Environmental Risk Factors for Breast Cancer

[Nia Imani]

Increasing research into the causes of, optimal treatments and ultimately a cure for breast cancer has always been a high priority for the National Breast Cancer Coalition Fund (NBCCF). The Coalition is committed to uncovering the causes of breast cancer and understanding how to prevent this disease from affecting future generations of women and those who love them.

It is generally believed that the environment plays some role in the development of breast cancer, but the extent of that role is not understood. In fact, there is much disagreement within the scientific and advocacy communities about the significance of the environment in the etiology of breast cancer. Despite the lack of a national strategy or vision, significant resources are devoted to this issue each year. NBCCF believes that this crucial issue must be approached thoughtfully and methodically and that a national strategy for increasing knowledge in this area must be developed.

This paper provides background information on some of the key issues surrounding the suspected relationship between the environment and breast cancer.

Suspected Relationship Between the Environment and Breast Cancer

Breast cancer is a complex disease that occurs in an environmentally complex world. About 90% of women who develop breast cancer do not have a family history of the disease. In addition, a large study of twins demonstrated that the majority of breast cancers cannot be explained by inherited factors (1). The incidence of breast cancer in Western industrialized countries, such as the United States, is much higher than the incidence in Africa and Asia (2). When women migrate from a country with low incidence to a country with high incidence, their daughters experience the breast cancer risk of the new country's population (2, 3). The discrepancy in incidence among various countries suggests that some of the differences in incidence may be explained by environmental exposures.

The relationship between environmental exposures and breast cancer is poorly understood. Some scientists hypothesize that certain subgroups of women have genetic variants that may make them more susceptible to adverse environmental exposures (gene-environment interaction) (4). In addition, there are different subtypes of breast cancer (i.e. pre and post menopausal breast cancer) that may arise from different environmental and endogenous risk factors (5). NBCCF believes that these and other factors related to our understanding of the impact of the environment on breast cancer traditionally have been understudied.

Lack of Consensus on a Definition of 'the Environment'

There is little agreement within the scientific and advocacy communities on how to define 'the environment' in this context. In September 1998, NBCCF hosted its Environmental Policy Summit to begin to develop a strategy for bringing us closer to understanding the relationship between breast cancer and the environment. The more than 50 experts that were brought together (activists, scientists, government officials, policymakers, and others) could not agree on the scope of this issue.

The primary points of contention fell within the following two areas: 1) External versus Internal Exposures and 2) Voluntary versus Involuntary Exposures. That is, some individuals working on this issue believe that 'the environment' should encompass external exposures (e.g. pesticides) and not internal exposures (e.g. age of menarche and menopause and circulating hormone levels), and others think that 'the environment' should include involuntary exposures (e.g. electromagnetic fields) and not voluntary exposures (e.g. diet). However, there is agreement among scientists that it is the interaction between all of these exposures that leads to breast cancer. Given this, NBCCF approaches 'the environment' broadly, and includes in its working definition internal and voluntary exposures as well as external and involuntary exposures. Thus, the Coalition defines an environmental exposure as any factor that is not an inherited genetic characteristic.

Challenges in Conducting Environmental Research

Identifying causal relationships between environmental factors and breast cancer is challenging. Laboratory experiments on animals are often used to generate hypotheses about the carcinogenicity of chemicals and other environmental exposures. However, it may not be possible to apply the results of some laboratory tests in animals to humans (6). Although many substances have been shown to cause mammary tumors in rats and mice, these substances do not necessarily cause breast cancer in humans. Humans and rodents metabolize substances at different rates and may have different thresholds for certain toxins. Moreover, humans usually experience lower doses of toxins and longer periods of exposure than the animals in high-dose laboratory tests (7).

In addition to laboratory tests, cluster analyses are also used to generate hypotheses about potential risk factors. Cluster analyses have been used to identify areas with unusually high rates of breast cancer, such as Long Island and the entire New York City to Philadelphia, Pennsylvania metropolitan area (8). Unfortunately, the identification of a cluster does not necessarily reveal whether an individual exposure is responsible for the elevated rate of disease or what that exposure is. In addition, simply due to chance, many small areas have a high rate of at least one type of cancer (9). Thus, laboratory tests and cluster analyses may generate hypotheses, but epidemiological methods must be used to accurately evaluate human risk from particular exposures.

Epidemiological studies examine exposures in human populations in order to determine risk factors for disease. To show that an exposure increases the risk of a disease, a study must include a group of people who have not been exposed to the suspected risk factor. Environmental contaminants, such as pesticides, are present everywhere in the environment at low levels, making it difficult to identify a group of unexposed people (10). Measuring a person's exposure to environmental contaminants is problematic because people are often exposed throughout their entire lifespan, and may not even be aware of their exposures (10). Studies that examine lifestyle risk factors often rely on self-reports of behaviors that occurred many years in the past. Participants in these studies may not remember such behaviors accurately.

