The most comprehensive study ever conducted to look for a direct connection between breast cancer and several environmental toxins has ended up with largely negative results.
And while that has breast cancer activists frustrated, it has also provided researchers with a wealth of data to mine in hopes of finally pursuing new directionsthis time, in a search for possible genetic susceptibilities to chemical carcinogens.
Two research papers, published in early August in Cancer Epidemiology, Biomarkers & Prevention, reported no association between increased rates of breast cancer and exposure to some pesticides and industrial chemicals (including DDT and polychlorinated biphenyls [PCBs], both of which have been banned for 30 years) and only a possibly weak association with exposure to chemicals found in air pollution known as polycyclic aromatic hydrocarbons (PAHs).
These results are from studies that form the cornerstone of the $30 million Long Island Breast Cancer Study Project (LIBCSP) mandated by Congress in 1993. This study, promoted by breast cancer activists and put into law by politicians, directed the federal government to conduct a study of likely environmental contaminants that could have contributed to the incidence of breast cancer in two Long Island counties (Nassau and Suffolk). It appeared that breast cancer rates were elevated there, relative to other areas in New York state.
Rejecting the notion that higher rates of breast cancer could have been caused by demographic or lifestyle factors, the Long Island activists looked to residues of pesticides, solvents, gasoline, and other chemicals left by industry and agriculture in the air, water, and soil to explain the increase in the disease. (See sidebar, p. 1349.)
To find out if environmental contaminants did contribute to the increased incidence of breast cancer, the National Cancer Institute, in collaboration with the National Institute of Environmental Health Sciences, was directed to study the current and past exposures of women to contaminated drinking water, indoor and ambient air pollution (including aircraft emissions), electromagnetic fields, pesticides and other toxic chemicals, and hazardous and municipal waste. The project also includes a family breast and ovarian cancer registry, laboratory research to better understand the development of breast cancer, and a geographic information system that allows researchers to explore theories about environmental risk factors.
The biggest and most ambitious study in the package, the 7-year, $8 million study of environmental pollutants, was the one that many activists had pinned their hopes on, but these same activists now question whether the chemicals that were studied were the right ones. "I dont know why they ever studied DDT and other chemicals that were already banned," said prominent early activist Barbara Balaban. "I didnt see any point to studying them then, and I dont see it now that the research has been published."
There werent many choices that Marilie Gammon, Ph.D., and her colleagues could make when they proposed to study the relationship between pollutants and breast cancer on Long Island.
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"No other NCI program has been so prohibitively dictated," said Debbie Winn, Ph.D., the NCIs acting co-program director of the LIBCSP. "Its very hard to find strong evidence of environmental causes of cancer in any case."
The objection then, and now, is that because breast cancer can take several decades to develop, researchers conducting an abbreviated casecontrol study would have to make educated guesses about what women were exposed to in the past. They would be limited to looking for chemicals that might show signs of telltale residual damage over time and their possible associations with newly developed breast cancer.
One of the most vocal opponents, Paolo Toniolo, M.D., from New York University, argued against the study design mandated by Congress and in favor of a better, more flexible design. The result of the "absurd task" that NCI was "forced to take on" has been "a basically futile project," says Toniolo now.
One of the studys primary investigators, Regina Santella, Ph.D., admits that she doubts the study would have ever been conducted had it not been congressionally mandated. "I was ambivalent about being in the study for that reason," said Santella, a professor of public health at Columbia University. "I still have that feeling," she added after the results were made public, "but I also feel we will eventually get a lot out of the study."
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The chemicals were PAHs, created by diesel fuel combustion, heavy air pollution, cigarette smoking, and burning of meat; and organochlorine compounds found in the pesticides DDT (and its breakdown product, DDE), chlordane, and dieldrin and also in PCBs, chemicals used in transformers, capacitors, and other electrical equipment. Although organochlorines have been banned since 1972, they persist in the environment, and can remain in the body for more than a decade. Some research has suggested that they act as environmental estrogens, which may suggest a relationship to increased risk of breast cancer.
