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Breast Cancer and the Environment: A Life Course Approach (2012)

Chapter:3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors

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Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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3

What We Have Learned from
Current Approaches to Studying
Environmental Risk Factors

As one of its tasks, the committee was asked to review and assess the strength of the science base regarding the relationship between breast cancer and the environment. This body of evidence has evolved over many years through diverse fields of inquiry, including epidemiologic investigations, experimental studies in laboratory animals, and in vitro laboratory research on questions at the molecular, genetic, cellular, and tissue levels. Indeed, since the rise in breast cancer diagnoses that became particularly steep around 30 years ago, tremendous efforts have been made to identify the causes.

In this chapter the committee reviews approaches to assessing evidence concerning risk for breast cancer, summarizes the existing evidence on a selection of factors, and offers its assessment of the implications of the evidence. For many of the environmental risk factors, the results of the committee’s review are far from conclusive. Reasons for the continuing gaps in knowledge are numerous. Chapter 4 discusses some of the challenges to studying causes of breast cancer and why the existing evidence permits few definitive conclusions. In some cases, recent advances using more sensitive tools to examine the pathobiology of breast cancer can be expected to provide new models for research in humans, animals, and in vitro systems.

Although the results of newer approaches to research on risk factors for breast cancer are promising, the extant literature is primarily grounded in older technologies and approaches. In light of this transitional state of the science, the committee nevertheless faced the question, what has been possible to discern from the work done so far? Here the committee outlines the scope of its review, describes evidentiary standards that have been used

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

by leading authoritative bodies, and reviews the evidence on a selected set of risk factors.

SCOPE OF THE REVIEW

As discussed in Chapters 1 and 2, the committee adopted a broad definition of “environment” that includes all factors not directly inherited through DNA. In selecting environmental factors for examination, the committee took into account several considerations, including variety in the types of potential risk factors and routes of exposure, availability of evidence for review, and indications of public concern. From the enormous list of candidates, the committee selected a limited set of factors in order to illustrate a variety of environmental exposures, and to emphasize the need for new approaches to investigate and increase the knowledge base of potential environmental risks for breast cancer. With an evolving understanding of the mechanisms for cancer development and concern about whether the right questions have yet been asked or asked using appropriate study designs, the committee saw limited value in a full review of evidence for an extensive list of environmental factors that is available from a number of other sources (e.g., International Agency for Research in Cancer [IARC], the World Cancer Research Fund/American Institute for Cancer Research [WCRF/AICR], the U.S. Environmental Protection Agency [EPA], and the National Toxicology Program [NTP]), nor was it feasible for the present study. Of the large number of environmental factors with potential but uncertain impact on breast cancer, the committee reviewed only a selected number that illustrated particular types of challenges in assessment. For example, the committee evaluated factors for which extensive epidemiologic evidence and systematic reviews were available (e.g., alcohol consumption), and it also reviewed chemicals for which studies evaluating breast cancer in humans were very limited (e.g., bisphenol A).

Little attention was given to several very familiar topics, such as dietary fat and micronutrients, that are receiving ongoing systematic review by other organizations. The committee also chose not to include established reproductive risk factors, such as age at menarche or first full-term pregnancy, and anthropometric features such as birthweight or attained height in its review of environmental factors. These risk factors have also received considerable attention elsewhere. In Chapter 7 the committee has included recommendations for additional research to confirm the appropriateness of using alterations in such reproductive and anthropometric intermediate endpoints as valid and reliable markers of alterations in risk for breast cancer.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

Process for the Evidence Review

Given the scope and time line of the committee’s study, it was not feasible to carry out formal, systematic reviews of the scale or depth of those carried out by the WCRF/AICR, IARC, or the Cochrane Collaboration. Such reviews entail examination of the results of exhaustive literature searches and extensive documentation.1 The committee found that given the changing science and the apparent gaps in the evidence base, it could most fruitfully apply its efforts in reviewing and speaking to a larger picture in the science of breast cancer and the environment.

The committee’s process for its review of the evidence was as follows: The committee turned first to the conclusions available from the extensive reviews by authoritative groups (WCRF/AICR, 2007, 2008, 2010; EPA, 2011b; IARC, 2011; NTP, 2011a). Where the results of a systematic review were available for particular risk factors, the committee preferentially drew on these resources. These sources were supplemented by review of additional literature identified by committee members and staff and in targeted searches by an Institute of Medicine (IOM) research librarian. The targeted searches on the committee’s selected risk factors discussed in this chapter used the PubMed and Embase databases in searches of the peer-reviewed, English-language literature published between January 2000 and October 2010, expecting that literature available before 2000 had been extensively reviewed by other authoritative reviews or subsequent publications. The searches were designed to identify literature on breast cancer in humans, mammary neoplasms in animals, and related in vitro and mechanistic studies. The process was supplemented by testimony from advocates, expert scientists, and members of the public.

Committee members examined these resources to evaluate the strength of the science base regarding the association of a given risk factor with breast cancer.

Hierarchy of Studies

Widely used standards of evidence for identifying and evaluating hazards or risks from potential carcinogens share several features. They

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1For example, the WCRF/AICR review released in 2007, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, took place over 6 years (WCRF/AICR, 2007, Appendix A, p. 396). It required the work of an expert task force to develop the systematic review methodology, and methods testing at two centers. Next, research teams at nine institutions in Europe and North America carried out systematic literature reviews. Finally, a panel of experts worked to assess the evidence and agree on recommendations. Since then, the Continuous Update Project has been following scientific developments in this field. Its updates capture new evidence since the last systematic literature review to permit review and meta-analysis (WCRF/AICR, 2010).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

typically rely only on published and peer-reviewed literature, and they ultimately reach conclusions about factors/agents based on the relevant studies, the strength of the results, and the coherence and plausibility of the evidence base. By virtue of their design, certain study types are given greater weight based on their relevance and freedom from bias.

Randomized controlled trials have an experimental design and, when well conducted, are considered the strongest form of epidemiologic study for directly determining causal associations between interventions or exposures and health outcomes. As discussed further in Chapter 4, randomization for many environmental exposures would be unethical or not feasible. In research on suspected environmental hazards, which is the focus of the committee’s work, most epidemiologic studies are observational rather than experimental. Observational studies evaluate the exposures to the factor of interest as they take place in the real world, not based on intervention by any scientist. Thus, the determination of who is and who is not exposed may be related to marketing practices; changes in formulations, regulations, and laws (e.g., for emissions into air, water, or soil, or for chemicals to be used in manufacture of consumer products) at the federal, state, or local level; disposal practices; and personal choices about consumer product use, or behaviors (eating pesticide-free produce or not; leaving windows open to ventilate home). Observational studies can be informative when the comparison populations are appropriately defined and sufficient attention is given to exposure assessment and to confounding.2 Other characteristics of observational studies that influence their validity are discussed in Chapter 4.

In addition to experimental (when available) and observational epidemiologic studies in humans, the committee drew on information from experimental studies in animals and studies carried out in vitro (in cells or tissues, rather than a whole organism) to inform its assessment of risk factors for breast cancer. As discussed in Chapter 4, these studies are powerful tools for exploring possible health effects, mechanisms of action, and the biologic plausibility of a factor’s association with a change in risk for breast cancer. The literature review included reports from experimental studies in animals conducted for regulatory purposes as well as from studies by researchers.

Categories of Evidence

Several organizations have developed methods and criteria to classify the strength of evidence for the carcinogenicity of an exposure or to convey the strength of an association between a risk factor and a particular

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2Confounding can occur when an exposure variable and the disease outcome are both related to one or more other variables not being studied. It is discussed further in Chapter 4.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

health effect. The criteria aim to be explicit about the weight, or relative importance, given to studies in humans and in animals or other experimental systems. For example, IARC, EPA, NTP, and the WCRF/AICR each have a set of categories and approaches to applying them that reflect their work to classify potential carcinogens or risk factors. These classification schemes are developed under different mandates and missions with regard to their role in informing decision making. Designations by IARC, NTP, and WCRF/AICR are qualitative and do not attempt to quantify risk in relation to dose, whereas EPA carries out more quantitative evaluations. Various IOM committees have also developed qualitative systems of classification of evidence for their work in evaluating associations between exposures and outcomes (e.g., IOM, 1991, 2001, 2010, 2011).

The IARC, EPA, and NTP classification systems focus on identifying substances that may pose a cancer hazard; that is, whether a given substance is “capable of causing cancer under some circumstances” (IARC, 2006b). These systems work first by separately evaluating and rating the three types of evidence—human, animal, and other relevant data, such as from cell cultures—in categories such as “sufficient evidence in animals” or “limited evidence in humans.” Second, the three evidence streams are integrated to reach an overall conclusion about the potential for a substance to be a carcinogen. Terms like “known” or “possible” carcinogen are used for the overall evidence categories. The IOM, WCRF, and Cochrane reviews primarily focus on the human evidence of risk (i.e., that an exposure is associated with an adverse human health outcome) and do not go through the formal exercise of rating the animal or other relevant evidence to reach conclusions about possible human carcinogenicity. The various IOM categories are applied to evidence for any relevant health outcome, not just cancers.

Strong and consistent positive epidemiologic evidence in rigorously conducted studies is prima facie evidence that the substance is a risk factor: People exposed to the agent were affected in sufficient numbers or the associated risk was sufficiently strong that it was possible to detect the breast cancer effect through epidemiologic study. There is a range of views within the scientific community as to whether strong nonhuman evidence of hazard should be a basis for concluding that a human risk exists. Formal translation of a hazard conclusion into a risk conclusion could involve quantitative evaluations of a number of factors, including the extent of the population that is exposed to the factor in question; the magnitude of exposure for specific segments of the population; and the extent to which the exposure to the substance accumulates with other exposures to pose risk to the population. But experimental evidence in nonhuman species or in vitro systems can indicate that the substance is a possible, biologically plausible risk factor, given sufficient dose at a relevant time. At present, in

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

the absence of adequate human data, nonhuman evidence of hazard is used as the basis for regulatory decision making.

A critical difference among the categories and approaches used by IARC, EPA, NTP, IOM, and WCRF/AICR is the role that data from experimental studies in animals and studies employing in vitro systems using human or other cell lines play in determining the category for a substance. Full descriptions of the classifications used by IARC, EPA, NTP, IOM studies of Gulf War exposures, and WCRF are provided in Appendix C. For each organization, strong and convincing evidence from human epidemiologic studies is a basis for concluding that a substance or risk factor is causally associated with human cancer. WCRF includes in its criteria for “convincing causal relationship” that there be strong experimental evidence from human or animal studies that typical human exposure can lead to relevant cancer outcomes.3 In rare circumstances (“exceptionally”) under the EPA, NTP, and IARC schemes, very strong animal and mechanistic evidence (EPA and IARC) or strong human mechanistic evidence (NTP) can lead to a conclusion that a substance causes human cancer when definitive epidemiologic evidence is absent. Also in those schemes, strong experimental evidence alone can lead to a finding that a substance is probably or possibly a human carcinogen. In one case (EPA), suggestive animal evidence is treated as suggestive evidence of carcinogenic potential. In contrast, the approach used in several IOM studies focuses on evaluating the strength of human data, using animal and in vitro studies only as supplemental evidence for considering the biologic plausibility of observed epidemiologic associations in making determinations about causality.

The classifications used by this committee take elements from systems used by IOM, IARC, and EPA. The committee chose to use terms that more explicitly identify the relative strengths of the epidemiologic data for pointing out known and probable risk factors being evaluated, along the lines of approaches used by IOM committees. Factors for which epidemiologic evidence shows a consistently positive association with breast cancer that is not explained by bias or confounding and that falls outside the realm of chance are considered as “risk factors” for breast cancer. Thus, because epidemiologic studies by their very nature include consideration of human exposures, they are able to observe “risk,” not just “hazard.” In contrast, mechanistic and animal studies address “hazard” (the potential to cause an effect), but are not observations of human “risk factors.” As noted above, other steps are needed to make judgments about whether substances identi-

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3Experimental evidence must fall into the WCRF/AICR (2007) Class I category, either in vivo data from studies using human volunteers, genetically modified animal models related to human cancer (e.g., gene knockout or transgenic mouse models), or rodent cancer models designed to investigate modifiers of the cancer process.
Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

fied experimentally in animals or in vitro as cancer hazards should be considered risk factors. However, analogous to IARC and EPA, the committee indicated in certain instances that it is possible or biologically plausible that certain substances are risk factors for breast cancer. The committee’s criteria thus reflect the important differences between studies that observe risk factors in human populations and those that evaluate hazard potential.

The committee chose these criteria in part because of its mandate to consider potential evidence-based actions that women could take to reduce their risk of breast cancer. It was conscious of a wish to note “risk factors” and distinguish them from hazards, as described above.

After careful consideration, the committee chose to convey its assessments of the literature using broad groupings that reflect very generally the state of the evidence available. For example, for a factor for which compelling evidence from studies in humans, often distilled by others’ systematic reviews, shows it to be an established risk factor for breast cancer, the committee used the designation assigned by the systematic reviews. Similarly, the committee noted as “probable” breast cancer risk factors those with strong but not definitive evidence from epidemiologic studies, sometimes with supporting evidence from animal or in vitro models.

Factors that did not fall into these categories were reviewed and discussed in terms of the need for additional questions to be answered, and some were flagged as possible, biologically plausible risk factors based on the hazard indicated in animal or in vitro studies or other relevant data. “Biologically plausible” meant consistent positive results for mammary tumors in animal bioassays or multiple, consistent in vitro studies demonstrating that a substance can modify a pathway or processes involved in breast carcinogenesis (e.g., modification of hormonal signaling pathways, mutagenesis of oncogenes or tumor suppressor genes, inhibition of apoptosis of precancerous breast cells, etc.). In some instances, concerns about the potential later effects of exposures that may occur at specific (earlier or later) times of life are underscored. For other factors, addressing the remaining uncertainty was considered not to be a high priority, given the limited population exposures to the substance.

In addition to reviewing the extent and strength of evidence indicating an association between a particular risk factor and breast cancer (and its direction: i.e., whether it is associated with an increase or a decrease in risk), the committee also reported on additional dimensions, when information was available. For example, quantitative estimates of the size of the effect in terms of relative risk or absolute risk, and accompanying measures of uncertainty in the form of confidence limits, are presented when available. The committee also noted information relevant to consideration of whether the timing of exposure influenced risk, such as the effects or associations pertaining to in utero or early-life exposures as compared with

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

adult exposures. Similarly, the review notes whether the exposure showed a relationship to a particular tumor type based on hormone receptor status or other molecular markers.

DISCUSSION OF SPECIFIC ENVIRONMENTAL FACTORS

In the remainder of the chapter the committee presents summaries describing the strength of the evidence regarding the association of its selection of environmental factors with breast cancer. These factors are listed in Box 3-1 and grouped by their initial characteristic uses (e.g., industrial chemicals), route of exposure (e.g., ingestion of diet-related substances), or other features. Some of the substances reviewed by the committee are mixtures or classes of chemicals (e.g., tobacco smoke, polychlorinated biphenyls [PCBs]) and others are single chemicals (e.g., ethylene oxide). In either case, the committee typically focused on the literature on that specific mixture, class, or single chemical. It generally did not attempt to evaluate the evidence on interactions among risk factors but recognized that this is an important area to address in advancing knowledge in the field.

These groupings and labels are not definitive; different groupings or group labels may be used when these factors are discussed by others. Also, many additional factors that were not reviewed by the committee could be included in several of these groups; the committee’s assessments concern only the specific factors listed.

The committee frequently uses relative risks (RRs) or similar measures in reporting evidence regarding the size of the association or effect for a given risk factor. A relative risk is an estimate of comparative risk derived from a defined population exposed to the factors, compared to an unexposed group. These measures of association do not convey the absolute risk that may be experienced by any one individual or group of individuals exposed to the factors. Chapters 2 and 6 describe these measures of risk further.

Exogenous Hormones

As described in Chapter 2, the breast is a hormonally responsive organ, and the majority of breast cancer that occurs responds to hormonal therapy. Thus it is no surprise that hormonal risk factors have been a major focus of breast cancer research. Prospective cohort studies have clearly shown an association between endogenous estrogen levels and development of breast cancer (Key et al., 2002). Because many of the established risk factors, such as age at menarche and age at first birth, are related to changes in the endogenous hormonal milieu, it was plausible to anticipate that exogenous factors that influence endogenous hormone levels may have an impact on

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

BOX 3-1
Environmental Factors Included in the Committee’s Evidence Review
a

Exogenous hormones

• Hormone therapy: androgens, estrogens, combined estrogen–progestin

• Oral contraceptives

Body fatness and abdominal fat

Adult weight gain

Physical activity

Dietary factors

• Alcohol consumption

• Dietary supplements and vitamins

• Zeranol and zearalenone

Tobacco smoke

• Active smoking

• Passive smoking

Radiation

• Ionizing (including X-rays and gamma rays)

• Non-ionizing (extremely low frequency electric and magnetic fields [ELF-EMF])

Shift work

Metals

• Aluminum

• Arsenic

• Cadmium

• Iron

• Lead

• Mercury

Consumer products and constituents

• Alkylphenols

• Bisphenol A (BPA)

• Nail products

• Hair dyes

• Parabens

• Perfluorinated compounds (PFOA, PFOS)

• Phthalates

• Polybrominated diphenyl ethers (PBDEs; flame retardants)

Industrial chemicals

• Benzene

• 1,3-Butadiene

• PCBs

• Ethylene oxide

• Vinyl chloride

Pesticides

• DDT/DDE

• Dieldrin and aldrin

• Atrazine and S-chloro triazine herbicides (atrazine)

Polycyclic aromatic hydrocarbons (PAHs)

Dioxins

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aThe committee reviewed a selected set of factors for illustration; the chemicals were not chosen to be representative of any class. Some epidemiologic, or animal data relevant to mammary tumorigenesis or breast cancer are available for numerous other chemicals.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

breast cancer incidence. Although much of the focus has been on influences specifically of estrogen, prospective studies have also shown an association with androgen concentrations and the risk of breast cancer (Helzlsouer et al., 1992; Key et al., 2002; Tworoger et al., 2006). Many factors are thought to affect breast cancer by influencing endogenous hormone levels. Exogenous hormone use is an obvious factor to consider in relation to breast cancer.

Exogenous hormone use by women is fairly common. The oral contraceptive pill was the leading method of contraception in the United States in 2006–2008, used by 10.7 million women (Mosher and Jones, 2010). Use of hormone therapy (HT) for relief of menopausal symptoms has also been widespread, but it has changed as findings have emerged about health risks associated with these products (Haas et al., 2004; Hersh et al., 2004). In a 1995 telephone survey of U.S. households (Keating et al., 1999), current use of menopausal hormone therapy was reported by 37.6 percent of women participating. National Health Interview Survey data from 2008 (DeSantis et al., 2011) report rates of combination HT use for women ages 50 and older of 0.9 to 2.8 percent, depending on race and ethnicity, and of estrogen-only HT from 2.1 to 5.9 percent, depending on race and ethnicity.

Evaluating the hormonal effects of exogenous hormone sources, such as oral contraceptives and hormone therapy, is challenging because of the use of a variety of single or combined hormone preparations and a multitude of dosages and delivery schedules. Additionally, hormones have differential effects on hormonally responsive tissue such as the ovaries, endometrium, and breast. Oral contraceptives are mostly combined hormonal preparations of estrogen and progestins and have been classified by IARC (2007) as Group I carcinogens; however, the effects are not consistent across all cancer types. Oral contraceptives modestly increase the risk of breast cancer among current users, as indicated by the Nurses’ Health Study II (multivariate RR = 1.33, 95% CI, 1.03–1.73) (Hunter et al., 2010), but this risk dissipates 4 years following cessation. On the other hand, oral contraceptives are associated with a long-term reduced risk of endometrial and ovarian cancers. The overall evaluation by IARC reflects this mixed risk profile: “Combined oral estrogen–progestogen contraceptives are carcinogenic to humans (Group 1). There is also convincing evidence in humans that these agents confer a protective effect against cancer of the endometrium and ovary” (IARC, 2007, p. 175).

IARC has also classified combined estrogen and progestin postmenopausal HT as “carcinogenic to humans” (Group 1). Data from randomized controlled clinical trials (19 trials involving 41,904 women) have shown that combined long-term menopausal hormone therapy with estrogen and progestins is associated with a significantly increased risk of breast cancer (Farquhar et al., 2009). The largest controlled clinical trial of combined

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

postmenopausal HT with estrogen and progestin was the Women’s Health Initiative (WHI), a 5-year randomized trial that was stopped early due to lack of a global health benefit with hormone therapy (Writing Group for the Women’s Health Initiative Investigators, 2002). After a mean of 5 years, the RR of invasive breast cancer among the combined HT group compared with the placebo was 1.26 (95% CI, 1.02–1.56). This risk translates into an absolute excess of 8 cases of invasive breast cancer per 10,000 person-years attributed to estrogen and progestin (Writing Group for the Women’s Health Initiative Investigators, 2002). After stopping combined hormone therapy, the excess risk declined (Chlebowski et al., 2009) in a manner similar to that observed after stopping combined oral contraceptive therapy. A rapid decline in breast cancer rates has been observed in the United States and several other countries following release of the WHI trial results (DeSantis et al., 2011; NCI, 2011) concomitant with declines in prevalence of combination HT use or prescriptions.

The effects of estrogen-only postmenopausal hormone therapy on breast cancer risk are not as clear as those of combined estrogen–progestin therapy. While estrogen-only therapy has been associated with a modestly increased risk of breast cancer in prospective cohort studies (Beral et al., 2011), this observation was not supported in the large randomized controlled clinical trial of estrogen-only therapy among women who had a hysterectomy (Anderson et al., 2004; LaCroix et al., 2011). The inconsistency in the findings between the observational study and the randomized controlled trial may imply some heterogeneity across subgroups in the population. Or, it may be partially due to misclassification of women in the observational study as taking only estrogen when they may have taken combined estrogen–progestin therapy at some point in their treatment. In addition, the timing of therapy with respect to onset of menopause may influence the magnitude of risk.

