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4
Challenges of Studying
Environmental Risk Factors
for Breast Cancer
T
he committee was asked to review the methodologic challenges
involved in conducting research on breast cancer and the environ-
ment. New insights into carcinogenesis are giving researchers new
opportunities to explore both the biology and the epidemiology of breast
cancer in relation to environmental exposures. Although progress has been
made in investigating the role (whether adverse or not) of environmental
factors in breast cancer, the scope of the potential research questions is
vast and the questions to be answered are complex. This chapter reviews
challenges facing researchers on a variety of fronts, including the nature of
the various forms of breast cancer; the diversity and complexity of environ-
mental factors; identifying and measuring exposures at appropriate times;
genetic complexity that is still unfolding; and the inherent limitations of
the laboratory and epidemiologic tools available to evaluate associations
between environmental exposures and disease.
COMPLEXITY OF BREAST CANCER
As noted in Chapter 2, breast cancer is a term that captures what is
likely to be several diseases. Tumor types have been categorized based on
several different characteristics, including age or menopausal status of the
woman at the time of diagnosis; the state of the tumor as in situ or invasive;
the extent of spread from the initial tumor site; cell type (lobular, ductal);
and molecular features of the cells, such as the presence or absence of hor-
mone or growth factor receptors (e.g., estrogen or progesterone receptors
[ER or PR], human epidermal growth factor receptor 2 [HER2]). Within
177
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178 BREAST CANCER AND THE ENVIRONMENT
each of these broad categories is considerable variability in tumor charac-
teristics and gene expression. A study examining the gene expression of 65
surgical samples of breast tumors from 42 individuals’ cancers found each
tumor to have a distinctive molecular portrait. The tumors showed great
variation in their patterns of gene expression, and the variation was multi-
dimensional: different sets of genes showed largely independent patterns of
variation (Perou et al., 2000). Further study of the molecular pathology of
breast cancer has shed additional light on the possible divergent evolution-
ary pathways of breast cancer progression, revealing still more complexity
(Bombonati and Sgroi, 2011), as discussed in Chapter 5.
While characterizations of tumor and cancer types, such as those noted
above, are proving increasingly useful as guides to clinical care and prog-
nosis, their relevance to etiology is not clear. Some associations have been
observed between certain tumor types and risk factors (e.g., obesity and
ER-positive [ER+]) tumors, but for the most part, the mechanistic basis for
these relationships remains to be clarified, as described further in Chapter 5.
Various schematics have been used to illustrate the complexity and
interconnectedness of potential factors in breast cancer causation. Howell
et al. (2005), for example, illustrate possible roles for genes, pathways, risk
factors, modifiable variables, and life events (Figure 4-1). In this represen-
tation of some of the known modifiable and unmodifiable risk factors for
breast cancer, alcohol serves as an example of a factor that might alter risk
for breast cancer in multiple ways. Through induction of aromatase activ-
ity, it may foster conversion of androgens to estrogens that have a causal
role in breast cancer (Etique et al., 2004). It has also been hypothesized to
contribute to genomic instability (Benassi-Evans and Fenech, 2011). Fur-
thermore, it may act indirectly in that its calories can contribute to obesity
that itself is associated with breast cancer.
Another illustration (Figure 4-2) of the numerous interrelated factors
important in the etiology of breast cancer comes from a complex systems
model developed by Robert Hiatt and colleagues as part of a project spon-
sored by the California Breast Cancer Research Program.1 The developers
of this model used expert opinion to select causal factors from four large
domains (Societal/Cultural, Physical/Chemical, Behavioral, and Biologi-
cal) to illustrate the multiple levels of causation that must be considered
along with how the factors are integrated across levels and over time. Even
though multiple key factors are present, all possible etiologic factors were
not included for relative simplicity in interpretation. The model focuses
solely on postmenopausal breast cancer because of the different etiologic
factors and pathways for premenopausal disease. It takes into account both
1 Personal communication, R. A. Hiatt, University of California, San Francisco, May 21,
2011.