Both lifestyle and contaminant exposures may be highly correlated with other factors that influence breast cancer risk, such as socioeconomic status, occupation, and reproductive factors. If these factors are not measured and analyzed correctly, a study's results may not be accurate. In addition, the various environmental and lifestyle exposures may each be associated with only small increases in individual breast cancer risk (10). They may also increase risk only in individuals with certain genetic characteristics (4). These situations make it difficult to identify the association between one risk factor and breast cancer, particularly in a study that has a small number of participants. Finally, an exposure may only affect breast cancer risk during a specific period of a women's life, such as the time from menarche to first full-term pregnancy (6). Therefore, epidemiological studies must consider the timing of an exposure in addition to the amount of exposure.

Key Issues Surrounding Breast Cancer and the Environment:

1) Known Risk Factors

There is general agreement among scientists that breast cancer is a 'multifactorial disease,' with many causes that interact with each other in ways that are not currently understood. While scientists have uncovered some of the risk factors associated with breast cancer, most of these risk factors account for very small increases or decreases in a woman's chances of developing breast cancer. Most of the known risk factors for breast cancer are highly prevalent in many societies, and the majority of women exposed to these risk factors never develop the disease (5,12).

The older a woman is, the higher her risk of breast cancer. Other factors known to increase the risk of breast cancer fall into three categories: genetic and family history, endogenous hormonal (reproductive), and external risk factors. Women with family members who have had breast or ovarian cancer are at an increased risk for breast cancer (4). Genetic risk factors include several known mutations in the BRCA1 and BRCA2 genes, which predispose a woman to breast cancer; however, carriers of such genetic variants constitute only 5-10% of all breast cancer cases (4, 13). Reproductive risk factors, which are related to the amount and timing of endogenous hormone production, include earlier age at menarche, later age at menopause, nulliparity (having no children), and later age of first full-term pregnancy (14). External risk factors include alcohol consumption, long-term use of hormonal replacement therapy, and ionizing radiation (15, 16, 17). Interestingly, breast-feeding most likely reduces the risk of breast cancer (14). Scientists believe that breast cancer develops through the combination and interaction of these and other unknown risk factors; that is, there is not a single cause of breast cancer.

2) Suspected Risk Factors

NBCCF strongly encourages researchers to investigate the relationship between breast cancer and environmental exposures. The following is a list of environmental factors that have been suspected of influencing breast cancer risk. Many other chemical and lifestyle exposures have not yet been examined for their possible link to breast cancer. The Coalition is committed to supporting new hypotheses and new avenues of innovative and promising breast cancer research.

Diethylstilbestrol (DES):

DES is a synthetic estrogen that was given to an estimated 2 million pregnant women from 1940 to 1971 to prevent premature delivery. There is an increased risk of vaginal cancer (clear cell adenocarcinoma) and reproductive anomalies in the daughters of DES users who were exposed to the drug in utero.

At present, evidence indicates that women who used DES during pregnancy may have a slightly increased risk of breast cancer (18, 19, 48). Researchers are also studying whether daughters exposed to DES in utero have a higher risk of breast cancer than women not exposed. One study, published in 2006, suggests women over 40 years of age who were exposed to DES in utero may be at increased risk (20). However, further follow up is necessary given the relatively small number of women diagnosed to date. Because breast cancer risk increases with age, continued surveillance and additional studies are needed before conclusions can be made about the extent of this drug's involvement in increasing breast cancer risk among women exposed in utero.

Pesticides and other organochlorines:

The group of chemicals known as organochlorines include pesticides, such as DDT and dieldrin, the triazine herbicides, and industrial chemicals, such as PCBs and dioxins. A variety of organochlorines cause mammary tumors (DDT and triazines) or other types of tumors in rats (6, 10, 11). The use of DDT and the production of PCBs has been banned or restricted in the United States since the 1970's, but these chemicals are still in use worldwide. Organochlorines, which bioaccumulate in the food chain, persist in the environment and can be found in human breast milk, adipose tissue, and blood (10). Almost everyone is exposed to these chemicals, primarily through consumption of fish, dairy products, and meat. Sometimes referred to as endocrine disrupters, many organochlorines mimic estrogen and have either a weakly estrogenic effect or a weakly anti-estrogenic effect on tissue (6, 10). Thus, like endogenous estrogen, these chemicals may influence a woman's risk of breast cancer.