In the Million Women Study, women initiating estrogen-only HT more than 5 years after menopause had little or no increase in risk of breast cancer, while those initiating therapy before or within 5 years of onset of menopause had an excess risk of breast cancer compared to never users of hormones (Beral et al., 2011). In the WHI estrogen-only trial, women taking estrogen-only hormone therapy had a decreased risk of breast cancer that was not statistically significant. The magnitude of risk, after a mean follow-up of 7 years, was an RR of 0.77 (95% CI, 0.59–1.01), which would translate to a reduction of 26–33 breast cancers per 10,000 person-years (Anderson et al., 2004). In subsequent follow-up the decreased risk of breast cancer persisted and, when considering the intervention and follow-up periods, was statistically significant (LaCroix et al., 2011). It is important to note that women in the estrogen-only arm of the WHI did not have a uterus and therefore were not at risk for endometrial cancer, which

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

has been clearly established as an increased risk with use of unopposed exogenous estrogen.

Androgenic hormones such as dehydroepiandrosterone (DHEA) are available as supplements that are claimed to enhance muscle performance or provide other health benefits, but they have not been studied in randomized clinical trials in relation to breast cancer. The evidence on the relation between higher endogenous concentrations of DHEA and its sulfated form, DHEAS, and breast cancer risk has been inconsistent in observational studies. Kaaks et al. (2005) observed increased risk of breast cancer with increasing serum measures of testosterone, androstenedione, and DHEAS in premenopausal women, and Tworoger et al. (2006) reported a positive association between endogenous DHEAS and estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) breast cancer in predominantly premenopausal women. Key et al. (2002) observed increasing breast cancer risk with endogenous levels of all sex hormones examined, including DHEAS in postmenopausal women. Another prospective study showed varying results for DHEA and DHEAS and by menopausal status (Gordon et al., 1990; Helzlsouer et al., 1992). Whether exogenous androgen supplements increase risk of breast cancer is uncertain, but based on studies of endogenous levels, this may depend on timing of supplement use with respect to menopause.

In summary, strong evidence has established that use of certain exogenous hormones affects breast cancer risk, and in particular that use of combined estrogen and progestin menopausal HT increases breast cancer risk. These hormones can have different effects on different tissues, and their effects may also differ depending on the timing of exposure. Additional discussion of the implications of risk associated with HT use appears in Chapter 6.

Body Fatness and Abdominal Fat

A relationship between body weight or body weight adjusted for height (as in the body mass index, or BMI) and breast cancer risk contingent on menopausal status has been observed for decades. Based on the 2007–2008 National Health and Nutrition Examination Survey (NHANES), the combined age-adjusted prevalence of overweight and obesity4 in U.S. adults was 68 percent (Flegal et al., 2010), and an estimated 32 percent of children

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4Body mass index (BMI) is an approximate measure of body fat based on height (in meters) and weight (in kilograms). BMI is defined as the individual’s body weight divided by the square of his or her height. BMI categories are underweight, . 18.5; normal weight, 18.5–24.9; overweight, 25–29.9; and obese, . 30. BMI has shortcomings as a proxy for body fat (Romero-Corral et al., 2008), but is widely used.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

and adolescents ages 2–19 were overweight or obese5 (Ogden et al., 2010). Among subpopulations of adult women (age 20), data from the 2007– 2008 NHANES showed that the prevalence of obesity ranged from 47 to 52 percent among non-Hispanic black women, 31 to 36 percent among non-Hispanic white women, and 38 to 47 percent among Hispanic women (Flegal et al., 2010). For women ages 60 and older, about 50 percent of non-Hispanic black women were obese compared to 31 percent of whites and 47 percent of Hispanic women (Flegal et al., 2010).

Numerous studies have evaluated the risk for breast cancer associated with greater body fatness. A systematic literature review carried out on behalf of WCRF/AICR included 43 cohort studies, 156 case–control studies, and 2 ecological studies examining a relationship between body fatness6 (as measured by BMI) and breast cancer (WCRF/AICR, 2007). Although data from these studies were inconsistent when grouped for all ages, consistent effects were observed when examined by menopausal status. A meta-analysis found that the premenopausal cohort data indicated a lower risk with greater body fatness, while the postmenopausal cohort data showed greater risk with increasingly greater body fatness. An updated meta-analysis of cohort studies, carried out as part of the continuous update, showed for premenopausal women a 7 percent decrease in risk for breast cancer per 5 kg/m2 increase in BMI, and for postmenopausal women a 13 percent increase in risk per 5 kg/m2 increase in BMI (WCRF/AICR, 2010).

In summary, the WCRF/AICR (2007) systematic review found clear and consistent evidence indicating that body fatness protects against premenopausal breast cancer, classifying it as a probable protective factor for cancer, despite limited understanding of the mechanisms involved. With an abundance of consistent epidemiologic evidence as well as an understanding of the mechanisms involved, WCRF/AICR classified the evidence on greater body fatness and increased risk of postmenopausal breast cancer as convincing for a causal association.

These findings require further clarification with regard to body weight or BMI at earlier life stages. Although body fatness is associated with a reduced breast cancer risk in premenopausal women, greater body fatness in prepubertal girls is associated with an earlier age of menarche (Kaplowitz et al., 2001; Lee et al., 2007; Biro et al., 2010), which in turn is a generally

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5In children and adolescents ages 2–19, overweight is defined as being at or above the 85th percentile of BMI for age, and obesity as at or above the 95th percentile of BMI for age, based on the 2000 Centers for Disease Control and Prevention sex-specific, BMI-for-age growth charts derived from nationally representative U.S. samples (Kuczmarski et al., 2002).

6This review used the term “body fatness” because of the finding that “the relationship between body fatness and cancer is continuous across the range of BMI” (WCRF/AICR, 2007, p. 214) rather than respecting specific cutpoints.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

recognized risk factor for breast cancer, particularly for ER+/PR+ cancers (Ma et al., 2006). But earlier menarche may have less association with risk for breast cancer among Hispanic women than among non-Hispanic white women (Hines et al., 2010). Furthermore, the associations between prepubertal obesity and early menarche may not result in an increased risk of breast cancer in adulthood. Data from the Nurses’ Health Study showed that the women with the greatest body fatness during childhood had a reduced risk of breast cancer compared with the women with the least body fatness (odds ratio [OR] = 0.67, 95% CI, 0.52–0.86) (Harris et al., 2011).7 Similarly, women exposed between ages 2 and 9 to severe caloric deprivation during the 1944–1945 Dutch famine showed indications of increased risk for breast cancer, despite delayed menarche and earlier menopause (van Noord, 2004).

Fat distributed intra-abdominally is more metabolically active than other body fat, and measures of abdominal fat predict “the risk of chronic diseases, such as metabolic disorders and cardiovascular disease, better than overall indicators of body fatness” (WCRF/AICR, 2007, p. 212). Waist circumference or waist-to-hip ratios are sometimes used as indicators of how fat is distributed. The systematic review by WCRF found eight cohort studies and three case–control studies examining waist circumference and postmenopausal breast cancer risk, and eight cohort studies and eight case– control studies looking at waist-to-hip ratio as a measure of abdominal fat. Nearly all of the studies (all of the waist circumference studies and most of the waist-to-hip ratio studies) showed increased risk of postmenopausal breast cancer with more abdominal fatness. The mechanisms of this relationship are thought to be based on increased levels of circulating estrogens and decreased insulin sensitivity in association with greater abdominal fatness independently of overall body fatness. Adipose tissue is the main site of estrogen synthesis in men and postmenopausal women (WCRF/AICR, 2007, p. 39), and increased adipose tissue can thus contribute increased circulating estrogens. Based on its systematic review of the literature, WCRF classified abdominal fatness as a probable cause of postmenopausal breast cancer.

Body fatness and abdominal fatness could influence cancer risk through several mechanisms (see additional discussion in Chapter 5). These include changes in circulating hormones such as estrogens, insulin, and insulin-like growth factors; decreases in insulin sensitivity; and increases in inflammatory responses. The mechanism through which body fatness might decrease breast cancer risk in premenopausal women is not well established, but potential clues might lie in the different tumor markers observed in pre- and

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7Body fatness in childhood was assessed using line drawings of nine figures illustrating a scale of increasing fatness (Harris et al., 2011).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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postmenopausal breast cancer. A meta-analysis of 9 cohort and 22 case– control studies assessed the association between body weight and ER and PR status (Suzuki et al., 2009). No associations were observed for estrogen receptor–negative/progesterone receptor–negative (ER–/PR–) or ER+/PR– tumors.8 The risk for ER+/PR+ tumors was 20 percent lower among premenopausal women and 82 percent higher among postmenopausal women in comparisons between the highest category of body weight and the reference group. The authors concluded that “the relation between body weight and breast cancer risk is critically dependent on the tumor’s ER/PR status and the woman’s menopausal status” (Suzuki et al., 2009, p. 698). A case series reported by Stark et al. (2009) found that excess body weight significantly decreased the diagnostic risk of triple-negative (ER–/PR–, HER2–) and ER–/PR–, HER+ disease relative to ER+ and/or PR+/HER2– subtypes. This association was not observed in African American participants.

An analysis of pooled tumor marker and epidemiologic risk factor data from 34 studies of the Breast Cancer Consortium (Yang et al., 2011) found increased BMI not to be associated with the risk of core basal phenotype (ER–/PR–/HER2–/[CK5 or CK5/6]+ or EGFR+). The analysis found obesity in women younger than age 50 to be a more frequent finding in ER–/PR– than in ER+/PR+ tumors, and obesity in women over age 50 was less frequent in PR– than in PR+ findings. These results support the hypothesis that different subtypes of breast cancer may have different etiologies.

Data are inconsistent on whether these associations, derived mostly from white populations, are also seen in African American populations. Palmer et al. (2007) found a reduced risk of breast cancer in African American women with BMIs of 25 or more at age 18 relative to those with BMIs of less than 20 for both pre- and postmenopausal breast cancer, and a lack of association of obesity with receptor-negative tumors. A recent case–control study using data from the Women’s Contraceptive and Reproductive Experiences Study found a high recent BMI to be associated with an increased risk of ER+/PR+ tumors among postmenopausal African American women (Berstad et al., 2010). BMI did not have a statistically significant association with breast cancer risk among postmenopausal African American women with ER–/PR– tumors in this study. However, Trivers et al. (2009) found a positive association between obesity and triple-negative disease (ER–/PR–/HER2–). ER–/PR– tumors were associated with black race, young age at first birth, having a recent birth, and being overweight.

In conclusion, data are still needed to shed light on the differences in the apparent effects of body fatness with regard to pre- and postmenopausal breast cancer, but it is likely that these differences can be explained by the differences in the likelihood of different tumor types at different life stages,

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8Tumor markers such as ER, PR, and HER2 are described in Chapter 2.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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and that obesity is primarily a risk factor for ER+/PR+ breast cancers. An additional focus on tumor types and ethnicities in ongoing research on body fatness as a risk factor for breast cancer may better refine understanding of these associations and help target preventive action. Many other aspects also remain to be understood. The conundrum remains how to reconcile the decreased risk associated with greater body fatness in premenopausal women and the increased risk for breast cancer associated with earlier menarche, which itself appears to be associated with greater body fatness in young girls.

Adult Weight Gain

WCRF included 7 cohort studies and 17 case–control studies of adult weight gain and postmenopausal breast cancer in their review. They classified adult weight gain as a probable cause of postmenopausal breast cancer (WCRF/AICR, 2007). Evidence added via the continuous update (WCRF/AICR, 2010) also provided plentiful, consistent epidemiologic evidence for this relationship, with a dose–response relationship apparent. Again, this relationship may be different for nonwhite populations. Palmer et al. (2007) did not find an association between adult weight gain and postmenopausal breast cancer risk in data from the Black Women’s Health study.

Preventing weight gain may be particularly important because it is not yet clear whether overweight and obese women can reduce their risk of postmenopausal breast cancer by losing weight. The Iowa Women’s Health Study (Harvie et al., 2005) and the Nurses’ Health Study (NHS) (Eliassen et al., 2006) observed reduced risk for women who lost weight compared with those who maintained a stable weight. However, other studies (Ahn et al., 2007; Teras et al., 2011) did not find reduced risk among women who lost weight. Additional research is needed to help focus prevention strategies.

Physical Activity

Physical activity has been defined as “bodily movement that is produced by the contraction of skeletal muscle that substantially increases energy expenditure” (HHS, 1996; IARC, 2002b, p. 6). It can be performed in various ways—as a part of one’s occupational duties; as a component of housework; through gardening, sports, or other recreational activities; or transport, such as the commute to and from a destination (IARC, 2002b; WCRF/AICR, 2007). Because of the wide range of types of physical activities, it is difficult to measure exposure consistently. Approaches include calorimetry, physiological markers, monitors (e.g., pedometers or heart rate monitors), behavioral observation, or surveys involving subject recall

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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(IARC, 2002b). Other challenges in studies of physical activity include differences in study design, confounding due to other variables that may influence engagement in physical activity, and a tendency for exaggerated recall of vigorous recreational activity compared to other total daily activity.

Despite these difficulties, the relationship between physical activity and breast cancer has been extensively studied. Systematic reviews have been carried out by IARC (2002b) and WCRF/AICR (2007, 2010). Of the 33 separate studies reviewed by IARC, 22 (8 of 14 cohort studies, 14 of 19 case–control studies) found reduced risk for the most physically active participants compared with the least active. The average observed relative decrease in risk was about 20 to 40 percent between the most active and the most sedentary, with some studies observing up to 70 percent risk reductions. Most of the studies that examined a dose–response relationship found evidence of a linear trend whereby risk of breast cancer decreased with increasing duration of activity, regardless of type of activity (recreational or occupational), menopausal status, time period in life, or level of intensity of activity.

In its more recent review, WCRF/AICR (2007) considered pre- and postmenopausal breast cancer separately. From its review of studies of physical activity (studies of total physical activity as well as occupational and recreational activity) in premenopausal women, the panel found ample evidence to review, but inconsistent results. For premenopausal breast cancer, WCRF/AICR found limited evidence supporting protection from physical activity. For postmenopausal breast cancer, the review found stronger evidence of a protective effect, noting

ample evidence from prospective studies showing lower risk of postmenopausal breast cancer with higher levels of physical activity, with a dose response relationship, although there was some heterogeneity. There was little evidence on frequency, duration, or intensity of activity. There is robust evidence for mechanisms operating in humans. (WCRF/AICR, 2007, p. 205)

They concluded that physical activity is a probable preventative factor against postmenopausal breast cancer.

Because of the abundance of human studies addressing physical activity and breast cancer incidence, systematic reviews have not relied heavily on experimental animal models to address a reduction of carcinogenicity after physical activity. However, many mechanisms have been proposed for physical activity’s protective effect against breast cancer and other cancers as well. Physical activity is closely tied to body fatness and weight gain, and it has a beneficial effect on an individual’s fat distribution. Physical activity is also thought to affect endogenous steroid hormone metabolism, reduce

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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circulating estrogen and androgen levels, and strengthen the immune system (WCRF/AICR, 2007).

Although the level of risk reduction for breast cancer that is achieved by performing physical activity varies widely among studies, the body of research on cancer as well as the broader literature on health, particularly on cardiovascular outcomes, suggests that being active can be of great benefit to pre- and postmenopausal women (IARC, 2002b; Thompson and Lim, 2003; Warburton et al., 2006; WCRF/AICR, 2007).

Dietary Factors

Alcohol Consumption

Consumption of alcoholic beverages is widespread in the United States. In the 2008 National Health Interview Survey, 58 percent of women over 18 identified themselves as current drinkers,9 and 15 percent as former drinkers (NIAAA, 2009). As stated by IARC (2010a), household income, education, and employment status are associated with current drinking status and more frequent drinking, but these factors have an inverse relationship with heavier drinking measures such as weekly heavy drinking (Midanik and Clark, 1994; Greenfield et al., 2000).

The association of alcohol consumption with breast cancer risk has been well studied. More than 100 epidemiologic studies have been conducted in all regions of the world, using both cohort and case–control epidemiologic designs. Recent systematic reviews of the scientific evidence have found a consistent association between greater self-reported consumption of alcohol and an increased risk for breast cancer (WCRF/AICR, 2007, 2008, 2010; IARC, 2010a). IARC (2010a) classified alcohol consumption as “carcinogenic to humans” (Group 1), based on evidence regarding cancer at several sites including the female breast, and WCRF/AICR classified the evidence that consumption of alcoholic drinks increases breast cancer risk for both pre- and postmenopausal women as “convincing” (WCRF/AICR, 2007, p. 157, 2008, 2010). Alcoholic beverages of all types (e.g., beer, liquor, wine) confer similar levels of risk after accounting for their differences in ethanol content.

The Collaborative Group on Hormonal Factors in Breast Cancer (2002) carried out a pooled analysis of 53 studies that included a total of 58,515 women with breast cancer. It found a linear increase in risk with increasing

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941.7 percent of women reported as abstaining from drinking, 45.1 percent reported as light drinkers (on average, three or fewer drinks per week in the past year), 8.3 percent as moderate drinkers (on average, more than three but no more than seven drinks per week), and 5 percent as heavier drinkers (on average, more than one drink per day in the past year) (NIAAA, 2009).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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consumption of alcoholic beverages. Results suggested an RR of about 1.5 (95% CI, 1.3–1.6) associated with consuming 45 g or more alcohol per day (one U.S. drink includes approximately 14 g of ethanol [CDC, 2011a], so 45 g is more than three typical drinks). Even self-reported alcohol intake of about 18 g per day is associated with some increase in risk (RR = 1.13, 95% CI, 1.07–1.20), with increasing risk of 7 percent corresponding to each increase of 10 g per day (Collaborative Group on Hormonal Factors in Breast Cancer, 2002; cited by IARC, 2010a). These results were consistent with an earlier meta-analysis of data from 38 epidemiologic studies that reported an 11 percent increase in risk of breast cancer for daily consumption of 13 g compared to nondrinkers (Longnecker, 1994). Most recently, the WCRF review (2007, p. 168) also found “ample, generally consistent evidence from case–control and cohort studies” and noted that a dose– response relationship is apparent, with no threshold identified. According to IARC (2010a, p. 1277), “the effects of duration or cessation of consumption of alcoholic beverages on the risk for breast cancer are uncertain.”

Studies measuring levels of alcohol consumption, like all observational epidemiologic studies, rely on subject recall and reporting. Because self-reports of current or past consumption of alcohol are generally believed to underestimate consumption, the relationships observed in multiple studies are noteworthy for the consistency of the positive association. Self-reported alcohol consumption has been evaluated against reports from the remote past and been found to be “reasonably reliable” for ranking subjects consistently by repeated measures (Longnecker et al., 1992). Such reliability, however, does not preclude differential reporting by cases versus controls. The main evidence against recall bias is the positive relationship of self-reported alcohol consumption with breast cancer in many large cohort studies where recall bias would not be a factor. These cohort studies go as far back as 1984 (Hiatt and Bawol, 1984) and have been confirmed repeatedly since then. For instance, a pooled analysis of six cohort studies with 322,647 women and 4,335 incident invasive breast cancers found that consumption of each additional 10 g of alcohol was associated with a 9 percent relative increase in risk (95% CI, 1.04–1.13) (Smith-Warner et al., 1998). Thus, the findings are probably not due to differential misclassification. If instead there is a tendency among all participants to underreport high levels of alcohol consumption, estimates of risk at lower levels of alcohol consumption may be overstated, and a threshold would be difficult to detect or identify. Estimates of risk at higher levels, which represent a relatively small proportion of women, may also be overestimated by underreporting of dose, but are more likely to represent increased breast cancer risks for this group.

The effects of alcohol consumption at various times in life have been examined by multiple case–control and cohort studies. Several earlier case– control studies suggested that risk might be elevated for women who were

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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first exposed to alcohol as young adults ages 18–35 (Harvey et al., 1987; van’t Veer et al., 1989; Young, 1989), but these were generally small studies and did not distinguish between early first exposure and exposure only at earlier ages. Other earlier studies (Hiatt et al., 1988; La Vecchia et al., 1989; Nasca et al., 1990) did not support higher risk associated with earlier exposures.

More recent studies (four cohort and four case–control studies), all of substantial size and conducted in a variety of populations worldwide (Freudenheim et al., 1995; Holmberg et al., 1995; Garland et al., 1999; Lenz et al., 2002; Horn-Ross et al., 2004; Tjonneland et al., 2004; Lin et al., 2005; Terry et al., 2006b), have examined exposure to alcohol at various times along the life course. All except one, in a population in Western New York with low overall alcohol consumption (Freudenheim et al., 1995), confirmed the modest relationship between alcohol consumption and increased risk of postmenopausal breast cancer (an RR of about 1.3, or a 30 percent increase with 1–2 drinks per day). Likewise, all except one found no evidence that alcohol consumption early in life was associated with an increased risk (Holmberg et al., 1995; Lenz et al., 2002; Horn-Ross et al., 2004; Tjonneland et al., 2004; Lin et al., 2005; Terry et al., 2006b). The exception was the NHS, which found that women who reported higher levels of alcohol consumption when they were ages 23–30 had a nonsignificant positive association with premenopausal breast cancer risk (Garland et al., 1999). In the other recent studies, it appears, if anything, that current alcohol consumption at older ages is more highly associated with breast cancer than consumption at younger ages (Holmberg et al., 1995; Horn-Ross et al., 2004; Tjonneland et al., 2004).

However, all of these were studies of adult women, and they relied on self-reported recall of alcohol consumption in adolescence and young adulthood. In contrast, a prospective study of the daughters of nurses who were asked to report their alcohol consumption confidentially at ages 16–23 years found an increased risk of benign breast disease (BBD) in surveys conducted 2 and 4 years later (OR = 1.5 per drink/day, 95% CI, 1.19–1.90) (Berkey et al., 2010). These results suggest that alcohol consumption early in life may increase breast cancer incidence in adulthood, given that BBD is an established risk factor for breast cancer.