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Unavoidable LOW PENETRANCE GENES HIGH PENETRANCE GENES
Aging
(inherited)
risk factors
CHEK2/ATM
Fibrosis genes
BRCA1/BRCA2 RE-EXPRESSION OF
FETAL GENES
RADIOSENSITIVITY GENOMIC INSTABILITY
Steroid hormone
‘Obesity genes’ ‘CAFs’
DENSITY TUMORIGENESIS
pathway
ESTROGEN
Early menarche
INFLAMMATION Late menopause
OBESITY
No or late 1st
pregnancy
Modifiable
Healthy diet Alcohol Exercise SERMs & AIs Oophorectomy HRT
risk factors/
management
AGE
FIGURE 4-1 Overview of risk factors associated with breast complexity.eps diagram summarizes the unavoidable (inherited) and
Figure 4-1 cancer. “The
modifiable risk factors that can ultimately lead to tumorigenesis. Genes/pathways/risk factors are shown in red; inherited or un-
modifiable factors are shown in green; modifiable variables are shown in blue; life events are represented by gray boxes; increased/
positive effects are denoted by solid arrows; and reduced/negative effects are denoted by dashed arrows. AIs, aromatase inhibi-
tors; ATM, ataxia telangiectasia mutated; BRCA1 and BRCA2 (genes in which deleterious germline mutations increase the risk of
cancer); CAFs, cancer-associated fibroblasts; CHEK2, CHK2, checkpoint homolog; HRT, hormone replacement therapy; SERMs,
selective estrogen receptor modulators.”
SOURCE: Adapted from Howell et al. (2005, p. 638). Used with permission; Howell, A., A. H. Sims, K. R. Ong, M. N. Harvie,
D. G. Evans, and R. B. Clarke. 2005. Mechanisms of disease: Prediction and prevention of breast cancer—cellular and molecular
179
interactions. Nat Clin Pract Oncol 2(12):635–646.
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SOCIETAL/
180
CULTURAL
PHYSICAL/
CHEMICAL
Country of Birth
Environmental tobacco
Education
Sleep disturbance
Occupation Endocrine disruptors
(e.g., BPA, organochlorines)
Race/Ethnicity
Latitude
Radiation/
Income Medical imaging
Breastfeeding
Vitamin D
HRT
Post Menopausal
Alcohol Breast Cancer
Genotoxins
Incidence
Phytoestrogens
(e.g., soy)
Age at first birth, parity Age
Physical Breast density
quality of data activity
Height High penetrance genes
(1 = strongest)
(e.g., BRCA1, BRCA2, TP53)
1 Tobacco use Age at
2
Endogenous hormones menopause
3
(e.g., IGF, estradiol)
strength of assoc Low penetrance genes
Obesity
Immune function
(1 = strongest) (e.g., CASP8, 2a35,
(inflammation) FGFR2)
1 Age at menarche
2
3
4 Insulin resistance
BEHAVIORAL Ancestry
BIOLOGICAL
• This model is specific to incidence, not survival
• Factors may differ by tumor subtype
FIGURE 4-2 Illustration of an evidence-based complex-systems model of postmenopausal breast cancer causation. This model dis-
plays multiple factors associated with postmenopausal breast cancer causation in four broad domains and shows their interconnec-
tions across levels (genes to society) by arrows that indicate variations in the strength of the associations and the quality of the data.
SOURCE: Personal communication, R. A. Hiatt, University of California, San Francisco, May 21, 2011. Developed with support
from the California Breast Cancer Figure 4-2 Hiatt Model for NAP 12-6-11.eps
Research Program.
type is small, landscape
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181
CHALLENGES OF STUDYING ENVIRONMENTAL RISK FACTORS
the strength of the associations as well as the quality of the data in the size
and hatching of the interconnecting arrows.
