Breast cancer and environmental risks: where is the link?

Introduction

Breast cancer is the leading cause of cancer morbidity and mortality in women. In the United States, female invasive breast cancer occurred between 1994 and 1998 at the rate of approximately 118 per 100,000 women (American Cancer Society, 2002). There were 24 cases per 100,000 deaths during the same period. Incidence rates increased by 0.5 percent per year between 1987 and 1998. In 2001, an estimated 192,200 new cases of invasive breast cancer were diagnosed among U.S. women. Despite decades of exploration and study, the mystery of what causes breast cancer continues to intrigue cancer researchers and oncologists. Much of the increase in incidence is attributed to reproductive factors, including early menarche (at less than 12 years of age), late menopause (55 years or more), delayed childbearing or no full-term pregnancy, lack of breastfeeding, oral contraceptive use, and postmenopausal obesity (American Cancer Society, 2002). Approximately 5 to 10 percent of breast cancer cases result from inherited mutation in breast cancer-susceptible genes such as BRCA1 and BRCA2 (Hulka & Moorman, 2001). Evidence also suggests that a number of modifiable factors in the environment react with genetic and individual predisposing factors and cause malignant tumors to develop in breast tissue (Safe, 1998). Some studies, however, have contradicted the suggested link of some environmental chemicals with breast cancer (Dorgan et al., 1999; Stellman et al., 2000; van't Veer et al., 1997). So the question remains: Which environmental agents are cancerous and which are not?

The purpose of the study reported here was to conduct a comprehensive literature review and assess the role of environmental agents in breast cancer. Families of environmental agents were considered, mainly focusing on xenoestrogens (chemicals that mimic estrogens), organochlorines (e.g., pesticides and herbicides), and polychlorinated biphenyls (PCBs). The role of other environmental agents, including ionizing radiation and electromagnetic fields, tobacco smoke, and heterocyclic amines in cooked meat, also are addressed.

Results and Discussion

Xenoestrogens

Estrogens play a critical role in the etiology of breast cancer. Estradiol promotes the growth of breast cancer cells in vivo and in vitro. Exogenous estrogens in both the environment and in the human diet increase the growth of breast cancer cells in vitro (Dees, Askari, Foster, Ahamed, & Wimalasena, 1997). Xenoestrogens mimic naturally occurring estrogen in the body. These chemicals are available in the form of polycarbonate plastics, food and cosmetic packaging, and even tin cans (McPherson, Steel, & Dixon, 2000; Sonnenschein & Soto, 1998). They include such pesticides as the nowbanned DDT (dichlorodiphenyltrichloroethane) and kepone. Other xenoestrogens include PCBs, natural plant products in human diets, and the drug diethylstilbestrol (DES), which was widely used for more than 20 years beginning in the 1940s to prevent spontaneous abortions in women.

Hormone replacement therapy (HRT) may play a significant role in the development of breast cancer during adolescence, the period of high growth rates and breast development (Ardies & Dees, 1998). Xenoestrogens are known to exaggerate the carcinogenic effects of radiation and may increase breast cancer risk among women who are subjected to prenatal exposure to these substances. One out of five women may have a genetic mutation in the way they respond to estrogen, thereby causing even more detrimental effects from xenoestrogens (Herrington & Klein, 2001).

Oral Contraceptives 

Studies have shown that recent use of oral contraceptives may slightly increase the risk of breast cancer among younger women (Moorman, Millikan, & Newman, 2001). A collaborative analysis of individual data on 53,297 cases and 100,239 controls suggests a moderately increased breast cancer risk among current oral contraceptive users (La Vecchia, Altieri, Franceschi, & Tavani, 2001), which tends to level off, or may even show a reduced risk, in 10 to 15 years after use is stopped (Heimdal, Skovlund, & Moller, 2002). Duration of use, age at first use, dose, and type of hormone within the contraceptives appear to have no significant effect on breast cancer risk, but women who begin to use contraceptives before the age of 20 years appear to have a higher relative risk than women who begin at an older age (McPherson et al., 2000). A population-based case control study in the Netherlands also showed an increased risk of breast cancer among long-term users of oral contraceptives (Rookus & van Leeuwen, 1994). A recent population-based case control study of 4,575 women with breast cancer and 4,682 controls from 35 to 64 years of age disputed the notion that current or former oral contraceptive use is associated with an increased risk of breast cancer (Marchbanks et al., 2002).

