Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers


  Failure of the FDA risk assessment process for bisphenol A.
Frederick S. vom Saal
Curators' Professor
Division of Biological Sciences
University of Missouri Columbia, MO 65211

A timeline of bisphenol A-related publications, statements by FDA officials about BPA, and FDA regulatory decisions

In 1997 and 1998 a number of articles appeared in scientific journals for the first time identifying that BPA resulted in effects on the reproductive and endocrine systems in animals at doses far below the presumed no adverse effect level (NOAEL) (Colerangle and Roy, 1997; Nagel et al., 1997; Steinmetz et al., 1997; Steinmetz et al., 1998; vom Saal et al., 1998). The findings reported by vom Saal et al. (1998) were followed by two coordinated studies that were designed to repeat the same experiment. However, each of these two studies reported no effects at the same low doses of BPA found by vom Saal et al. (1998) to cause adverse effects on the male reproductive system in mice.

Both of these studies that failed to find adverse effects were designed and funded by the Society of the Plastics Industry (SPI) (Cagen et al., 1999) and the Bisphenol A Sector Group of the European Chemical Industry Council (CEFIC) (Ashby et al., 1999); these publications did not acknowledge source of funding, which was reported elsewhere (Toloken, 1998). Of great importance, both of these industry-funded studies also failed to find any effects of the positive control estrogenic drug diethylstilbestrol (DES). DES was included in these studies as the “positive control” because it is one of the most studied estrogenic compounds. DES has been shown to cause cancer and reproductive abnormalities in the offspring of women administered DES during pregnancy prior to it being banned for this use in 1972 (Newbold, 1995). vom Saal and colleagues have reported that very low doses of DES caused adverse effects that were not detected by either Ashby et al. (1999) nor Cagen et al. (1999) (Timms et al., 2005; vom Saal et al., 1997). In addition, there are a large number of studies conducted by scientists at the US National Toxicology Program (NTP) and elsewhere showing low-dose effects of DES not found by either Ashby or by Cagen (reviewed in: vom Saal, 2008).

The failure to find a positive effect of the positive control chemical in an experiment means that the experiment has, by definition, failed. This led the BPA panel formed by the Center for the Evaluation of Risks to Human Reproduction (CERHR) to report (November 26 2007 final draft report on BPA) that it had rejected these two industry-funded studies from consideration. The CERHR panel stated with regard to both the Ashby et al. (1999)) and Cagen et al. (1999) studies: “This paper is inadequate for the evaluation process due to absence of response of the positive control group”.

In addition to the “fatal flaw” due to the absence of finding an effect of the positive control chemical DES, in the study by Ashby et al. (1999) the animals that had not been treated with BPA or DES had the traits of animals that had, in fact, been exposed to estrogen. Thus, rather than having a finding of no effect due to all animals appearing normal, the absence of the finding of any effect of BPA or DES was due to the animals all being similar to the untreated animals, but all animals (treated and untreated) were abnormal. Exactly the same results occurred when Ashby and colleagues attempted to repeat (using the same type of animal, same type of feed, etc.) a study conducted by scientists at the Japanese NIH, who had reported that exposure of adult rats to very low doses of BPA caused a decrease in testicular sperm production (Sakaue et al., 2001).

The findings reported by Ashby et al. (Ashby et al., 2003) are remarkable in that the BPA-treated males had exactly the low sperm levels as those reported by Sakaue et al. (2001), but the untreated males also had very low sperm production, suggesting that they had also been exposed to estrogen. While Ashby et al. (2003) stated “No explanation for our failure to replicate the effects reported by Sakaue et al. is evident”, what appears obvious to anyone who looks carefully at the comparison of Ashby et al. (2003) and Sakaue et al. (2001), or a comparison of Ashby et al. (1999) and vom Saal et al. (1998), is that all of the animals in Ashby’s laboratory were contaminated by estrogen from some unknown source; these findings were reviewed in detail in a peer-reviewed publication (vom Saal and Welshons, 2006).