Diagrams such as these, which attempt to depict the multiplicity of
factors that seem to have a role in breast cancer, help underline the biologi-
cal complexity of the pathways along which those factors may be acting,
the difficulty of distinguishing truly causal effects from associations with
intermediate factors, and the challenges of designing, conducting, and
interpreting studies that try to evaluate risk factors for the various forms
of this disease.
Although these challenges share similarities across the spectrum of risk
factors evaluated in this report, they may be particularly acute for evaluat-
ing risk relationships from exposures to environmental chemicals. For stud-
ies in humans, these include the issues inherent to estimating and assessing
exposures, the study design and analytic challenges of environmental epi-
demiology, and efforts to account for genetic differences in susceptibility to
cancer and potential gene–environment interactions. The next portion of
this chapter pays particular attention to the challenges in studying environ-
mental chemicals. Studies in animals and in vitro systems pose their own
technical obstacles and challenges of interpretation and extrapolation to
humans, which are discussed in a subsequent portion of the chapter.
STUDYING ENVIRONMENTAL CHEMICAL AND
PHYSICAL EXPOSURES THROUGH HUMAN STUDIES
As noted previously, the committee has adopted a broad approach to
the definition of “environment.” A subset of environmental exposures that
are of potential concern in the etiology of breast cancer is that of specific
chemical and physical agents that might influence breast cancer develop-
ment. Although information on exposure and the toxicology of many
chemicals may be incomplete, for many other chemicals, knowledge of
some their properties indicates that they are unlikely to be mutagenic or
carcinogenic.
Whether other agents in the environment are able to causally contribute
to breast cancer is highly dependent upon both the duration and magni-
tude (dose) of exposure. One of the most difficult problems in conducting
epidemiologic studies on environmental exposures and health effects is to
obtain reasonably accurate measurements or estimates of exposures rel-
evant to the disease process. These exposures may occur at low or varying
levels or both, for which the relevant time period—the window when the
exposure might influence the development of a tumor—is unknown, or they
may have occurred years or decades previously. The sections that follow
address some of the specific challenges associated with assessing exposures
to environmental and physical agents and illustrate the need for additional
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182 BREAST CANCER AND THE ENVIRONMENT
or more refined tools to aid in disentangling the possible contributions of
these environmental factors to breast cancer.
Assessing Exposures to Chemical and Physical Agents in the Environment
Both the nature of the exposures to chemical and physical agents and
the limited means for measuring or assessing them pose challenges for
observational research. Human exposures to substances in the environ-
ment take place throughout the life course, and in all settings. People are
exposed to myriad substances in air, water, and food encountered in homes,
schools, workplaces, and even before birth via in utero exposures. A per-
son is exposed not only to individual chemicals, but to mixtures of many
different substances, at varying doses simultaneously or at different times.
Sometimes it is possible to identify individuals or groups, such as workers
in particular occupations, whose typical exposures are considerably higher
than those of the average person.
Epidemiologic studies assess whether groups with higher exposures are
more likely to experience the outcome of interest, cancer for example, than
groups with lower exposures. Determining who is exposed and the degree
of their exposures are critical to accurately assessing the association with
the health outcome. However, errors in classifying who is more and who is
less exposed (exposure misclassification) could limit the ability of a study to
show an association with the risk factor where there is one. Thus, accurate
exposure assessment is a critical component of human studies to evaluate
risk factors for breast cancer or any health outcome.
Historically, studies in occupational settings have been an important
means for identifying most chemical carcinogens because in occupational
settings, chemical use is often documented and exposure levels tend to be
higher than elsewhere. Assessment of exposures in occupational studies are
facilitated by extensive sources of data, such as job histories, understanding
of production processes and chemicals used, and data from personal or area
sampling to measure exposures, as required by the Occupational Safety and
Health Administration (OSHA) and standard industrial hygiene practices.
Exposure of certain workers to some chemicals may be thousands (or more)
times greater than that experienced by the general public, while other work-
ers with different job tasks might experience a wide range of exposures.