Many studies have examined the relationship between breast cancer risk and a person's blood levels of DDT, DDE (the main breakdown product of DDT), and PCBs. Although evidence is inconsistent, most of the larger, more recent studies have found little or no association between blood levels of these chemicals and breast cancer risk (10, 21, 22). In addition, results have been inconsistent for studies that have examined breast cancer risk and levels of DDT, DDE, PCB, and dioxin in adipose tissue (10). There is limited data on dieldrin and breast cancer risk, but one recent study found that the risk of breast cancer was doubled in women with high dieldrin blood levels (22). Further study of these and other organochlorines is needed. Future research should examine interactions with particular reproductive, genetic, and tumor characteristics (10, 23).

Polycyclic aromatic hydrocarbons (PAHs):

Found in air pollution, cigarette smoke, and cooked meat, these chemicals have been shown to cause mammary gland cancer in animals. The California EPA Air Resources Board recently released a report confirming a causal link between cigarette smoke exposure and breast cancer (see below for more information on cigarette smoke). More research is still necessary however in order to better understand the effect of PAHs on human health (6).

Environmental Tobacco Smoke (ETS):

Environmental Tobacco Smoke (also known as second-hand smoke) is a complex mixture of chemicals generated during the burning and smoking of tobacco products to which non-smokers are exposed. Researchers have identified over 4,000 individual constituents in ETS, many of which are known or suspected human carcinogens and toxic agents. ETS has been found to be a critical source of exposure to toxic air contaminants indoors as well as outdoors. (42)

California became the first state to declare ETS a toxic air pollutant in January 2006 after a report released by the California EPA (CalEPA) Air Resources Board found ETS has numerous health effects linked to its exposure including breast cancer in non-smoking, pre-menopausal women. The report, entitled "Health Effects of Exposure to Environmental Tobacco Smoke," can be accessed at OEHHA Air, 1997 Final Report on Health Effects of Exposure to ETS . The World Health Organization (WHO) has announced that it will release worldwide policy recommendations for protection against exposure to second-hand tobacco smoke based on the CalEPA report's findings.

Diet:

Many aspects of diet have been examined in relation to breast cancer risk, such as consumption of vegetables, fruits, grains and fiber. In addition, beta-carotene, and the vitamins A, C and E have also been studied. Evidence for an association between these dietary factors and breast cancer has been largely inconsistent and modest at best. (26).

The latest and largest prospective study to look at diet, carried out by the Women's Health Initiative, found no significant decrease in breast cancer incidence among postmenopausal women who modified their diets to reduce their total fat intake and increase their consumption of vegetables and fruits when compared to women who did not change their diet. Even subgroup analyses from this study (which included a slightly significant finding for women who began the trial with very high fat intake of more than 76g per day) have been modest (43).

A past summary analysis involving eight prospective studies was also unable to find an association between breast cancer risk and consumption of fruits and vegetables (27). In contrast, a summary analysis of mostly case-control studies did find that consumption of fruits and vegetables reduces the risk of breast cancer (28).

Whereas diets high in fat have been shown to increase the occurrence of mammary tumors in rodents, results from epidemiological studies of high fat intake and breast cancer risk have been inconsistent (26, 31). Recent large and well-done cohort studies have also not found an overall association between breast cancer and total intake of fat or any specific type of fat (32).

Evidence indicates that high consumption of meat may increase risk of breast cancer (29). This increase in risk may be due, in part, to certain chemicals (heterocyclic amines) that are produced when meat is cooked at high temperatures (30).

Some evidence indicates that phytoestrogens, compounds found in foods such as soy, broccoli, and berries, may substantially reduce the risk of breast cancer (33, 34). However, this beneficial effect is more often seen among adult women who integrated phytoestrogens into their diets early on in life, either before puberty or during adolescence (35, 44). Studies looking at whether women who increase their intake of phytoestrogens later on in life are at an increased risk of breast cancer have so far been inconsistent and inconclusive (45, 46, 50). More studies of these and other dietary factors are needed, including more cellular-level research to assess the influence of phytoestrogens on breast tissue. Study designs should include better nutritional surveys and better control of confounding factors. Because personal accounts of dietary history can be inaccurate, intervention studies of dietary factors are necessary.

Electromagnetic Fields (EMFs) and Artificial Light:

It has been hypothesized that increased exposure to electromagnetic fields and light at night is associated with increased breast cancer risk. Some evidence indicates that these exposures reduce melatonin production, and that melatonin production may protect against breast cancer (24, 25, 49). It is unclear whether EMF and light at night exposure are associated with breast cancer risk. Most studies do not show a relationship (24, 25, 47).

