Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund, September 16, 2008

I am pleased to have the opportunity to testify as president of the National Research Center for Women & Families. Our nonprofit research and education center does not accept contributions from companies that make medical products that we evaluate, or competing companies, and so I have no conflicts of interest.

Our Center is dedicated to improving the health and safety of adults and children, and we do that by scrutinizing medical and scientific research to determine what is known and not known about specific treatments and prevention strategies, and to compare their safety and effectiveness.

In addition, I am a fellow at the University of Pennsylvania Center for Bioethics, and a board member for two nonprofit organizations that work to improve resources for the FDA: the Alliance for a Stronger FDA, and the Reagan Udall Foundation.

I was trained in epidemiology at Yale Medical School; I have worked on federal health policy issues in Congress, the White House, the Institute of Medicine, and for nonprofit organizations for 25 years; and I have reviewed FDA safety issues for almost 20 years.

Bisphenol A (BPA)

BPA is used in a variety of products including reusable water bottles, baby bottles, and plastic tableware. Epoxy resins made with BPA are used to coat the insides of canned foods and beverages.

There is no debate that BPA leaches out of plastic into liquids and foods. The Centers for Disease Control and Prevention (CDC) found measurable amounts of BPA in the bodies of more than 90 percent of the U.S. population studied.¹

FDA Draft Assessment Conclusion

The FDA Draft Assessment concluded “that an adequate margin of safety exists for BPA at current levels of exposure from food contact uses.”

The FDA’s conclusions are primarily drawn from two-industry funded studies, one of which was sponsored by the American Plastics Council and the other by the Society of Plastics Industry.²

In contrast to the industry-funded studies, more than 150 government-funded BPA experiments on lab animals and tissues reported adverse effects, while only 14 did not. These statistics were compiled by the journal published by the American Chemical Society, the professional association for chemists.

However, 13 out of 13 industry-funded studies found no adverse effects.³ It seems that “He who pays the piper calls the tune.”

In addition, the FDA’s estimates of exposure are based on questionable data. On page 7, the FDA draft report explains that the studies by FDA laboratories were done in the early 1990’s-more than 12 years ago. The study was based on only 14 samples of infant formula representing 5 brands purchased in Washington, DC supermarkets. Is that representative of all infant formula cans in the early 1990s or today? No. In an update from this past June, an FDA official pointed out that studies of more recent samples of infant formula have found a more dramatic range of BPA levels. The FDA has stuck with their old estimate of 6.6 ppb as the maximum level, but it is not the maximum level, as the FDA well knows. In fact, 6.6 ppb is lower than the level found in several other studies.⁴

What Does “Some Concern” Mean?

The FDA Draft Assessment focuses on cancer and reproductive and developmental toxicity of BPA. They quote the National Toxicology Program’s report, which concluded that “some concern” exists for developmental toxicity, and less concern for other risks.

Unfortunately, the terminology used is misleading. The National Toxicology Program is judging their “concerns” on the basis of how conclusive the research evidence is. The research on rats and mice and tissue can’t be considered conclusive regarding human health. But, this does not mean there is conclusive evidence that there is no need for concern. The lack of conclusive evidence is not the same thing as the evidence of safety.

On the contrary, the weight of the evidence, especially the unbiased evidence of government-funded research, is that we should be concerned.

The FDA relies on industry for research everyday, but in this case there is an abundance of well-designed studies that are being discounted for inappropriate reasons, such as the lack of good laboratory practices (GLP). GLP are industry standards – they have nothing to do with whether the study is well designed or not. A poorly designed study using GLP will not provide accurate safety information, and that is exactly the problem we have with the industry studies FDA relied on. In academia, science is built on replication by different scientists in different labs.

Most Independent Studies Show Risks of BPA

Well-respected scientists from across the country have found that BPA is potentially dangerous for humans. Many of these scientists worked together on the Chapel Hill Consensus Statement on BPA, which expressed strong concerns about the impact of BPA on human health.

The Statement also noted increases in neurobehavioral problems, such as attention deficit hyperactivity disorder and autism, increases in childhood and adult obesity and Type II diabetes, decrease in sperm count, and increases in hormonally mediated cancers, such as prostate cancer.⁵

Several newly published studies support the concerns of the Chapel Hill Consensus Statement. Several of these studies were not published in time to be considered by the National Toxiciology Program or the FDA.

