Breast Cancer and the Environment A Life Course Approach (2012) / Chapter Skim
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4 Challenges of Studying Environmental Risk Factors for Breast Cancer
4 Challenges of Studying Environmental Risk Factors for Breast Cancer
Pages 177-238
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From page 177... ...
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 environmental 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.
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Some associations have been observed between certain tumor types and risk factors (e.g., obesity and ER-positive [ER+]
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Genes/pathways/risk factors are shown in red; inherited or unmodifiable 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 inhibitors; ATM, ataxia telangiectasia mutated; BRCA1 and BRCA2 (genes in which deleterious germline mutations increase the risk of cancer)
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From page 180... ...
This model displays multiple factors associated with postmenopausal breast cancer causation in four broad domains and shows their interconnections across levels (genes to society) by arrows that indicate variations in the strength of the associations and the quality of the data.
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From page 181... ...
Although these challenges share similarities across the spectrum of risk factors evaluated in this report, they may be particularly acute for evaluating risk relationships from exposures to environmental chemicals. For studies in humans, these include the issues inherent to estimating and assessing exposures, the study design and analytic challenges of environmental epidemiology, and efforts to account for genetic differences in susceptibility to cancer and potential gene–environment interactions.
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From page 182... ...
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.
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From page 183... ...
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 studies lacked the power to detect breast carcinogens.
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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]
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From page 185... ...
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 present 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)
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Sweetman; Environ Sci Technol 2009, 43, 386–392. Copyright © 2008 American Chemical Society.
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; structured questionnaires relying on participants to report product use; measurements taken in air, water, soil, or other environmental media; and measurements in biological specimens (e.g., blood lead, urinary metabolites of pesticides, cotinine from the breakdown of nicotine to indicate tobacco smoke exposure)
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Early reports suggested that increased breast cancer risk appeared to be limited primarily to women who were exposed during puberty. Although more recent analyses suggest elevated risks even among those exposed later in life, early exposure remains particularly important (Land et al., 2003; Preston et al., 2007)
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From page 189... ...
Thus, new methodologies for the measurement of suspected breast carcinogens in the environment can lead to higher quality epidemiologic studies, both retrospective and prospective. The modalities needed include improving measurements in the environment and assessing variation over time and space; determining routes of exposures and how they vary over time and over the life course; using emissions inventories along with environmental dispersion modeling; measuring compounds and their metabolites in biospecimens; understanding pharmacodynamics and pharmacokinetics and how they vary by age, body weight, nutrition, comorbidity, or other factors; developing biomarkers for early biologic effects (DNA adducts, methylation, tissue changes, gene expression, etc.)
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. HUMAN EPIDEMIOLOGIC STUDY DESIGN AND IMPLEMENTATION As introduced in Chapter 2, various types of human epidemiologic studies are conducted: (1)
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It occurs when another risk factor for the disease under study occurs more or less frequently in those who are exposed as compared with the unexposed. An association observed between the exposure under study and the disease outcome might be the result of the alternative risk factor that is associated with, but not the result of, the exposure being studied.
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Potential confounding by "unknown factors" is often cited as a precaution in ascribing causality to an exposure associated with disease and, in fact, was a central argument used in questioning whether smoking was causing lung cancer (e.g., Fisher, 1958a,b)
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From page 193... ...
For instance, if the exposures encountered by the population truly increase risk by, say, 5 to 10 percent, even a very large study with a few thousand cases will generally not be of sufficient size to reliably generate a statistically significant estimate of increased risk. Interpretation of Attributable Risk and Population Attributable Risk Chapter 2 introduced some of the measures that are used to estimate the disease risk associated with factors of interest, including attributable risk (AR)
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If some of the factors related to being married but not related to childbearing are associated with breast cancer risk, then single nulliparous women who "become parous" to reduce breast cancer risk may not have the same risk as the general parous population, which has more married people in it. ARs or PARs can be calculated separately for several risk factors related to a disease such as breast cancer, but these separate estimates cannot be added together.
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. The first problem is confusing the attributable risk with the proportion of cases who have any of the risk factors included in the PAR.
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Rockhill and colleagues (1998) note that breast cancer risk factors are poor predictors of breast cancer occurrence; the vast majority of women with these risk factors do not develop breast cancer.