Hormone Replacement Therapy

Observational evidence suggests that the risk of breast cancer may be increased only if hormone replacement therapy (HRT) is used long term (10 years or more) and that the risk falls when use ceases (Marsden, 2002). Among current users, or those who stopped use one to four years previously, the relative risk of having breast cancer diagnosed increases by a factor of 1.023 for each year of hormone use (Collaborative Group on Hormonal Factors in Breast Cancer, 1997). In a recent case control study in Ontario, Canada, long-term HRT increased the risk of breast cancer, and estrogen-progestin therapy was found to be more detrimental than estrogen use alone (Kirsh & Kreiger, 2002). A nested case control study added to the evidence that long-term use of HRT is associated with an increased risk of breast cancer and that such use may be related particularly to lobular tumors (Chen, Weiss, Newcomb, Barlow, & White, 2002). A meta-analysis, however, did not find consistent evidence to support the hypothesis that estrogen replacement therapy increases the risk of breast cancer (Bush, Whiteman, & Flaws, 2001). Nor did evidence support the theory that the combined therapy or HRT increases the risk of breast cancer more than estrogen alone. HRT use in women with a family history of breast cancer was not associated with a significantly increased incidence of breast cancer but was associated with a significantly reduced total mortality rate (relative risk = 0.67; 95 percent confidence interval [CI] = 0.51-0.89) (Sellers et al., 1997).

A recently completed large controlled trial indicated that estrogen-plus-progestin treatment had more harmful than beneficial outcomes (Writing Group for the Women's Health Initiative Investigators, 2002). After a mean of 5.2 years of follow-up, absolute excess risks per 10,000 person-years attributable to estrogen-plus-progestin were seven more coronary-heart-disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers. The study did not support estrogen-plus-progestin treatment for primary prevention of chronic diseases.

Organochlorines

Organochlorines (OCs) are defined as a heterogeneous group of manmade organic compounds that contain covalently bonded chlorine atoms (Hoffman, 1996). They were first produced in massive quantities following World War II. Many have been used as pesticides, both as insecticides (e.g., dichlorodiphenyltrichloroethane [DDT], lindane, aldrin, dieldrin) and as herbicides (e.g., 4-chloro-2-methylphenoxyacetic acid [MCPA], dichloprop, 2,4-dichlorophenoxyacetic acid [2,4-D], and 2,4,-5-trichlorophenoxyacetic acid [2,4,5-T]). OCs are also used as flame retardants, as coolants in hydraulic systems, as dielectrics in transformers, and for a variety of other industrial purposes.

Considerable inter-individual variation exists with respect to effects caused by OCs. Higher average body burden is associated with residing in the South; working in plastic refineries; living on farms; and being nonwhite, male, older, or below the poverty level (Hoffman, 1996). Lactation is the single most effective pathway of OC excretion, thereby providing a protective effect because of quick elimination. Humans who are exposed to OCs for prolonged periods also have manifested depression in numbers of natural killer (NK) cells, which are crucial in the immunological defense against early stages of cancer (Svensson, Hallberg, Nilsson, Schutz, & Hagmar, 1994).

DDE, DDT, Pesticides, and Herbicides

Breast cancer risk from organochlorine exposure was addressed in five recent case control studies reviewed by Hoffman (1996). In only one of the reported studies was there essentially no difference in concentrations of polychlorinated biphenyls (PCBs), DDT, and DDE (dichlorodiphenyldichloroethane, a degradation product of DDT) between breast tissue samples obtained from deceased patients with breast cancer and tissue samples from controls. In two of the other studies, case patients had significantly higher tissue levels of DDT, DDE, PCB, and lindane. DDT and DDE levels in young Canadian women were found to be nearly twice as high in women who had never breastfed than in women with a breastfeeding history of at least 12 months. In another study, 121,700 married registered nurses from 11 states were followed up every two years for incidence of breast cancer. Cases and controls did not differ significantly in terms of blood levels of DDE and PCBs (Hunter et al., 1997). Blood levels of DDT also did not differ between cases and controls in Vietnamese women (Schecter, Toniolo, Dai, Thuy, & Wolff, 1997). No excess risk of breast cancer was observed in a cohort of 701 women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). A multicenter case control study included 347 women with breast cancer from Germany, the Netherlands, Northern Ireland, Switzerland, and Spain as well as 374 population and hospital controls. The odds ratio (OR) of breast cancer, for the highest versus the lowest quartile of DDE distribution, was 0.73 (95 percent CI = 0.44-1.21), indicating that DDE did not increase risk of breast cancer (van't Veer et al., 1997).