Researchers at Yale just published the first study of the effect of BPA on primates, which demonstrated “an adverse effect of BPA on the brain…and further amplifies concerns about the widespread use of BPA…in food preparation and storage.”⁶

A study that is published online in Environmental Health Perspectives and will soon be in print concluded that low doses of BPA could inhibit the release of a key hormone (adiponectin) that protects humans from the metabolic syndrome, thereby linking BPA to an increase in heart attacks and Type II diabetes.

In addition, a study in this month’s issue of Endocrinology found that young female mice exposed to BPA showed brain and behavior traits more typical of male mice.

A study in the June issue of Cancer Research showed a correlation between rats that had early BPA exposure and those that developed prostate cancer in later life. The study was done by Shuk-mei Ho, head of environmental health at the University of Cincinnati, and Gail Prins, physiology professor at the University of Illinois in Chicago.

Risks vs. Benefits

Companies that make plastics and plastic food and beverage containers have said that BPA has been used for years and therefore it is safe. We’d like to believe it, but wishing doesn’t make it so. There are several disturbing disease trends that coincide with the increased use of BPA, such as Type II diabetes, learning disabilities, and breast cancer. And, of course, the lag time between exposure to a carcinogen and developing cancer is usually 15-20 years or more. If it weren’t so long, we’d have a lot of Americans dying of lung cancer in their 20’s and 30s.

What Should The FDA Do?

The most disturbing aspect of the FDA report is the conclusion that BPA at current levels is safe when the FDA does not know what current levels are and doesn’t have well-designed research to conclude that they are safe.

The FDA estimates of BPA are based on studies of 14 samples sold more than 12 years ago, in supermarkets in Washington, D.C. We need more recent measurements in a larger number of products sampled from stores across the country.

The draft assessment states: “FDA does not have a specific list of BPA-containing end products as provided to consumers.” Why not? Without it, we don’t really know what the exposure is, and consumers can’t avoid BPA-tainted products.

The FDA should not draw conclusions that are biased and premature.

While the FDA is deciding what to do about BPA in food containers, they should at the very least empower consumers by requiring that food and beverage containers list whether or not they contain BPA.

But ultimately, it is not fair to consumers to give them information (this container has BPA!) without explaining the implications. For that reason, the FDA should ban the use of BPA or at the very least require reduced levels of BPA until more conclusive studies can be performed to assure the American public that the chemical is safe. I think we can all agree that there is no clear evidence that the products are safe, the only question is whether they are unsafe.

Alternatives to BPA Available

Alternatives include oleoresinous, vinyl, or PET film lamination to line cans, and glass bottles, polypropylene bottles and bottles with polymeric liners for baby bottles.

Other Countries Are Reducing BPA Exposure-But Not The U.S.

Japan has taken measures to reduce BPA in consumer products, such as canned beverages and plastic tableware. They are using different linings for beverage cans, which either contain no BPA or leach only a small amount of BPA, and plastic tableware that had BPA has been replaced with tableware that does not.⁷

In the United States, the NTP points out that “exposure to bisphenol A may be increasing” and the median levels of BPA in human urine doubled from 1988 to 2004.⁸

Responsible retailers are not waiting for the FDA to act. Wal-Mart and Toys-R-Us have pledged to remove products containing BPA from their shelves at the end of 2008.⁹ Bottle manufacturers such as Playtex and Nalgene are using non-BPA materials for their products.

Keeping Consumers Safe?

It is your job and the job of the FDA to make sure that food and beverage containers don’t increase the risks of food and beverages. The bottom line is we just don’t know if BPA in infant formula cans and other food containers is safe.

More than 100 studies have raised doubts about the safety of BPA, and alternatives to BPA are available. If the FDA is to err, it should be on the side of consumer safety, not corporate profits, by banning BPA in baby bottles, plastic tableware, foods and beverages, and other products.