Physical activity (exercise):

Many studies have examined the relationship between physical activity and breast cancer. Most studies have found that both occupational and recreational physical activity can reduce the risk of breast cancer (36). Studies that have examined recreational physical activity have shown a 12% to 60% reduction in risk. However, some well-done prospective studies showed no reduction in risk (36, 37). Future studies should examine different aspects of physical activity such as frequency, duration, timing, and intensity.

Viruses:

The Epstein-Barr virus (EBV) is a human herpes-virus that causes infectious mononucleosis. It has been associated with the development of several cancers in humans, including Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma. Another virus, mouse mammary tumor virus (MMTV), induces mammary tumors in mice. Studies have detected DNA sequences from both of these viruses in human breast cancer cells, but not in normal breast tissue (38, 39, 40, 41). One recent study found that the EBV virus was more frequently associated with aggressive breast tumors (40). It is still unknown whether these viruses contribute to the development of human breast cancer, or whether they simply infect tumor cells that already exist.

Other exposures:

Researchers are just beginning to study the broader classes of chemicals that are mammary carcinogens in animals and chemicals that are endocrine disruptors. This definition includes chlorinated solvents and nitro-aromatic compounds because they cause mammary tumors in animal studies, and alkylphenols, phthalates, and bisphenols because they are hormonally active. Many other chemicals have not yet been tested to see if they are mammary carcinogens or endocrine disruptors, so further screening is necessary. There are currently thousands of industrial chemicals in use, and the vast majority of these have not been tested adequately for safety.

Conclusion

The impact of the environment on breast cancer risk is poorly understood. The National Breast Cancer Coalition Fund's Environmental Initiative is developing public policy and research strategies for increasing knowledge in this area. The goal of the Initiative is to further the understanding of breast cancer etiology, and specifically the relationship between breast cancer and the environment. Understanding the causes of breast cancer is essential to understanding how to prevent the disease.

References:

1. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343(2):78-85.

2. Kelsey JL, Horn-Ross PL. Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 1993;15:7-16.

3. Buell P. Changing incidence of breast cancer in Japanese-American women. J Natl Cancer Inst 1973;51:1479-83.

4. Newman B, Millikan RC, King M-C. Genetic epidemiology of breast and ovarian cancers. Epidemiol Rev 1997;19:69-79.

5. Newman B, Moorman PG, Millikan R, et al. The Carolina Breast Cancer Study: integrating population-based epidemiology and molecular biology. Breast Cancer Res Treat 1995;35:51-60.

6. Wolff MS, Collman GW, Barrett JC, Huff J. Breast cancer and environmental risk factors: epidemiological and experimental findings. Annu Rev Pharmacol Toxicol 1996;36:573-96.

7. Ames BN, Gold LS. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci USA 1990;87(19):7772-6.

8. Kulldorff M, Feuer EJ, Miller BA, Freedman LS. Breast cancer clusters in the northeast United States: a geographic analysis. Am J Epidemiol 1997;146(2):161-70.

9. Neutra R, Swan S, Mack T. Clusters galore: insights about environmental clusters from probability theory. Sci Total Environ 1992;127:187-200.

10. Laden F, Hunter DJ. Environmental risk factors and female breast cancer. Annu Rev Public Health 1998;19:101-23.

11. Steingraber S. Mechanisms, proof, and unmet needs: the perspective of a cancer activist. Environ Health Perspect 1997;105(Suppl 3):685-7.

12. Rockhill B, Weinberg CR, Newman B. Population attributable fraction estimation for established breast cancer risk factors: considering the issues of high prevalence and unmodifiability. Am J Epidemiol 1998;147:826-33.

13. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. JAMA 1997;277:997-1003.

14. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993;15:36-47.

15. Rosenberg L, Metzger LS, Palmer JR. Alcohol consumption and risk of breast cancer: a review of the epidemiologic evidence. Epidemiol Rev 1993;15:133-44.

16. Sillero-Arenas M, Delgado-Rodriquez M, Rodigues-Canteras R, et al. Menopausal hormone replacement therapy and breast cancer: a meta-analysis. Obstet Gynecol 1992;79:286-94.

17. John EM, Kelsey JL. Radiation and other environmental exposures and breast cancer. Epidemiol Rev 1993;15:157-62.

18. Colton T, Greenberg ER, Noller K, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up. JAMA 1993;269(16):2096-100.

19. Calle EE, Mervis CA, Thun MJ, et al. Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women. Am J Epidemiol 1996;144(7):645-52.

20. Palmer JR, Wise LA, Hatch EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1509-14.

21. Helzlsouer KJ, Alberg AJ, Huang HY, et al. Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. Cancer Epidemiol Biomarkers Prev 1999;8(6):525-32.