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If such studies were to rely on following women from the time of these exposures, they would have to be carried out over decades to discern differences in rates of breast cancer. A strategy to circumvent this need is for epidemiologists to examine whether the exposure influences an intermediate marker of breast cancer risk, such as age of pubertal onset, that is measureable long before the usual onset of breast cancer.
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screening for prostate cancer. Very few factors other than screening or a sudden shift in diagnostic criteria for cancer can account for rapid changes in cancer incidence.
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Identifying modifiable risk factors that are disproportionately associated with indolent tumors might make it possible to reduce the nominal incidence of breast cancer and spare some women what is essentially unnecessary treatment, but it would have limited benefit for women with more aggressive tumors. Also, because overdiagnosis associated with cancer screening leads to an increase in incidence without necessarily changing the risk of dying of the cancer, it can artifactually inflate survival rates and cure rates of cancer, independent of any actual benefits of screening or improvements in therapy over time (Welch et al., 2000)
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They could focus on environmental exposures, medical information from electronic health system data, or other sources of relevant exposures, covariates, and intermediate outcomes. Studies could also be designed to systematically focus on (1)
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that have not been tested with the technologies available to date, it is unlikely that stronger associations with common variants exist. GENE–ENVIRONMENT INTERACTIONS Much of breast cancer causation is assumed to be due to the interplay between inherited susceptibility to the disease and exposure to environmental risk factors or lifestyle choices.
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Even when a study is not investigating the interactions of genes and environmental factors, the ability of those studies to identify environmental risk factors may be compromised by those relationships. Moreover, when exposures become pervasive, all the variability will tend to appear to be due to genetic factors.
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From page 203... ...
(1999) observed in a case–control study with data on 154 postmenopausal cases that women who carried at least one Val allele at codon 462 in the CYP1A1 gene and whose blood levels of total PCB concentration were above the study median had an increased risk of breast cancer (OR = 2.9, 95% CI, 1.2–7.5)
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, an autosomal recessive disorder characterized by extreme sensitivity to radiation, is the result of truncation mutations at the ATM gene. There is strong biological plausibility to the hypothesis that women with ATM mutations, who are less able to respond to DNA damage, will be at higher risk of breast cancer generally and that the breast cancer risk from a given dose of radiation will be greater in women who carry the ATM mutation than in those who do not.
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This by no means makes it irrelevant to quantify these individual associations. For the purposes of risk prediction, all these risk factors appear largely to multiply together -- the more genetic or environmental risk factors a women has, the higher her risk.
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analysis, discrimination between cases and controls on the basis of the number of risk SNPs was relatively poor, but it was equivalent to the discriminatory ability of the clinical standard, the Gail model (Gail et al., 1989) , which uses established breast cancer risk factors.
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, but this situation may change as more genetic risk loci are discovered. Another hope for the use of genetic variability in understanding risk is that environmental risk factors that have not been convincingly associated with risk of breast cancer among all women will be convincingly associated with risk among a genetically defined "susceptible" stratum.
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. However, even once these are discovered, much less than half of the inherited variability in breast cancer risk will have been explained (Park et al., 2010)
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A major limitation is the difficulty of establishing exposure to many hypothesized environmental factors, such as exposures that may have occurred in utero, childhood, or early adulthood, or exposures that require sophisticated and potentially expensive biological measurements, especially of biological samples such as adipose or breast tissue. Despite the need for new and improved methods to estimate these exposures, most of the established breast cancer risk factors can be readily ascertained at interview or by questionnaire.
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From page 210... ...
In rodents as in humans, mammary tumors may arise through several modes of action, such as from endocrine-related effects on tissue development and growth or through genotoxic effects on breast cells. Studies in rodent models have also shown the importance of exposure during critical windows of development on mammary cancer risk later in life, in terms of either direct carcinogenic effects or alterations in susceptibility to subsequent exposure to carcinogens.
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. Parity induces changes in gene expression that are highly conserved among rat strains, thereby conferring increased resistance to development of mammary tumors, even in susceptible rat strains (Blakely et al., 2006)
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Puberty is an important exposure period for later susceptibility for human breast carcinogenesis because of the rapid rate of tissue growth and development. For example, a meta-analysis by Henderson et al.