References:

1. Hileman, B., (2007, April). Bisphenol A on Trial, Chemical & Engineering News Government & Policy, Vol. 85, Number 16. http://pubs.acs.org/cen/government/85/8516gov2.html
2. Ibid.
3. Hileman B., (2007, April). Ibid.
4. Bailey, A, June 2, 2008 Update on Cumulative Exposure to BPA, Memorandum to the File, Division of Food Contacts Notification, http://www.fda.gov/ohrms/dockets/AC/08/briefing/2008-0038b1_01_07_FDA%20Reference%20Material-FDA%20Memo%20Cumulative.pdf
5. vom Saal, F., (2007). Chapel Hill Bisphenol A Expert Panel Consensus Statement: Integration of Mechanism, Effects in Animals and Potential to Impact Human Health at Current Levels of Exposure, Reproductive Toxicology.
6. Leranth, C., et.al., (2008). Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates, Yale University School of Medicine, The National Academy of Sciences. http://www.pnas.org/content/early/2008/09/02/0806139105.abstract?sid=a6820950-175f-4d84-86b1-035e4b42213b
7. Advanced Industrial Science and Technology. 2007. Risk Assessment Document: Bisphenol A.
8. National Toxicology Program, U.S. Department of Health and Human Services, Center for the Evaluation of Risks to Human Reproduction, (September 2008). NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A. NIH Publication No. 08-5994.
9. Parker-Pope, T., (2008, April 22). A Hard Plastic is Raising Hard Questions, The New York Times.

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund, September 8, 2008

I am pleased to have the opportunity to testify as president of the National Research Center for Women & Families. Our nonprofit, research, and education center does not accept contributions from companies that make medical products that we evaluate, or competing companies, and so I have no conflicts of interest.

Our Center is dedicated to improving the health and safety and adults and children, and we do that by scrutinizing medical and scientific research to determine what is known and not known about specific treatments and prevention strategies, and to compare their safety and effectiveness.

In addition, I am a fellow at the University of Pennsylvania Center for Bioethics, and a board member for two nonprofit organizations that work to improve resources for the FDA: the Alliance for a Stronger FDA, and the Reagan Udall Foundation.

I was trained in epidemiology at Yale Medical School; I have worked on federal health policy issues in Congress, the White House, the Institute of Medicine, and for nonprofit organizations for 25 years; and I have testified at FDA advisory committee meetings on numerous safety issues for almost 20 years.

Osteoporosis is a serious disease. Fortunately, there are numerous treatments available, and those options should help the FDA determine whether the risks of this drug, Fablyn, outweigh the benefits.

I have examined the data that were made available to you, I have reviewed the FDA’s summary of the data, and I have listened to the presentation today. The data from The PEARL Study indicate that Fablyn at .5 mg significantly decreases the risk of new or worsening radiographic vertebral fractures by about 50% — but that is only from 2% to 1% during the first year and from 4.6% to 2.2% during the first two years. Over three years, the risk reduction is somewhat lower, from about 6.4% to 3.8%.

However, most of those fractures were asymptomatic. The results were not significant and were much less impressive for clinical vertebral fracture – from only 1.7% to 1.2% through the third year.

Since Fablyn’s reduction of vertebral fracture seems to decrease over time for radiographic fractures and is not significant for symptomatic fractures, it is very unfortunate that no 5-year data were made available for FDA analysis. Preliminary data are not adequate to judge this product.

The safety data from the same study are apparently available through the 5th year, and the risks are significant. Women taking this osteoporosis drug were significantly more likely to die during the 5 years of the study. Surprisingly, it seems that at 3 years the death rate was similar for either the .5 mg dose or the .25 mg dose, but at 5 years the death rate was higher for women taking the lower dosage (.25 mg) than the .50 mg. Even so, the death rate was higher for women taking Fablyn than for the placebo group, and these findings are obviously worrisome. The increased risk of death was primarily from cancer, stroke, and other non-coronary vascular causes – which is consistent with mortality data from women taking other SERMS.

In addition, the number of serious adverse reactions also is higher among women taking Fablyn, especially for those classified as “treatment-related.” These include pulmonary emboli, uterine polyps, and deep vein thrombosis.

What Does This Mean for Women?

Clearly, the benefits of this drug are quite small – primarily in preventing new vertebral fractures that can be diagnosed with x-rays but have no symptoms of pain or discomfort. In contrast, women taking this drug were more likely to die, and slightly more likely to have serious adverse reactions, such as pulmonary emboli and gynecological symptoms requiring invasive procedures.