One would think that such obvious flaws would be recognized by anyone who took the time to examine these published studies. Scientists have recognized that there were fatal flaws in the studies conducted by Ashby et al. (1999) and by Cagen et al. (1999). In marked contrast, Dr. George Pauli at the US Food and Drug Administration (FDA) for many years was the FDA’s spokesman who repeatedly assured the public and legislators about the safety of BPA (he retired in 2006). Dr. Pauli stated in an interview concerning the Ashby and the Cagen publications (Endocrine-Estrogen Letter 5(10) May 20, 1999) that “the agency is following the low dose issue closely and has seen no reason to take any actions.” Addressing the bisphenol A issue, he said that "it is troubling that people who appear in good faith to replicate [the vom Saal study] haven't been able to replicate those findings. When you have larger studies intended to replicate a smaller study, and when you do not see the effects, it certainly casts doubt on relying on one study and ignoring the larger ones," Pauli said.

Dr. Pauli also said that FDA cannot take actions based on vom Saal's research until it has been replicated. "Until you can replicate something, you can't interpret its significance," he said. "Our conclusion is we should go with the track record. We have evaluated [food contact uses of bisphenol A] in a thorough manner, and concluded its use is safe. We haven't seen anything that would persuade us to change that. ” [NOTE: It is not accurate to state that the FDA had actually thoroughly evaluated food-contact uses of BPA, and the CERHR panel identified that the Ashby study was not “a larger study” as claimed by Dr. Pauli. Finally, even though the findings in the initial vom Saal study have been replicated and extended by other NIH-funded scientists, neither Dr. Pauli or other FDA officials have ever acknowledged that fact].

Not unexpected was the use of Dr. Pauli’s statements in public relations documents released by the plastic industry trade organizations: Dr. Pauli’s comments in 1999 were followed by a joint statement by the American Plastics Council and the Society of the Plastics Industry that: “As recently as May 1999, FDA official George Pauli was cited by Consumer Reports as saying that FDA "stands by its decades old approval of polycarbonate baby bottles as safe.” Since 1999, Dr. Pauli has been quoted in numerous articles stating that the position of the FDA was that BPA was safe due to the presence in the scientific literature of studies that did not report finding effects of low doses of this chemical.

In 2005 Dr. Pauli presented the FDA’s position on BPA in response to questions posed by the California Assembly that was considering legislation to ban the use of BPA in some infant products.

April, 6 2005 Letter from George Pauli to California Assembly considering a bill by Rep Wilma Chan to ban BPA in baby products.
George Pauli, Ph.D.
Associate Director for Science and Policy
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

Question 1: Is it correct that polycarbonate plastic and epoxy resins are currently regulated by FDA for use in contact with food?
Response by Dr. Pauli:
“Yes. Polycarbonate resins were approved for use in contact with food on May 22, 1963.” Approval was based on the fact that BPA “had been in use for some time… The standard for safety for the approval was a reasonable certainty that the materials would not be harmful under the intended conditions of use.”

This approval of BPA by the FDA was thus based on the assumbtion that bisphenol A was Generally Regarded As Safe (GRAS). [FDA has defined "safe" (21 CFR 170.3(i)) as a reasonable certainty in the minds of competent scientists that the substance is not harmful under its intended conditions of use. [A description of GRAS as applied by the FDA for chemicals such as BPA is posted at: http://www.cfsan.fda.gov/~dms/grasguid.html]

Question 2: Does FDA consider products made from polycarbonate plastic and epoxy resins to be safe for use in contact with food or beverages?
Response by Dr. Pauli:
“Yes. FDA is aware of several reports stating that bisphenol A has estrogenic activity and that, in spite of evidence that bisphenol A is harmless when consumed by animals in amounts far (orders of magnitude) higher than humans would consume, such estrogenic activity persists at very low doses. However, other reports appear to dispute any reason to expect harm at the low exposures that humans experience. FDA continues to closely follow the research in this area. However, based on all the evidence available at this time. FDA sees no reason to change it long-held positions that current uses with food are safe.”

The American Chemistry Council (ACC) also sent documents to the California Assembly regarding BPA.
Bisphenol A Safety Overview, presented to the California Assembly by the American Chemistry Council, December 2005. “Reported low-dose effects have not been replicated in repeat studies conducted in independent laboratories. The vast majority of available data shows no low dose effect whatsoever.”