As reported by IARC (2010a), risk related to alcohol consumption does not vary substantially by menopausal status, childbearing patterns, use of hormones, or family history of breast cancer. While this appears to be true for the evidence from most case–control studies, suggestive evidence from at least three large cohort studies indicates there may be a significant interaction between alcohol consumption and use of HT (Gapstur et al., 1992; Chen et al., 2002; Horn-Ross et al., 2004). Among 41,873 postmenopausal women in the Iowa Women’s Health Study, there was an 80 to 90 percent

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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higher risk of breast cancer for moderate (5–14.9 g/day) alcohol consumption (RR = 1.88, 95% CI, 1.3–2.72) and heavy (15 g/day or more) alcohol consumption (RR = 1.83, 95% CI, 1.18–2.85), but no association for alcohol consumption and breast cancer among women who never used estrogen (Gapstur et al., 1992). Similarly, in a follow-up of 44,187 postmenopausal women in the NHS, alcohol consumption was significantly associated with breast cancer risk in women taking postmenopausal hormones, but not in women who previously or never used HT (Chen et al., 2002). In the California Teachers Study (CTS), women whose alcohol consumption was an average of 20 g/day or more and who used estrogen plus progestin HT had more than twice the risk of developing breast cancer (RR = 2.24, 95% CI, 1.59–3.14), while never users of HT had no elevated breast cancer risk associated with alcohol consumption (RR = 0.94, 95% CI, 0.54–1.65) (Horn-Ross et al., 2004).

WCRF/AICR (2008, p. 83) reported findings from the Swedish Mammography Cohort that alcohol intake was associated with increased risk for ER+/PR+ tumors, but not for ER–/PR– or ER+/PR– tumors (Suzuki et al., 2005). The Iowa Women’s Health Study found alcohol intake to be most strongly associated with ER–/PR– tumors (Gapstur et al., 1995). A dose–response meta-analysis by Suzuki et al. (2008) indicated a statistically significant increased risk for all ER+, all ER–, ER+/PR+, and ER+/PR– tumors, but not for ER–/PR– tumors. This analysis indicated a 27 percent higher risk (95% CI, 1.17–1.38) of developing ER+ tumors and 14 percent higher risk (95% CI, 1.03–1.26) of developing ER– tumors in the highest versus lowest alcohol consumption group (Suzuki et al., 2008, as summarized by AHRQ, 2010). Barnes et al. (2010) noted an inverse relationship between alcohol consumption and ER–/PR– tumors.

Studies in laboratory animals provide additional evidence of the effect of alcohol exposure on mammary tumor formation. The Agency for Healthcare Research and Quality, or AHRQ (2010), reviewed nine experimental animal studies evaluating mammary tumorigenesis caused or enhanced by alcohol. Of these studies, six (four of which administered a cocarcinogen) reported increased tumorigenesis, and three studies (one of which administered a cocarcinogen) did not support a link between ethanol and increased mammary cancer risk.

Alcohol may increase breast cancer incidence through numerous possible mechanisms. Studies in humans indicate that alcohol may affect breast cancer risk through formation of genotoxic metabolites (particularly acetaldehyde), as well as by inducing changes in levels of hormones such as estrogens, prolactin, or dehydroepiandrosterone (Seitz and Maurer, 2007; AHRQ, 2010). Mechanistic studies in animals have investigated the effects of alcohol on alteration in levels of hormones or hormone receptors, biotransformation and accumulation of genotoxic metabolites such

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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as acetaldehyde, DNA adduct formation, suppression of cellular immunity, increase in terminal-end bud density and decrease in alveolar bud structures, enhanced tumor progression, and effect on DNA synthesis (AHRQ, 2010). In vitro studies reviewed by AHRQ (2010) further suggested increased cyclic adenosine monophosphate, change in potassium channels, and modulation of gene expression. In summary, alcohol may contribute to breast cancer risk through multiple mechanisms, although the relative importance of these mechanisms is unclear (AHRQ, 2010).

Regarding timing of exposure, Hilakivi-Clarke et al. (2004, reviewed by AHRQ, 2010) reported that in utero exposure to alcohol resulted in increases in mammary tumor incidence and multiplicity when animals were later exposed to the laboratory carcinogen 7,12-dimethylbenz[ a](DMBA). In a study by Polanco et al. (2010), 6.7 percent alcohol in diet was administered to pregnant rats on days 11–21 of gestation, and offspring received an intraperitoneal injection of N-nitroso-N-methylurea (MNU) at day 50. Compared with controls that did not receive alcohol exposure in utero, the alcohol-exposed offspring had greater numbers of tumors, decreased latency, more malignant tumors, more ER-alpha negative tumors (50 percent compared to approximately 15 percent in controls), and increased estradiol levels.

Some evidence shows gene–environment interactions in the risk for breast cancer from alcohol consumption. Polymorphisms in genes that control key enzymes involved in metabolism of alcohol (alcohol dehydrogenase [ADH], aldehyde dehydrogenase [ALDH], cytochrome P-450 [CYP2E1], xanthine oxidoreductase [XOR]) may result in increased levels of reactive intermediates and thereby result in altered risk for breast cancer in certain populations (AHRQ, 2010). ADH and CYP2E1 catalyze the conversion of alcohol to aldehyde, whereas ALDH and XOR catalyze the conversion of acetaldehyde to acetate, which is further metabolized (AHRQ, 2010). Polymorphisms that result in the forms of these enzymes that increase the rate of conversion of alcohol to acetaldehyde or decrease the metabolism of aldehyde result in higher levels of acetaldehyde, a cytotoxic and genotoxic metabolite that has been implicated in oral, colon, breast, and other cancers from alcohol exposure (AHRQ, 2010).

One variant of the ALDH2 gene that results in a nearly inactive form of ALDH is found only in Asian populations (Seitz and Stickel, 2010). Approximately 10 percent of the Japanese population are reported to be homozygous for the inactive form of ALDH, and about 40 percent of Asians are reported to be heterozygous, resulting in greatly reduced (10 percent of normal) ALDH activity (Seitz and Stickel, 2010). However, both Caucasian and Asian populations have a polymorphism in ADH that results in variants with faster conversion of alcohol to acetaldehyde (Seitz and Stickel, 2010). The enzyme encoded by the ADH1C*1 allele not only

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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catalyzes a higher rate of alcohol conversion to acetaldehyde, but also affects the metabolism of estrogen and other steroid hormones (Seitz and Maurer, 2007).

Several studies have reported increased risk for women with more active variants of ADH, primarily in women who consumed high amounts of alcohol. Seitz and Stickel (2010) report that high alcohol intake (60 g/day) and the ADH1C*1 allele in Caucasians (n = 400) were associated with increased risk of breast cancer as well as cancer of the digestive tract, liver, and colon, although the studies cited do not mention breast cancer. In other studies, increased cancer risks were reported primarily for moderate to heavy drinkers, for those who are homozygous for this allele, and for premenopausal women. Terry et al. (2006a) reported increased breast cancer risk in premenopausal women with a lifetime alcohol intake rate of 15–30 g/day who were homozygous for the more active ADH1C*1 allele (ADH1C*1,1) compared to nondrinkers with intermediate or slow ADH1C genotypes (OR = 2.9, 95% CI, 1.2–7.1). At the same alcohol intake rate, risks were not significantly elevated for postmenopausal women with the ADH1C*1,1 genotype or for women who were intermediate (ADH1C*1,2) or slow metabolizers (ADH1C*2,2). Similarly, Freudenheim et al. (1999) reported the highest increase in breast cancer risk (OR = 3.6, 95% CI, 1.5–8.8) for premenopausal women with the ADH1C*1,1 genotype who consumed more than the median number of drinks per month (>6.5/month averaged over the past 20 years) compared to those who consumed less alcohol and did not have this genotype. Coutelle et al. (2004) did not specifically examine pre- versus postmenopausal women, but reported that frequency of the ADH1C*1 allele was greater in breast cancer cases than in controls who were heavy drinkers but who did not have cancer (62% compared to 41.9%). This study also reported that women with the ADH1C*1,1 genotype had a greater risk of breast cancer than those with ADH1C*1,2 or ADH1C*2,2 genotypes (OR = 1.8, 95% CI, 1.4 –2.3). In addition, women with the ADH1C*1,1 genotype who consumed more than 20 g/day of alcohol had a greater risk of breast cancer than those with this genotype who consumed <20 g/day (OR = 1.4, 95% CI, 1.0–3.35).

Studies that have not found increased risks for more active ADH variants appear to be those involving lower alcohol intake, small sample size, or postmenopausal women. Benzon Larsen et al. (2010) reported that among 809 postmenopausal breast cancer cases and 809 controls within the prospective Diet, Cancer, and Health Study, women with ADH polymorphisms with faster conversion of alcohol to aldehyde did not have higher breast cancer risks; in fact, variants for slow metabolizers were associated with slightly higher risks (14% per 10 g of alcohol intake/day). A study as a part of the NHS (Hines et al., 2000) did not find an effect of alcohol on breast cancer risk or interaction with ADH1C polymorphism for pre- or

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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postmenopausal women. However, this study had relatively small sample sizes, particularly for premenopausal women (88 cases versus 94 controls), for an analysis that considered alcohol intake (none, 10 g/day, >10 g/day) and ADH polymorphism groups (slow, fast, intermediate). Visvanathan et al. (2007) likewise stated that the lack of increase in breast cancer risk for more active variants of ADH may be attributed to low alcohol consumption in their study population (median of 13 g/wk).

Polymorphisms in ADH are also thought to affect breast cancer risk through the involvement of ADH in metabolism of estrogens as well as by acetaldehyde formation (Seitz and Maurer, 2007). The effect of ADH on estrogen and acetaldehyde production may be combined as indicated by evidence of particularly high blood acetaldehyde levels for women consuming alcohol during the period of the menstrual cycle when estradiol levels peaked (Seitz and Maurer, 2007).

By contrast, Kawase et al. (2009) did not find an increased risk of breast cancer in Japanese women (456 breast cancer cases versus 912 age- and menopausal status-matched controls) for alcohol drinking and polymorphisms in ADHI1B or ALDH2. Kawase et al. hypothesized that Japanese women may not drink enough alcohol or other factors may cause different outcomes among populations. Studies in Japanese populations have, however, found that the inactive form of ALDH2 is associated with increased risks of other cancers such as oropharyngolaryngeal and esophageal cancers. Evidence reviewed by AHRQ (2010) indicates that breast tissue contains ADH, CYP2E1, and XOR rather than ALDH2 for metabolism of acetaldehyde, indicating that acetaldehyde is metabolized in breast tissue by XOR rather than enzymes associated with ALDH2.

Other gene–environmental interactions for alcohol and breast cancer have been reported. High alcohol intake and a homozygous variant of enzymes related to the one-carbon metabolism enzyme methylenetetrahydrofolate reductase have been associated with increased risk in postmenopausal but not premenopausal women (Platek et al., 2009). A study has also found an association with increased risk of breast cancer for women with a specific polymorphism in the mitochondria genome and who consumed alcohol compared with those who did not drink (Pezzotti et al., 2009).

A further issue pertains to confounding from other ingredients and contaminants in alcoholic beverages, which may have associations with cancer risk (Seitz and Simanowski, 1988; HHS, 2000; Baan et al., 2007; Monteiro et al., 2008).

In conclusion, evidence from human, animal, and in vitro studies supports a modest but causal relationship between alcohol consumption and breast cancer for both premenopausal and postmenopausal women. The reduction of alcohol consumption is an action women can take to reduce their breast cancer risk, even though the overall risk is rather small for

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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lighter drinkers. Also entering into the choices women must make is the well-documented protective effect of low-level alcohol consumption (<3 drinks/day) on coronary artery disease, a more common cause of death in postmenopausal women (Klatsky, 2010). There is no clear threshold for the onset of increased risk of breast cancer. The choice of whether to consume alcohol, or how much, must remain an individual one.

Vitamins and Dietary Supplements

In the Dietary Supplement Health and Education Act of 1994, Congress defined dietary supplements as products, other than tobacco, that (1) supplement the diet; (2) contain one or more dietary ingredients “(including vitamins; minerals; herbs or other botanicals; amino acids; and other substances) or their constituents”; (3) are intended to be taken orally in pill, capsule, or liquid form; and (4) are clearly labeled as dietary supplements on the front panel of their packaging (NIH, 2011). Dietary supplements can come in many forms—as combinations of ingredients such as botanicals or herbs, as multivitamin supplements, or as supplements containing individual vitamins or ingredients. The committee focused primarily on studies of multivitamin and single-substance supplements. However, terms such as “multivitamin” have “no standard scientific, regulatory or marketplace definitions” (Yetley, 2007, p. 269S). Formulations of combination vitamin and mineral supplements therefore vary in content, which presents challenges in conducting and comparing studies.

Unlike many factors, the evidence on dietary supplements includes results from experimental studies in humans. In large-scale, randomized, double-blind, placebo-controlled trials, neither antioxidant supplementation (Hercberg et al., 2004) nor supplements of folic acid plus vitamins B6 and B12 (Zhang et al., 2008) showed an association with differences in risk for breast cancer.10 However, mandatory folate fortification in the United States since 1998 (NIH, 2011) may have made it difficult to detect an effect associated with the additional supplementation in the study. Large-scale observational studies of multivitamin use have been inconsistent. The Swedish Mammography Cohort with 974 incident cases of breast cancer among 35,329 women, ages 49–83 over a mean 9.5-year follow-up, found an RR of 1.19 (95% CI, 1.04–1.37) among those reporting use of multivitamins (Larsson et al., 2010). Women reporting “ever” use of multivitamins in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial (Stolzenberg-Solomon

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10Hercberg et al. (2004) followed 7,876 women ages 35–60 from the general population for a median of 7.5 years for cancer incidence and mortality, and Zhang et al. (2008) followed 5,442 women ages 42 and older with preexisting cardiovascular disease or three or more coronary risk factors for 7.3 years for cancer incidence.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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et al., 2006) had an RR for postmenopausal breast cancer of 1.18 (95% CI, 0.95–1.48); this study reported a statistically significant increase in breast cancer risk with folate supplementation (RR = 1.19, 95% CI, 1.01–1.41). Other studies, mostly in premenopausal women, found no statistically significant association of multivitamin use with breast cancer risk (Feigelson et al., 2003; Ishitani et al., 2008; Maruti et al., 2009; Neuhouser et al., 2009). Studies of use of individual supplements, such as vitamins C, D, E, and A, have also shown conflicting results or no differences in risk with supplement intake (Verhoeven et al., 1997; Nissen et al., 2003; Stolzenberg-Solomon et al., 2006; Robien et al., 2007). In its systematic review, the WCRF/AICR included vitamins A, B6, B12, C, D, and E and riboflavin, folate, calcium, iron, selenium, carotenoids, and isoflavones in its evidence category of “limited–no conclusion” for both premenopausal and postmenopausal breast cancer (WCRF/AICR, 2007).

Nondietary phytoestrogen-containing supplements are widely used by women for the treatment of menopausal symptoms. A meta-analysis of 92 randomized controlled trials that studied women undergoing treatment of menopausal symptoms with phytoestrogen-containing supplements showed no statistically significant increase in breast cancer risk in any of the individual studies or in the meta-analysis of all 92 studies (Tempfer et al., 2009). However, the median duration of the studies included in the meta-analysis was only 6.2 months and breast cancer was not a primary endpoint, so even substantial effects of long-term use of phytoestrogen supplements cannot be ruled out. Although there was no statistically significant risk for breast cancer with increasing duration of supplement use, the duration of use in most studies was far too short to make a confident statement about risk. In addition, the exact composition of the phytoestrogens studied varied among supplements and was poorly characterized.

Multiple factors make dietary supplementation a challenging focus of study. In general, multivitamin and mineral supplements are used by women who practice healthier lifestyles and are therefore more likely to have regular breast cancer screening. This clustering of characteristics makes observational studies of the relationship between use of these supplements and health outcomes difficult to interpret. Healthier lifestyles might result in downward bias (fewer cancers, decreased likelihood of observing an association), while regular screening might result in upward bias (more cancers diagnosed). Furthermore, dietary supplement use was often assessed through self-administered questionnaires, which can introduce errors resulting from poor recall. In addition, not all studies collected specific information about brand names and product names of the supplements. The specific ingredients and the amount of each ingredient in a supplement vary widely, and if researchers combine a wide range of types of supplements, the analysis may not be meaningful. These and other limitations pose seri-

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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ous challenges for the conduct of studies on the effects of multivitamins, or their initiation and duration of use at various life stages.

In vitro studies aimed at evaluating the relationship between dietary supplement products or ingredients and breast cancer risk are nearly all carried out using established breast cancer cell lines or in cellular assay systems with immortalized cells treated with chemical carcinogens or ionizing radiation, in addition to the vitamin or supplement of interest. The relevance of these studies to human carcinogenesis is difficult to interpret.

Because of the widespread use of dietary supplements, and the variety of substances involved, it is important that continued attention be paid to the potential risks or benefits they may pose for breast cancer. However, as noted above, refined research approaches will be needed because of the multiplicity of challenges to this type of research.

Zeranol and Zearalenone

Zearalenone is a mycotoxin product from fungi of the genus Fusarium. It is a common contaminant of grains and thus is present in the diet, albeit at low levels. A synthetic form of a reduction product of zearalenone, called zeranol (Ralgro), is one of six growth promoters approved by the Food and Drug Administration (FDA) and is widely used in feedlot beef production in the United States and many other countries. Both zeranol and are relatively potent nonsteroidal estrogens (Peters, 1972), with the estrogenic activity of zeranol substantially greater than that of zearalenone (Mirocha et al., 1979; Shier et al., 2001).

The primary route of exposure is oral, via diet. Zearalenone does not degrade during the cooking and processing of foods (European Commission, 2000). Low-level exposure from contamination of cereal grains occurs, and mean daily U.S. exposures have been estimated as 0.03 μg/kg/day (Zinedine et al., 2007). Outbreaks of Fusarium contamination of corn and other commodities can occasionally lead to very high levels in foods (Zinedine et al., 2007). In the United States, the largest potential source of exposure is likely to be through residues of zeranol in meat from sheep and cattle implanted with Ralgro pellets, a process that is monitored by the FDA. Although use of zeranol is permitted in the United States, the European Union prohibits the use of hormones or the import of hormone-treated beef products from the United States or Canada where zeranol is used as a growth promoter (European Commission, 2007).

No epidemiologic studies are known to have addressed whether exposures to zearalenone or zeranol could contribute to breast cancer (or any cancer) risk.

Studies in animals include a 2-year bioassay of zearalenone by the NTP (1982b). The final evaluation concluded that zearalenone was carcinogenic

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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in a specific strain of mice, but not in the rat strain tested. There was no report of increased mammary tumors in either rats or mice, although in mice “estrogen-related, dose-dependent effects were seen in several tissues (fibrosis in the uterus, cystic ducts in mammary glands)” (European Commission, 2000, p. 5). The European Commission (2000) concluded the tumors observed in the NTP bioassay (liver and pituitary) were related to the estrogenic effects of the compound. The IARC (1993) evaluation of zearalenone drew on the NTP bioassay data and concluded that “there is limited evidence in experimental animals for the carcinogenicity of zearalenone,” with an overall characterization as “not classifiable as to its carcinogenicity to humans” (Group 3).

Sheep and pigs appear to be more sensitive than rodents to the estrogenic effects of zearalenone (European Commission, 2000). Large differences among species in sensitivity to the estrogenicity of zearalenone are thought to result from differences in metabolic capacity and presence of various estrogenic metabolites of zearalenone (Ueno et al., 1983; Pompa et al., 1988; Malekinejad et al., 2006). How human sensitivity compares with the pig, sheep, or rodent requires further study.

Mechanistic research shows that zeranol binds to the ligand-binding domain of human estrogen receptor alpha and beta in a manner similar to estradiol-17β (E2) (Takemura et al., 2007). Zeranol has also been demonstrated to stimulate the growth of human MCF-7 breast cancer cell lines in vitro (Makela et al., 1994; Zava et al., 1997), and to enlarge existing mammary tumors in mice (Schoental, 1974), reflecting its estrogen receptor-agonist properties.

Because zearalenone and zeranol are rather potent (nonsteroidal) xenoestrogens, timing of exposure may be important. A few recent studies have explored early-life exposures to low levels of zearalenone and biological effects. For example, fetal and neonatal exposure of rats to levels near those of human exposure (0.2 μg/kg in utero and first 5 days of life) was observed to affect terminal end bud length (Belli et al., 2010), and uterine hyperplasia was induced in young pigs fed relatively low levels (20 μg/kg) of zearalenone for 48 days (Gajecka et al., 2011). While these and other recent studies are intriguing, they are too few to reach any firm conclusions regarding the potential impact of low-level exposure to these compounds early in life on breast cancer risk in humans, or at other specific life stages. Interestingly, prepubertal exposure of rats to a low dose (20 μg, or about 1 mg/kg) of zearalenone was shown to significantly reduce the incidence of mammary adenocarcinomas induced by treatment with MNU or DMBA, possibly by increasing differentiation of the mammary epithelial tree (Hilakivi-Clarke et al., 1999; Nikaido et al., 2003).

Due to a paucity of epidemiologic studies and of animal bioassays and mechanistic studies that address mammary tumor endpoints and explore

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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the impact of timing of exposure, at this point, although it is biologically plausible, no conclusion can be reached on the role of zearalenone or zeranol in the etiology of breast cancer. It remains an area for further study.

Tobacco Smoke

That tobacco smoke may be implicated as a possible risk factor in breast cancer etiology is not surprising; smoking has wide-ranging impacts on general health and is established as a carcinogen and causal agent in many forms of cancer (IARC, 2004). Tobacco smoke is a complex mixture that includes many toxic substances, more than 50 of which are known, probable, or possible human carcinogens (e.g., polonium-210, benzene, several metals, and vinyl chloride) (IARC, 2004; NTP, 2011a). Exposure to tobacco smoke occurs through active smoking, with smoke directly inhaled by the smoker, and through what is termed passive smoking or secondhand smoke exposures.11 Many of the same compounds are present in both directly inhaled and secondhand smoke, but their amounts and proportions differ (IARC, 2004), which results in differing toxicities.

Before 1993, more than 50 epidemiologic studies examined the relationship between breast cancer and exposure to tobacco smoke. Although the quality of studies was highly variable, the better conducted studies did not suggest a causal relationship (Palmer and Rosenberg, 1993). An IARC review published in 2004 included studies conducted before 2002, and it relied heavily on a pooled analysis of 53 case–control and cohort studies by the Collaborative Group on Hormonal Factors in Breast Cancer Study (2002) that contended that apparent associations with smoking were confounded by alcohol consumption. The IARC (2004) conclusions were that neither active nor passive smoking was associated with increased risk of breast cancer.

