doi:10.1289/ehp.0800173.

Synopsis by John Peterson Myers

Thirty-six scientists conclude in a peer-reviewed commentary that the FDA's draft decision on bisphenol A uses unacceptable criteria for selecting data and depends heavily upon a key paper that is fatally flawed.

Note: this synopsis is written by one of the authors (Myers) of the commentary in EHP.

Both the US Food and Drug Administration (FDA) and its European counterpart, the European Food Safety Authority (EFSA) give special prominence in their reviews of bisphenol A to two industry funded studies that find the plastic monomer to be safe. 

Reviewing the rationale for this approach, thirty-six BPA experts conclude that the choice of these studies is based upon flawed criteria that favor industry-funded research while devaluing hundreds of studies funded by the US National Institute of Health and its counterparts in other countries.  The studies used by the FDA and EFSA have "serious conceptual and methodological flaws" and fail to use the most appropriate and sensitive state-of-the-art assays.

The scientists also present a detailed analysis of the paper that the FDA has identified as its 'gold-standard' and find it contains fatal errors that render it useless for regulatory assessments.

This paper, published earlier in 2008 by Rochelle Tyl from RTI International and 12 other authors, was published in the peer-reviewed journal Toxicological Sciences in April 2008.  Because of its large sample size and because it adhered to what are known as 'Good Laboratory Practices (GLP) standards, the FDA favored its findings over those of other studies with smaller samples and that did not follow GLP guidelines. They paid particular attention to Tyl et al.'s conclusions that they found no effects on prostate development, timing of puberty or mammary gland development after exposure during fetal development.  These findings contradicted multiple studies by other scientists who had reported these and other effects.  The FDA concluded that Tyl et al.'s research were more reliable, despite multiple replications of the other findings.

In the new commentary in Environmental Health Perspectives, the thirty-six authors report that Tyl et al. have three serious flaws:

1.  The average size of the prostate in control mice reported by Tyl et al. was almost 75% bigger than has been reported in all other laboratories using this strain of mice.  This indicates that either their dissection was done improperly or the mice were diseased.  In either event, this one flaw means that Tyl et al. would be incapable of finding the roughly 35% increase in prostate weight that has been reported by others to be caused by fetal exposure to bisphenol A.  Therefore Tyl et al. cannot be used to judge whether prostate effects are reliable.

2. Tyl et al. required a large dose of estradiol to cause an effect in their positive control.  This means that their mice were unexpectedly insensitive to estrogen and therefore not an appropriate model to use in testing for low dose effects of bisphenol A. 

3.  The assays used by Tyl et al. were out-of-date and incapable of detecting most of the effects that other scientists had reported based upon studies using current scientific approaches.

The commentary also addresses the broader issue of why using adherence to GLP standards is an inappropriate reason for excluding NIH-funded research.  GLP standards were developed in the 1970s in response to massive deceptive practices by contract labs reporting to federal agencies on effects of chemical exposures.  They are designed to insure good record keeping and proper care of animals, but do nothing to ensure the reliability or validity of the scientific findings.  This is demonstrated by the flaws found not just in the GLP-adhering Tyl et al. paper, but also 3 other highly criticized GLP papers that have been published by industry scientists which report no low-dose effects of BPA.

The commentary concludes that NIH-funded research is more likely to yield reliable and valid scientific findings than industry-funded GLP work because it undergoes far more rigorous reviews. 

First, the principal scientists must have demonstrated competence in the research and must employ state of the art experimental methods, assays, and laboratory environments simply to be competitive for NIH funding.  The peer-review process for grant proposals is extremely rigorous. 

Second, the results are published in peer-reviewed journals with detailed assessments by independent experts examining all aspects of the study.  Many of the NIH-funded studies rejected by FDA were published in some of the best and most competitive peer-reviewed journals in the world, including Science, Nature and the Proceedings of the National Academy of Sciences.

Third, the findings of NIH-funded studies are regularly subjected to challenge by independent efforts to replicate the findings.  Indeed, other academic experts have replicated the very findings that Tyl et al. claim can't be repeated.

The commentary concludes:

"Public health decisions should be based upon studies using appropriate protocols and the most sensitive assay. They should not be based upon criteria that include or exclude data depending upon whether the studies are GLP or not. Simply meeting GLP requirements is insufficient to guarantee scientific reliability and validity."

 

 

References:

Tyl RW, C Myers, M Marr, CS Sloan, N Castillo, MM Veselica, et al. 2008a. Two-Generation Reproductive Toxicity Study of Dietary Bisphenol A (BPA) in CD-1® (Swiss) Mice. Toxicological Sciences 104:362-384.

 Other flawed GLP studies:

Ashby J, H Tinwell and J Haseman. 1999. Lack of effects for low dose levels of bisphenol A (BPA) and diethylstilbestrol (DES) on the prostate gland of CF1 mice exposed in utero. Regulatory Toxicology and Pharmacology 30:156-166.

Cagen SZ, JM Waechter, SS Dimond, WJ Breslin, JH Butala, FW Jekat, et al. 1999. Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A. Toxicological Sciences 50:36-44.

Tyl RW, CB Myers, MC Marr, BF Thomas, AR Keimowitz, DR Brine, et al. 2002. Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicological Science 68(1):121-146.

Discussions of flaws:

National Toxicology Program. 2001. Final report of the Endocrine Disruptors Low Dose Peer Review Panel. In: Endocrine Disruptors Low Dose Peer Review. Raleigh, NC. Available: http://ntp.niehs.nih.gov/go/14446 [accessed 6 October 2008].

Center for the Evaluation of Risks to Human Reproduction. 2007. NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A (November 26, 2007). Center for the Evaluation of Risks to Human Reproduction, National Toxicology Program, National Institutes of Health. Available: http://cerhr.niehs.nih.gov/chemicals/bisphenol/BPAFinalEPVF112607.pdf [accessed 28 July 2008].

 

Also see:  The FDA flunks.  The Pump Handle