In a nested case control study in New York City women, breast cancer incidence increased fourfold with an elevation of serum DDE concentrations from 2.0 nanograms per milliliter (ng/mL) to 19.1 ng/mL (Wolff, Toniolo, Lee, Rivera, & Dublin, 1993). In another study, concentrations of organochlorines, 8-OHdG (8-hydroxy-2-deoxyguanosine, a biomarker of oxidative DNA damage), DDT, and DDE were measured in 44 cancerous and 21 noncancerous breast tissues (Charles et al., 2001). Overall, no significant differences were observed in the level of the organochlorines between the tissues. No significant differences were observed in 8-OHdG levels in cancerous versus noncancerous tissue, and no correlation was demonstrated between the organochlorines and 8-OHdG. The data thus do not support the hypothesis that oxidative DNA damage caused by exposure to organochlorines is an important risk factor in breast cancer.

A study in conjunction with the Long Island Breast Cancer Study Project (Stellman et al., 2000), examined the association of breast cancer risk and adipose concentrations of organochlorine pesticides and PCBs. Concentrations of organochlorine pesticides and PCBs were measured in the breast adipose tissue from 232 women with breast cancer and 323 hospital controls. After adjustment for age and body mass index, adipose concentrations of 1,1-dicloro-2,2-di (4-chlorophenyl) ethylene, total pesticides, and total PCBs did not differ significantly between cases and controls. Breast cancer risk among Long Island residents was not elevated compared with that among residents of the adjacent borough of Queens. The study did not provide convincing evidence that the body burden of organochlorine pesticides and PCBs is associated with breast cancer.

Atrazine 

Atrazine, an organochlorine compound, has been widely used as an herbicide in the United States, mainly in corn production. In a recent study, Hopenhayn-Rich, Stump, and Browning (2002) examined the association between environmental exposure to atrazine and the incidence of breast cancer in Kentucky over a five-year period. Exposure indices were derived from public drinking-water measurements, acres of corn planted, and pounds of atrazine sold. Data on atrazine concentrations in drinking-water supplies were provided by the Kentucky Division of Water, Drinking Water Branch, of the state government. Data were collected from all public water systems, including community water systems (CWSs), which supply water to the same population year-round; non-transient non-community water systems (NTNCWSs), which supply water to at least 25 of the same people at least six months per year (e.g., schools, factories, office buildings, and some hospitals); and transient non-community water systems (TNCWSs), which provide water in places such as gas stations or compounds. Atrazine levels were examined for each type of water system separately. NTNCWS and TNCWS data were grouped together as non-community water system (NCWS) data and compared with data for CWSs. Data on breast cancer incidence were obtained from the Kentucky Cancer Registry. No association was found for breast cancer across all exposure indices, both by county and by area development district.

Dieldrin

Dieldrin is a pesticide that was used in treatment of apples and other food crops until the late 1970s and was used in termite control until 1985, when it was banned. In a prospective study of 7,712 women followed up for 17 years, 268 developed invasive breast cancer. Each woman was matched with two breast-cancer-free women from the remaining cohort. Dieldrin exposure was associated with a significantly increased dose-related risk of breast cancer (Hoyer, Grandjean, Jorgensen, Brock, & Hartvig, 1998). In a subsequent study, the same group showed that exposure to dieldrin may affect not only the risk of developing breast cancer but also survival (Hoyer, Jorgensen, Brock, & Grandjean, 2000).

Lindane

Lindane (gamma-isomer of hexachlorocyclohexane, HCH), more commonly known as Bio-well, Kwell, Thionex, or Scabene, is a pesticide commonly used on fruit, vegetables, and forest crops. It is used against a large number of pests, such as wireworm and leatherjackets, and is also used by prescription to treat head lice and mites (scabies) in humans.

Technical-grade HCH, a mixture of several chemical forms of HCH, has been found in the soil and surface water at hazardous waste sites. Gamma-HCH (lindane) can remain in the air for as long as 17 weeks depending on moisture in the air and temperature. In soil, sediments, and water, it is broken down to less toxic substances by algae, fungi, and bacteria. Gamma-HCH is generally absent from drinking water because it is broken down quickly in water (ATSDR, 2002).