Since 2004, two scientific consensus reviews concluded, based on high-quality studies, that the available evidence supports causal associations between breast cancer and active smoking or premenopausal breast cancer and exposure to secondhand smoke, or both (CalEPA, 2005; Collishaw et al., 2009). A 2006 U.S. Surgeon General’s report concluded that the evidence on passive smoking was suggestive but not conclusive for a causal relationship with increased risk of breast cancer (HHS, 2006). The most recent IARC review characterized the evidence on active smoking as limited and the evidence on passive smoking as inconclusive (Secretan et al., 2009).



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11Throughout the report the phrases “passive smoking” and “secondhand smoke” are used interchangeably to refer to exposure to smoke emitted by the burning end of a cigarette, cigar, or pipe or smoke exhaled by a smoker.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Active Smoking

The epidemiologic literature on active smoking is often characterized as mixed, with some studies finding statistically significant associations between smoking and breast cancer while others do not. Many earlier studies were limited by the use of crude measures of exposure, small sample sizes, and lack of control for key covariates. Moreover, some of these studies of risks to smokers included women with passive smoke exposure in their “unexposed” referent groups, potentially reducing statistical power to distinguish the impact of active smoking. Over time, assessments of exposure to tobacco smoke have been refined in many studies.

Age at smoking initiation may play an important role in the tobacco smoke–breast cancer association, and tobacco smoke may be one of the carcinogens that is more potent at certain stages of life. As noted in Chapter 2, the breast does not fully mature until after a first full-term pregnancy. A meta-analysis examined the effect of smoking before a first pregnancy in 23 studies published from 1988 through 2009 (DeRoo et al., 2011). The summary risk ratio was 1.10 (95% CI, 1.07–1.14), indicating a weak association with increased risk for early initiation of smoking. For women who smoked only after a first pregnancy, the summary risk ratio was 1.07, but it was not a statistically significant increase in risk (95% CI, 0.99–1.15) (DeRoo et al., 2011).

A subsequent report from the NHS found a statistically significant increase in risk associated with greater smoking intensity (i.e., pack-years of smoking) from menarche to a first birth (p for trend <.001) (Xue et al., 2011). At 1–5 pack-years of smoking before a first birth, the hazard ratio (HR) is 1.11 (95% CI, 1.04–1.20); for 16 or more pack-years, the HR is 1.25 (95% CI, 1.11–1.40). No increase in risk was evident for pack-years smoked from after a first pregnancy to menopause. For 31 or more pack-years, the HR was 1.05 (95% CI, 0.92–1.19). However, pack-years of smoking after menopause may be associated with a slight reduction in risk (p for trend = .02) (Xue et al., 2011). For 16 or more pack-years of postmenopausal smoking, the HR was 0.88 (95% CI, 0.79–0.99).

Recent reports from the Women’s Health Initiative that were not included in the meta-analysis by DeRoo et al. (2011) have also examined the effects of smoking on postmenopausal breast cancer risks. Using data from the observational arm of the Women’s Health Initiative, Luo et al. (2011b) found a higher risk with younger age at initiation of smoking. For women who started smoking between ages 15 and 19, the HR was 1.21 (95% CI, 1.01–1.44); whereas for those who initiated smoking after age 30, the HR was 1.00 (95% CI, 0.76–1.32). Similarly, initiation of smoking before first full-term pregnancy was associated with a statistically significant increase in risk (HR = 1.28, 95% CI, 1.06–1.55); the risk with

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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initiation after a first pregnancy was elevated but not statistically significant (HR = 1.17, 95% CI, 0.90–1.52). These results suggest that failure to stratify by age at initiation of smoking, or during critical windows of time, may obscure evidence of an association between smoking and breast cancer.

An additional analysis of data from the observational portion of the Women’s Health Initiative found that postmenopausal obesity may modify the association between smoking and breast cancer risk (Luo et al., 2011a). For women who were obese based on BMI at entry into the study (BMI 30), smoking did not increase breast cancer risk on the basis of age at initiation of smoking (< age 20: HR = 1.00, 95% CI, 0.85–1.18; p for trend = .73), pack-years of smoking (. 50 pack-years: HR = 1.15, 95% CI, 0.89–1.48; p for trend = .84), or other measures. By comparison, women who were not obese (BMI <30) had an increased risk with both earlier initiation of smoking (e.g., < age 20: HR = 1.19, 95% CI, 1.08–1.31) and pack-years (e.g., 50 pack-years: HR = 1.20, 95% CI, 1.00–1.43), supported by statistically significant trends.

Other recent reports have considered smoking in relation to ethnicity or particular types of breast cancer. Brown et al. (2010) concluded that their data did not show a consistent association between smoking and significant increases in breast cancer risk among U.S.- or foreign-born Asian women. For example, the results for current smokers showed an OR of 0.9 (95% CI, 0.6–1.3) while ex-smokers had an OR of 1.6 (95% CI, 1.1–2.2). The small number of women who started smoking before age 16 (11 cases, 9 controls) had an OR of 2.92 (95% CI, 1.1–7.9) whereas women who began smoking at ages 16–18 had an elevated but not statistically significant risk (OR = 1.18, 95% CI, 0.7–1.9) compared with women who had never smoked.

A study that examined risk for triple negative breast cancer found no statistically significant increase in risk over nonsmokers based on smoking status, age at initiation, or duration of smoking (Kabat et al., 2011). By comparison, women with estrogen receptor–positive (ER+) cancers were at significantly increased risk with earlier initiation (< age 20: HR = 1.16, 95% CI, 1.05–1.28) and longer duration of smoking ( 30 years: HR = 1.14, 95% CI, 1.01–1.28). In a study focused on DCIS, smoking was not associated with an increased risk based on smoking status, age at initiation, or duration of smoking (Kabat et al., 2010).

A growing body of epidemiologic research is investigating genetic susceptibilities to effects from active smoking. One area of study is risk differences according to women’s N-acetyltransferase 2 (NAT2) gene alleles. NAT2 codes for enzymes responsible for metabolism of chemicals not normally present in the body, including the detoxification of aromatic amines, which are present in tobacco smoke (Ambrosone at al., 2008). Genetic variations in NAT2 result in what are broadly described as slow or fast

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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acetylator types. Although the specific alleles used to determine acetylator status may vary among studies, meta-analyses found a fairly consistent positive association (overall relative risk of 1.4–1.5) between active smoking and breast cancer risk for women, perhaps especially postmenopausal women, who have been long-term heavy smokers and have a slow acetylator form of NAT2 (Terry and Goodman, 2006; Ambrosone et al., 2008; Zhang et al., 2010). However, a recent Canadian study not included in these meta-analyses found that heavy smoking (>20 pack-years) was associated with a statistically significant increase in risk among fast acetylators (OR = 1.93, 95% CI, 1.01–3.69) but not slow acetylators (OR = 1.27, 95% CI, 0.75–2.15) (Conlon et al., 2010).

An analysis that compared data on Hispanic and non-Hispanic white women found that Hispanic women were less likely to have slow-acetylator forms of NAT2 and had no change in breast cancer risk based on smoking and NAT2 status (Baumgartner et al., 2009). Among the non-Hispanic white women who were categorized as very slow acetylators (i.e., carrying two from among the NAT2*5A, *5B, and *5C alleles), ever, former, or current smokers were at statistically significant increased risk over never smokers, with odds ratios of more than 2.0 (Baumgartner et al., 2009). Risks for those characterized as slow acetylators (but not “very slow”) were generally elevated but not statistically significantly so.

Thus the evidence generally appears to indicate a gene–environment interaction involving women genetically predisposed to inefficient detoxification of carcinogenic exposures in tobacco smoke, although this is an evolving area of research.

Passive Smoking

Ideally, studies of the effects of secondhand smoke compare the breast cancer experience of exposed women to that of women who have never been exposed. Early studies of the relationship between breast cancer and secondhand smoke exposure are likely to have underestimated exposure by relying only on measures such as spousal smoking status. This approach neglects exposures in the workplace or public settings, which may equal or exceed exposure in the home (Reynolds et al., 2009), and exposure in childhood and adolescence, which may be a particularly vulnerable period, based on evidence for active smoking. To the extent that exposure to secondhand smoke alters breast cancer risk, underestimation of exposure by neglecting exposure sources such as these contributes to a bias toward no association.

A 2005 review by the California Environmental Protection Agency of various health hazards associated with exposure to secondhand smoke included a meta-analysis of 19 epidemiologic studies of breast cancer

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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(CalEPA, 2005). The conclusion of the review group was that the epidemiologic and toxicologic evidence was consistent with a causal association between exposure to secondhand smoke and breast cancer in “younger, primarily premenopausal women,” but that the evidence for older or postmenopausal women was inconclusive (CalEPA, 2005, p. ES-8). The meta-analysis produced an overall estimate for exposed women of RR = 1.25 (95% CI, 1.08–1.44) (CalEPA, 2005; also reported in Miller et al., 2007). When the analysis was restricted to five studies with more comprehensive exposure assessment, the overall estimate was RR = 1.91 (95% CI, 1.53– 2.39). An analysis of the 14 studies that had data on younger, primarily premenopausal women produced an overall estimate of RR = 1.68 (95% CI, 1.31–2.15); the estimate for the five studies with more comprehensive exposure assessment was RR = 2.20 (95%CI, 1.69–2.87) (CalEPA, 2005; Miller et al., 2007).

In 2006, the U.S. Surgeon General’s report The Health Consequences of Involuntary Exposure to Tobacco Smoke, which included consideration of many of the same studies as the California review, concluded, “The evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke and breast cancer” (HHS, 2006, p. 13). The conclusion was based on a review of the findings from seven prospective cohort studies, 14 case–control studies, and a meta-analysis of all of these studies. The meta-analysis found that women who had ever been exposed to secondhand smoke (10 studies) were at increased risk of breast cancer (RR = 1.40, 95% CI, 1.12–1.76). With stratification by menopausal status, the increase in risk was statistically significant for premenopausal women (6 studies; RR = 1.85, 95% CI, 1.19–2.87) but not for postmenopausal women (5 studies; RR = 1.04, 95% CI, 0.84–1.30). This report noted that its conclusion reflected, in part, an assessment that the biological plausibility of the association was weak (HHS, 2006).

A 2009 Canadian review considered the assessments in both the California report and the Surgeon General’s report, as well as three later studies that had not been included in the analyses for those previous reports (Collishaw et al., 2009; also summarized in Johnson et al., 2011). The Canadian review group noted the similarity of the results for the meta-analyses in the California and Surgeon General’s reports and found an association between increased risk for breast cancer and exposure to secondhand smoke biologically plausible. The conclusion was that “the association between [second hand smoke] and breast cancer in younger, primarily premenopausal women who have never smoked is consistent with causality” but that the evidence was insufficient to reach conclusions regarding postmenopausal breast cancer and secondhand smoke (Collishaw et al., 2009, p. 3).

The results from two large cohort studies published after the expert

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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reviews from California, the Surgeon General, and Canada have suggested a small but statistically significant increased risk for breast cancer among postmenopausal women with higher levels of secondhand smoke exposure (Reynolds et al., 2009; Luo et al., 2011b). A prospective study of 57,523 women enrolled in the California Teachers Study who were lifetime nonsmokers found indications that postmenopausal women reporting high levels of secondhand smoke exposure may be at higher risk of developing breast cancer (Reynolds et al., 2009). Similar results were recently reported for secondhand smoke exposures in a cohort of 41,022 postmenopausal women enrolled in the WHI Observational Study who never smoked (Luo et al., 2011b). For those with the highest secondhand smoke exposures (10 years in childhood, 20 years at home in adulthood, and 10 years at work in adulthood), the OR for postmenopausal invasive breast cancer was 1.32 (95% CI, 1.04–1.67) as compared with those who never smoked and never experienced secondhand smoke exposures (Luo et al., 2011b). Since 1982, the NHS has followed 36,017 women who never smoked. Follow-up to 2006 has not shown a significant association between breast cancer risk and passive smoking in childhood or adulthood (Xue et al., 2011).

Although epidemiologic studies have suggested that early age of initiation of active smoking and smoking before a first full-term pregnancy are associated with higher breast cancer risk, there is little evidence for risk from exposure to secondhand smoke only in childhood (e.g., HHS, 2006; Chuang et al., 2011; Luo et al., 2011b).

Animal and In Vitro Studies

At least 20 components of tobacco smoke have been classified by IARC as known or suspected human carcinogens and have induced mammary tumors in rodents (Collishaw et al., 2009). Tobacco smoke is also known to contain carcinogens that distribute to breast tissue. Several metabolites of these compounds have been shown to cause DNA damage, reflected by the presence of DNA adducts, in the breast tissue of current smokers, former smokers, and those passively exposed to tobacco smoke (Morabia, 2002).

One of the few animal studies that have tested the effect of exposure to tobacco smoke rather than its components explored the effects of exposure in virgin and pregnant Sprague Dawley rats subsequently treated with the carcinogen MNU (Steinetz et al., 2006). Groups of 50-day-old animals (25 animals each) were exposed to either filtered air or cigarette smoke (described as equivalent to smoking 2.7 packs per day). At 100 days, the animals were given doses of the carcinogen MNU. Smaller groups of control animals (10 animals each) had the same exposures to air or smoke but received no MNU. Among those exposed to MNU, tumor development was earliest and greatest in the virgin rats exposed to cigarette smoke and

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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latest and least in the pregnant rats exposed to air. Pregnancy was protective against the effects of MNU, but exposure to cigarette smoke resulted in increased tumor development. However, rats exposed to cigarette smoke without subsequent MNU exposure did not develop mammary tumors.

Conclusions

Recent scientific consensus reviews have been able to draw on newer studies with better assessments of tobacco smoke exposure than in the past. A 2009 IARC review declared that limited evidence exists to support a causal association between active smoking and breast cancer (Secretan et al., 2009), which constitutes a change from the organization’s 2004 conclusion that the evidence on tobacco smoke suggested a lack of breast carcinogenicity (IARC, 2004). Others have concluded that the current evidence is consistent with a causal association between active smoking and breast cancer (Collishaw et al., 2009). Some studies implicate active smoking as a risk factor for breast cancer in two subgroups: women who initiated smoking at an early age or before their first full-term pregnancy, and women with genetic characteristics that result in slow metabolism and detoxification of components of tobacco smoke (NAT2 slow acetylators).

For exposure to secondhand smoke, IARC found the evidence inconclusive (Secretan et al., 2009), while others have found the evidence to be suggestive of an association (HHS, 2006) or even consistent with a causal association with breast cancer in younger, premenopausal women (CalEPA, 2005; Collishaw et al., 2009). Within the committee there were differing interpretations of the existing data. Some were persuaded that the available evidence supports a causal association between exposure to secondhand smoke and risk for breast cancer, while others view the data as indicating a possible but not conclusive relationship. For most other smoking-related diseases, the relative risks are much stronger for active smoking than passive smoking. Thus findings of equivalent or stronger relative risks for breast cancer with passive smoking than with active smoking are difficult to explain mechanistically.

Because smoking is known to increase the risk of many types of cancer and has numerous negative health effects, substantial efforts to minimize exposure through public health interventions already exist. Although the overall magnitude of the reported effect of exposure to active or passive smoking on risk for breast cancer is not large, some susceptible subgroups appear to have a relative risk that is elevated over that of never smokers. Evidence of an increased risk for breast cancer reinforces the importance of smoking prevention and cessation programs and policies supporting smoke-free environments.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Radiation

The term “radiation” encompasses a broad spectrum of energies and can be divided into ionizing and non-ionizing radiation. Ionizing radiation has the ability to remove electrons from an atom, creating ions. Nonionizing radiation, on the other hand, is lower in frequency and has insufficient energy to eject electrons from the atom.

Ionizing Radiation

There are two main types of ionizing radiation: photons, including X-rays and γ (gamma)-rays, and particulate radiation, including α (alpha) and β (beta) particles. Alpha and beta particles deliver their energy over shorter distances than photons and tend to pose most carcinogenic risk at very short distances once they enter the body. X-ray and γ-ray exposure are well documented as carcinogens, with sufficient evidence substantiating their role as risk factors for breast cancer. This evidence includes the experience of increased risk for breast cancer among younger members of the population of atomic bomb survivors (IARC, 2000).

In the general population, the most prominent source of exposure to ionizing radiation is from medical diagnostic procedures. X-rays are an important component of diagnostic imaging and are used in procedures ranging from radiographs to fluoroscopy to computed tomography (CT) scans. γ-rays are often delivered in nuclear medical examinations that may use radioactive tracers. X-rays and γ-rays are breast carcinogens in premenopausal women (IARC, 2000). Furthermore, risk of breast cancer is significantly increased following treatment to the chest in pediatric or young adult cancer patients (Henderson et al., 2010). Although it is widely accepted that carcinogenic sensitivity is highest when ionizing radiation exposure occurs in childhood (Carmichael et al., 2003), risk persists even for women of postmenopausal age (Berrington de Gonzalez et al., 2009). Chapter 5 further discusses some of the findings regarding effects from medical treatments at different life stages. Sufficient literature exists on early-life exposure to ionizing radiation (specifically including breast cancer), but exposure in later years may be an area for further research.

Animal data also support the evidence for ionizing radiation–induced breast cancer, with evidence of mammary adenocarcinomas observed in Sprague Dawley rats (IARC, 2000). In vitro data have helped to elucidate the carcinogenic mechanisms behind ionizing radiation. Radiation-induced breast cancer is a complex phenomenon, most likely influenced by the accumulation of genetic and epigenetic alterations (Carmichael et al., 2003). Rather than acting as a single carcinogenetic event, exposure to ionizing radiation is thought to give rise to cancer through the combined effects of

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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induced genetic instability, cellular transformation, and chromosomal damage (IARC, 2000).

Important contributions to breast cancer risk from exposure to ionizing radiation are examined in detail in Appendix F of this document. As an established risk factor for breast cancer, exposures need to be minimized. The committee discusses opportunities for action to reduce risk from ionizing radiation in Chapter 6 and research needs in Chapter 7.

Non-Ionizing Radiation (ELF-EMF)

Non-ionizing radiation can be found as microwave (microwave appliances and telecommunications), infrared (heat lamps), or radiofrequency (radio) radiation. Lower still on the energy or frequency scale is radiation from extremely low frequency electromagnetic fields, ELF-EMF, which arises from electrical current and is of very low energy (energy is proportional to frequency). Non-ionizing radiation may interact with biological systems, and it is therefore of interest to environmental scientists and biologists. Most of the epidemiologic studies on the possible relationship of non-ionizing radiation to breast cancer have examined ELF-EMF.

Non-ionizing radiation is particularly challenging to study. ELF-EMF exposure is “ubiquitous and unmemorable,” with all individuals who live near or use electricity exposed to it in some form. Because one cannot see or feel its presence, it is virtually impossible for an individual to record or quantify the frequency of exposure (IARC, 2002a). It is often difficult to distinguish high exposures from low exposures when they differ by only an order of magnitude (Kheifets et al., 1995; IARC, 2002a). Various researchers have postulated different metrics of exposure as being most relevant, such as average, peak, or rate of oscillation. The relatively small range of ELF-EMF exposures and the choice of different exposure metrics can affect the statistical power of epidemiologic studies.

Meta-analyses that have synthesized the findings from studies of breast cancer are consistent in showing no association, and they exclude the possibility of all but very small associations between ELF-EMF and breast cancer. A 2010 meta-analysis of 15 case–control studies from 2000 to 2009, involving 24,338 cases and 60,628 controls, found no significant association between breast cancer risk in relation to ELF-EMF exposure, even when stratifying by menopausal status or the source of exposure (Chen et al., 2010). This conclusion is consistent with a previous meta-analysis that looked at studies from 1996 to 2000 (Erren, 2001).

Studies have also assessed risk associated with specific modes of exposure. For example, case–control studies (Davis et al., 2002; London et al., 2003; Schoenfeld et al., 2003) found no association between ELF-EMF exposure from household exposures and appliances and breast cancer.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Although electric blankets were once raised as a source of concern as a potential risk factor for breast cancer, studies found no apparent associations between electric blanket use and breast cancer (Vena et al., 1991, 1994; Laden et al., 2000; Zheng et al., 2000; McElroy et al., 2001; Kabat et al., 2003). Furthermore, none of these studies found associations based on menopausal status, parity, estrogen receptor status, or hours of use. Early studies looking at occupational exposures to magnetic fields have shown little or no overall effect of ELF-EMF exposure on breast cancer, although some studies have linked exposure with a slight increase in risk for ER+ breast cancer (Van Wijngaarden et al., 2001; Kliukiene et al., 2003; Labreche et al., 2003). These findings, some researchers argue, are primarily the result of faulty study design; many of these studies were small and had little information on potential confounding factors (Forssen et al., 2005).

Occupational ELF-EMF exposure has been raised as a potential risk factor among men with breast cancer. Some studies in the early 1990s found an association between ELF-EMF fields and breast cancer in men (Demers et al., 1991; Matanoski et al., 1991; Loomis, 1992; Guenel et al., 1993; Floderus et al., 1994), while others (Rosenbaum et al., 1994; Theriault et al., 1994; Cantor et al., 1995; Stenlund and Floderus, 1997; Forssen et al., 2000) found no correlation. Studies of non-ionizing radiation and male breast cancer have generally been restricted to small cohorts and are largely inconclusive. Occupational exposure to ELF-EMF as a risk factor for male breast cancer is a potential area for future research; men are often exposed to occupational ELF-EMF in higher doses than women, and do not have confounding factors such as hormonal cycles or pregnancies.

Animal studies have examined the effects of the various forms of non-ionizing radiation. Results have been largely inconclusive; difficulty in interpreting the data is compounded by the fact that results may vary from strain to strain, based on diet, housing conditions, lighting, or laboratory (Anderson et al., 2000b; Fedrowitz et al., 2004). A proposed mechanism for non-ionizing radiation-induced carcinogenicity involves the hormone melatonin. Melatonin, produced by the pineal gland, is thought to inhibit estrogen-mediated cell proliferation. ELF-EMF exposure is hypothesized to suppress melatonin and thereby inhibit its protective effects.

Although IARC (2002a) has classified ELF-EMF as possibly carcinogenic to humans (Group 2B), few studies have assessed whether ELF-EMF has differential effects at various life stages, and the committee is not aware of studies that have examined the effect of timing of exposure through the life course on breast cancer risks. This is a potential area for future research.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Shift Work

According to IARC (2010b), the average prevalence of shift work involving night work in the United States is 14.8 percent (16.7% in men and 12.4% in women). It is most common among those in health care, transportation, communication, leisure and hospitality, and the service, mining, and industrial manufacturing sectors. It is more common in younger workers, decreasing to a prevalence of about 10 percent after age 55 (IARC, 2010b).