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Ultimately this study protocol may be helpful in identifying some candidate risk factors that may not directly cause tumors later in life themselves, but that may, when exposures occur early in life, modulate risk of mammary tumors associated with subsequent exposure to potent carcinogens. It also raises questions about the predictive value of the standard protocols used in pesticide, pharmaceutical, and industrial chemical testing, as the standard 2-year chronic bioassay protocols (e.g., FDA, 1997; EPA, 1998a; Makris, 2011)
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In a committee compilation of information from IARC and NTP reports, 89 percent of agents that IARC has found to have sufficient or limited evidence of human breast cancer also showed evidence of mammary tumors in rats or mice. Strain and Species Similarities and Differences in Mammary Tumor Susceptibility Another consideration in the selection of animals for testing is whether the strain used is sufficiently sensitive to detect the carcinogenic activity of an agent that poses a risk to humans.
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or resistant (e.g., Copenhagen, Wistar-Kyoto) to most chemical carcinogens, radiation, and hormonal agents, as well as having a corresponding high or low rate of spontaneous mammary tumors (Kacew et al., 1995; Russo and Russo, 1996; Ullrich et al., 1996; Ren et al., 2008)
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Table 4-2 shows the background incidences for different types of mammary tumors in strains used in the National Toxicology Program testing program (NTP, 2008, 2010a,b) , and compares them to human rates.
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. importance of these lesions for prediction of human cancer risk is controversial.
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. Other modifiable risk factors are not apparent, and obesity was identified in one review as protective in women (Goehring and Morabia, 1997)
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. However, this potential mechanism may be less likely for mammary tumor formation, given the limited fraction of chemicals positive for mammary carcinogenesis in tests conducted with maximum tolerated dosing.
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Thus dose-related reductions in body weight may mask chemical-related increases in mammary tumors. Early mortality due to competing causes of death, including other cancers or toxicity, particularly at the highest dose tested, also decreases study power to observe mammary as well as other tumor types (Rudel et al., 2007)
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. As with humans, female mice and rats have greater occurrence of spontaneous mammary tumors than males, reflecting endocrine-related influences (see Table 4-2)
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. Although spontaneous and virally induced mouse mammary tumors differ in histology and morphology from breast tumors in humans, tumors in genetically engineered mice resemble those in humans (Cardiff and Kenney, 2011)
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Even if it does not contribute substantially to the overall elimination of the substance from the body, tissue-specific biotransformation could be significant for activating a compound to a carcinogenic form in a particular tissue. Thus, for potential mammary carcinogens, it is important to understand if there are tissue-specific differences in biotransformation of xenobiotics in breast tissue in humans versus experimental animals.
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Nonstandard Whole Animal Carcinogenicity and Related Studies Mouse mammary tumors and the associated MMTV were among the first tumor types investigated in studies of animal carcinogenicity, including
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. To aid in the investigation of human breast cancers, however, specific mouse models have been developed in which mammary tumors do express hormone receptors (e.g., estrogen and progesterone receptors)
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Figure 4-6 shows mammary gland whole mounts from Long Evans rats exposed during late gestation to atrazine or TCDD (Birnbaum and Fenton, 2003)
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has envisioned a new toxicity testing system, focusing on upstream events: chemical perturbations of cellular response networks (i.e., complex biochemical interactions that maintain normal cellular function)
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Scand J Work Environ Health 4(1)
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2011. A compendium of the mouse mammary tumor biolo gist: From the initial observations in the house mouse to the development of genetically engineered mice.
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2006. Endocrine-disrupting compounds and mammary gland development: Early exposure and later life consequences.
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1998. Characterization of cytochrome P450 enzymes in human breast tissue from reduction mammaplasties.
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1996. Expres sion of cytochromes P450 in human breast tissue and tumors.
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polymorphisms, and breast cancer risk among African American women and white women in North Carolina: A population-based case–control study. Breast Cancer Res 7(1)
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1995. Proportion of breast cancer cases in the United States explained by well-established risk factors.
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2009. The influence of olive oil on Sprague Dawley rats DMBA-induced mammary tumors.
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1982. A different perspective on breast cancer risk factors: Some implications of the nonattributable risk.
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2010a. Performance of common genetic variants in breast-cancer risk models.
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