This variability makes it easier to distinguish people who are exposed to
very high levels from those with lesser exposure. The greater the contrast,
the firmer the conclusions that can be drawn about differences in risk of
disease. When exposure levels are low, contrasts are smaller and exposure
misclassification is likely to be relatively greater. Determining exposures
can be more difficult in environmental settings, particularly for chemicals
that are not regularly monitored in air or food, or for chemicals for which
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183
CHALLENGES OF STUDYING ENVIRONMENTAL RISK FACTORS
exposure occurs indoors as a result of specific behaviors or products used.
For these reasons, environmental epidemiologic studies are a less effective
or efficient approach than occupational epidemiologic studies for demon-
strating associations between chemicals and increased rates of disease.
Few of the chemicals identified by the International Agency for
Research on Cancer (IARC) or the U.S. Environmental Protection Agency
(EPA) as human carcinogens have been classified as such on the basis of
studies showing breast cancer in humans. One cannot conclude, however,
that these chemicals do not contribute to breast cancer. For virtually all
carcinogens identified by IARC and EPA, the evidence base has primarily
been from occupational epidemiologic studies for reasons described. For the
vast majority of these chemicals, the cohorts were assembled and followed
during the 1940s through the 1970s, periods when most industrial firms
employed only men.
Historically, therefore, most epidemiologic studies of cancer in the
workplace omitted women from the analysis because there were too few
present to observe an effect. Because breast cancer is rare in men, such stud-
ies lacked the power to detect breast carcinogens. (Power is a function of
the expected number of cases of disease in the studies, the level and variabil-
ity of exposure, the validity of the exposure assessment, and the strength
of the true underlying association.) Not only are studies of breast cancer
in men underpowered, but also, extrapolation of cancer findings from men
to women, which may be justified for other forms of cancer, might not be
appropriate for breast cancer.
Beyond the Workplace: Environmental Chemical Exposures
Outside the workplace, exposures to chemicals arise in multiple loca-
tions (home, car, ambient air pollution); from multiple activities, including
commuting, cleaning, gardening, and smoking; and through different routes
of exposure (ingestion, inhalation, dermal absorption).
The home, where people typically spend most of their time2 (Klepeis et
al., 1995), provides opportunities for exposure to many chemicals, includ-
ing naturally occurring chemicals in the diet as well as chemicals from food
packaging, processing, or cooking; the release of volatile chemicals from
carpets, furniture, clothing treatments, and cleaning products; home use of
pesticides; use of cosmetics and personal care products; tobacco smoke; and
infiltration of ambient air pollution. Typically, thousands of synthetic and
naturally occurring chemicals are present in people’s homes and diet, most
at relatively low concentrations.
2 Surveydata indicate that on average people spend 69 percent of their time in a residence
and 87 percent of their time in enclosed buildings (Klepeis et al., 1995).
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184 BREAST CANCER AND THE ENVIRONMENT
The 20th century saw a substantial increase in the synthesis of new
chemicals. Tens of thousands of chemicals are used in commerce, and more
than 3,000 industrial chemicals (excluding polymers), mostly organic com-
pounds, are produced or imported into the United States at rates exceed-
ing 1 million pounds per year (EPA, 1998b). These are known as high
production volume chemicals. A 1998 EPA report found that insufficient
testing had been done to evaluate the health effects of all but a few of these
chemicals. Of 2,800 chemicals investigated, 93 percent lacked one or more
of the six basic toxicity tests,3 and 43 percent of the chemicals had under-
gone none of these tests, which are considered necessary for a minimum
understanding of a chemical’s toxicity. The percentage of chemicals with
complete or at least some toxicity information was considerably higher for
chemicals with potential for greater exposure through industrial releases or
for those in consumer or children’s products. In addition, not all of these
3,000 chemicals are of high priority for testing, because they belong to
chemical classes or structural groups for which there is less concern regard-
ing mutagenicity, carcinogencity, or endocrine effects. The High Production
Volume Chemicals Program (HPV Program) is an international program to
assess the potential hazard of chemicals produced in high volumes. Produc-
tion levels of specific chemicals can change over time as demand for them
increases or declines.