It has been proposed that shift work is a risk factor in breast cancer etiology. This phenomenon has been studied through epidemiologic, animal and in vitro studies, and was reviewed extensively by IARC in 2010. In the past decade, eight major epidemiologic studies have examined the relation between shift work and risk for breast cancer among female workers, although these studies had vastly differing definitions of shift work (IARC, 2010b). Among the two prospective cohort studies (Schernhammer et al., 2001; Schernhammer and Hankinson, 2005), one nationwide census-based cohort study (Schwartzbaum et al., 2007), three nested case–control studies (Tynes et al., 1996; Hansen, 2001; Lie et al., 2006), and two case–control studies (Davis et al., 2001; O’Leary et al., 2006), the majority studied postmenopausal women (IARC, 2010b). A notable limitation of the data from these studies is the lack of racial diversity, with only one study including a small subset of Latina and African American women (O’Leary et al., 2006). Despite differences in study methodologies, meta-analyses and systematic reviews of the literature consistently note an increase in relative risk of breast cancer associated with shift work (Megdal et al., 2005; Hansen, 2006; Kolstad, 2008; IARC, 2010b). Megdal et al. (2005) reported an aggregate RR estimate based on 13 combined studies of 1.48 (95% CI, 1.36–1.61).

Animal and in vitro studies on shift work–induced breast cancer are more difficult to design and conduct. Because “shift work” itself cannot be imposed on animals, experimental studies have used models of alteration of light and dark environments, which affect circadian pacemaker function. The exposure to light during the night, and the altered sleep cycle that ensues, has been proposed as the mechanism for shift work–induced breast cancer (Straif et al., 2007).

Numerous animal studies have evaluated the effect of varying light cycles on mammary tumorigenesis in animal models. In CBA mice, continuous light exposure increased the incidence of different spontaneous tumors from a variety of tissues in females, and also reduced overall life span (Anisimov et al., 2004). However, the numbers for mammary adenocarcinomas were very small—one spontaneous adenocarcinoma in light/dark exposed mice, and two adenocarcinomas in the light/light exposed group, with 50 animals in each group (Anisimov et al., 2004). Anderson et

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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al. (2000a) demonstrated in rats that constant light exposure followed by exposure to a chemical carcinogen such as DMBA results in an increased incidence of mammary tumors when compared to an alternating light/dark cycle. Cos et al. (2006) examined the effects of constant light or different patterns of “light at night” on established DMBA-induced mammary carcinomas in female Sprague Dawley rats. They found that female rats exposed to light at night, especially those under a constant dim light during the darkness phase, showed (1) significantly higher rates of tumor growth as well as lower survival than controls (typical 12-hour light–dark cycle), (2) elevated serum estradiol concentration, and (3) decreased nocturnal excretion of 6-sulfatoxymelatonin, but no differences between nocturnal and diurnal levels. They concluded from this that circadian and endocrine disruption induced by light pollution could induce the growth of mammary tumors. The role of stress induced from the constant light exposure cannot be ruled out. It could be a fundamental part of the mechanism of action, and stress would also be relevant to humans with constant disruption of light at night/circadian rhythm. Other studies have shown that light exposure at night increases the growth of different kinds of transplantable tumors in rats (Dauchy et al., 1997, 1999; Blask et al., 2002).

Melatonin is hypothesized to play an important role in shift work– induced breast cancer; this hormone transmits informational cues of environmental light and darkness from the eye to the hypothalamus, to all tissues of the body, helping to set an organism’s biological clock. Importantly, “melatonin has anti-proliferative effects on human cancer cells cultured in vitro” (IARC, 2010b, p. 663). According to the melatonin hypothesis, light exposure at night results in a reduction in the circulating levels of melatonin, which removes its check on estrogen, allowing for rising levels of estrogen to promote cell proliferation and increase the risk for malignant transformation (Graham et al., 2001). As an antiestrogen, melatonin down-regulates ERα transcription and alters its functional activity (Molis et al., 1994; Rato et al., 1999; del Río et al., 2004; Cini et al., 2005). Despite numerous in vitro studies on the oncostatic effects of melatonin, there is insufficient evidence regarding the use of melatonin supplements to determine their impact on risk of breast cancer, making this a potential subject area for future studies.

IARC (2010b, p. 764) concluded that “shift work that involves circadian disruption is probably carcinogenic to humans.” To understand the role of “light at night” in breast cancer etiology, further studies are needed on its influence on women who do not perform shift work, but who are exposed to light at night in their homes.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Metals

Metals are ubiquitous in the environment and human exposures derive from natural background sources in food, water, and air as well as from extraction, manufacture, and uses in multiple tools, products, medical devices, and building materials. Exposures to metals in the workplace and to the general population were reduced in the latter part of the 20th century with occupational health and safety standards and reductions in environmental emissions and levels. The most notable results of these restrictions include the dramatic declines in blood lead levels since the early 1970s with the ban on lead in gasoline and a reduction in lead use in other consumer products such as paint. The revised drinking water standard for arsenic in 2001 reduced a main source of arsenic exposure from natural occurrence in some parts of the United States. Primary sources of cadmium exposure include cigarette smoke and shellfish consumption. Recent reductions have been made in allowable levels of cadmium and lead in consumer products.

A systematic review of evidence by IARC (Straif et al., 2009) has classified several different metals (arsenic and inorganic arsenic compounds, beryllium, cadmium, chromium, nickel, and their related compounds) as “carcinogenic to humans” (Group 1). These classifications are based on sufficient evidence from human studies that these metals cause tumors in the lung and some other sites, and not on findings regarding breast cancer.

Despite the considerable evidence linking certain metals (e.g., nickel, hexavalent chromium, cadmium, and arsenic) to lung cancer from inhalation and arsenic to internal cancers (primarily bladder, lung, and liver) and skin cancer by ingestion, no clear epidemiologic data have indicated metal exposures to be a risk factor for breast cancer (ATSDR, 2005, 2007, 2008a,b; NTP, 2011a). Much of the evidence for metals and lung cancer in humans arises from studies of worker populations, which have historically included few women. Other than for lung cancer, however, worker studies have shown little evidence for other cancers from metals exposure, indicating insufficient systemic exposure to produce tumors at distant sites. Exposures through routes other than inhalation likewise provide little evidence of breast cancer. With the exception of arsenic, general population exposures to metals through consumer products, medicinal applications, implanted medical devices (McGregor et al., 2000), and elevated levels in drinking water or food have been associated with health effects other than cancer risks, although relatively few studies examining cancer risks have been published for nonoccupational populations (ATSDR, 2005, 2007, 2008a,b; NTP, 2011a).

Arsenic has the most epidemiologic data for evaluating breast cancer risk. A number of large population studies on cancer rates from exposure to elevated arsenic levels in drinking water are available, although most

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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focus on target sites that have consistently shown increased cancer rates (e.g., lung, bladder, skin) and only a few report risks for breast cancer (summarized by ATSDR, 2007). Tsai et al. (1999) reported no increase in breast cancer mortality rates for women exposed to high levels of arsenic in well water in Southwest Taiwan, based on 8,874 breast cancer deaths and over 1.4 million person-years of exposure (SMR compared to local reference = 1.01, 95% CI, 0.74–1.34; SMR compared to national reference = 0.67, 95% CI, 0.48–0.89). Likewise, for a region in northern Chile with over 400,000 people exposed to high arsenic levels in drinking water and in air, breast cancer was used as a control cancer because it has not shown increased risks from arsenic in other studies (Rivara et al., 1997). Compared to a control region with 1.7 million people, breast cancer mortality risks were lower, although not significantly, for the arsenic-exposed region (RR = 0.7, 95% CI, 0.39–1.08) (Rivara et al., 1997).

Studies have reported correlations between levels of various metals (either increased or decreased) in tissues or specimens (e.g., hair, blood, urine) from breast cancer patients or in tumor cells, but most of these studies have small sample sizes and little control for confounding factors. A somewhat larger case–control study of urinary cadmium levels in 246 breast cancer cases in a population in Wisconsin found a two-fold higher risk of breast cancer for women in the highest urinary cadmium quartile compared with those in the lowest fourth (OR = 2.29, 95% CI, 1.3–4.2) after adjustment for several other risk factors (e.g., age, family history of breast cancer, postmenopausal hormone use) (McElroy et al., 2006). Adjustment for smoking (never, former, current) had no effect on the results, although quantifying smoking duration and intensity and hence cadmium exposure from smoking (e.g., pack-years) may have been better able to distinguish an effect. In this study and others that measure levels of metals at the time of the study, it is not possible to distinguish whether metals have a role in the causal pathway for breast cancer or if breast cancer patients or tumor cells have abnormal metal absorption, distribution, metabolism, or excretion. Little evidence associates cadmium exposure with excess cancers of the breast for populations that have much higher cadmium exposures from environmental contamination such as those in Japan, England, or Belgium, although ATSDR (2008a) notes that the statistical power of these studies to detect cancers was not high. These populations have been well studied for kidney and other noncancer effects. A recent IARC review concluded that there was limited evidence from epidemiologic sources for kidney and prostate cancer (Straif et al., 2009).

A few studies in humans have examined associations between levels of urinary cadmium, blood lead, and hormone levels or hormonal effects at different life stages. Urinary cadmium was associated with elevated levels of testosterone, but not estrone, in postmenopausal women (Nagata et

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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al., 2005). Higher blood lead levels, alone or in combination with urinary cadmium levels, were reported to be related to markers of delay of menarche in prepubertal girls. Interestingly, the association was considerably stronger in girls with elevated urinary cadmium in addition to high blood lead (Gollenberg et al., 2010). A delay in age of menarche runs counter to an elevation in risk because early (not late) age of menarche is a risk factor for breast cancer.

Overall, animal studies examining the carcinogenicity of metals such as arsenic, hexavalent chromium, nickel, cadmium, or cobalt have not reported increases in mammary tumors (ATSDR, 2005, 2007, 2008a,b; NTP, 2011a). One animal study found that cadmium administered by injection to pregnant rats mimicked the effects of estrogen in the uterus and mammary glands of the offspring, supporting the hypothesis that cadmium exposure is a potential risk factor for breast cancer (Johnson et al., 2003). The type and magnitude of dosing, however, was not comparable to what would likely occur in humans through environmental exposure. Johnson et al. (2003) compared intraperitoneal injection of up to 5 μg/kg of cadmium on gestation days 12 and 17 to the World Health Organization provisional tolerable intake from the diet of 7 μg/kg/week. However, the systemic dose from dietary intake is reduced by gastrointestinal bioavailability, and the amount absorbed from the diet over 7 days is spread out over much smaller incremental doses than the high acute dose that would result from injection. 12 Lower dosing may also result in less fetal exposure because of more efficient maternal sequestering.

High levels of arsenic, cadmium, and the transition metals such as iron, nickel, chromium, copper, and lead have been associated with free radical generation and oxidative stress, particularly in studies carried out in vitro (Davidson et al., 2007). Prolonged or repeated oxidative stress is a well-known mechanism of carcinogenicity in general. In vitro studies indicate that many metals such as cadmium, arsenic, aluminum, and a number of divalent metals can interact with the estrogen receptor, thereby potentially affecting breast cancer risk; however, with the possible exception of cadmium, little research has investigated this issue. For cadmium, the findings are not entirely consistent on whether estrogen receptor binding results in the expected downstream effects such as expression of genes involved in cell signaling and proliferation critical to breast cancer cell growth. Studies observing such effects have indicated the relative potency of cadmium to be 100 to 1,000 times less than that of estradiol; other studies reported little

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12Adjusting for body weight scaling by a factor of 3/4 (Rhomberg and Lewandowski, 2004) results in the 5 μg/kg dose to a 0.250 kg rat over 5 days being 4 times lower than the 7 μg/kg dose to a 70 kg human over 7 days. However, the dose to the rat is injected at one time and the dose to the human would be spread out over 7 days.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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estrogenic effect in vitro over a wide range of concentrations (Silva et al., 2006, and studies reviewed therein). Cadmium has also been reported to transform normal cultured breast epithelial cells in vitro through an estrogen-independent mechanism into cells with characteristics of malignant breast tumor cells (Benbrahim-Tallaa et al., 2009). Concentrations used, however, exceeded those reported to be cytotoxic in other studies (Choe et al., 2003; Silva et al., 2006). Other possible mechanisms suggested include indirect effects such as interactions with other essential enzyme pathways or by depletion of essential metals (e.g., those protective of oxidative stress) or nutrients (e.g., antioxidants).

All told, the evidence available for metals as risk factors for breast cancer indicates biologic plausibility for increased risk of breast cancer in association with exposure to certain metals, particularly cadmium and possibly arsenic, but metals are unlikely to be a major risk factor at environmentally relevant doses. Much of the evidence is from in vitro studies using concentrations of metals that are considerably higher than would occur in humans from environmental exposures.

Consumer Products and Constituents

Alkylphenols

Alkylphenols are a group of chemical intermediates as well as degradation products of alkylphenol ethoxylates. Alkylphenol ethoxylates, and particularly nonylphenol ethoxylate, are widely used non-ionic surfactants added for foam control, wetting, and antifog/antistatic, and as stabilizers in a variety of household, industrial/commercial, and agricultural products such as adhesives, sealants, detergents/cleaners, and pesticides (Lani, 2010). Nonoxynol-9 is an alkylphenol used as a spermicide in contraceptives. Alkylphenols are also plastic or resin additives. The U.S. Department of Health and Human Services Household Products Database lists nonylphenyl polyethoxylate in paints, certain cleaners, and hair color products (HHS, 2010b), and nonylphenol in hardeners and epoxy for household maintenance products (HHS, 2010a).

As a result of widespread use and degradation of alkylphenol ethoxylates, alkylphenols have been detected in municipal and industrial discharges and in receiving water bodies and sediment (Fenet et al., 2003; Gross et al., 2004). NHANES reported urinary levels of 4-tert-octylphenol in survey years 2003–2004 at approximately 0.3 to 0.4 µg/L at the 50th percentile and 1.3 to 2.5 µg/L at the 95th percentile, depending on age or ethnic grouping (CDC, 2009a). Urinary levels of orthophenylphenol measured in the 1999–2000 survey were similar to those of octylphenol in 2003–2004, but had decreased to undetectable levels at the 50th and 75th

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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percentiles in 2001–2002 (no data for 2003–2004). No data were reported for nonylphenol.

Alkylphenols, particularly larger compounds such as octylphenol and nonylphenol, are more lipophilic and persistent in the environment than their parent compounds (Lani, 2010). In vitro studies in breast cancer cell lines also indicate a trend for increasing estrogenic effects with larger alkyl groups such as for octyl- and nonylphenol (Terasaka et al., 2006; Sun et al., 2008). Among the alkylphenol compounds, 4-nonylphenol accounts for 80 percent of the alkylphenol in the environment (Oh et al., 2008) and is the most studied alkylphenol for its potential endocrine disrupting effects. The amount of research on this compound, however, is considerably less than for the related compound, bisphenol A. Alkylphenols have not been evaluated for carcinogenicity by regulatory agencies in the United States (e.g., NTP, EPA) or international groups (e.g., IARC). NTP has immunotoxicology, behavioral toxicology, and multigenerational reproductive studies under way (HHS, 2010b). In addition to estrogenic effects demonstrated in vitro, a few studies in laboratory animals indicate the potential of nonylphenol to alter mammary gland development and increase mammary tumor formation.

Nonylphenol administered by oral gavage at 100 mg/kg (but not at 10 mg/kg) on gestational days 15–19 in rats resulted in advanced lobular development of the mammary glands of the offspring on postnatal day 22 (Moon et al., 2007). Transgenic mice consuming nonylphenol in honey for 32 weeks, beginning at 5–6 weeks of age, showed increased mammary tumor rates at a dose of 45 mg/kg/day, but not at a dose of 30 mg/kg/day (Acevedo et al., 2005). By comparison, an equivalently estrogenic dose of estradiol-17b (E2) of 0.01 mg/kg/day (based on higher estrogen receptor binding affinity of E2 relative to nonylphenol) did not increase mammary cancer risk. Acevedo et al. (2005) thus concluded that nonylphenol may be a more potent mammary gland carcinogen than predicted by its relative binding affinity to E2. Given widespread exposure and hazards identified from in vitro and animal studies at relatively high doses, alkylphenols are candidates for further investigation. Similar to many other relatively unstudied chemicals with endocrine activity, more research is needed to define what risks are posed to the population exposed at low levels in the environment.

Bisphenol A

Bisphenol A, or BPA, is a plasticizer and one of the highest volume chemicals produced worldwide (Vandenberg et al., 2007). It is used in the production of products such as polycarbonate plastics, epoxy resins that line metal cans, dental appliances and composite fillings, and also as a component in thermal paper used for certain receipts. BPA is characterized

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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by widespread use and frequent exposure in developed countries. Human exposure is most likely through the oral route, although transdermal exposure (bathing in contaminated water, handling cash register receipts) (Biedermann et al., 2010), and inhalation are also possible (Stahlhut et al., 2009). Concern has arisen about BPA’s leaching from medical products or consumer products such as cans, plastic food wrap, paper towels, paper receipts, and especially from polycarbonate baby bottles. Although studies on BPA are numerous, they are difficult to interpret, and they illustrate the complexities of breast cancer risk research.

BPA has not been evaluated for carcinogenicity by IARC, WCRF/AICR, or EPA (2011a), although EPA (2010b) has summarized the existing literature as part of an Action Plan to be implemented. Several panels have reviewed toxicological findings about BPA (EFSA, 2006, 2008; vom Saal et al., 2007; FDA, 2008; NTP, 2008; JECFA, 2010). Some of NTP’s findings are noted below.

Human studies on BPA have focused primarily on exposure, and exposure is ubiquitous. NHANES data showed that 90 to 95 percent of the U.S. population has detectable levels in urine (Calafat et al., 2008). BPA has been found in virtually all human tissues and in follicular fluid, maternal serum, fetal serum, umbilical cord blood, amniotic fluid, and the placenta (Vandenberg et al., 2007, 2010). Furthermore, the short half-life of BPA means that any detectable exposure was recent, implying that BPA exposure is also continuous. Indeed, the cessation of consumption of packaged food for 3 days resulted in a 66 percent reduction of urinary BPA, which returned to pre-intervention levels once consumption resumed (Rudel et al., 2011). A study of the pharmacokinetics of BPA in adult volunteers with a controlled high dietary exposure13 suggests that serum concentrations are roughly 42 times lower than urinary levels and below the limit of detection of 1.3 nM (Teeguarden et al., 2011).

Epidemiologic studies on the potential health effects of BPA exposure are limited in both quantity and quality for various reasons. Because of its short half-life, current measurements may not be a sound basis for estimating past exposures. In addition, exposure studies may be unable to distinguish the potential effects of BPA from those of the myriad of other estrogenic compounds that are present in most people examined (Vandenberg et al., 2007). Concern for early-life exposure and developmental effects also further complicates studies; the exposure, pharmacokinetics, and metabolism of BPA in adults cannot always be extrapolated to make predictions for the fetus, infant, or child.

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13The estimated average consumption of BPA was 0.27 µg/kg body weight (range, 0.03– 0.86), 21 percent greater than the 95th percentile of aggregate exposure in the adult U.S. population (Teeguarden et al., 2011).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Various studies have been conducted to assess the potential for BPA to induce cancer in rodents, including one set of NTP studies as well as studies that are not cancer bioassays, but that evaluate the structure and function of the mammary gland in pubertal or young adult animals following early-life exposure. The in vivo data have been difficult to interpret. Two-year dietary cancer bioassays were conducted by NTP in 1982 using the standard protocol at that time. Rats and mice of both sexes beginning at 5 weeks of age were exposed for 104 weeks to high levels of BPA in feed. BPA was not shown to induce neoplastic or non-neoplastic lesions in the mammary glands of female rats or mice (NTP, 1982a), although suggestive carcinogenicity observations were reported for other sites (hematopoietic and testicular cancers). The NTP (1982a, p. vii) concluded, “Under the conditions of this bioassay, there was no convincing evidence that bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex.”

The study has received criticism by Keri et al. (2007) for many reasons common to studying estrogenic compounds using standard cancer bioassayprotocols (see Chapter 4). Prenatal exposure was not included, as also noted recently by NTP (2008). Also, the high dosing can be problematic when assessing endocrine disrupting compounds such as BPA, where dose response often defies conventional toxicological relationships; in some cases, low doses may have important physiological effects, while in others, high doses may be inhibitory (Watson et al., 2007; Kochukov et al., 2009). It also can be difficult to completely eliminate exposure to endocrine disrupting or estrogenic compounds in the control group; cages are often made of BPA polymers, and phytoestrogen-free diets must be followed (Keri et al., 2007).

Animal studies have suggested that perinatal subcutaneous exposure (via osmotic minipumps) to low doses of BPA can cause a variety of tissue changes in the peripubertal mammary gland that may signal an increased susceptibility to tumors in later life (Muñoz-de-Toro et al., 2005; Durando et al., 2007; Vandenberg et al., 2007). Furthermore, low-level exposure subcutaneously administered to pregnant rats has led to preneoplastic lesions—ductal hyperplasia and carcinoma in situ—in their offspring in adulthood (Durando et al., 2007; Murray et al., 2007). However, no data currently exist to determine whether lesions of the severity and extent seen in these studies contribute to the occurrence of invasive carcinoma (NTP, 2008). Because most of the existing data are based on subcutaneous exposure rather than oral dosing, it is difficult to determine whether the pharmacokinetics in animals are informative for human oral or dermal exposure. However, oral exposure of pregnant rats to BPA at a dose of 250 µg/kg body weight has also been studied and observed to similarly affect mammary gland development of offspring in the peripubertal period; exposure at a lower dose (25 µg/kg) showed effects on relevant gene expression (Moral et al., 2008).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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NTP (2008) found “minimal concern” for BPA’s effects on the mammary gland for females at the fetal, infant, and child stages at current levels of human exposure. In doing so, it noted that “[t]hese studies in laboratory animals provide only limited evidence for adverse effects on development and more research is needed to better understand their implications for human health. However, because these effects in animals occur at bisphenol A exposure levels similar to those experienced by humans, the possibility that bisphenol A may alter human development cannot be dismissed” (NTP, 2008, p. 7).