As you consider what this would mean for women in the U.S., not in a research study, keep in mind that there were very rigorous exclusion criteria for the major study of Fablyn. If you look on page 18 of the FDA memo, there is a long list of exclusions, such as atrial fibrillation, history of breast cancer or DCIS, history of various types of hip or vertebral fractures, or stroke or MI within the last 6 months. In addition, only women with specific bone mineral density levels – not too high and not too low – were included in the study. It is not likely that the women excluded from the study would be excluded from taking Fablyn if it were sold in the U.S., and we don’t know what impact that would have on safety or efficacy, or the likely risks vs. benefits.

Osteoporosis can be a serious and debilitating disease, but there are other treatments available.

In the ideal world, we could tell patients what the risks and benefits seem to be for each medication, and let them decide. In the real world, however, that doesn’t work well for several reasons.

#1: In our experience, many doctors don’t know all the details of research findings and are not at all likely to recall all the exclusion criteria that were used in this study.

#2: Even those doctors who know the details of research findings don’t do a good job of explaining them to patients.

#3: Just under 1% of the women in the study are black. The 18% who are Asian women are primarily living in India, not the U.S. So, we don’t know if the risks or benefits would be different for African American women or other Asian women. And, although 5 % of the women are Hispanic, they were apparently from Argentina and other countries, not the U.S. Since most of the women in the study are not from the U.S., and many from countries such as Croatia and India where diet and exercise might be quite different than the U.S., and that would affect osteoporosis, we don’t really know what the impact of Fablyn would be on the mortality of women living in the U.S.

#4: The data from these studies are short-term. We don’t know the long-term risks or benefits. For cancer, for example, one would not expect risks to show up within 3-5 years, and certainly they would not be statistically significant. In the U.S., women live an average of 80 years, and women who have already lived to be post-menopausal live even longer. So, it is not enough to know the 3-5 year risks and benefits for women who could live another 20-30 years after they start taking an osteoporosis drug.

In conclusion, the data on Fablyn are incomplete to draw the conclusion that the benefits outweigh the risks, and the data thus far suggest that the risks probably outweigh the benefits.

It is the job of the FDA, with your help, to determine if this drug is safe and effective, and if the benefits outweigh the risks. Those decisions should be based on science, not wishful thinking. It is not enough to say “this drug will probably decrease breast cancer” or “this drug will probably continue to reduce fractures over time.” For example, we know that other SERMS, such as tamoxifen, are only effective for 5 years, and not after that. We need more data to determine if this drug does more good than harm for women suffering from osteoporosis.

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund: June 8, 2006

I am Dr. Diana Zuckerman, President of the National Research Center for Women & Families. Our independent, nonprofit organization is a think tank that gathers and explains research information and uses it to improve the health and safety of women, children, and families.

I am speaking from the perspective of someone trained in psychology and epidemiology, who was a university faculty member and researcher at Harvard and Yale and taught courses in research methods before moving to Washington, DC to work on health issues in the U.S. Congress, U.S. Department of Health and Human Services, White House, and for nonprofit organizations.

I have read every published epidemiological study on breast implants and will briefly discuss what is known and not known, based on those studies. I will also tell you about a criminal investigation of one of the implant manufacturers, Mentor, and the many calls and emails we have received from women in Canada who are finding it impossible to have their leaking silicone gel breast implants removed in a timely manner.

Who Conducts Research on Breast Implants?

Clinical trials are a major source of information on the short-term risks of silicone breast implants. In clinical trials, the goal is to follow women prospectively to determine what complications and health problems occur, and to compare that to a control group. Although silicone implants have been on the market for 40 years, the only well-designed clinical trials have data for only 2-3 years and they do not include a control group. The clinical trials have been conducted by the implant companies as part of their effort to obtain approval to market the implants in Canada and the post construction cleaning services carmel.

Epidemiological studies are the major source of information about what actually happens to women who have breast implants for at least five years. Almost every published epidemiological study on breast implants has been paid for by companies that sell or sold breast implants. In fact, one company in the U.S. has received many millions of dollars from Dow Corning to conduct most of these studies, almost all of them in Europe, and every one of those studies has concluded that implants are safe. However, careful scrutiny of the results in the peer-reviewed articles indicates serious health problems among women with those implants. For example, one recent study reported that women with breast implants were significantly more likely to report breast pain and take anti-depressants, but still concluded that breast implants were safe.

