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Vol. 12 Issue 4, Fall 2007
Two leading researchers on health effects of exposure to endocrine-disrupting chemicals, Dr. Andreas Kortenkamp, Head of the Centre for Toxicology at the University of London School of Pharmacy, and Dr. Mary Wolff, Professor of Community and Preventive Medicine at the Mount Sinai School of Medicine in New York City, presented their work on September 27, 2007.
Speakers also included two faculty members of the Weill Medical College of Cornell University, Dr. Ruth Rosenblatt, Director of Women’s Imaging, who spoke on the latest developments in breast cancer detection, and Dr. Kevin Holcomb, Assistant Professor of Clinical Obstetrics and Gynecology, who presented the latest research on vaccines against the human papilloma virus, a virus known to cause cervical cancer.
A panel including representatives from the Young Survival Coalition, the Witness® Project of Harlem, Susan G. Komen for the Cure/Greater NYC, and the New York State Breast Cancer Support and Education Network, rounded out the day with a lively discussion on challenges, successes, and opportunities for collaborative efforts to reduce the risk of breast cancer.
BCERF was honored to bring Dr. Andreas Kortenkamp to address the Forum to present his cutting-edge toxicology research on how exposure to mixtures of environmental pollutants may increase the risk of breast cancer. Many environmental pollutants may mimic estrogen, a hormone known to increase breast cancer risk.
His talk, entitled Estrogens, Environmental Pollutants and Breast Cancer: a Re-evaluation from a Mixture Effect Perspective focused on new thinking with regard to the role of chemical exposure in breast cancer risk. Two concepts inform this new line of thought: the timing of exposures with regard to critical early life periods, and “cocktail effects;” that is, the combined action of multiple chemicals, also taking into account the presence of the individual’s own natural hormones. These two concepts, Dr. Kortenkamp explained, increase the biological plausibility for a role of environmental pollutants in breast cancer risk.
Dr. Kortenkamp laid out the paradoxical role of natural, or endogenous, estrogens: they are essential for breast development, but also involved in breast cancer risk (hence the established risk factors of early menarche and late menopause, which result in more estrogen reaching the sensitive structures in the breast over a lifetime). Recent pooled analysis of nine prospective, case-control studies on blood serum levels of estradiol (the more potent of the endogenous estrogens) showed significant increases in breast cancer risk with higher levels. This work further strengthens scientific understanding of the important role of estrogen in breast cancer development.
Dr. Kortenkamp then described the most pronounced example of involvement of “outside” or exogenous estrogens in breast cancer risk, with two large epidemiological studies in the US (the Women’s Health Initiative) and Britain (the Million Woman Study) finding tens of thousands of excess breast cancer cases associated with the use of hormone replacement therapy (see The Ribbon, Volume 12, Number 3, The Recent Decline in Breast Cancer Incidence: What is its Relationship to Hormone Therapy Use?)
What other exogenous estrogens might play a role in breast cancer risk? Organochlorine chemicals, such as DDT and its metabolite DDE, have endocrine disrupting behavior, and DDE is highly persistent in the environment. Over 50 studies in the last decade and a half have tried to examine the role of these compounds in breast cancer risk. There have been, Dr. Kortenkamp pointed out, far fewer studies of other estrogen-mimicking environmental pollutants, such as PCBs, and fewer yet of phenolic compounds, such as parabens and bisphenol A. With regard to the organochlorine studies, the results were very mixed. Earlier studies, especially with DDE, demonstrated a link with breast cancer, but other studies did not see this link. A pooled analysis of all these studies came to the conclusion that the data provided do not support an association between DDE body burden levels and breast cancer risk.
Dr. Kortenkamp warned against dismissing a role for these chemicals in breast cancer risk based on this previous generation of studies, and identified their important methodological limitations and conceptual shortcomings. He mentioned a very recently published epidemiological study that does address the issue of critical early life periods, which found a strong association between exposure to a form of DDT in childhood and subsequent breast cancer risk (see Research Brief by Dr. Suzanne Snedeker in this issue). He encourages epidemiologists to address combined exposures, as well as to continue addressing windows of vulnerability to exposures, as this recent DDT study will need corroboration.
In his own current work Dr. Kortenkamp provides toxicological data to fill these research gaps. “The estrogen hypothesis of breast cancer should be extended to encompass mixture effects between weakly estrogenic agents and endogenous hormones,” he says. One of his research questions is: are mixture effects to be expected when every component is present at low, otherwise ineffective doses? His research group addressed this in a model experiment combining estradiol with eleven weakly active estrogenic agents at levels that individually did not produce any detectable effects. They found that, in combination, these chemicals were able to more than double the effect of the endogenous hormone, “demonstrating that,” Dr. Kortenkamp explained, “in principle, weak outside estrogens, at low levels, can exacerbate the actions of potent endogenous hormones.” This is not synergism, but rather low levels of multiple environmental estrogens acting in concert with estrogens from the body.