Currently, the in vivo data are insufficient to determine BPA’s effects in adult organisms.

Because of the lack of epidemiologic evidence on BPA and breast cancer risk and limitations of in vivo study designs, current BPA data primarily come from in vitro models. Although such data often do not speak specifically to breast cancer endpoints, they have shed some light on BPA’s mechanisms of action. BPA is a well-established xenoestrogen and endocrine disruptor, and it has been shown to mimic, enhance, or inhibit endogenous estrogen activity (Wetherill et al., 2007). BPA selectively binds to both estrogen receptors (ERα and -β), with a higher affinity for ERβ (Kuiper et al., 1997; Routledge et al., 2000; Matthews et al., 2001). Although endocrine disruption is an indirect mechanism for cancer, it has been hypothesized that it is important because of the morphogenic nature of hormones; exposure to even low doses of hormonally active chemicals, especially during development, can alter cellular or tissue organization over time, creating an environment susceptible to diseases such as cancer (Soto and Sonnenschein, 2010). Evidence implicating BPA as genotoxic is conflicting and difficult to interpret. A number of in vitro assays have shown no mutagenic activity (Tennant et al., 1987; Schweikl et al., 1998; Schrader et al., 2002; Keri et al., 2007), but others have shown genotoxic activity correlated with morphological transformation or aneuploidy (Galloway et al., 1998; Hilliard et al., 1998), DNA adduct formation (Tsutsui et al., 1998), or double-stranded breaks (Iso et al., 2006).

Another emerging facet of BPA mechanistic research involves susceptibility at various life stages. It has been proposed that BPA can epigenetically alter or suppress gene expression through endocrine receptor mediated pathways, with effects accumulating over time to increase risk of neoplasia (Doherty et al., 2010; Weng et al., 2010).

In sum, the role of BPA in human breast cancer is not known. Current researchers have not reached a consensus on the effects of BPA in breast cancer etiology, but the effects of BPA extend to other systems, with potentially harmful effects to the fetal, infant, or child brain and behavior (NTP, 2008). The results of a large body of research have shown that BPA has estrogenic effects and effects on the androgen receptor, the thyroid gland,

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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male and female reproductive systems, and immunity. It has also been associated with abnormal liver enzyme concentrations and self-reported cardiovascular disease and diabetes (Lang et al., 2008). Active research efforts are continuing to further clarify its health effects (NIEHS, 2009; FDA, 2010). Because of the complex nature of BPA’s action and mechanisms of activity that overlap with those of other xenobiotics, further research should take a mechanistic and systems biology approach to address additive or other cumulative actions of estrogenic compounds and their roles in overall health.

Nail Products

Potential health risks from exposures to chemicals of concern in consumer nail products have attracted public attention. Nail products contain a number of chemicals that are known or suspected carcinogens, as well as agents implicated for risk of breast cancer by virtue of their endocrine disrupting properties. Nail product constituents may include toluene, benzoyl peroxide, formaldehyde, and phthalates (California Department of Health Services, 1999; EPA, 2004).

Relatively little human health research has been done in this area. An early occupational mortality study in California indicated that cosmetologists, including manicurists, had significantly elevated risks for breast cancer mortality (Singleton and Beaumont, 1989), although a U.S. mortality study covering a decade later failed to find such an association (Robinson and Walker, 1999). In terms of incidence, a 1984 study linking licensed cosmetologists to the Connecticut cancer registry noted that women licensed between 1925 and 1934, before the dramatic increase in the nail salon sector, experienced a significant excess of breast cancer compared to the general population in Connecticut (Teta et al., 1984).

The nail salon industry in the United States, now dominated by female Asian immigrant workers, has expanded rapidly over the past two decades (Quach et al., 2008). Although few studies have explicitly addressed cancer risks from use of nail products, a recent California study of nail salon workers suggested that, despite lack of evidence of an excess of breast cancer in the nail salon workforce, the industry is young and further follow-up of workers is needed (Quach et al., 2010). Notably, evidence shows that nail salon workers are exposed to several chemicals of concern, including toluene, methyl methacrylate, and total volatile organic compounds at levels higher than recommended guidelines (Quach et al., 2011).

Animal studies have been carried out on many of the individual chemical components of nail products, some of which are established as known or reasonably anticipated to be human carcinogens (e.g., formaldehyde [IARC, 2006a; NTP, 2011a], styrene [NTP, 2011a]). Some of these chemi-

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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cals (e.g., toluene, dibutyl phthalate) are also being tested for endocrine disrupting properties based on widespread exposure to them (EPA, 2009b). The committee is not aware of animal data evaluating the effects of mixtures similar to those in nail care products.

Nail care products represent a range of easily obtainable and widely used over-the-counter commodities for which there is sparse information on formulations, chemical exposures, and health risks. Women in the nail salon workforce may be the most highly exposed, but widespread lower level exposure of consumers suggests that this is an area for further inquiry.

Hair Dyes for Personal Use

Hair dyes can be classified as oxidative or non-oxidative. Oxidative hair dyes are permanent dyes and make up the majority (about 80 percent or higher) of the hair dyes that are sold (Baan et al., 2008; IARC, 2010c). They are complex chemical mixtures: several ingredients (particularly para- and ortho-aminophenols, phenylenediamines, meta-aminophenols, and metadiaminobenzenes) are mixed in the presence of hydrogen peroxide to produce the color through a chemical reaction within the hair shaft. The darker the hair dye color, the higher the concentration of chemical ingredients. Non-oxidative hair dyes are semipermanent or temporary dyes, and they may also be called direct dyes. With non-oxidative coloring products, there is no chemical reaction to produce the hair color, and the color will wash out with repeated shampooing. They use high–molecular weight compounds that may contain multiple different dyes to obtain the specific color. Because of the chemical process involved with oxidative dye products and the potential to produce reactive species during the process, it has been previously hypothesized that permanent hair dyes would be more likely than non-oxidative dye products to be associated with cancer (Bolt and Golka, 2007).

Oxidative hair dyes were introduced at the end of the 19th century, and their formulations have changed over time (IARC, 2010c). The use of some chemical ingredients in permanent hair dyes was discontinued in the 1970s. Thus, the association of cancer outcomes with product use before and after 1980 has been examined in some studies. Occupational exposures to hair dyes by hairdressers and barbers have also been examined (IARC, 2010c).

A meta-analysis by Takkouche et al. (2005) included 12 case–control studies (involving 5,019 cases and 8,486 controls) and 2 cohort studies on personal use of hair dyes. All but two case–control studies examined the association of breast cancer with permanent hair dyes, and all of the case–control studies explored an association of breast cancer risk with any type of hair dye use. Intensive exposure, defined as more than 200 lifetime exposures to hair dye, was examined in the 2 cohort studies and 7 of

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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the 12 case–control studies. Among all studies, no statistically significant association was seen between risk of breast cancer and any hair dye use (RR = 1.06, 95% CI, 0.95–1.18) or, from 9 studies, for intensive use (RR = 0.99, 95% CI, 0.89–1.11) (Takkouche et al., 2005). Additionally, a study reporting detailed information on type of hair dye use and color reported no statistically significant association for use of either dark color products or light color products, or age at first use, duration of use, number of applications, or years since first use (Zheng et al., 2002).

An IARC (2010c) review examined hair dyes as occupational and personal exposures. For cancer in general, there was inadequate evidence in humans for the carcinogenicity of personal use of hair dyes; the overall evaluation was that personal use of hair dyes was not classifiable as to its carcinogenicity. For breast cancer, no association was seen for occupational exposures, and the epidemiologic evidence on breast cancer and personal use of hair dyes was considered “inadequate” to reach a conclusion on carcinogenicity (IARC, 2010c, p. 644).

IARC (2010c) categorized the animal evidence regarding carcinogenicity in general as “limited,” but noted some studies in rats showed benign lesions of the mammary glands after exposure to oxidative hair dye formulations or components. The majority of rodent studies have exposed adult animals by skin painting: shaving a patch of fur, followed by a direct application of the hair dye. The studies are difficult to interpret because of the variety of product formulations and strengths that may be in use. Most of the animal studies reviewed in the most recent IARC review were conducted in the 1970s and 1980s, and product formulations change over time.

Epidemiologic evidence from case–control and cohort studies does not suggest an association between hair dye use and breast cancer. Limitations of some of the studies include lack of specificity for type of hair dyes used (oxidative versus non-oxidative) and details on color, type, or duration of use. In addition, formulations have changed over time, and they differ based on the region of the world in which they are produced and sold. Strengths of the epidemiologic evidence include studies conducted in a variety of populations, including those with exposure to dark hair colors, examinations by intensity of exposure, and consistent findings of no association among those studies with detailed exposure information. Based on the available human evidence, personal use of hair dyes is unlikely to be an important risk factor for breast cancer.

Parabens

Parabens are a class of synthetic chemicals called para-hydroxybenzoates. They are the most widely used preservatives in cosmetic products, and they are also used in a wide variety of foods and drugs. They can be found in

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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some underarm deodorants and antiperspirants, but most major brands do not currently contain them (NCI, 2008, citing FDA). They meet several criteria of an “ideal preservative”: a broad spectrum of antimicrobial activity, especially against yeasts and molds; virtual lack of color and taste; stability over a wide pH range; and extremely low acute and chronic toxicity (Soni et al., 2005). They have, however, been found to be weakly estrogenic (Golden et al., 2005) and concerns have been raised about their effects in combination with other potentially estrogenic compounds (Darbre and Harvey, 2008).

Few epidemiologic studies are of relevance to paraben exposure and breast cancer. A population-based case–control study with response rates of 75 to 78 percent showed no evidence of an association between breast cancer and the use of underarm deodorant or antiperspirant, with or without underarm shaving (Mirick et al., 2002). However, because parabens also have other uses—in other personal care products, as antimicrobials to food products up to concentrations of 0.1 percent, and as preservatives in drugs—the extent to which women using antiperspirants or deodorants were more exposed than the study controls is unclear. The only other study specifically addressing cancer endpoints is a case-only survey with a very low response rate (32.5%) that reported that frequency and earlier onset of antiperspirant or deodorant use were associated with an earlier age of breast cancer diagnosis (McGrath, 2003). With no control subjects and lack of age adjustment, the study design does not permit reliable assessment of breast cancer risk associated with underarm deodorant use. For example, a possible interpretation of the survey of cases is that younger women use more antiperspirant than older women. As shown by this same study, underarm antiperspirant use in women increased dramatically from the 1960s up to 2000. As a result, younger women are more likely to use deodorant at an earlier age and more frequently than older women. Breast cancer rates also increased during this period, but are not necessarily related. A cohort study of girls ages 6–8 at entry showed no association between urinary concentrations of benzophenone-3 (a sunscreen) or parabens and signs of early puberty (Wolff et al., 2010). The 1 year of follow-up of this young population is too short to have breast cancer endpoints. The National Cancer Institute (NCI, 2008, p. 1) states, “there is no conclusive research linking the use of underarm antiperspirants or deodorants and the subsequent development of breast cancer.”

In an extensive review of the clinical, experimental animal, and in vitro mechanistic studies of parabens, Golden and colleagues (2005) concluded that in the aggregate, the evidence is extremely weak that parabens, acting through endocrine or estrogenic or endocrine disruption mechanisms, have adverse effects on human health, including breast cancer. The review notes that parabens are 1 thousand to 1 million times less potent

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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than 17β-estradiol and the likelihood of exposure to concentrations that could exert hormonal effects is remote. They conclude that it is “biologically implausible” that exposure to parabens (in utero, or by transdermal, oral, or any other route) increases the risk of any estrogen-mediated endpoint in humans. However, the authors did not make comparisons taking into account pharmacokinetics, persistence, and other aspects of exposure related to the amount of active compound available for interaction with the receptor.

A researcher from the Procter and Gamble Company proposed a new method to refine estimates of exposure to parabens through topically applied cosmetics and food (Cowan-Ellsberry and Robison, 2009). Use of conservative estimates of parabens concentrations in products, application or ingestion frequency, dwell time of topical substances, absorption, and clearance/metabolism led to an aggregate exposure estimate of 1.3 mg/kg/day, and cruder estimates of up to 4.1 mg/kg/day; these levels are below the acceptable daily intake (ADI) for parabens of 10 mg/kg/day (Soni et al., 2005). Regarding estrogenicity, the more branched and longer chained the paraben, the greater the estrogen binding activity (FAO/WHO, 2005; Integrated Laboratory Systems, 2005).

The Cosmetic Ingredient Review, a group established by the cosmetic industry in collaboration with the FDA, has concluded, based on an expert panel review of the epidemiologic evidence in combination with animal toxicology and in vitro mechanistic studies, that use of parabens in cosmetics is safe and is not carcinogenic (Cosmetic Ingredient Review, 2008). The FDA (2007) has concluded that “at the present time there is no reason for consumers to be concerned about the use of cosmetics containing parabens.”

On the other hand, in 2005 the European Food Safety Authority withdrew propyl paraben from an ADI, for parabens as a group, because of concerns about the estrogenic and reproductive effects (FAO/WHO, 2007). Male reproductive toxicity was discovered for propyl paraben in animal studies at the same dose as the ADI. Similar toxicity was seen with butyl paraben (not used in Europe as a food additive). The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) in 2007 also withdrew the compound from the group ADI. After review of the toxicological literature it noted, “There are insufficient data to conclude whether the effects observed with parabens of higher alkyl chain length [butyl and propyl] in males are mediated via an estrogenic, anti-androgenic or some other mechanism” (FAO/WHO, 2007, p. 29).

A comprehensive toxicological profile sponsored by the NTP reported butyl paraben to be noncarcinogenic to rats and mice (Integrated Laboratory Systems, 2005). However, because of data gaps, the NTP selected the compound for carcinogenicity evaluation and other toxicological studies.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Perfluorinated Compounds

Perfluorinated compounds such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been produced since the 1950s and used extensively in the production of industrial chemicals and in surfactants and surface protectors for products such as nonstick cookware and fabric stain and water repellants. The majority of human exposure is probably through diet and drinking water, possibly related to wastewater treatment plants that may concentrate perfluorinated compounds (Steenland et al., 2010). They may also be ingested in dust from treated products (Trudel et al., 2008; Steenland et al., 2010). Testing through NHANES has shown recently declining but nearly universal exposure to PFOA and PFOS in the United States (Calafat et al., 2007). With this widespread exposure, these chemicals have garnered attention for potential long-term adverse health outcomes (White et al., 2011a,b). EPA has not yet completed an assessment of their health risks, and they have not been reviewed by IARC.

The epidemiologic studies to date are limited in number and scope. Grice et al. (2007) surveyed 1,895 past and present workers in perfluoroocatanesulfonyl flouride production and used a job exposure matrix to estimate PFOS exposure in women reporting breast cancer and other conditions validated from medical records. Only 263 women were among 1,400 workers returning questionnaires, with 4 breast cancers reported among them (the expected number of breast cancers for this age distribution of women was not reported). According to the authors, the PFOS exposures of study participants were “substantially higher than exposures in the general population” (Grice et al., 2007, p. 728). This study was limited in its ability to detect health effects, but no association was found with breast cancer or the other conditions of interest. Other studies (reviewed in Olsen et al., 2009) have found no consistent relationship between PFOA and PFOS exposure and human fetal development (e.g., birthweight, ponderal index); no cancer endpoints were evaluated. Studies to assess the impact of PFOA on the onset of puberty as a risk factor for breast cancer are under way as part of the NIH-supported Breast Cancer and the Environment Research Centers (Hiatt et al., 2009).

Few studies have been conducted to assess PFOA or PFOS in animals. Various tumors have been observed in animals, including equivocal findings of mammary tumors in an early unpublished study by a producer of the compound (Sibinski, 1987; EPA, 2005a). Recent animal studies indicate that PFOA exposure at critical developmental stages can alter mammary gland growth in mice, among other developmental effects (Macon et al., 2011; White et al., 2011a,b). For example, effects were seen in mice exposed to PFOA in utero or chronically to low levels in drinking water before adulthood (White et al., 2011b). The second half of gesta-

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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tion is an especially sensitive period (White et al., 2007). Effects on the in utero development of mammary glands in CD-1 mice have been observed at fairly low doses (0.01 mg/kg/d to dams during gestation) (Macon et al., 2011). Effects on mammary gland development have been also observed in peroxisome proliferator-activated receptor alpha (PPARα) knockout mice, indicating that it is unlikely that PPARα plays any role in adverse impacts on mammary development (Zhao et al., 2010). Stimulatory effects on mammary development from peripubertal exposure to PFOA were associated with increased ovarian steroid hormone production, and with increased growth factors in mammary glands, independent of PPARα (Zhao et al., 2010), indicating that PFOA may act through an endocrine-disruption mechanism.

The potential carcinogenicity of PFOS/PFOA in the mammary gland and effects of exposure during various stages of life provide biologic plausibility to the hypothesis that PFOA may impact breast cancer and remain important topics for future research.

Phthalates

Phthalates, known as “plasticizers,” are added to plastics to increase flexibility, and are widely found in consumer products, including plastics used in food packaging, rain gear, footwear, and toys (NTP, 2006a; Rudel et al., 2011). They are also used in cosmetics and personal care products because of their viscosity and lipophilicity, and they are used in perfumes, lotions, suspension agents for aerosols, deodorants, and nail polish (Witorsch and Thomas, 2010). They are also present in some medical devices, blood storage bags, and intravenous tubing (CDC, 2011b). Human exposure to phthalates occurs through ingestion, inhalation, and dermal contact. They have been found to be metabolized and excreted quickly (Anderson et al., 2001). Human studies have identified phthalates in amniotic fluid (Silva et al., 2004), in breast milk (Parmar et al., 1985; Dostal et al., 1987), and in urine of people of all ages (CDC, 2003, 2005; Sathyanarayana et al., 2008).

Concerns have been raised about phthalates because of evidence from laboratory animals that they can act as anti-androgens to affect the development of the male reproductive system at low levels (NRC, 2008). The age of the animal is important for the development of health effects, with the fetus being the most sensitive life stage (NRC, 2008). In 2011, diethylhexyl phthalate was reevaluated by IARC and assigned to category 2B—possibly carcinogenic to humans—because of evidence that it induces Leydig cell tumors of the testes, liver tumors, and pancreatic tumors (Grosse et al., 2011). EPA (2011b) has made a similar classification. The European Union (EU) has banned several phthalates from cosmetics, and both the EU and

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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the United States have restricted the concentration of several phthalates in children’s toys.

Data relevant to the possible role of phthalates as a risk factor for breast cancer are limited. A case–control study of 233 women with breast cancer and 221 age-matched controls in Mexico measured urinary levels of phthalates prior to treatment (Lopez-Carillo et al., 2010). After adjustment for other breast cancer risk factors, a significantly elevated risk was found with higher urinary concentrations of monoethyl phthalate (MEP), the main metabolite of diethyl phthalate (DEP) (OR = 2.20, 95% CI, 1.33–3.63). The association was stronger for younger women with premenopausal breast cancer (OR = 4.13, 95% 1.60–10.70). Statistically significant negative or inverse associations were noted for exposure to monobenzyl phthalate (MBzP) (OR = 0.46, 95% CI, 0.27–0.79) and mono (3-carboxylpropyl) phthalate (MCPP) (OR = 0.46, 95% CI, 0.27–0.79). The findings in this study may have been influenced by the fact that the measurements were from urine collected from controls at home and from cases in the hospital, where exposures to phthalates could have been greater.

Some studies have observed effects on timing of puberty, attributed to phthalates’ hypothesized action as hormonally active environmental agents. Chou et al. (2009) studied pubertal timing in 30 Taiwanese girls with early thelarche (breast development), 26 with central precocious puberty,14 and 33 normal controls. Girls with premature pubertal timing had higher (p = .005) levels of monomethyl phthalate (MMP) than controls. Monobutyl phthalate and mono-(2-ethylhexl) phthalate were not associated with premature thelarche. Wolff et al. (2010) measured a panel of nine phthalates and other endocrine disruptors prior to pubertal onset in a cohort of 1,149 ethnically diverse American girls. There was a weak and statistically non-significant association between early puberty and a group of low–molecular weight phthalates and a weak association with later pubic hair development and a group of high–molecular weight phthalates.

Few animal and in vitro studies have assessed the effects of phthalates in females, and few directly assess mammary tumors as endpoints, particularly for in utero and early-life exposure. Standard carcinogenesis assays that expose adult rodents to di(2-ethylhexyl)phthalate (DEHP) or diisononyl phthalate (DINP) find tumors at multiple sites, including the testes, but not the mammary gland (EPA, 1997; CPSC, 2001). A study looking at in vivo and in vitro effects of phthalates found conflicting results regarding their estrogenicity; phthalates were able to induce an estrogenic effect in breast cancer cells in vitro, but were unable to do so in an immature rat

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14Girls with central precocious puberty had maturation of the breasts and external genitalia, advanced bone age, and obvious pituitary gonadotropin activity stimulating the gonads (Chou et al., 2009).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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model (Hong et al., 2005). More recent studies have found that DEHP is a potent and effective ligand for activation of the constitutive androstate receptor (CAR), a ligand-activated nuclear hormone receptor. The implications of these findings are not yet clear, but they do raise a new mechanism of action for this class of compounds that might be viewed as “endocrine disrupting” in a genetic subset of the population (those with certain CAR splice variants) (DeKeyser et al., 2009, 2011). Butyl benzyl phthalate has been shown to induce genomic changes in the rat mammary gland after neonatal and prepubertal exposure (Moral et al., 2007). In utero exposure in rats affected gene expression and proliferation in the mammary gland, mainly at the beginning of puberty, and also induced more proliferating terminal end buds by age 35 days (Moral et al., 2011). Effects on male and female mammary development were also observed in rats exposed to dibutylphthalate in utero and via lactation (Lee et al., 2004). The generalizability of these findings to other phthalates is not known. Further studies regarding early-life exposures and mammary lesions related to carcinogenesis and the potential mechanisms of the effects of phthalates are necessary to understand their role as a potential risk factor for breast cancer.