22. HOyer AP, Grandjean P, JOrgensen T, et al. Organochlorine exposure and risk of breast cancer. Lancet 1998;352:1816-20.

23. Millikan R, DeVoto E, Newman B, Savitz D. Studying environmental influences and breast cancer risk: suggestions for an integrated population-based approach. Breast Cancer Res Treat 1995;35:79-89.

24. Brainard GC, Kavet R, Kheifets LI. The relationship between electromagnetic field and light exposures to melatonin and breast cancer risk: a review of the relevant literature. J Pineal Res 1999;26(2):65-100.

25. Kheifets LI. Industrialization, electromagnetic fields, and breast cancer risk. Environ Health Perspect 1999;107(Suppl 1):145-54.

26. Clavel-Chapelon F, Niravong M, Joseph RR. Diet and breast cancer: review of the epidemiologic literature. Cancer Detect Prev 1997;21(5):426-40.

27. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA 2001;285(6):769-76.

28. Gandini S, Merzenich H, Robertson C, Boyle P. Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and the intake of associated micronutrients. Eur J Cancer 2000;36(5):636-46.

29. Bingham SA. High-meat diets and cancer risk. Proc Nutr Soc 1999;58(2):243-8.

30. Zheng W, Gustafson DR, Sinha R, et al. Well-done meat intake and the risk of breast cancer. J Natl Cancer Inst 1998;90(22):1724-9.

31. Hunter DJ, Willett WC. Diet, body size, and breast cancer. Epidemiol Rev 1993;15:110-32.

32. Holmes MD, Hunter DJ, Colditz GA, et al. Association of dietary intake of fat and fatty acids with risk of breast cancer. JAMA 1999;281(10):914-20.

33. Gottlieb N. Soybean in a haystack? Pinpointing an anti-cancer effect. J Natl Cancer Inst 1999;91(19):1610-2.

34. Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997;350(9083):990-4.

35. Wu AH, Ziegler RG, Nomura AM, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr 1998;68(6 Suppl):1437S-1443S.

36. Gammon MD, John EM, Britton JA. Recreational and occupational physical activities and risk of breast cancer. J Natl Cancer Inst 1998;90(2):100-17.

37. Rockhill B, Willett WC, Hunter DJ, et al. Physical activity and breast cancer risk in a cohort of young women. J Natl Cancer Inst 1998;90(15):1155-60.

38. Labrecque LG, Barnes DM, Fentiman IS, Griffin BE. Epstein-Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res 1995;55:39-45.

39. Luqmani YA, Shousha S. Presence of Epstein-Barr virus in breast carcinoma. Int J Oncol 1995;6:899-903.

40. Bonnet M, Guinebretiere JM, Kremmer E, et al. Detection of Epstein-Barr virus in invasive breast cancers. J Natl Cancer Inst 1999;91(16):1376-81.

41. Wang Y, Holland JF, Bleiweiss IJ, et al. Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res 1995;55(22):5173-9.

42. California Environmental Protection Agency's Office of Environmental Health Hazard Assessment (OEHHA). Health Effects of Exposure to Environmental Tobacco Smoke (Final Report). OEHHA Air, 1997 Final Report on Health Effects of Exposure to ETS . Last accessed 2/27/2006.

43. Prentice RL, Caan B, Chlebowski RT, et al. Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295(6):629-42.

44. Adlercreutz H. Phytoestrogens and Breast Cancer. J Steroid Biochem Mol Biol. 2002;83:113-8.

45. den Tonkelaar I, Keinan-Boker L, Van't Veer P, et al. Urinary Phytoestrogens and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2001;10:223-8.

46. Keinan-Boker L, van Der Schouw YT, Grobbee DE, et al. Dietary phytoestrogens and breast cancer risk. Am J Clin Nutr. 2004;79(2):282-8.

47. Schoenfeld ER, O'Leary ES, Henderson K, et al. Electromagnetic fields and breast cancer on Long Island: a case-control study. Am J Epidemiol. 2003;158(1):47-58.

48. Titus-Ernstoff L, Hatch EE, Hoover RN, et al. Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer. 2001 84(1):126-33.

49. McElroy JA, Newcomb PA, Titus-Ernstoff L. Duration of sleep and breast cancer risk in a large population-based case-control study. J Sleep Res. 2006 Sep; 15(3):241-9.

Messina M, McCaskill-Stevens W, Lampe JW. Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J Natl Cancer Inst 2006;98:1275-84.

Source: Environmental Risk Factors for Breast Cancer*-*National Breast Cancer Coalition Fund