He goes on to ask, will cocktail effects occur at environmentally relevant doses? He discussed data on estrogenic agents measured in European human tissue samples, showing the closely correlated expected and observed effects from mixtures, as well as a scenario modeled on data from a highly contaminated population in Spain. He also discussed how this data could contribute to better prioritization of chemicals for biomonitoring.
Dr. Kortenkamp’s own and other research he discussed at the Forum is demonstrating that the added contribution of estrogenic environmental pollutants to endogenous estrogenic load is likely in certain situations, although the contribution of any single chemical – including, for example, the organochlorines that have been studied individually – is small. He points out that all mixture analysis to date is based only on those chemicals that are currently known to be estrogen mimics, and that the effect of conjugations have not yet been taken into account.
As Dr. Kortenkamp encourages a proactive approach in a recent briefing paper for the World Wild Life Fund – UK (link at: http://www.wwf.org.uk/news/n_0000003135.asp): “Given the role of estrogen in breast cancer, it would be prudent to reduce exposures to chemicals that can mimic estrogen. Consideration should therefore be given to replacing such chemicals with safer alternatives, where possible.”
Dr. Mary Wolff (who presented later in the day but whose talk is described here due to its relevance to Dr. Kortenkamp’s) presented on Relevant Environmental Exposures in the 21st Century: Hormonally Active Agents and Potential Health Effects. She discussed the history of interest in endocrine-disrupting chemicals, its beginning marked by the Wingspread Conference in 1991, leading into a list of such chemicals published in Environmental Health Perspectives by Theo Colburn and colleagues in 1993. Dr. Wolff described the history of studying the better-known exposures, such as dioxins, DDT, PCBs and lead, which, although in decline in the west in recent decades, can still be found at significant levels in the developing world. The “new generation” of endocrine-disrupting chemical research addresses, for example, phthalates and bisphenol A; toxicological and epidemiological work on these chemicals is at a much earlier stage.
Dr. Wolff plays a leading role in two major epidemiologic efforts to move forward the research on endocrine-disrupting chemicals and health effects. She leads the Mount Sinai Center for Children’s Environmental Health and Disease Prevention Research, one of eight centers established by the NIEHS in conjunction with the EPA. She also leads one of the sites (Fox Chase Cancer Center/Mount Sinai collaboration) of the Breast Cancer and Environment Research Center’s (BCERC) “Environmental and Genetic Determinants of Puberty” study. Both of these efforts produce data on the effects of hormone disrupting chemicals prenatally and in young girls.
The Mount Sinai Center, which is running a number of studies, includes efforts to monitor prenatal exposures and birth outcomes in over 400 mothers in the NYC region. Maternal blood and urine is collected in the third trimester of participants’ pregnancies, and infants/children are examined at three days old, and at one, two, four, and six years of age. Chemicals monitored include DDT /DDE (though in dramatic decline), PCBs, organophosphate pesticides, phenols, and phthalates. Endpoints monitored include birth outcomes such as birth weight and length, and neurodevelopment. The study model, Dr. Wolff explained, includes analysis of any relationship between each compound and the various outcomes. Dr. Wolff emphasized that her own focus is becoming the lesser-studied chemicals, such as bisphenol A and phthalates, which are international in scope, widely detected in children and pregnant women, and showing links with some of the outcomes the Center is examining. She discussed where exposures to these chemicals might be coming from, suggesting sources ranging from diet, to air contamination, to personal care products.
Dr. Wolff also discussed work on early puberty that she is conducting with the BCERC. The Environmental and Genetic Determinants of Puberty study hypothesis is that hormonal environmental exposures may alter pubertal onset. The collection of urinary and blood biomarkers of environmental chemicals is one of the exposure measurement approaches in the study, about which Dr. Wolff and colleagues published an article early this year. (This article, “Pilot Study of Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols in Girls,” published in Environmental Health Perspectives, January 2007 was reviewed by Dr. Suzanne Snedeker in The Ribbon, Volume 12, No 1).
This work includes a variety of hypothesis-generating findings, such as the implications for various race/ethnicity differences in exposure biomarker measurements. In her talk, Dr. Wolff provided data on four biomarkers (two phthalates, two phenols) for the black, Hispanic and white participants, showing dramatically different patterns for each: white participants showing the highest levels for benzophenone-3, a phenol found in sunscreens; blacks and Hispanics showing higher levels of monoethyl phthalate, found in personal care products; whites with the highest levels of mono93-carboxypropyl) phthalate, found in soft plastics; and black participants with the highest levels of 2,5-dichlorophenol, found in mothballs.
Dr. Wolff displayed a chart showing significant research gaps in the cumulative animal and human evidence on health effects for endocrine disrupting chemicals. The multiple studies in which she plays a leadership role will be contributing significantly to closing those gaps.