More importantly, a small number of studies have been conducted by independent researchers, not using implant company funds or funds from plastic surgeons. These include government-funded researchers in Canada and the U.S. Their findings almost always indicate problems with implants that are in direct contradiction to the findings of the studies funded by implant companies. I will focus on their findings today.

What do we Know about the Health Effects of Ruptured Silicone Gel Implants?

The FDA funded, designed, and conducted the best study on the health of women with ruptured silicone implants. FDA scientists concluded that most women with implants for 11 years or more have at least one ruptured implant, even if they don’t realize it. They also found that 21% of women with implants for at least 7 years have at least one implant that is leaking silicone outside the scar tissue, and that women with leaking implants were more likely to report fibromyalgia or several other painful and debilitating autoimmune diseases. The FDA study is superior to other studies because it focused on women who were basically happy with their implants, and who had implants for at least 7 years. That length of time is key. Other studies have included women who had implants for an average of 7 years — but not at least 7 years.

Most women who have had problems with rupture had implants for a long time — usually much longer than seven years.

Cosmetic Problems

More independently funded research is needed on the risks of ruptured silicone gel implants. Meanwhile, let’s look at some of the cosmetic results of silicone gel implant problems.

Here is a 29-year old woman who had her implants removed after 7 years. Her capsular contracture was so painful that she apparently preferred getting her implants out to keeping them in. This photograph is from the FDA’s website.

That is obviously not a good outcome, but here is a woman who wasn’t so lucky — Sharyn Noakes. Her ruptured implant had leaked into her healthy breasts. When the silicone was removed, this is all that was left of her breasts.

And this is Kathy Nye, a breast cancer survivor who suffered from necrosis and her implant extruded through her skin. Inamed reported a 6% necrosis rate among reconstruction patients in their Core study.

Signs and Symptoms

Now that you have seen some of the cosmetic problems, let’s take a look at the women’s symptoms. In data presented to the FDA, Inamed and Mentor both found that women with implants for only two years had a significant increase in auto-immune symptoms such as joint pain and nervous system symptoms. FDA asked a statistician to determine if this was due to aging. It wasn’t. And, these findings are consistent with what we have heard from thousands of women with silicone breast implants. Most were happy with their implants for years and never suspected that their increasing problems with fatigue or aches and pains might be related to their implants. The women’s personal experiences are not conclusive evidence, but they indicate a pattern that needs to be considered — especially since they are consistent with Inamed and Mentor’s own data showing an increase in autoimmune symptoms over a period of only two years on a cohort of young augmentation patients.

What do we Know about the Health Risks of Silicone Gel Implants More Generally?

Aleina Tweed, an epidemiologist at the British Columbia Centre of Excellence for Research on Women, conducted a study of breast augmentation patients in Canada, most of whom had implants for 10 years or longer. She found that the women with implants visited doctors and specialists more often, and were four times as likely to be hospitalized, compared to other women the same age from the same communities.

Why has that important Canadian study received so little attention? Probably because no one was paid to do PR on the study. In contrast, studies funded by Dow Corning, the maker of silicone, have received enormous publicity. You may have heard that hundreds of studies, including studies at Harvard and the Mayo Clinic and a report of the U.S. Institute of Medicine, provide clear proof that breast implants are safe. However, the Institute of Medicine report is outdated – completed in 1999 and based on studies conducted before that. And, it was based on the other studies that are so often quoted, such as the Mayo Clinic study and the Harvard study – studies that were all funded by Dow Corning and other implant makers.

Almost all the studies included in the Institute of Medicine report suffered from the same shortcomings: they were too small, and they lacked statistical power because they included women who had implants for too short a period of time. For example, the Mayo Clinic study included only 749 women with breast implants, only 125 of whom were reconstruction patients. To be in the study, women had to have implants for at least one month. The average length of time was about 7.5 years, which means that only about 375 women had implants for more than 8 years. Since diseases like lupus, scleroderma, and rheumatoid arthritis are not very common among women in their 20’s and 30’s, this study doesn’t have the power to detect most of the diseases it measured. The authors themselves acknowledged that major shortcoming.