The facts are quite different from those presented above by the FDA and the ACC. In 2005 a peer-reviewed article that discussed differences between the BPA publications funded by the chemical industry as opposed to findings from studies funded by government agencies such as NIH was published by vom Saal and Hughes in the NIH journal Environmental Health Perspectives (vom Saal and Hughes, 2005). This review identified that as of 2005, out of 115 studies investigating “low doses” of BPA in experiments conducted with laboratory animals, over 90% of government-funded studies conducted by academic and government scientists with no financial conflicts concerning BPA reported finding harm, while 100% of industry-funded studies reported no harm. Thus, the statements above by both Dr. Pauli and the ACC concerning the available scientific literature were not consistent with the published scientific literature on BPA, which anyone capable of doing a web-based literature search would have been able to determine. As of the beginning of 2009, there have been over 200 low dose BPA studies conducted with experimental animals and over 200 mechanistic studies conducted with animal and human cells in culture demonstrating that BPA is a potent estrogenic chemical as well as identifying the molecular mechanisms mediating adverse effects.

TABLE 1. Association between Human Health Trends and Adverse Health Effects in Laboratory Animals at Human Exposure Levels of BPA

BPA effects in mice and rats
Human health trends
Prostate hyperplasia and cancer
Mammary hyperplasia and cancer
  Prostate cancer increase
Breast cancer increase
Abnormal urethra/obstruction
Sperm count decrease
Early puberty in females
Ovarian cysts/uterine fibroids
Abnormal oocyte chromosomes
Male and female reproductive system

Sperm count decrease
Early sexual maturation
PCOS/uterine fibroids

Body weight increase
Insulin resistance
Metabolic disease
  Obesity increase
Type 2 diabetes
Hyperactivity/impaired learning
Abnormal play behavior
Abnormal socio-sexual behavior
Brain and behavior


BPA effects in mice & rats Human health trends Prostate hyperplasia and cancer Mammary hyperplasia and cancer Cancer Prostate cancer increase Breast cancer increase Abnormal urethra/obstruction Sperm count decrease Early puberty in females Ovarian cysts/uterine fibroids Abnormal oocyte chromosomes Male and female reproductive system Hypospadias Sperm count decrease Early sexual maturation PCOS/uterine fibroids Miscarriage Body weight increase Insulin resistance Metabolic disease Obesity increase Type 2 diabetes Hyperactivity/impaired learning Abnormal play behavior Abnormal socio-sexual behavior Brain and behavior ADHD Autism

The use of the CD-SD rat in BPA research
Vom Saal and Hughes (2005) identified that in addition to source of funding being a major predictor of outcome in low-dose BPA experiments, the second major predictor of “no harm” in BPA experiments was the use of a rat (the CD-SD strain) that is unresponsive to doses of the estrogenic drug ethinylestradiol that are found in birth control pills. [The use of this rat that has been selectively bred for hyper-fertility and rapid postnatal growth by regulatory agencies has generated so much interest that it was the subject of an article in Discover magazine (February, 2009, p 44)]. No study using the CD-SD rat has reported finding any effect that would be detected in a standard toxicological study conducted for risk assessment purposes (vom Saal, 2008).

The FDA 2008 draft risk assessment of BPA
The issue of the insensitivity of the CD-SD rat to any estrogen is of great importance, since one of the two BPA studies that was used by the FDA in its draft risk assessment in 2008 (while all other studies were considered of little value) involved the use of the CD-SD rat (Tyl et al., 2002). Since this rat is unresponsive to even potent estrogenic drugs, it is clearly inappropriate as a model animal to examine effects of low doses of BPA. However, the FDA appeared to be completely unaware of this issue when it used the Tyl et al. (2002) as a major study to declare BPA safe in its draft risk assessment.

Good Laboratory Practices (GLP) as a determining factor in the FDA selection of studies to use in its 2008 draft risk assessment
A primary factor in the decision by the FDA to use the Tyl et al.. (2002) study that was funded by the Society of the Plastics Industry and co-authored by employees of the major BPA manufacturers (Dow Chemical, Bayer, Aristech, GE) was that it used Good Laboratory Practices (GLP). As pointed out by 36 scientists who criticized the FDA for misinterpreting GLP as being synonymous with “good science” (Myers et al., 2008), GLP is primarily a record-keeping system instituted to stop the fraud that was occurring a contract laboratories hired by chemical manufacturers to conduct hazard testing. As demonstrated by the use of a rat that clearly was inappropriate for examining low- dose effects of BPA, GLP does not mean that the experiment is properly designed or that it reaches valid conclusions of safety.