Human exposure to HCH can occur through air contaminated by factories where HCH is used, such as fertilizer-manufacturing sites, and through eating or drinking of contaminated plants, meat, water, and milk. The toxicity of the isomers varies. With respect to acute exposure, gamma-HCH is the most toxic, followed by alpha-, delta-, and beta-HCH. With chronic exposure, beta-HCH is the most toxic isomer, because of its longer biological half-life in the body.

Dorgan and co-authors (1999) assessed the relationship between serum levels of five DDT metabolites, 13 other organochlorine pesticides, and 27 PCBs and the development of breast cancer. Results indicated that women with serum levels in the upper quartile of HCH concentrations were at twice the risk for breast cancer as those with lower-quartile concentrations of the chemical. No dose-response relationship (i.e., increasing occurrence of disease with increasing levels of exposure) was observed among these women, however. Women with serum levels of other organochlorine pesticides and PCBs showed no increased risk for breast cancer, although positive associations were suggested for PCB-118 and PCB-138.

Polychlorinated Biphenyls

Polychlorinated biphenyls (PCBs) are mixtures of up to 209 individual chlorinated compounds, known as congeners. The congeners are named according to their different degrees of chlorination. The half-lives of PCBs vary according to the specific congeners involved. PCBs have been used as coolants and lubricants in transformers, capacitors, and other electrical equipment because they do not burn easily and are good insulators. The manufacture of PCBs was halted in the United States in 1977 because of evidence that they build up in the environment and can cause harmful health defects. Products made before 1977 that may contain PCBs include old fluorescent lighting fixtures, electrical devices containing PCB capacitors, electrical transformers, old microscopes, and hydraulic oils.

PCBs enter the air, water, and soil during their manufacture, use, and disposal; they also are released by accidental spills and leaks during transport and by leaks or fires in products containing PCBs. PCBs still can be released into the environment from hazardous waste sites, illegal or improper disposal of industrial wastes and consumer products, leaks from old electrical transformers containing PCBs, and burning of some wastes in incinerators. PCBs do not readily break down in the environment and thus may remain there for many years. Humans consume PCBs when they eat contaminated fish and marine life (ATSDR, 2002).

Polychlorinated Biphenyls and DDE

In a case control study in Quebec, Canada, breast cancer risk was significantly associated with exposure to dioxin-like PCBs (Demers et al., 2002). Another study, in Cordoba, Spain, also suggested that breast fat concentrations of specific congeners (PCB-28 and PCB-52) may predict breast cancer (Lucena, Allam, Costabeber, Villarejo, & Navajas, 2001). Not all congeners behave equally; estimating joint effects of all congeners may be misleading and even inappropriate because of possible interactions between some congeners. For example, one study at the Yale University School of Medicine demonstrated a protective effect on breast cancer risk for two congeners, PCB-156 and PCB-153, while two other congeners, PCB-180 and PCB-183, had an adverse effect (Holford et al., 2000). Dorgan et al. (1999) found no association between PCBs and breast cancer in a nested case-control study using the Columbia, Missouri Breast Cancer Serum Bank.

Reports on the effects of PCBs and DDE with respect to breast cancer have been mixed. Two studies carried out at a university did not find any significant association of PCBs and DDE with breast cancer (Zheng, Holford, Mayne, et al., 2000; Zheng, Holford, Tessari, et al., 2000). Another nested case control study done at the Johns Hopkins University did not find any added risk of breast cancer from exposure to high concentrations of DDE and PCBs, even after 20 years of follow-up (Helzlsouer et al., 1999). Studies showed that effects of PCBs and DDE might differ by race. The adjusted odds ratio for breast cancer comparing the highest to the lowest quartile of DDE was 1.41 for African-American women and 0.98 for white women (Millikan et al., 2000). The odds ratio comparing the highest to the lowest quartile of total PCBs was 1.74 in African-American women and 1.03 in white women. Some other factors, such as income, parity, breastfeeding, and body mass index also influence the relationship of organochlorines and breast cancer.

Other Environmental Agents

Radon and Radium 

The groundwater found in limestone, sandstone, and granite formations may have large concentrations of radon and radium. Radon and radium move easily from water to air, creating a greater health risk. The classic health effects of occupational exposure to radium include bone cancer, carcinomas of paranasal sinuses, and bone fractures. Breast cancer and thyroid cancers are probable effects of occupational exposure of high doses of radium (Stebbings, 2001).