So, while I agree with the Institute of Medicine that there is not sufficient evidence to conclude that implants cause autoimmune disease, the report can’t be considered conclusive proof that implants don’t cause autoimmune disease.

The U.S. government has also funded some important studies of breast implants, and like the Canadian study, they tend to report serious health problems for women who have implants for a long period of time. The National Cancer Institute study found a doubling of brain cancer, lung cancer, and suicide. It is an exceptionally well-designed study, because all the women in the study had breast implants for at least 12 years. Another major strength of the study is that it compared women with silicone implants to women who underwent other kinds of plastic surgery, such as liposuction. This is important because all plastic surgery patients tend to be above average in health and income, but also tend to smoke more than other women.

How do the many implant studies funded by Dow Corning compare to the government funded studies in Canada and the U.S.? Many of the Dow Corning studies focused on women with implants for a short period of time, and at least one on women with ruptures for a short period of time. Many measured illness in terms of hospitalization rather than diagnosis. Remember that most women getting breast augmentation are in their 20’s or 30s, with many in their teens. Think of how unlikely it is that a 30-year old woman will be hospitalized for rheumatoid arthritis.

Inamed and Mentor Research Quality and Integrity

Inamed and Mentor both started clinical trials to analyze the safety of silicone gel breast implants in 1990. Both companies lost track of almost all of their patients to follow-up within 5 years. If only they had done a good job on those studies, we would have great long-term data today. But they didn’t, and so we don’t.

The companies both were given the opportunity to test their silicone gel implants on thousands of patients in the Adjunct Studies that they conducted. They enrolled thousands of patients and then failed to follow-up on most of them, making those studies useless.

Last year, shortly after Inamed and Mentor silicone implants were considered by advisory committees in Canada and the U.S., I heard from several Mentor employees who expressed concerns about the accuracy of the data that Mentor provided to the FDA, and also informed me that the patch used on Mentor implants leaks silicone and should be fixed. I contacted the FDA and arranged for the Mentor employees to speak to FDA officials. As a result, the FDA started a criminal investigation, interviewing me and several former Mentor employees. I was told several weeks ago that the investigation is still underway. I would be glad to put those former Mentor employees in touch with officials at Health Canada as well.

What Does Approval Matter?

Although there are restrictions on silicone gel breast implants in Canada and the U.S., tens of thousands of women have continued to get them. Many of those women were not breast cancer patients.

Even so, approval matters. If Health Canada approves silicone gel breast implants, it will send a clear message that it believes that the implants are safe, and more teenage girls and women will certainly choose silicone implants as a result.

The study by Aleina Tweed shows that in Canada, women with breast implants have more health problems and their efforts to get well are costly to the Canadian system. Most of the women had at least one surgery to fix an implant problem, and 17% had four or more additional surgeries. Tweed’s findings are especially striking to us because our Center hears from many Canadian women with breast implants who tell us that they can’t get help from most Canadian plastic surgeons. Many have discovered — often after years of symptoms – that their implants are leaking. They need a plastic surgeon to remove them, and often can’t afford to pay for the surgery. But the waiting list is very long. We know a patient who contacted Dr. Mitchell Brown’s office this spring, because she heard he is an excellent surgeon who knows how to remove leaking silicone implants. She was told she would need to wait until December 2006 just to see him for a consultation. She was told that if she needed surgery, that would have to wait until December 2007. My staff found that hard to believe, so we also contacted Dr. Brown’s office more than a week later and we were told the exact same thing. My staff asked if there was a shorter wait if she could pay for the surgery, and we were told that the wait was much shorter.

We know several patients who tried to arrange surgery with other Canadian plastic surgeons. They were told that silicone would likely leak during the surgery and that they could be left looking deformed, They were discouraged from removing their implants, and told that at least they should replace them with new implants.

If Health Canada approves silicone gel breast implants, the number of teenagers and women needing to have leaking silicone implants removed will increase dramatically. To allow that to happen in a country where few plastic surgeons know how to remove leaking silicone gel breast implants, and those that do have very long waiting lists is not ethical or appropriate. And, according to Aleina Tweed’s research, it will cost the Canadian healthcare system dearly.