An incident that has received little attention is that on the evening of August 25, 2001, someone appears to have set polycarbonate cages on fire in the Research Triangle Institute where the study reported in Tyl et al. (2002) was conducted. An investigation of this incident was reported in a document sent to the EPA by Batelle (Columbis, OH) dated November 14, 2001, identifying that the burning of polycarbonate cages made out of BPA had, in fact, resulted in distribution of BPA through the air handling system, exposing experimental animals to measurable levels of BPA.

The second GLP study used by the FDA to declare BPA safe in it draft risk assessment was also conducted by the same group that conducted the CD-SD rat GLP study. This study by Tyl et al. (2008a) used CD-1 mice, which over 20 other independently published studies have reported to show adverse effects in response to low doses of BPA, including studies published by the reproductive toxicology laboratory of the National Toxicology Program that uses this mouse as its model animal (Newbold et al., 2007). In marked contrast to the CD-SD rat, this mouse is responsive to very low doses of estrogenic drugs such as DES and ethinylestradiol, as well as BPA (Gupta, 2000; Newbold et al., 2004; Timms et al., 2005); in organ culture the prostate of fetal CD-1 mice responded with an increase in size to 0.1 pg/ml (parts per trillion) of DES and 50 parts per trillion of BPA (Gupta, 2000), and this is one of the studies to replicate and extend the initial findings reported by vom Saal et al. (1998). However, in the Tyl laboratory, a very high dose of the positive control estrogen (100 micrograms/kg body weight of estradiol) was required to elicit responses (Tyl et al., 2008b), which is reminiscent of the problems associated with the mouse and rat studies conducted in the Ashby laboratory at Zeneca Corporation, where the animals appeared unresponsive to low doses of estrogenic chemicals (both BPA and DES) because of possible laboratory contamination.

Recent findings show that estradiol is able to alter gene activity in fetal CD-1 mouse tissues in cell culture at a dose below one part per trillion (Richter et al., 2007b), or more than 100-million-times lower than the dose that was used as the “positive control” dose in the Tyl et al (2008a) study of BPA in CD-1 mice; this is thus similar to the finding for DES reported by Gupta (2000). It is illogical to attribute this enormous difference, observed in multiple studies, to pharmacokinetic effects.

The FDA officials who conducted the BPA risk assessment do not appear to understand the importance of examining the dose of the positive control estrogenic chemical required to elicit a response in assessing the validity of the research findings in experiments.

Furthermore, as pointed out in detail by Myers et al. (2009), the data presented for some organ weights for control males in the Tyl et al. (2008a) study are clearly abnormal relative to data from young-adult male CD-1 mice reported by other investigators (Gupta, 2000; Ruhlen et al., 2008). In response to the criticism that the prostates in control mice in the Tyl et al. 2008a) study were almost twice the size reported for control male CD-1 mice in other studies (Gupta, 2000; Ruhlen et al., 2008), the lead author, Dr. Rochelle Tyl, testified at the FDA’s BPA subpanel meeting on September 16, 2008 that the animals used in her study were 6 months old and that the mean weight of prostates in normal CD-1 male mice at 6 months was within the range she reported. It was immediately identified for the BPA subpanel that, in direct contrast to Dr. Tyl’s testimony, her animals were reported in her publication as being 14 weeks old (3.5 months) at the time of organ collection, not 6-months old as she had just testified to the subpanel. In addition, the prostate in 6- month-old healthy CD-1 male mice is not grossly enlarged, and prostates of the size she reported would only be found in diseased animals, which is very rare for CD-1 male mice at either 3 or 6 months of age. [NOTE: the FDA established a special BPA subpanel to review the draft risk assessment and hold a public hearing on September 16, 2008. Subsequently, this subpanel reported its findings to the FDA’s standing Science Board in October 2008.]

The fact that Dr. Tyl would misrepresent the age of the animals she examined in testimony at the FDA’s BPA subpanel public hearing in an attempt to justify the data collected in her GLP study of BPA is very disturbing, and this misrepresentation of the facts by Dr. Tyl should be a consideration in any future use of data from this study.