Polybrominated Diphenyl Ethers

Polybrominated diphenyl ethers (PBDEs) and other brominated and chlorinated flame retardants (BFRs/CFRs) represent a large class of organohalogenated compounds that were introduced in the 1970s (ATSDR, 2004) and are widely used as flame retardants in plastics, foams, textiles, electronic devices, and building materials (Darnerud et al., 2001; Costa et al., 2008; Lorber, 2008). In the 1970s, some flame retardants were voluntarily removed from the market. This action included polybrominated biphenyls (PBBs) after humans and livestock were accidentally poisoned and brominated tris (tris(2,3-dibromopropyl) phosphate) because of concerns about children’s exposures from its use in children’s pajamas. Two commercial mixtures of PBDEs have recently been phased out in the United States and banned in California: penta-BDE, which was used in commercial foam, and octa-BDE, which was used in textile coatings and in certain plastics. However, a variety of mostly untested halogenated flame retardants remain on the market, some in frequent use. IARC has not evaluated PBDEs. An EPA toxicological review on one of the penta-BDEs noted, “No studies currently exist on the potential carcinogenicity of BDE-99 [2,2´ 4,4´5-pentabromodiphenyl ether] in humans or experimental animals. Under the Guidelines for Carcinogen Risk Assessment (EPA, 2005b), there is ‘inadequate information to assess the carcinogenic potential’ of BDE-99 at this time” (EPA, 2008, p. 66).

Although routes of human exposure have not been well characterized

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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(Lorber, 2008), reports began to emerge in the late 1990s of high and rapidly rising body burden levels of PDBEs in humans (Hites, 2004; Sjodin et al., 2004; Suvorov and Takser, 2008), particularly in California (Petreas et al., 2003, 2011; Sjodin et al., 2008; Zota et al., 2008; Windham et al., 2010). The few studies of contemporary body burden levels appear to show considerable variation. Early studies concluded that all age groups had fairly similar levels of serum PBDE, except for infants and children from 0 to 4 years (Thomsen et al., 2002). Other studies have demonstrated an inverse association between age and PBDE body burden, with higher levels at younger ages, thought to be associated with breastfeeding and hand-to-mouth behavior in young children (Schecter et al., 2005; Betts, 2008; Costa et al., 2008; Rose et al., 2010). However, the NHANES data also provide some evidence for high exposure among Americans over age 60 (Sjodin et al., 2008), a disproportionate relationship that may be a result of consumers retaining PBDE-treated furniture over long periods of time (Betts, 2008).

Data on the carcinogenic potential of PBDEs in humans are extremely sparse, and to date, there have been few studies related to breast cancer. Elevated rates of total cancer, although not specifically breast cancer, have been reported among populations living in the Zhejiang province of China, an area with documented high levels of PBDE environmental contamination (Yuan et al., 2008; Zhao et al., 2008, 2009; Wen et al., 2009). Otherwise, only three small case–control studies have been published. Two Swedish studies found a modest, but statistically nonsignificant, increase in risk for non-Hodgkin’s lymphoma (Hardell et al., 1998), and a statistically significant three-fold increase in risk of testicular cancer in men whose mothers had serum levels of total PBDEs above the 75th percentile (Hardell et al., 2006). A California hospital-based case–control study of breast cancer failed to find an association between measured adipose levels of total PBDEs and breast cancer, although the study was small and the use of benign breast disease controls may have resulted in overmatching, hence making it more difficult to detect an association if one existed (Hurley et al., 2011).

Deca-BDE is believed to have a lower range of toxicities than the phased-out PBDEs, but it degrades to lower brominated forms that have much longer half-lives and greater toxicity. Deca-BDE has been classified by EPA (2008) as having suggestive evidence of carcinogenic potential, based on bioassays conducted 25 years ago showing statistically significant increases in male mice of hepatocellular carcinomas and adenomas (combined incidence) and marginal increases in thyroid gland follicular cell adenomas, as well as liver nodules in male and female rats (NTP, 1986). Standard 2-year carcinogenicity bioassays for the octa- and penta-BDEs have not been conducted, but NTP plans to test hexa-BDE 153 in long-term carcinogenesis studies (NTP, 2011b).

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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PBDEs and their hydroxylated metabolites and breakdown products have well-established endocrine-disrupting effects (Darnerud, 2008; Legler, 2008; Mercado-Feliciano and Bigsby, 2008a,b; Talsness et al., 2008). They also may modulate sex hormone activity. For example, several PBDE congeners and hydroxylated PBDEs have been found to be estrogen agonists in cell line assays based on ER-dependent luciferase reporter gene expression (Meerts et al., 2001), and other findings have also been indicative of estrogenic activity (Mercado-Feliciano and Bigsby, 2008a,b). Antiestrogenic activity for PBDEs and metabolites has been suggested and is currently an ongoing topic of research. For example, 22 hydroxylated PBDEs were found to significantly inhibit human placental aromatase activity (Cantón et al., 2008).

At present, the epidemiologic, animal, and in vitro evidence is insufficient to assess whether PBDEs are a risk factor for breast cancer. Despite phase-out or banning of certain formulations, the ubiquitousness and persistence of many PBDEs and continuing exposures to the deca-BDEs and their degradation products indicate the need for future research on their potential relationship to breast cancer.

Industrial Chemicals

Benzene

Benzene is a colorless, highly flammable liquid of both naturally occurring and man-made origins, and it is widely used in the United States for industrial purposes. It is present in gasoline and used as a gasoline additive (ATSDR, 2011a). It is also present in tobacco smoke. Commercial production dates back to the mid-1800s (NTP, 2011a). Benzene can evaporate rapidly into the air, where it can react with other chemicals, and it is also found in water and in soil, where it can persist for longer periods (ATSDR, 2011a). Early case reports and case studies indicated an increased risk of cancer in humans, particularly acute myeloid leukemia, and repeated epidemiologic findings of associations between benzene exposure and increased risk of acute myeloid leukemia have established benzene as a known human leukemogen (IARC, 1982, 1987; Baan et al., 2009; NTP, 2011a; Zhang et al., 2011). Associations of cigarette smoking with leukemias may be due to the benzene in tobacco smoke (Korte et al., 2000). More recent epidemiologic studies have also found an association between benzene exposure and increased risk of lymphatic and hematopoietic cancers (ATSDR, 2011a).

Benzene is classified as a human carcinogen by IARC (1982, 1987). In general, however, epidemiologic studies of benzene have focused on exposure in male workers and on the risk for hematopoietic cancers; few studies have examined risks for breast cancer. A study of a cohort of 797

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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benzene-exposed women working in an Italian shoe factory found elevated standardized incidence and mortality ratios for breast cancer based on small numbers of cases (standardized mortality ratio 151.1, 95% CI, 78.6–290.3 for latency period 30 years), lending “moderate support to the hypothesis that benzene constitutes a risk factor for breast cancer” (Costantini et al., 2009, p. 8). A case–referent study of premenopausal women (ages 40 and older) in western New York state found an increased risk for women considered likely to have had moderate to high exposure to benzene (OR = 1.95, 95% CI, 1.14–3.33) (Petralia et al., 1999). Petralia et al. also found risk increased with duration of exposure. Exposure as calculated was estimated based on employment histories and job-exposure matrixes. Two studies addressed breast cancer in exposed men. A study of Danish men occupationally exposed to gasoline and combustion products found an association with the development of breast cancer, especially if time of first employment occurred before age 40 (OR = 5.4, 95% CI, 2.4–11.9) (Hansen, 2000). An increased risk was also seen among male motor vehicle mechanics in a multination European case–control study (OR = 2.1, 95% CI, 1.0–4.4) (Villeneuve et al., 2010).

In animal studies, an increase in malignant mammary tumors was observed in rats and mice exposed to benzene by inhalation (Cronkite et al., 1984; Maltoni et al., 1989) and oral routes (Maltoni et al., 1989). Benzene is metabolized to an epoxide and other active metabolites. It has been proposed to operate through a genotoxic mechanism, eliciting clastogenic effects (causing disruption or breakage of chromosomes) (Dean, 1978, 1985; IARC, 1982; ATSDR, 1997). Evidence of this phenomenon has also been demonstrated in benzene-exposed workers, with more than 20 cytogenetic studies reporting changes in structural or numerical chromosomal aberrations (ATSDR, 1997; CalEPA, 2001).

In summary, evidence in animals suggests a basis for concern regarding increased risk for breast cancer from exposure to benzene, and there is also suggestive evidence from human studies. Because benzene is a known carcinogen for other endpoints, some efforts to minimize exposure of the public and workers are in place through various regulations, including the Clean Air Act, the Clean Water Act, and occupational safety standards (NTP, 2011a). Nonetheless, benzene from ambient and indoor air can be a significant contributor to low-level environmental risk estimates for leukemia. Further research will be needed to clarify the relationship between benzene exposure and risk of human breast cancer and relevant mechanisms that may be operating. If it can be developed, stronger human evidence of increased risk for breast cancer and the mechanisms involved would have important implications for its regulation, and also would provide insights relevant for other environmental contaminants.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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1,3-Butadiene

1,3-Butadiene is a gaseous hydrocarbon used primarily to make synthetic rubber and plastics such as acrylics. It is also present in gasoline, automobile exhaust, and cigarette smoke (NTP, 2011a). Exposure occurs primarily through inhalation of contaminated air and can result in effects on the nervous system or serious irritation of the eyes, nose, and throat (ATSDR, 2009). Levels are generally low in urban and suburban environments, unless near a factory producing the substance (ATSDR, 2009). 1,3-Butadiene is classified as a known human carcinogen, inducing hematopoietic cancers in occupational settings (IARC, 2008a; Baan et al., 2009; NTP, 2011a).

No human studies have evaluated the risk of breast cancer from exposure to 1,3-butadiene. Existing studies of butadiene are primarily of male workers in butadiene production and styrene butadiene rubber production. Other population-based studies have not evaluated breast cancer as an endpoint.

1,3-Butadiene causes malignant and benign mammary tumors in both mice and rats, at high and low doses (IARC, 2008). IARC (2008) found strong evidence that genotoxicity is the main mechanism for carcinogenesis. Butadiene is metabolized to DNA-reactive epoxides, and the urinary metabolites of these epoxides are observed in exposed humans. DNA adducts are observed in the lymphocytes of workers (IARC, 2008). Mutations in ras proto-oncogenes and p53 tumor suppressor genes were also identified in various butadiene tumors in mice.

Evidence in animals suggests biologic plausibility of increased risk for breast cancer from exposure to 1,3-butadiene. Because it is a known human hematopoietic carcinogen, efforts to control exposure are already in place (NTP, 2011a). While a finding of breast cancer in occupationally exposed women would have a significant impact for understanding the potential for chemicals to cause cancer, cohorts of heavily exposed women would be difficult to find and study.

Polychlorinated Biphenyls

PCBs are considered persistent organochlorines, and they include 209 possible forms or congeners (Calle et al., 2002). PCBs have been extensively used in the United States as industrial chemicals for purposes ranging from dielectric fluids to plasticizers to pesticide extenders to lubricants, and in consumer goods, but their U.S. production was ended in 1977 (Calle et al., 2002). Although PCBs are no longer produced, environmental contamination remains from old sealants, paints, transformers, and waste material (EFSA, 2010). PCBs bind strongly to soil and can also be taken

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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up by small organisms and fish (ATSDR, 2001). The lipophilicity of PCBs allows them to concentrate in the food chain, accumulate in the body, and resist metabolism (Hunter et al., 1997). IARC (1987) has classified PCBs as probably carcinogenic to humans and characterized the epidemiologic evidence as “limited.”

The interest in PCBs as a potential risk factor for breast cancer is because of their (1) persistence in the body, (2) estrogenic and endocrine disrupting properties, and (3) tumorigenic effects in animals (Moysich et al., 2002). Although PCBs have been extensively studied, the epidemiologic evidence for a link to breast cancer is inconsistent (Helzlsouer et al., 1999; Snedeker, 2001; Laden et al., 2002; Negri et al., 2003; Starek, 2003; Lopez-Cervantes et al., 2004; Brody et al., 2007; Gatto et al., 2007; Iwasaki et al., 2008; Salehi et al., 2008; Golden and Kimbrough, 2009; Itoh et al., 2009; Silver et al., 2009; Xu et al., 2010). A number of meta-analyses (Laden et al., 2002; Lopez-Cervantes et al., 2004; Salehi et al., 2008) have concluded that overall, there is no association. It is not clear whether the exposure periods studied, usually from adult life and a relatively short time before the diagnosis of breast cancer, are the most plausible from a life course perspective on breast development.

A more consistent pattern is emerging from studies addressing the degree to which polymorphisms in the cytochrome P-450 1A1 (CYP1A1) gene may influence the relation between PCB exposure and breast cancer risk. Several studies have reported elevated risks associated with high PCB levels among women with the CYPA1-m2 genotype (Moysich et al., 1999; Laden et al., 2002; Zhang et al., 2004; Li et al., 2005). Such polymorphisms were associated with a statistically significant increased breast cancer risk among women with elevated body burdens of PCBs; no correlation was found in women with low serum levels (Moysich et al., 1999). Findings regarding genetic polymorphisms and susceptibility to breast cancer risk are still preliminary and require further study; they are discussed further in Chapter 4.

Some evidence shows that PCB exposures in utero or in early life may influence pubertal development, but these relationships are not clear. Some studies have suggested delayed menarche and breast development in girls with higher blood levels of some PCB congeners (Den Hond et al., 2002; Wolff et al., 2008), but others have suggested no association with maternal levels (Gladen et al., 2000; Vasiliu et al., 2004).

Study of PCBs is complicated by the abundance of congeners, some with estrogenic and some with antiestrogenic properties. Epidemiologic studies have not been able to adequately consider ways in which different forms of PCBs might interact synergistically or antagonistically to influence breast cancer risk (Calle et al., 2002; Brody et al., 2007; Salehi et al., 2008). Furthermore, measurement of PCB levels at the time a breast cancer is diag-

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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nosed or at any single point will not adequately represent past exposure history because factors such as weight change and lactation history will influence metabolism and excretion (Verner et al., 2011), while changes in behaviors could alter exposures, particularly through the food chain.

Long-term animal carcinogenesis studies on mixtures of PCBs or specific congeners have found associations with increased liver tumors, but they have not found increases in mammary tumors (NTP, 2006a,b). However, the studies have been conducted with adult rats, and most studies have not assessed the effect of PCB exposure at earlier ages.

The large number of epidemiologic studies on this topic demonstrates consistency in showing no overall effect of PCB exposures on breast cancer risk. However, exposure was assessed in most cases in adult life, often during the period after PCB production ceased, when body burdens were declining. Some recent work suggests that women inheriting a variant of the cytochrome P-450 1A1 gene may be at higher risk for breast cancer from elevated PCB levels. A few investigations into early-life exposures have examined intermediate outcomes. Further research on early-life exposures and/or genetically defined subsets may be warranted.

Ethylene Oxide

Ethylene oxide, a colorless gas with a distinct odor, is used primarily for industrial and medical sterilization (IARC, 2008). Exposure to ethylene oxide occurs mainly in the workplace or in hospital settings. It is classified as a human carcinogen by both IARC (2008; Baan et al., 2009) and NTP (2011a) on the basis of a mix of evidence from epidemiologic, animal, and mechanistic studies. Mechanistic evidence of genotoxicity was a critical component of the IARC assessment.

IARC’s review characterized the overall body of epidemiologic evidence on the carcinogenicity of ethylene oxide as “limited” (IARC, 2008; Baan et al., 2009). The studies specifically concerning breast cancer incidence had varied results, with some finding no association and others finding a borderline significant excess risk (Norman et al., 1995). The study considered the most informative (Steenland et al., 2003) examined the breast cancer experience of a large occupational cohort. Risk among women with the highest level of exposure was significantly higher (OR = 1.74, 95% CI, 1.16–2.65) compared with women who had no exposure. This risk remained high (OR = 1.87, 95% CI, 1.12–3.10) among a subset of women for whom information on parity and history of breast cancer in a first degree relative was available for calculation of an adjusted odds ratio.

In peer-reviewed inhalation studies by NTP (1987), incidence of adenocarcinoma or adenosquamous carcinoma of the mammary gland were found elevated in female mice in the low-dose group. The finding in the

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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high-dose group was marginally increased. In vitro and mechanistic findings have been extensive. Ethylene oxide is an epoxide, and various epoxides, or chemicals metabolized to epoxides, have been found to cause malignant mammary tumors in laboratory animal studies (Melnick and Sills, 2001). Ethylene oxide has been shown to cause point mutations in ras proto-oncogenes and the p53 tumor suppressor gene (Houle et al., 2006). IARC (2008, p. 286) concluded that “the genotoxicity data in experimental systems consistently demonstrate that ethylene oxide is a mutagen and clastogen across all phylogenetic levels tested.”

There are insufficient data to determine whether ethylene oxide exposure during different life stages has a role in altering breast cancer risk. Nevertheless, the limited epidemiologic research on this compound does provide some support for an effect from adult exposures, and the animal bioassay data and the compound’s mechanism of action provide biological plausibility for the compound being a risk factor for breast cancer.

Vinyl Chloride

Vinyl chloride, also known as chloroethene, chloroethylene, and ethylene monochloride, is a colorless gas with a mild odor that is used in the production of plastics. Exposure occurs primarily in occupational settings via inhalation (ATSDR, 2006), and low-level environmental exposures occur through contaminated drinking water and in ambient air near manufacturing facilities. Vinyl chloride was once used as a propellant in hair sprays, deodorants, and other consumer products, but this use was phased out in the 1970s. IARC (2008) classifies vinyl chloride as carcinogenic to humans, with the human evidence showing cancers in the liver.

Data from human studies have not been adequate to evaluate a relationship between vinyl chloride and breast cancer. IARC (2008, p. 372) stated that “although concern has been raised about a potential association between exposure to vinyl chloride and the risk for breast cancer, human studies to date are not informative on this issue because of the very small numbers of women included.” An earlier review by the WHO International Program on Chemical Safety similarly concluded that a substantial body of epidemiologic studies with which to assess vinyl chloride is not available and would be difficult to conduct because women in most Western countries have little or no exposure to vinyl chloride, occupational or otherwise (IPCS, 1999). Vinyl chloride has been extensively tested for carcinogenicity in laboratory animals. The animal evidence on vinyl chloride was recently summarized by IARC (2008). Many of the papers from 1976 to 1983 found mammary adenocarcinomas in mice and mammary tumors in rats upon inhalation of vinyl chloride.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Mechanistic studies show that vinyl chloride is oxidized to chloroethylene oxide, which can rearrange to chloroacetaldehyde, and that these metabolites can react with nucleic acid bases to form DNA adducts in animals, which can initiate the genotoxic damage leading to carcinogenesis (IARC, 2008). There is, however, a paucity of data on the occurrence of such adducts in vinyl chloride-exposed humans. The mechanism that leads to base misincorporation following adduct formation is still unclear. Similarly, data are insufficient to draw a conclusion about the effects of timing of exposure to vinyl chloride on breast cancer.

Although considerable animal evidence indicates that the potential for induction of breast cancer from vinyl chloride is biologically plausible, the lack of substantial exposure opportunities for women makes this compound a low priority for future research.

Pesticides

DDT/DDE

Dichlorodiphenyltrichloroethane (DDT), an insecticide used extensively over the past century, was banned in the United States and other developed countries in the early 1970s because of its adverse ecological impacts. DDT and its major metabolite dichlorodiphenyldichloroethylene (DDE) have persistent and lipophilic properties that led to bioconcentration through the food chain. Because of continued use of DDT in developing countries for malarial control and the very long environmental half-life of DDE, these compounds remain present in the environment and in the population today (Petreas et al., 2004; CDC, 2008; Woodruff and Morello-Frosch, 2011).

Neither DDT nor DDE are mutagenic, but both possess estrogenic properties. Although structurally similar, there are substantial differences in the endocrine activity of DDT and DDE. Li et al. (2008) demonstrated that both p,p´-DDE and p,p´-DDT exhibited agonist activity toward ER-alpha, but DDE acted as an antagonist to both androgen and progesterone receptors, and p,p´-DDT had no effect on the progesterone receptor. There is good consensus among expert agencies regarding DDT’s potential carcinogenicity. IARC (1991) has classified DDT as “possibly carcinogenic to humans” (Group 2B); NTP has classified it as “reasonably anticipated” to be a human carcinogen (NTP, 2011a); and EPA has classified it as a “probable” human carcinogen (EPA, 2011c). Such classifications, however, are not specific to breast cancer.

Of the organochlorine pesticides, DDT/DDE has been one of the most studied for risk of breast cancer in humans, with numerous epidemiologic studies over the past decade. Several reviews (Snedeker, 2001; Calle et al.,

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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2002; Brody and Rudel, 2003; Brody et al., 2007) and a careful meta-analysis of 22 studies (Lopez-Cervantes et al., 2004) concluded that evidence was insufficient to infer a risk of breast cancer from DDT exposure.

As in most studies of cancer in relation to environmental chemicals, DDT/DDE exposure levels for most of the studies exploring risk for breast cancer were based on measurements in biologic samples taken near the time of diagnosis for cases, or at a similar time for noncases. A much-cited exception is a California study of 129 women with and 129 women without a diagnosis of breast cancer for whom archived blood samples drawn in the 1960s were assayed for levels of DDT/DDE (Cohn et al., 2007). In this study, although there was no evidence of an association between DDT/DDE exposure and breast cancer in general, the small subset of women who would have been under age 14 in 1945 (a time of peak DDT use) had a statistically significant five-fold higher risk. Although provocative in the context of potential windows of exposure, some skepticism has been expressed about the interpretation of these results because the high exposures that the “baby boomer” generation would have experienced might be expected to predict increasing rates of breast cancer in that birth cohort, but on the contrary their rates have been declining (Tarone, 2008). A previous nested case–control study that also used serum specimens drawn in the 1960s found no association with breast cancer risk, but the analysis did not stratify by birth cohort (Krieger et al., 1994). Similarly, no association was seen in a study that used blood samples obtained in 1974, 20 years before case status (Helzlsouer et al., 1999). A prospective study from Japan found no evidence for higher levels of DDT/DDE at a baseline measurement among the 144 women who had developed breast cancer during follow-up than among the controls (Iwasaki et al., 2008). Neither the Helzlsouer nor the Iwasaki study reported data on exposure concentrations assessed before adulthood.