In an experimental study, human breast cancer cells, MCF-7 cells, were exposed to different levels of radon (10 to 15,000 micrograys [[micro]Gy]) or served as controls. MCF-7 cells were found to proliferate significantly at an intermediate dose of radon, indicating the carcinogenic potential of radon (Soto, Quindos, Cos, & Sanchez-Barcelo, 1996). A study conducted at a school district in Missouri showed an elevated level of radon at the school and a moderately increased risk for breast cancer among female employees compared with the general population (Neuberger, Pierce, & Lai, 1997).

Benzene and Benzene Compounds

Benzene is a colorless liquid with a sweet odor that evaporates quickly and dissolves slightly in water (ATSDR, 2002). It is highly flammable and is found in car exhaust, burning objects, plastic refineries, resins, nylon, synthetic fibers, rubbers, lubricants, dyes, detergents, drugs, and pesticides. The most prominent sources in the environment are car exhaust, cigarette smoke, and the burning of crude oil. Indoor benzene sources are glues, paints, furniture wax, and detergents. Benzene also can enter groundwater from leaking underground storage tanks or hazardous waste sites. Typically, benzene passes into the air from water and soil. In the air, it reacts with other chemicals and degrades within a few days. It can also attach to rain or snow and return to the earth's surface in precipitation.

In a case control study of pre-menopausal breast cancer, researchers obtained occupational histories and other information through interviews and used job-exposure matrices to assess exposure to polycyclic aromatic hydrocarbons (PAHs) and benzene. The odds ratios of breast cancer were 1.64 (95 percent CI = 0.64-4.21) for a low-dose exposure and 1.95 (95 percent CI = 1.14-3.33) for a high-dose exposure to benzene (Petralia et al., 1999). A dose-response relationship was not evident for the intensity of exposure to benzene or to PAH.

Zheng and colleagues (1999) conducted studies on the association of benzene-containing compounds and the risk of female breast cancer as part of the Long Island Breast Cancer Study Project. By directly comparing beta-benzene hexachloride levels in breast adipose tissue from 304 incident breast cancer cases and 186 controls, this study examined the hypothesis that exposure to beta-benzene hydrochloride increases the risk of breast cancer in females. Overall, no significant differences were observed between cases and controls in breast adipose-tissue levels of beta-benzene hexachloride.

Electromagnetic Fields

There is no persuasive scientific evidence to show that low-level, low-frequency electromagnetic fields (EMF) can influence carcinogenesis. In a nationwide cohort study conducted between 1970 and 1989 in Finland, 383,700 subjects were identified by records as living within 500 meters of overhead power lines (Verkasalo, Pukkala, Kaprio, Heikkila, & Koskenvuo, 1996). The voltage of the magnetic fields ranged from 110 kilovolts (kV) to 400 kV. The study confirmed 1,229 cases of breast cancer, of which 945 occurred in women exposed for less than 0.2 microtesla ([micro]T) years, 130 in women exposed for 0.2-0.39 [micro]T years. The study found no significant increase in breast cancer related to strength of the magnetic field.

Chronic exposure to industrial-strength magnetic fields (60 hertz [Hz], 28.3 [micro]T), the presence of high levels of light at night (LAN), or both reduces circulating levels of the hormone melatonin, which, in turn, allows estrogen level to rise and stimulate the turnover of breast epithelial stem cells, increasing the risk of malignant transformation (Davis, Mirick, & Stevens, 2001). Laboratory-based studies of women exposed to EMF did not, however, show any effect on the blood levels of melatonin or estradiol (Graham, Cook, Gerkovich, & Sastre, 2001). Breast cancer risk according to electric blanket or mattress cover use was addressed in a multicenter case control study involving 1,949 breast cancer patients identified from statewide tumor registries in Massachusetts, New Hampshire, and Wisconsin. The risk of breast cancer was similar among those who had ever used these devices (RR = 0.93; 95 percent CI = 0.82-1.06) and lower among current users than among those who had never used the devices (RR = 0.79; 95 percent CI = 0.66-0.95) (McElroy et al., 2001). A case control study identified 528 subjects with breast cancer and matched five controls for each case. Jobs involving radiotherapy, radioisotopes, or fluoroscopic equipments were not linked to breast cancer risk (Boice, Mandel, & Doody, 1995).