Holding the Forum in New York City gave BCERF the opportunity to feature Weill Medical College faculty. Forum participants received up-to-date information on two areas of focus at Weill, from faculty who generously came to join us between seeing patients at the Medical College.
Prophylactic human papilloma virus vaccines. Dr. Kevin Holcomb, Assistant Professor of Clinical Obstetrics and Gynecology, presented the latest research on vaccines against the human papilloma virus, a virus known to cause cervical cancer. He described the clinical trials being conducted and the extremely high prophylactic efficacy they are showing in preventing incident HPV infection and subsequent pre-cancer. Dr. Holcomb also discussed the challenges of delivering vaccines in low-resource settings, and responded to questions about the presence of aluminum in the vaccine, as well as confirming the absence of mercury.
New developments in breast cancer detection. Dr. Ruth Rosenblatt, Director of Women’s Imaging, spoke on the latest developments in breast cancer detection, covering digital mammography, breast magnetic resonance imaging (MRI), and breast specific gamma camera (BSGI). She compared conventional and digital mammography, showing the same results for detecting breast cancer in women over 50 (postmenopausal), the same results for women with average and low breast density, and more sensitivity for detecting breast cancer in women with dense breast tissue and younger women. There are advantages to digital mammography, such as the speed of image acquisition, the greater contrast, and the ability to efficiently share images, but also many challenges and limitations, such as high maintenance costs. She described ultrasound as an important adjunct tool. Dr. Rosenblatt described MRI, and when it is indicated, for example when other imaging studies are ambiguous or difficult, as with implants, or for high-risk women. She emphasized that MRI does not replace mammography. She then shared information on BSGI, which involves injecting a small amount of a “tracer.” The tracer is taken up in cancerous cells because they have increased blood flow and metabolic activity, and then a specially developed camera show the image. She gave examples of indications for use of this technology, such as to sort out scar tissue from recurrent breast cancer in women with history of breast cancer.
At most BCERF Forums we are able to provide time for representatives from breast cancer or other relevant organizations, local to the region in which the Forum is bring held, to address participants about their organizations’ goals and activities. This Forum’s panel featured the following organizations and representatives.
The Young Survival Coalition (YSC)
http://www.youngsurvival.org/
CEO Michelle Przypyszny, who has been with YSC for seven years, has seen this organization, headquartered in New York City, grow to 14,000 constituents, 11 staff and eight affiliates. The YSC was founded by three young breast cancer survivors in 1998, all who were under the age of 35 at diagnosis. The YSC has grown to fill the gap in information and resources that were available to young women then, and remains the only international, non-profit network of breast cancer survivors and supporters dedicated to the concerns and issues that are unique to young women and breast cancer.
The Witness Project® of Harlem and Esperanza y Vida
http://www.witnessprojectharlem.org/
Lina Jandorf, the Director of Cancer Community Outreach in the Department of Oncological Sciences at Mount Sinai Hospital, directs these two faith-based community projects. The Witness Project® is a breast and cervical education program targeting African American women, and is based on an educational model first developed at the University of Arkansas in 1991 in response to racial disparities in breast cancer. The project seeks to address these disparities by having cancer survivors share their stories about diagnosis and treatment in community settings. Similarly, Esperanza y Vida is a breast and cervical education program that reaches out to the Hispanic/Latino community in churches and community centers across the city.
Susan G. Komen for the Cure/Greater NYC
http://wwww.komennyc.org/
Board member Marge Neuwirth sat in for Executive Director Donna Lawrence, representing the New York City affiliate of this national support and granting organization. Ms. Neuwirth discussed the uniqueness of the NYC affiliate. For example, up to 75 percent of funds raised are distributed to programs in the NYC region, including the Witness Project®. In 2007, Komen Greater NYC is awarding close to $3.2 million in grants: $2 million will support 34 community-based organizations that provide breast health programs to underserved women, $245,000 will increase capacity of local researchers to enroll women in breast cancer trials and help fund local breast cancer conference and education programs, and close to $1 million will go for research.
New York State Breast Cancer Support and Education Network (SEN)
http://nysbcsen.org/
Susan Cohen is Chair of the SEN, the only statewide network of community-based breast cancer organizations in the state. SEN facilitates the over 20 member organizations sharing programs and resources, inter-organization referrals for services, and a support and education system. Public health and environmental policy initiatives are one strong focus of the Network, and Ms. Cohen shared details of 2007 efforts. She also represented Manhattan Legal Services on the panel, where she uses advocacy skills developed in anti-poverty work, and transfers them over to breast cancer advocacy.
BCERF thanks all the speakers and the over forty participants, all of whom contributed to a lively event of information sharing and collaborative thinking. We also thank Ms. Ali Beck, Coordinator of the Cancer Prevention Program at NewYork-Presbyterian Hospital for all her assistance in planning the event.
Program on Breast Cancer and Environmental Risk Factors
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Vet Box 31, Ithaca, NY 14853-6401
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