What is clear from the above is that while the Tyl et al. (2008a) study was conducted using GLP guidelines, this did not ensure that the data collected were valid. The prostate data presented by Tyl et al. (2008a) are not valid: either non-prostatic tissue was collected along with the prostate by technicians who were not properly trained or the animals were severely diseased. Since the authors stated that histopathologic examination of the tissues was conducted, and no pathology was reported, disease can be eliminated as a possibility if the data reported are accurate. This finding thus raises concern that other aspects of the study were also not conducted properly. The FDA draft risk assessment disagrees with the assessment of the NTP-CERHR assessment of BPA as well as the consensus of 38 scientists convened by the NIH to assess the health effects of BPA and the decision by the Canadian Ministry of Health to declare BPA a “toxic chemical”

An unusual aspect of the release of the FDA draft risk assessment on August 15, 2008 was that it preceded the release of the final report by the National Toxicology Program (NTP) based on its two-year review of the published studies concerning BPA by a CERHR panel. The NTP concluded that there was some concern for adverse effects of BPA on some aspects of the reproductive system (in particularly the prostate) and development (in particular neuro-behavioral development), with the primary threat occurring during early life (NTP, 2008). There was consensus of 38 scientists that BPA caused a number of adverse effects in animals and was thus a potential threat to humans, particularly during early life (vom Saal et al., 2007). There was thus agreement of two scientific reports that BPA posed a potential threat to human health at current levels of human exposure. In addition, at the same time as the NTP was identifying some concern over the potential for BPA to adversely affect human health, the Canadian Ministry of Health and Canadian Ministry of the Environment together declared BPA a “toxic chemical” (Canada, 2008). In fact, BPA was identified by the Canadian government as the highest priority chemical for regulatory action prior to it being banned for use in infant products in 2008.

The FDA draft BPA report was released just prior to a vote on August 18, 2008 on a bill to ban BPA in some infant products in the California Senate (the bill had been previously passed by the California House), and in large part due to the FDA position that BPA was safe, the California bill was defeated by only 4 votes. This led to news reports identifying that: “The timing of the announcement by FDA raises eyebrows considering the California legislature is about to vote on a measure to remove the toxic chemical from some children’s products... Time and again, FDA has sided with special interests instead of the public interest on this chemical.” (http://ecochildsplay.com/2008/08/19/california-fails-to-pass-chemical…) The public soon learned that the FDA had ignored scientific reports and, instead, based its draft risk assessment primarily on documents provided to it by the American Chemistry Council, according to an investigation by the Milwaukee Journal Sentinel newspaper (Plastics industry behind FDA research on bisphenol A, study finds. By Susanne Rust and Meg Kissinger, Oct. 22, 2008). In the first paragraph of the FDA BPA draft risk assessment the FDA restates the conditions that have to be met in order for chemicals such as BPA to be declared safe by the FDA (these conditions are spelled out in the document identifying the criteria for establishing a chemical as “generally regarded as safe (GRAS).

“Safety for food additives is defined in 21 CFR §170.3(i): Safe or safety means that there is reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. This definition goes on to state that complete certainty of absolute harmlessness is scientifically impossible to establish.” It is clear that the conditions required to declare BPA safe are not met, in that there is consensus among scientists that BPA is potentially harmful under intended conditions of use (NTP, 2008; vom Saal et al., 2007).

The FDA point person chosen to defend BPA as safe since the retirement of Dr. Pauli is Dr. Norris Alderson, Associate Commissioner for Science, FDA. Dr. Alderson provided testimony at a Congressional hearing (Subcommittee on Commerce, Trade and Consumer Protection Committee on Energy and Commerce) on the safety of BPA (dated June 10, 2008). In this testimony Dr. Alderson strongly defended the safety of BPA.

Dr Alderson also wrote a letter (dated December 3, 2008) to the FDA’s Science Board after the FDA’s Science Board voted unanimously to accept the recommendation of the BPA subcommittee that the FDA’s draft risk assessment was “flawed”. The letter by Dr. Alderson concerned the FDA’s response to the Science Board’s acceptance of the harsh criticism of the draft BPA risk assessment in the BPA subpanel report. In this letter to the FDA’s science board he stated: “FDA is currently developing a protocol for a neurodevelopmental study in rodents… The aims of this study are to evaluate the effects of BPA on standard developmental neurotoxicity endpoints and sexually dimorphic endpoints.”

The FDA’s BPA subpanel stated in their review of the FDA draft risk assessment released on October 31, 2008 that the FDA had arbitrarily dismissed from consideration numerous studies determined to be of “high utility” by the CERHR BPA panel. The BPA subpanel stated that the FDA should include these studies and conduct another risk assessment for BPA. The FDA’s Science Board had unanimously accepted the recommendations of the BPA science advisory subpanel, but the FDA has ignored the recommendations that were made in the BPA subpanel’s report.