Other chemicals of potential concern are by-products of industrial
processes (e.g., dioxins), and the amounts produced cannot be measured
as directly as those of deliberately produced chemicals. Opportunities for
exposure may change in line with changes in production volumes, but they
also may vary independently if industrial processes become more effective
in reducing environmental release of a chemical during production. Among
the substances reviewed in this report as potential risk factors for breast
cancer, environmental releases from different sources have varied, and some
have declined over recent years (e.g., dioxin, Figure 4-3 [EPA, 2006]; or
perfluorooctanoic acid, Figure 4-4 [Paul et al., 2009]).
Hazard Versus Risk
In the assessment of the impact of environmental chemicals on humans,
there is an important distinction between hazard and risk. A chemical may
be identified as harmful or a hazard, but the risk it poses to people depends
on both its toxic potency and the nature of the exposure, especially the
amount to which people are exposed but also potentially the timing of the
exposure. While thousands of chemicals are produced in or imported into
3 The
tests evaluate acute toxicity, chronic toxicity, developmental and reproductive toxicity,
mutagenicity, ecotoxicity, and environmental fate.
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185
CHALLENGES OF STUDYING ENVIRONMENTAL RISK FACTORS
Grams
15,000
13,965
Other sources
Bleached wood pulp and paper mills
12,000 Cement kilns
Medical waste incineration
Municipal waste combustion
9,000
6,000
3,442
3,000
1,422
0
1987 1995 2000
FIGURE 4-3 Sources and amounts (g/yr) of dioxin-like compounds released in the
United States in 1987, 1995,4-3 2000.
Figure and Dioxin releases.eps
SOURCE: EPA (2006).
the United States, not all of them pose risks to the general population. Some
are used only in specific industrial processes, where potential exposure is
limited to those in the workplace. Some chemicals have low potency, gen-
erally causing health effects only at very high exposures. Thus, a chemical
known to be a hazard on the basis of toxicologic studies, but with low
potency and to which people are exposed at low concentrations, may pres-
ent little risk of cancer or other adverse health effects.
Route of Exposure
In occupational settings, inhalation and dermal contact are frequently
the primary routes of exposure (Eaton and Klaason, 1996), although inci-
dental ingestion pathways can occur. In the home, opportunities exist for
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186 BREAST CANCER AND THE ENVIRONMENT
Temporal trends (normalized percentage)
FIGURE 4-4 Estimated releases of perfluorooctane sulfonyl fluoride (POSF) from
Figure 4-4.eps
1970 to 2012 and exponential temporal trends in biota. POSF breaks down into
bitmap, landscape
perfluorooctanesulfonic acid (PFOS). Note: 2012 is when aqueous fire-fighting
foams (AFFFs) are scheduled to be restricted and treated carpets end their natural
life. The projection to zero is based on 3M’s production only, therefore some emis-
sions will continue from remaining producers. Temporal trends in biota have been
normalized to 100 percent for each species/dataset. Usage is depicted as follows:
carpets (—), paper and packaging (- • -), apparel (- - -), performance chemicals
(– • •), AFFFs (• • •). Biota trend lines are as follows: ringed seals from Arctic lo-
cations, Qeqertarsuaq (purple) and Ittoqqortoormiit (yellow); Baltic guillemot eggs
(pooled: light green; and mean: dark green); polar bears from western (light blue)
and eastern Canadian Arctic (dark blue); herring gulls from Norway (orange); and
lake trout from Lake Ontario (red).
SOURCE: Paul et al. (2009, p. 390). Published in: Alexander G. Paul; Kevin C.