Tobacco Smoking

Cigarette smoking is an established cause of a variety of cancers, but evidence of its role in breast cancer etiology is inconclusive. Several known carcinogens found in tobacco, such as polycyclic hydrocarbons, aromatic amines, and N-nitrosamines, may induce mammary tumors (Terry & Rohan, 2002). Studies in humans demonstrate that mammary carcinogens such as polycyclic aromatic hydrocarbons and 4-aminobiphenyl are frequently higher in smokers than in nonsmokers (Hecht, 2002).

Recent studies suggest that both active and passive smokers have an increased risk of breast cancer compared with women who have never been either actively or passively exposed. In a case control study in Germany, using 468 cases with breast cancer and 1,093 controls, former smokers and current smokers had odds ratios of 1.2 (95 percent CI = 0.8 to 1.7) and 1.5 (95 percent CI = 1.0 to 2.2), respectively. Among those who had never smoked actively, passive smoking was associated with an odds ratio of 1.6 (95 percent CI = 1.1-2.4) (Kropp & Chang-Claude, 2002). Some studies suggested that smoking for a long duration (40 years or more) and at a heavy intensity (20 cigarettes per day) may be associated with increased risk of breast cancer (Terry, Miller, & Rohan, 2002). Studies also showed a stronger risk of breast cancer with smoking in families with a history of breast cancer, ovarian cancer, or both (Couch et al., 2001).

The effects of smoking are often compounded by drinking. In a meta-analysis of 22,255 women with breast cancer and 40,832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared with never-smokers, RR for ever-smokers = 1.03, and 95 percent CI = 0.98-1.07; RR for current smokers = 0.99, and 95 percent CI = 0.02-1.05) (Collaborative Group on Hormonal Factors in Breast Cancer, 2002).

Genetic variability must be considered in a person's susceptibility to breast cancer if women with breast cancer are exposed to tobacco smoke. Active smoking showed significant dose-response relationships with breast cancer risk among women born with the slow-acting gene (slow acetylators) for N-acetyl-transferase (NAT2), an enzyme known to detoxify carcinogenic compounds in cigarette smoke. In contrast, passive smoking was associated with higher risk in rapid acetylators (Chang-Claude, Kropp, Jager, Bartsch, & Risch, 2002). The slow-acetylator genotype is found in 10 to 20 percent of Asians, 35 percent of African-Americans, and 65 to 90 percent of people of Middle Eastern descent (Kmietowicz, 1996).

Heterocyclic Amines

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons, compounds that potentially promote cancer development (Felton, Knize, Salmon, Malfatti, & Kulp, 2002). HCAs are by-products of a reaction between amino acids and creatine. The reaction is triggered when food from animal muscle--beef, pork, poultry, and fish--is cooked at high temperatures (300 to 400[degrees]F). Frying, broiling, and barbecuing generate the most HCAs. Longer cooking times increase the formation of HCAs.

The HCA PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine) showed the greatest correlation with the risk of breast cancer in the study population. PhIP can cause DNA damage by cell mutations, strand breaks, and cell transformations. Polymorphic N-acetyltransferase-2 (NAT2) catalyzes the activation of HCAs via O-acetylation, suggesting that NAT2 genotypes with high O-acetyltransferase activity (rapid/intermediate acetylator phenotype) increase the risk of breast cancer in women who consume well-done meat (Deitz et al., 2000).

Case control studies in Uruguay showed a strong relationship between HCA exposure from meat intake and breast cancer (De Stefani, Ronco, Mendilaharsu, Guidobono, & Deneo-Pellegrini, 1997). In a nested casecontrol study of 41,836 women, breast cancer risk was 4.6 times higher among women who consumed very-well-done meat compared with those who ate rare or medium-done meat (Zheng et al., 1998). In another study, however, conducted among Californian women, no significant association was found between breast cancer and HCA, as estimated from interview data on meat type, degree of cooking (e.g., well done), and cooking method (pan-fried and barbecued) (Delfino et al., 2000).

Conclusion

Table 1 summarizes quantitative data on the strength of statistical associations between major environmental chemicals, including xenoestrogens, organochlorines, and PCBs, and breast cancer incidence. Evidence is inconclusive on the link between oral-contraceptive use and breast cancer. The risk of breast cancer appears to be higher with combined estrogen and progesterone therapy. New evidence from a large clinical trial suggests that the use of hormone replacement therapy for primary prevention of chronic diseases is no longer supported because the current regimens have more harmful than beneficial outcomes. Further studies are needed to show that modified dosing or refined HRT regimens can reduce risk from diseases including breast cancer, cardiovascular and cerebrovascular events, and pulmonary embolism.