In vivo animal data provide little support for the hypothesis that DDT or its metabolites could increase breast cancer risk in humans (NTP, 1978; IARC, 1991). However, such studies typically do not include early-life exposures. DDT and DDE are not mutagenic, but both have estrogenic activity (Andersen et al., 1999; Snedeker, 2001). Evidence also shows that administering DDT together with the known carcinogen DMBA can induce cellular and chromosomal alterations in the rat mammary gland (Uppala et al., 2005).

While the role of DDT in breast cancer risk remains unclear, it is possible that early-life exposures to this legacy chemical may play a role in the development of disease.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Dieldrin and Aldrin

Dieldrin and aldrin are persistent organochlorines. Aldrin breaks down to dieldrin in the body and in the environment, and they are closely related in structure. Until the 1970s, they were widely used as insecticides to control damage to crops, but concerns about damaging effects to the environment and health led EPA to ban dieldrin and aldrin for agricultural uses in 1970 and for all uses in 1987 (CDC, 2009b; ATSDR, 2011b). Because dieldrin persists in soil and is a water contaminant, exposure may occur by eating contaminated food (Snedeker, 2001; ATSDR, 2011b). Body burdens of dieldrin have declined, but are still measurable in U.S. adults (CDC, 2009b) due to its high lipophilicity and long biological half-life.

Epidemiologic evidence regarding exposure to dieldrin and subsequent risk of breast cancer is limited and often conflicting. Much of the early interest in dieldrin as a potential risk factor for breast cancer followed publication of the Copenhagen City Heart Study, a prospective study of 7,712 women with 268 cases of breast cancer in 17 years of follow-up (Hoyer et al., 1998). On the basis of serum samples from women who were exposed in the late 1970s, the women in the highest quartile of exposure had twice the risk of breast cancer when compared to the women in the lowest quartile. However, a prospective cohort study of 7,224 Missouri women serum donors was unable to find a similar association with breast cancer risk among 105 breast cancer cases identified during up to 9.5 years of follow-up (Dorgan et al., 1999). A subsequent population-based, case– control study found no substantial elevation in breast cancer risk in relation to the highest quintile of lipid-adjusted serum levels of dieldrin (Gammon et al., 2002).

Animal evidence on dieldrin exposure and mammary gland cancer is also insufficient to reach conclusions regarding hazard. Studies of carcinogenicity in mice via oral administration tend to demonstrate hepatic carcinogenicity as the primary effect (IARC, 1987, p. 185). Although xenoestrogenic potential has been a hypothesized mechanism for dieldrin, it is at best a weak estrogen whose estrogenic potential has not been adequately demonstrated (Snedeker, 2001). With the E-SCREEN assay, which assesses cellular proliferation in estrogen-dependent breast tumor cells, dieldrin is able to induce cellular proliferation only in the highest concentration that can be tested (Snedeker, 2001).

The potential influence of timing of exposure to dieldrin is difficult to assess. Most of the epidemiologic studies have relied on the levels of dieldrin in serum collected after the subject had developed breast cancer, so there is little information that can address whether timing of exposure is important. However, because dieldrin is no longer used and tissue and

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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environmental levels are declining, the committee does not see this area as a priority for additional research.

Atrazine and S-Chloro Triazine Herbicides

Atrazine is an S-chloro triazine herbicide used extensively in U.S. agriculture. Low-level contamination of groundwater with atrazine and other triazine herbicides is fairly common; as a result, its potential health effects have been the subject of substantial scrutiny. Exposure to atrazine via diet is very low. The primary nonoccupational route of exposure is through contamination of drinking water supplies. Such contamination is common, but based on monitoring carried out by EPA (2010a), it is usually at levels that are very low from a population risk perspective. The NHANES III study failed to identify atrazine metabolites in the urine in any of more than 4,000 samples collected between 1999 and 2004 (CDC, 2009b). Although many contaminants of groundwater persist for long periods once present, repeated analysis of atrazine-contaminated aquifers demonstrates that it does not generally persist. Thus exposures via groundwater, when they occur, are likely to be periodic. For example, samples of a drinking water supply in Ohio found no detectable atrazine (<2 ppb) in March, but a strong peak at 36 ppb in mid-April, with levels returning below the detection limit by mid-May (EPA, 2010a). Similar patterns have been seen in other water supplies (EPA, 2010a).

In reviews examining the risk of cancer in general, IARC found atrazine to be not classifiable regarding carcinogenicity in humans (IARC, 1999), and EPA found atrazine unlikely to cause cancer in humans (EPA, 2010a). In 2009, EPA began a reevaluation of the health effects of atrazine; that effort is ongoing (EPA, 2010a).

The few human studies examining atrazine as a potential risk factor for breast cancer have not indicated an association (Sathiakumar et al., 2011). However, most of the studies have been ecological in nature or otherwise would have had difficulty discerning an effect (e.g., studies carried out in occupational populations with few women).

Atrazine does not have direct estrogenic activity, but may indirectly modulate sex hormone levels by affecting steroidogenesis (Fan et al., 2007; Higley et al., 2010; Tinfo et al., 2011). Results of studies in animals have been complicated by findings that atrazine administered to Sprague Dawley female rats affects neuroendocrine pathways to accelerate reproductive senescence and cause mammary tumors not observed in mice or other rat strains (IARC, 1999; Rayner et al., 2005; Enoch et al., 2007; EPA, 2009a; Davis et al., 2011; Hovey et al., 2011). The hormonal manifestations of reproductive aging in humans are very different from those of Sprague Dawley rats, so this mechanism is not thought to be relevant to

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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humans (IARC, 1999). Similar conclusions were drawn regarding a chloro-S-triazine herbicide, cyanazine, from a 2-year bioassay in Sprague Dawley rats (Bogdanffy et al., 2000).

No epidemiologic studies have examined the effects of timing of exposure to atrazine. There are conflicting data from animal studies regarding whether low-dose atrazine exposures in utero can contribute to developmental abnormalities of mammary tissue in offspring (IARC, 1999; EPA, 2009a). Collectively, these data indicate that maternal atrazine exposure has no long-term effects on mammary gland development in female offspring beyond a transitory response to high doses. However, the degree to which atrazine may have effects by modulating steroidogenesis remains an area for further study.

PAHs

Polycyclic aromatic hydrocarbons, or PAHs, exist in more than 100 forms. They are formed from incomplete burning of coal, oil, gas, wood, tobacco, and other organic substances. They are also produced by high-temperature cooking. Humans can be exposed to PAHs through industrial and urban air pollution, tobacco smoke, and diet.

Evaluation of the carcinogenicity of PAHs is complicated by the hundreds of forms of PAHs with differing compositions and properties. An IARC review evaluated evidence through 2005 on 60 PAH compounds, with separate classifications for individual PAH compounds (IARC, 2010d). Benzo(a)pyrene (BaP) was declared carcinogenic to humans (Group 1) “based on sufficient evidence in animals and strong evidence that the mechanisms of carcinogenesis in animals also operate in exposed human beings” (IARC, 2005, p. 23). Cyclopenta[cd]pyrene, dibenz[a,h]anthracene, and dibenzo[a,l]pyrene were classified as probably carcinogenic to humans (Group 2A) based on sufficient evidence in animals and compelling genotoxicity evidence. IARC also found sufficient evidence in humans for the carcinogenicity of a variety of occupational exposures involving PAHs (i.e., during coal gasification, coke production, coal-tar distillation, paving and roofing, and chimney sweeping). The main epidemiologic findings were of increased risk of lung or skin cancer but not breast cancer. Typically, however, such studies are dominated by men and inhalation or dermal exposure.

PAHs’ effects on breast cancer risk have been evaluated in a number of noteworthy epidemiologic studies published since 2005, but the results have been inconsistent. A meta-analysis of 10 dietary studies as well as a large prospective cohort study with 8 years of follow-up and 3,818 cases of invasive breast cancer found no correlation between darkly cooked meats and breast cancer (Steck et al., 2007; Kabat et al., 2009). A few studies have attempted to elucidate risks from specific time periods of

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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exposure. A case–control study from western New York used historical levels of total suspended particulates (TSPs) in the air as a proxy for PAH exposure. Residential histories were used to link study participants to TSP levels at specific times in their lives (e.g., birth, menarche). In women with postmenopausal breast cancer, potential exposure to high concentrations of TSPs at birth was associated with an elevated risk that was on the borderline of significance (OR = 2.4, 95% CI, 0.97–6.09), although the relationship could have been related to unmeasured confounding factors (Bonner et al., 2005). A more recent study from the same group examined exposure to traffic emissions at specific times on the basis of residence (Nie et al., 2007). Higher exposure at the time of menarche was associated with increased risk for premenopausal breast cancer (OR = 2.05, 95% CI, 0.92–4.54, p for trend = .03). Higher exposures at the time a woman had her first birth were associated with a significantly increased risk for postmenopausal breast cancer (OR = 2.57, 95% CI, 1.16–5.69, p for trend = .19) (Nie et al., 2007).

PAHs’ effects on DNA have been explored in a series of case–control studies in the Long Island Breast Cancer Study. The presence of PAH-DNA adducts, which form after exposure to PAHs and are measured in lymphocytes, were associated with a 29 to 35 percent increase in the risk of breast cancer, with no dose–response relationship (Gammon et al., 2002, 2004). A later analysis in the same study confirmed slightly elevated risks (HR = 1.2, 95% CI, 0.63–2.28) for breast cancer–specific mortality associated with PAH-DNA adducts (Sagiv et al., 2009). In contrast to the generally positive studies from Long Island (Gammon and Santella, 2008), results from the Shanghai Women’s Health Study (354 cases, 708 controls) found no association between PAH metabolites and oxidative stress markers and breast cancer (Lee et al., 2010). Thus, overall results of epidemiologic studies of PAHs and breast cancer have relied on indirect measures of exposure and been inconsistent.

Inconsistencies in the results from epidemiologic findings on PAHs follow from a number of limitations. Case–control designs depend on respondent recall of information on diet, smoking, and environmental exposures from the past, proxy measures of exposure, or assays of measures of PAH exposure (PAH-DNA adducts) after the diagnosis of breast cancer. In addition, PAH-DNA adducts may be a measure of exposure rather than of the host’s biologic response to PAH. Although the studies from western New York have been generally consistent in their levels of risk estimates, and the studies from the Long Island Breast Cancer Study and western New York have linked PAH-DNA adducts to breast cancer and suggested a number of molecular mechanisms, including gene–environment interactions (Gammon and Santella, 2008), epidemiologic studies of PAHs in breast cancer etiology provide modest support for their carcinogenicity in human breast cancer.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Biologic mechanisms by which PAHs may affect breast cancer risk have been explored rather extensively. PAHs have often been implicated as inducers of mammary tumors in rodents (Tannheimer et al., 1997). However, some of the earlier, most cited evidence of rodent carcinogenicity involved direct applications of PAHs to the mammary gland (Cavalieri et al., 1988; IARC, 2010d). Studies have shown that PAHs are aryl hydrocarbon receptor (AhR) agonists that bind and activate AhR, a receptor that regulates xenobiotic metabolism and initiates homeostatic responses. The nature of the response to AhR binding is specific to the compound bound. AhR affects the expression of CYP 1 enzymes involved in the metabolism of PAHs (IARC, 2010d), and this is hypothesized to lead to greater formation of active metabolites and ultimately DNA mutations (Kemp et al., 2006). Cross talk of AhR with steroid and nuclear receptors can affect many estrogen-dependent pathways, and this cross talk can be influenced by an AhR ligand to PAHs (Hockings et al., 2006). PAHs exhibit weak estrogenic and antiestrogenic activity (Santodonato, 1997), and BaP weakly binds to estrogen receptor α (Pliskova et al., 2005). It is difficult to extrapolate such findings to the potential for breast cancer following human systemic exposure.

However, it is clear that, following oral exposure, various carcinogenic PAHs, including BaP, are absorbed and widely distributed to most tissues, and that PAHs are gradually taken up and also released by fatty tissues (IARC, 2010d), such as mammary tissue. Various enzymes involved in metabolizing carcinogenic PAHs such as BaP to epoxides (e.g., CYP1A1, CYP1B1, and epoxide hydrolase involved in forming diol epoxides [IARC, 2010d]) are present in human breast (Williams and Phillips, 2000). Numerous studies demonstrate and characterize covalent DNA-adducts formed in human mammary tissues from donors or various established cell lines exposed to certain carcinogenic PAHs. Mechanistic and in vitro studies are difficult to interpret due to the complexity of the carcinogenesis. There is a strong chain of mechanistic evidence linking BaP exposure to the cause of a specific mutation in human lung cancer, which, together with numerous studies demonstrating animal carcinogenesis, led IARC (2010d) to declare BaP to be carcinogenic to humans. While overall the mechanistic evidence on various PAHs support the biological plausibility that they may influence breast cancer risk, all the elements of such a chain are not present for any of the PAHs and breast cancer. Animal studies on PAHs have not sufficiently addressed breast cancer endpoints or mammary tumors, and further investigation is required to specifically address carcinogenicity in the mammary gland. Future epidemiologic, in vivo, and in vitro research is needed to further assess the role of PAHs in breast cancer etiology.

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Dioxins

The dioxins are a family of highly persistent, lipophilic, and toxic by-products of industrial processes and incineration. The dioxin-like compounds include various furans and coplanar PCBs, but the congener 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) is considered the most potent of the dioxins and dioxin-like chemicals (CDC, 2009b) and has been a major focus of concerns about carcinogenicity. The release of into the environment has declined since the 1970s, and average tissue concentrations in U.S. adults also appear to have declined (CDC, 2009b). In NHANES data from 2003–2004, mean TCDD levels were below the limit of detection (CDC, 2009b). TCDD has been classified by IARC (1997; Baan et al., 2009) as a human carcinogen (Group 1) and by EPA as carcinogenic to humans (EPA, 2000), although the classification of dioxins as “known human carcinogens” by IARC and EPA remains controversial (NRC, 2006). Evidence implicating TCDD and related dioxins as human carcinogens has primarily been based on overall excess cancer mortality in highly exposed occupational cohorts of men and on elevated incidence of some cancers among residents of Seveso, Italy, who experienced high levels of exposure from a major 1976 industrial accident.

Evidence regarding an association between dioxin exposure and breast cancer is more limited. Repeated reviews have found the epidemiologic evidence on the relation between TCDD exposure and breast cancer, including data on the experience of the Seveso residents, inconclusive (IOM, 2011). Follow-up of the Seveso population over 20 years has not found an excess of breast cancer, although the eight observed cases among the small population living in the most contaminated area were more than the expected number (RR = 1.43, 95% CI, 0.71–2.87) (Pesatori et al., 2009). A significant elevation of breast cancer, based on 15 cases, was initially reported associated with a measured 10-fold increase in TCDD levels in blood samples collected from women enrolled in the Seveso Women’s Health Study (crude HR = 2.1, 95% CI, 1.0–4.6), a cohort of 981 young women (ages 0–40) enrolled shortly after the Seveso incident in 1976 (Warner et al., 2002). In a 32-year follow-up of the Seveso cohort, with 33 diagnosed breast cancer cases and with adjustment for other risk factors for breast cancer, the risk association was very similar to that from the population-based study, and no longer statistically significant (HR = 1.44, 95% CI, 0.89–2.33) (Warner et al., 2011). Two small hospital-based case–control studies have found that levels of dioxins measured in adipose samples from women undergoing surgery for breast cancer or for benign breast conditions were not significantly different between the cases and controls (Hardell et al., 1996; Reynolds et al., 2005).

Several large and well-conducted TCDD-related cancer bioassays

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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(Kociba et al., 1978; NTP, 1982a,b, 2004) have reported induction of several types of cancer in both rats and mice. In all studies in which TCDD elicited an increase in tumors, the increase was site specific, most frequently the liver. Mammary tumors were not increased in any study. In some studies, mammary gland tumors in Sprague Dawley rats were significantly reduced at the highest doses (Kociba et al., 1978; NTP, 2006b). Thus, although evidence is clear that TCDD causes liver tumors in experimental animals, none of the standard 2-year in vivo animal oncogenicity bioassays have identified the mammary gland as a target for carcinogenesis from dioxins alone. In all these studies, exposure began when the animals were weaned. However, a single dose of 1 μg/kg TCDD on day 15 of gestation produced alterations in terminal end buds and fewer lobules in 50-day-old offspring. Although this prenatal TCDD treatment did not alter the labeling index in the mammary terminal ductal structures of 21- and 50-day-old rats, it did result in an increase in the number of chemically induced mammary adenocarcinomas in rats (Brown et al., 1998). Other studies have also shown that early-life exposure to TCDD can alter mammary gland development (Brown and Lamartiniere, 1995; Vorderstrasse et al., 2004; Wang et al., 2011). Thus, the potential for exposure to TCDD and other dioxins to alter mammary gland development early in life cannot be excluded.

TCDD and other dioxins are generally not mutagenic and do not bind to the estrogen receptor, although one study found that TCDD can induce oxidative stress and subsequent DNA strand breaks in MCF7 breast cancer cells (Lin et al., 2007).

Dioxins’ mode of action as a putative hepatocarcinogen requires binding and activation of the AhR, which causes a cascade of downstream effects on gene expression for genes involved in a variety of biological processes. Whether such changes in AhR-mediated gene expression might alter mammary tumor development later in life has been studied in animals. Two in vivo studies examining whether early-life exposure to dioxins can increase the incidence of carcinogen-initiated mammary tumors did not provide evidence of such an effect (Desaulniers et al., 2004; Wang et al., 2011). It has also been hypothesized that through interactions with other factors, early-life exposure to dioxins may modify mammary gland development and eventually tumorigenesis. A novel mouse experiment that combined maternal TCDD exposure and a high-fat diet in mothers and offspring found that this combined exposure increased mammary cancer incidence in the offspring by two-fold after oral administration of a standard cancer-inducing agent (La Merrill et al., 2010). The maternal oral TCDD dose was high relative to human intakes, resulting in less sequestration by the maternal liver and proportionally more fetal exposure than would be seen at lower doses or from a similar cumulative dose from chronic repeated exposure at lower doses (Bell et al., 2007). These data are indicative of a

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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potential hazard at sufficient doses in combination with a high-fat diet, but the animal exposure experience is not directly equivalent to typical human exposures.

Although 3-methylcholanthrene has been shown to stimulate estrogen receptor alpha in several different ER response assays (Shipley and Waxman, 2006), TCDD and other dioxin analogs induced tissue-specific inhibition of estrogen-induced genes and pathways (Safe and Wormke, 2003; Safe, 2005). Indeed, several structural analogs of chlorinated dioxins have been proposed as tamoxifen-like antiestrogens for treatment of ER-negative breast cancer (Zhang et al., 2009).

Neither human nor animal evidence suggests that exposure to TCDD or other dioxin-like chemicals is directly associated with an increased risk for breast cancer. Some intriguing animal evidence suggests the possibility that early exposure to TCDD may interact with other factors, such as a high-fat diet, to alter breast cancer risks. Although human exposure to TCDD may have declined from peak levels, TCDD persists in the body, and further research may help clarify the nature of its potential interactions with other exposures.

SUMMARY

From the committee’s qualitative review of relevant literature on the factors it selected, it found that the factors with the clearest evidence from epidemiologic studies of increased risk of breast cancer were combination HT products, current use of oral contraceptives, overweight and obesity among postmenopausal women, alcohol consumption, and exposure to ionizing radiation. Greater physical activity is associated with decreased risk. Some major reviews have concluded that the evidence on active smoking is consistent with a causal association with breast cancer, and other large-scale reviews describe the evidence as limited. For several other factors reviewed by the committee, the available epidemiologic evidence is less strong but suggests a possible association with increased risk: passive smoking, shift work involving night work, benzene, 1,3-butadiene, and ethylene oxide. In some cases—for example, BPA, zearalenone, vinyl chloride, and alkylphenols—human epidemiologic evidence regarding breast cancer is not available or inconclusive, but findings from animal or mechanistic studies suggest some basis for biological plausibility of an association. A few factors, such as non-ionizing radiation and personal use of hair dyes, have not been associated with breast cancer risk in multiple, well-designed human studies. For several other factors, evidence was too limited or inconsistent to reach a conclusion (e.g., nail products, phthalates). In all cases, these conclusions are based on assessments of the currently available evidence. It is always possible for new evidence to point to different conclusions, as

Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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science evolves, new methodologies are applied, and research strategies to examine timing of exposure are developed.

For this review, the evidence was typically considered singly for each chemical or mixture addressed. As discussed further in the next chapter, effects attributed to any one factor evaluated in a study may in fact be due, or due in part, to other factors that might co-occur.

For most of the factors examined, the committee’s review found information on the potential for exposure at different life stages to affect risk to be limited or nonexistent. Similarly, the evidence available rarely reported on types of tumors grouped on the basis of characteristics such as hormone receptor status. The committee sees a need for future research to better reflect the growing understanding of a life course perspective whereby the potential for influencing breast cancer risk may depend exquisitely on the timing of exposure, and an appreciation of the potential for different factors to play a role in specific, etiologically distinct varieties of breast cancer based on histologic or molecular subtype.

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Suggested Citation:"3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Breast cancer remains the most common invasive cancer among women. The primary patients of breast cancer are adult women who are approaching or have reached menopause; 90 percent of new cases in U.S. women in 2009 were diagnosed at age 45 or older. Growing knowledge of the complexity of breast cancer stimulated a transition in breast cancer research toward elucidating how external factors may influence the etiology of breast cancer.

Breast Cancer and the Environment reviews the current evidence on a selection of environmental risk factors for breast cancer, considers gene-environment interactions in breast cancer, and explores evidence-based actions that might reduce the risk of breast cancer. The book also recommends further integrative research into the elements of the biology of breast development and carcinogenesis, including the influence of exposure to a variety of environmental factors during potential windows of susceptibility during the full life course, potential interventions to reduce risk, and better tools for assessing the carcinogenicity of environmental factors. For a limited set of risk factors, evidence suggests that action can be taken in ways that may reduce risk for breast cancer for many women: avoiding unnecessary medical radiation throughout life, avoiding the use of some forms of postmenopausal hormone therapy, avoiding smoking, limiting alcohol consumption, increasing physical activity, and minimizing weight gain.

Breast Cancer and the Environment sets a direction and a focus for future research efforts. The book will be of special interest to medical researchers, patient advocacy groups, and public health professionals.

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