The response of the FDA was to state that they would begin conducting research to determine whether BPA was safe rather than do what was determined to be the required course of action by the Science Board when it voted to accept the BPA subpanel report, namely, that the FDA should conduct an entirely new risk assessment that included non-GLP research reporting harm at low doses of BPA.

The decision by the FDA administration to ignore the advise of its BPA subpanel and Science Board was reported in an article in the Washington Post. FDA Will Continue To Study Chemical: No Action Planned on Bisphenol A, By Lyndsey Layton, December 16, 2008; Page A03. “The Food and Drug Administration, criticized by its own scientific advisers for ignoring available data about health risks posed by a chemical found in everyday plastic, said yesterday it has no plans to amend its position on the substance but will continue to study it.” In fact, not reported anywhere is that this neurotoxicity study that Dr. Alderson refers to will use the estrogen-insensitive CD-SD rat. There are over 50 studies that have been published in peerreviewed journals by academic and government scientists showing effects of low doses of BPA on the brain and behavior. The idea that a study conducted with a model animal already identified as inappropriate for use in BPA research would in any way alter the opinion by scientists that BPA poses a hazard to neuro-behavioral development, as determined by the NTP in its evaluation of BPA, is ridiculous. This is clearly an attempt by the Dr. Alderson and the FDA to delay action on BPA while accomplishing absolutely nothing with this proposed experiment. More research is always needed to identify mechanisms of toxicity of chemicals to which the vast majority of humans are exposed, which is the case for BPA (Calafat et al., 2008), which appears to be due to continuous exposure from a wide variety of sources (Stahlhut et al., 2009). This exposure is now related to heart disease and diabetes in adults in the USA based on data from NHANES 2003/4 (Lang et al., 2008; vom Saal and Myers, 2008). The current number of animal experiments showing adverse effects at low doses of BPA is 197 studies, with over 200 additional mechanistic studies involving examination of molecular pathways in animal and human cells in culture (vom Saal, 2008).

The proposition by the FDA that it is acceptable to continue to declares BPA completely safe while it spends years conducting additional research is grounds for a congressional investigation, since this directly violates the requirement that “there is reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use”.

Ashby J, Tinwell H, Haseman J. (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. Reg Tox Pharm 30, 156-166.

Ashby J, Tinwell H, Lefevre PA, Joiner R, Haseman J. (2003) The effect on sperm production in adult Sprague-Dawley rats exposed by gavage to bisphenol A between postnatal days 91-97. Toxicol. Sci. 74, 129-138.

Cagen SZ, Waechter JM, Dimond SS, Breslin WJ, Butala JH, Jekat FW, Joiner RL, Shiotsuka RN, Veenstra GE, Harris LR. (1999) Normal reproductive organ development in CF-1 mice following prenatal exposure to Bisphenol A. Tox Sci 11, 15-29.

Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. (2008) Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect 116, 39-44.

Canada E. 2008. Draft Screening Assessment for The Challenge Phenol, 4,4' -(1-methylethylidene)bis- (Bisphenol A).

Chemical Abstracts Service Registry Number 80-05-7. http://www.ec.gc.ca/substances/ese/eng/challenge/batch2/batch2_80-05-7.cfm. .

Colerangle JB, Roy D. (1997) Profound effects of the weak environmental estrogen-like chemical bisphenol A on the growth of the mammary gland of Noble rats. J Steroid Biochem Mol Biol 60, 153-160.

Gupta C. (2000) The role of estrogen receptor, androgen receptor and growth factors in diethylstilbestrol-induced programming of prostate differentiation. Urol Res 28, 223-229.

Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D. (2008) Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300, 1303-1310.

Myers JP, vom Saal FS, Akingbemi BT, Arizono K, Belcher S, Colborn T, et. al. (2009) Why public health agencies cannot depend on good laboratory practices as a criterion for selecting data: the case of bisphenol A. Environ Health Perspect 117, 309-315.

Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. (1997) Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105, 70-76.

Newbold R. (1995) Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect 103, 83-87.

Newbold RR, Jefferson WN, Padilla-Banks E. (2007) Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol 24, 253-258.