Among pesticides and herbicides, dieldrin most likely poses the greatest threat; more research is needed on the relationship between lindane and breast cancer. Benzene is a known human carcinogen; however, the Long Island Breast Cancer Study Project did not find a risk of breast cancer from exposure to benzene and benzene compounds. Exposure to electromagnetic fields proved to be insignificant for assessing the risk of breast cancer. Evidence is not conclusive about whether tobacco smoke alone could cause breast cancer. Smoking or regular exposure to second-hand smoke is, however, definitely an added risk when associated with genetic factors. Similarly, heterocyclic amines produced when meat is cooked at high temperatures do pose a threat to breast tissue; however, it is very difficult to separate this effect from individual lifestyle eating habits and amounts of xenoestrogen exposure, either through use of oral contraceptives or through use of hormone replacement therapy. Further studies are needed to assess the link between xenoestrogens and heterocyclic amines and breast cancer.

TABLE 1 Risk of Breast Cancer in Relation to Suspected Risk Factors

Author, Year             Study Design, N     Odds Ratio/Relative Risk
                                             (95% Confidence Intervals)

Oral contraceptives
Marchbanks et al.,      Case control study;  RR = 1.0 (0.8-1.3) among
2002                    4,575 women with     current users;
                        breast cancer and    RR = 0.9 (0.8-1.0) among
                        4,682 controls       previous users
Rookus & van Leeuwen,   Case control study   RR = 1.3 (0.9-1.9) among
1994                    in the Netherlands;  long-term users
                        918 cases and 918
                        controls
Hormone replacement therapy
Chen et al., 2002       Nested case control  OR = 3.07 (1.55-6.06) for
                        study; 705 cases     lobular breast cancer among
                        and 692 age-matched  users 57 months or more; OR
                        controls             = 3.91 (2.05-7.44) for
                                             lobular breast cancer among
                                             current users
Collaborative Group on  Meta-analysis;       RR = 1.35 (1.21-1.49) for
Hormonal Factors in     52,705 cases and     HRT users for
Breast Cancer, 1997     108,411 controls     [greater than or equal to]5
                                             years
Kirsh & Kreiger, 2002   404 incident cases   OR = 3.48 (1.00-12.11)
                        and 403 age-matched  among estrogen-plus-
                        controls; Ontario,   progestin users;
                        Canada               OR = 1.74 (0.93-3.24) among
                                             estrogen users
Organochlorines
van't Veer et al.,      A multicenter study  OR = 0.73 (0.44-1.21)
1997                    of 265
                        postmenopausal
                        women with breast
                        cancer and 341
                        controls
Wolff et al., 1993      Nested case control  RR = 4.0 for DDE when a
                        study; 58 cases,     dose of 19.1 ng/mL (90th
                        171 matched          percentile) is compared
                        controls             with 2.0 ng/mL (10th
                                             percentile)
Polychlorinated biphenyls
Demers et al., 2002     Case control study;  OR = 1.6 (1.01-2.53) for
                        314 cases and 523    PCB 118;
                        control; Quebec      OR = 1.8 (1.11-2.94) for
                        City, Canada         PCB 156
Lucena et al., 2001     134 women treated    OR = 9.6 (3.8-24.4) for
                        by excision biopsy   PCB 28
                        because of breast
                        lump; PCB congener
                        levels estimated in
                        breast fat
Zheng et al., 2000      Case-control study;  OR = 0.96 (0.67 to 1.36)
                        475 cases and 502    for DDE;
                        controls             OR = 0.95 (0.68 to 1.32)
                                             for PCBs

Acknowledgements: The study was supported by the Summer Faculty Research Grants of the University of Southern Mississippi. The authors appreciate the technical and editorial suggestions made by Dr. Welford C. Roberts.

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Corresponding Author: Amal K. Mitra, Associate Professor of Epidemiology and Biostatistics, Center for Community Health, University of Southern Mississippi, Hattiesburg, MS 39406-5122. E-mail: [e-mail].

Amal K. Mitra, M.D., M.P.H., Dr.P.H.

Fazlay S. Faruque, Ph.D., P.G.

Amanda L. Avis, M.P.H.