The 30-member research team, most of whom were from New York, sought to test and interview each woman in those two Long Island counties who was newly diagnosed with breast cancer, as well as an equal number of healthy women. The study included 1,508 patients whose breast cancer was diagnosed between August 1996 and August 1997 and an age-matched control population of equal size. The researchers took blood and urine from the participants (as well as tumor tissue from women with breast cancer), and retrieved soil, water, and carpet samples from the homes of women who had lived there for at least 15 years. (An analysis of those samples is not yet available.)
The first paper to sum up the findings, published in the August issue of Breast Cancer Research and Treatment, confirmed many well-known breast cancer risk factors, including age, family history, having a first child at a later age (28 and older), never having children, and having a higher income.
But the recent reports on the two primary hypotheses of the study were the most eagerly awaited.
The organochlorine study found no doseresponse relationship between cancer and level of organochlorines, nor was risk increased in relation to organochlorines among women who had not breastfed or were overweight, postmenopausal, or long-term residents of the area. "This was a straight measure of what organochlorines were in the blood of the women at the time they were tested, and there was no relationship to risk of breast cancer," said Gammon.
While most of the scientific community may think the results sound the death knell for organochlorines connection to breast cancer, activists dont agree, said Santella. "They say that exposure may have happened in utero or in adolescence, and I cant argue against it because a long-term cohort study wasnt conducted."
The PAH results were much more interesting, according to Gammon. Researchers measured the level of adducts formed by the binding of PAHs to DNA. "They are indicators of what your body has been exposed to, but more importantly, how your body has reacted to it," Gammon said. Women who had the highest level of PAH-DNA adducts had a 50% increased risk for breast cancer compared with women with the lowest level of adducts. The results, while not straightforward, are "provocative," she said. "There was no dose response, which sheds some doubt on the observed increase, although there could be a threshold effect. Its not something to ignore."
Santella and Gammon suspect that the PAH results tell a story about how different women respond to exposurethat a persons unique genetics may decide whether or not a chemical could promote the development of cancer.
"We tried our hardest and I think we did the best study we could do, given the circumstances," Gammon said. "But we are not done yet."
In fact, Gammon said that the really interesting part of the projectthe opportunity to provide novel scientific insightshas just begun. Many of the researchers involved in the Long Island environmental study plan to examine blood samples gathered from 2200 subjects as well as tumor tissue from about 1000 patients to hunt for genetic factors that may make some women more susceptible to a chemicals carcinogenic effects.
To probe this connection, LIBCSP researchers have received approval for as many as 17 different substudiesand more are pending. These studies will examine interaction between the chemicals and variation in genes responsible for preventing them from harming the body, such as estrogen metabolizing genes and DNA repair mechanisms.
"While [the LIBCSP] study has not given us any big answer, it will allow us to investigate the geneenvironment [connection] in an entirely new way," said Mary Wolff, Ph.D., at Mt. Sinai Medical Center in New York, who is also involved with the LIBCSP studies.
"I think well get our money out of it," she said. "If we understand how one set of endocrine disrupters works, it may be that other chemicals have similar activities."
"Advocates are not particularly interested in the genetics of chemical exposure, but that is where the action is," Santella added. For example, PAH-DNA adduct levels can represent a composite of factors, including recent exposure, metabolic capacity of that individual, and DNA repair capacity, she said.
"This could explain how the women respond to PAH exposure," Santella said. "They may not be able to detoxify the chemicals, or they have different capacities to repair damaged DNA."
"This is where the field is going," said epidemiologist John Weincke, Ph.D., of the University of California at San Francisco. "Whats unique about these studies is that [the effects] of organochlorines and PAHs have been characterized much more than other studies have been able to do," he said.
And Wolff said she hasnt finished looking at organochlorines, because she wonders if susceptible subgroups could be affected by low-level exposure to organochlorines, just as they may be to PAHs. "I dont feel the subject is closed," she said. "I wish it was that simple." Using NCI funds, the researchers are also following the Long Island patients to see if exposure level influences survival.
Debbie Basile, president of Long Islands Babylon Breast Cancer Coalition, said it is a "good idea" to see what environmental contaminants "do to our DNA. You can basically look at these studies as either half empty or half full," she said. "Some ask why we studied chemicals that have already been banned. I say we now know that there isnt a direct link to these chemicals, so lets look a little further."
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