Newbold RR, Jefferson WN, Padilla-Banks E, Haseman J. (2004) Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects. Reprod Toxicol 18, 399-406.

NTP. 2008. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A. September 2008. http://cerhr.niehs.nih.gov/chemicals/bisphenol/bisphenoleval. html. Accessed September 3, 2008. (Program NT, ed): NIH Publication No. 08 – 5994.

Richter CA, Taylor JA, Ruhlen RR, Welshons WV, vom Saal FS. (2007b) Estradiol and bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate cells. Environ Health Perspect 115, 902-908.

Ruhlen RL, Howdeshell KL, Mao J, Taylor JA, Bronson FH, Newbold RR, Welshons WV, vom Saal FS. (2008) Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the "fetal estrogenization syndrome" and obesity in CD-1 mice. Environ Health Perspect 116, 322-328.

Sakaue M, Ohsako S, Ishimura R, Kurosawa S, Kurohmaru M, Hayashi Y, Aoki Y, Yonemoto J, Tohyama C. (2001) Bisphenol A affects spermatogenesis in the adult rat even at a low dose. J Occupational Health 43, 185-190.

Stahlhut RW, Welshons WV, Swan SH. (2009) Bisphenol A data in NHANES suggest longer than expected half-life, substantial non-food exposure, or both. Environ Health Perspect, doi: 10.1289/ehp.0800376 (available at http://dx.doi.org/) Online 0800328 January 0802009.

Steinmetz R, Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N. (1997) The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinol 138, 1780-1786.

Steinmetz R, Mitchner NA, Grant A, Allen DL, Bigsby RM, Ben-Jonathan N. (1998) The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract. Endocrinol 139, 2741-2747.

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 mouse prostate and urethra. Proc Natl Acad Sci 102, 7014-7019.

Toloken S. (1998) SPI study disputes endocrine disruptor findings. Plastic News October 16.

Tyl R, Myers C, Marr M, Sloan CS, Castillo N, Veselica MM, Seely JC, Dimond SS, Van Miller JP, Shiotsuka RS, et al. (2008b) Two-Generation Reproductive Toxicity Evaluation of Dietary 17ß- Estradiol (E2; CAS No. 50-28-2) in CD-1® (Swiss) Mice. Toxicol Sci 102, 392-412.

Tyl RW, Myers C, Marr M, Sloan CS, Castillo N, Veselica MM, Seely JC, Dimond SS, Van Miller JP, Shiotsuka RS, et al. (2008a) Two-Generation Reproductive Toxicity Study of Dietary Bisphenol A (BPA) in CD-1® (Swiss) Mice. Toxicol Sci 102, 362-284.

Tyl RW, Myers CB, Marr MC, Thomas BF, Keimowitz AR, Brine DR, Veselica MM, Fail PA, Chang TY, Seely JC, et al. (2002) Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci 68, 121-146.

vom Saal FS. 2008. Bisphenol A: Update of current published studies. Available: http://endocrinedisruptors.missouri.edu/vomsaal/vomsaal.html [accessed Febriary 22, 2008].

vom Saal FS, Akingbemi BT, Belcher SM, Birnbaum LS, Crain DA, Eriksen M, Farabollini F, Guillette LJ, Jr., Hauser R, Heindel JJ, et al. (2007) Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 24, 131-138.

vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV. (1998) A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicol Ind Health 14, 239-260.

vom Saal FS, Hughes C. (2005) An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environ Health Perspect 113, 926-933.

vom Saal FS, Myers JP. (2008) Bisphenol A and risk of metabolic disorders. JAMA 300, 1353-1355.

vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV. (1997) Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Nat Acad Sci 94, 2056-2061.

vom Saal FS, Welshons WV. (2006) Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A. Environ Res 100, 50-76.



OSF Home
 About this website
Book Basics
  Synopsis & excerpts
  The bottom line
  Key points
  The big challenge
  Chemicals implicated
  The controversy
New Science
  Broad trends
  Basic mechanisms
  Brain & behavior
  Disease resistance
  Human impacts
  Low dose effects
  Mixtures and synergy
  Ubiquity of exposure
  Natural vs. synthetic
  New exposures
  Wildlife impacts
Recent Important    Results
Myths vs. Reality
Useful Links
Important Events
Important Books
Other Sources
Other Languages
About the Authors
Talk to us: email