Jones; Andrew J. Sweetman; Environ Sci Technol 2009, 43, 386–392. Copyright ©
2008 American Chemical Society.
exposure via ingestion, inhalation, and dermal contact. Pesticide exposures,
for example, can occur through consumption of food (from agricultural
applications), inhalation (directly from exposure to sprays and foggers or
subsequently from volatilization of residues of past use or resuspension of
contaminated dust), and dermal absorption (from contact with residues on
the surfaces of tables, countertops, or household objects). Various assess-
ments have found that concentrations of some volatile and semivolatile
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187
CHALLENGES OF STUDYING ENVIRONMENTAL RISK FACTORS
chemicals are much higher in indoor spaces, such as homes and schools,
than in outdoor areas around the home (Sax et al., 2006; Turpin et al.,
2007; Ward et al., 2009; Rudel et al., 2010). Dermal exposure may be the
predominant exposure pathway for chemicals in some cleaning or personal
care products.
Each chemical must be examined for how it is used as well as its vola-
tility and ability to pass through the skin. Sometimes potential routes of
exposure can be overlooked—for example, in taking showers, people may
experience both dermal and inhalational exposure to some volatile organic
compounds (VOCs) in the water supply. Typically, however, this exposure
to VOCs is primarily via inhalation and may equal the exposure from
drinking water (Jo et al., 1990).
Measurement of Exposure
In occupational studies, job titles and records from industrial hygiene
measurements (individual air monitoring, or air sampling from work areas)
are frequently used to estimate exposures. For population studies, research-
ers may use location of residence or distance from a source of concern
(transmission wires, freeways, factories); structured questionnaires relying
on participants to report product use; measurements taken in air, water,
soil, or other environmental media; and measurements in biological speci-
mens (e.g., blood lead, urinary metabolites of pesticides, cotinine from the
breakdown of nicotine to indicate tobacco smoke exposure). The utility of
these chemical measurements in both environmental and biological samples
depends on when the samples are taken relative to the disease in question;
the half-life in the environment or human body, respectively; and the vari-
ability in actual exposures over time. In the 1990s, researchers began to
develop biomarkers as a means not only to improve estimation of exposure,
but also to document intermediate steps along the pathway between expo-
sure and effect. For example, markers of oxidative stress, DNA adducts,
and epigenetic marks such as methyl groups can provide evidence that tis-
sues have been affected. Such markers may suggest a mechanism by which
an exposure may increase or decrease the risk of breast cancer; however, it
can be difficult to demonstrate a direct relationship between the exposure
and the marker, and between the marker and subsequent disease.
Importance of Timing of Exposure
Understanding the link between chemical exposure and disease is espe-
cially challenging when studying chronic diseases that develop gradually
over many years, such as cancer. Because the first steps in carcinogenesis
may begin decades before the diagnosis of a cancer, relevant exposures
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228 BREAST CANCER AND THE ENVIRONMENT
fish, worms), and high-throughput whole-genome analytical methods to
evaluate mechanisms of toxicity. The ultimate end is to generate data
with the new tools for use in the protection of human health and the
environment.
An important consideration in the development of tests that have
adequate coverage will be the degree to which they cover the pathways
involved in the general mechanisms underlying breast cancer—mutagenesis,
estrogen receptor signaling, epigenetic programming, growth promotion
via mitogenic cell signaling, microenvironmental change, and modulation
of immune functioning. This will require attention in selection of cell types
and environments relevant to breast cancer.
SUMMARY
Better understanding of the contribution of environmental factors to
breast cancer entails understanding the multiple challenges in carrying out
and interpreting studies in humans, animals, and in vitro systems. For stud-
ies in humans, these include the issues inherent in estimating and assessing
exposures, the study design and analytic challenges of environmental epi-
demiology, and efforts to account for genetic differences in susceptibility
to cancer and potential gene–environment interactions. Studies in animals
and in vitro systems bring with them their own technical obstacles and
challenges of interpretation and extrapolation to humans. An understand-
ing of these challenges informs understanding of the existing data and their
implications for next steps for action and research.
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