Laboratory research has shown that numerous environmental pollutants cause mammary gland tumors in animals; are hormonally active, specifically mimicking estrogen, which is a breast cancer risk factor; or affect susceptibility of the mammary gland to carcinogenesis. An assessment of epidemiologic research on these pollutants identified in toxicologic studies can guide future research and exposure reduction aimed at prevention.

The PubMed database was searched for relevant literature and systematic critical reviews were entered in a database available at URL: silentspring.org/sciencereview and URL: komen.org/environment (accessed April 10, 2007). Based on a relatively small number of studies, the evidence to date generally supports an association between breast cancer and polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in conjunction with certain genetic polymorphisms involved in carcinogen activation and steroid hormone metabolism.

Evidence regarding dioxins and organic solvents is sparse and methodologically limited but suggestive of an association. Methodologic problems include inadequate exposure assessment, a lack of access to highly exposed and unexposed populations, and a lack of preclinical markers to identify associations that may be obscured by disease latency. Among chemicals identified in toxicologic research as relevant to breast cancer, many have not been investigated in humans. The development of better exposure assessment methods is needed to fill this gap. In the interim, weaknesses in the epidemiologic literature argue for greater reliance on toxicologic studies to develop national policies to reduce chemical exposures that may be associated with breast cancer. Substantial research progress in the last 5 years suggests that the investigation of environmental pollutants will lead to strategies to reduce breast cancer risk.

RATIONALE

Laboratory research provides evidence that environmental pollutants may contribute to breast cancer risk by damaging DNA, promoting tumor growth, or increasing susceptibility by altering mammary gland development. Although to our knowledge most chemicals have never been tested for these effects, 216 potential mammary carcinogens have been identified in animals. In vitro assays have identified approximately 250 chemicals that mimic or interfere with estrogen, which stimulates proliferation of estrogen-sensitive breast cancer cells in laboratory studies and presumably underlies many of the established breast cancer risk factors. In an emerging area of research into developmental toxicity, animal studies show that maternal exposure during pregnancy to atrazine or bisphenol A affects differentiation of the mammary glands in the offspring, which remain in a less differentiated state that is more susceptible to carcinogen exposure.

If these mechanisms similarly affect humans, reducing or eliminating chemical exposures could have substantial public health benefits, because breast cancer is the mostly commonly diagnosed invasive cancer in women and the leading cause of cancer death in women ages 25 to 60 years. Furthermore, exposure to the chemicals identified as animal mammary carcinogens and estrogen mimics is substantial; these compounds are widely detected in human tissues and in environments, such as homes, where women spend time. Compounds of interest include, for example, benzene from gasoline, polycyclic aromatic hydrocarbons (PAHs) from vehicle exhaust and air pollution, disinfection products from chlorinated drinking water, polychlorinated biphenyls (PCBs), dioxin, chlorinated solvents, and some pesticides.

We reviewed epidemiologic research, with an emphasis on the last 5 years, to investigate how well the field has addressed questions raised by the laboratory studies. Our goals were to summarize and integrate findings for the most frequently studied pollutants, identify methodologic challenges, and recommend directions for future research. As background for this assessment, we first introduce key methodologic issues that underlie our evaluations of the epidemiologic literature.

EXPOSURE ASSESSMENT METHODS

Designing meaningful exposure measures is 1 of the most significant challenges in translating mechanistic observations from the laboratory, in which exposure parameters are known and controlled, to epidemiologic studies. The goal in epidemiologic breast cancer studies is to observe the chemical agent(s), pathway (ingestion, inhalation, dermal absorption), dose, timing with respect to disease latency, and timing with respect to possible critical periods of development, and, when quantification is difficult, to at least correctly rank study participants’ exposures.

Unfortunately, the exposure assessment strategies that underlie current knowledge regarding breast cancer risk are ill suited to studies of environmental pollutants. Most of what is known regarding risk factors relies on self-reported exposures (e.g., family history, number of births, age at first full-term pregnancy, alcohol use, physical activity), and the clearest findings concerning effects of exogenous chemicals come from clinical trials of pharmaceuticals in which exposure is specified and controlled (e.g., tamoxifen, hormone replacement therapy). In contrast, individuals cannot self-report their exposure to ambient environmental pollutants, and self-reports on chemical exposures from consumer products are subject to multiple forms of bias, including incomplete recall, differential recall between cases and controls, influences of social desirability, and poor reporting of exposure from products used by others. With regard to clinical trials, the intentional exposure of individuals to possible toxicants with no benefit to those individuals does not meet standard ethical guidelines for research on humans.

The predominant exposure assessment strategies in studies of environmental pollutants and breast cancer are job history, residential location in combination with models derived from environmental monitoring, and biomarkers in blood and adipose tissues. Although each of these methods has strengths, none of these methods can be considered a ‘gold standard.’

Job histories and residential histories have the potential to assess exposure at multiple points in time, to integrate exposures across time, and to integrate exposures to real-world chemical mixtures. However, misclassification results from errors in modeling, incomplete historical information both for the individual and the setting, and missing or incomplete information regarding behaviors that modify exposure (e.g., use of protective gear at work or amount of time spent outside). The assessment of mixtures, for example, in ambient air, leaves questions concerning which chemical or group of chemicals are responsible for observed effects. Geographic location with respect to an accidental exposure, for example, the industrial explosion at Seveso, Italy, can be a uniquely valuable exposure assessment tool because the agent, relative dose, and timing of exposure are likely to be known and to differ markedly from a comparison population. The collapse of the World Trade Center in 2001 and flooding in New Orleans in 2005 are examples in which the chemical exposure is complex, and environmental sampling after the incident is needed for future studies to develop indicators of exposure based on where children and adults were located during and after these incidents. More generally, the development of geographic information systems (GIS)- computer mapping database technologies for linking locations with environmental data - will expand exposure assessment opportunities if the underlying environmental monitoring data accrue through regulatory and environmental tracking programs.

Biologic measurements have the advantages of integrating an individual’s exposure from all sources and her/his physiologic response. They may, but often do not, measure chemicals in the most relevant target tissue - the mammary gland - and levels in blood, urine, or other biological compartments may not reflect localized tissue levels. If the biomarker measures a metabolite (eg, dichlorodiphenyldichloroethylene [DDE]) of the agent of interest (eg, dichlorodiphenyltrichloroethane [DDT]), individual variation in metabolism and excretion may increase exposure misclassification. To our knowledge to date, biomarkers have been developed for only a few of the chemicals of interest in breast cancer studies, and existing technologies are expensive to apply in studies large enough to reliably detect the modest risks typical of the established breast cancer risk factors. Many biomarkers are too intrusive to allow for repeated measures and most are impractical for assessing exposure across relevant time periods (eg, when research questions require assessment of exposures in the past or over long time periods, or when a chemical is quickly cleared from the body), so that carefully timed measures are needed. In addition, for biomarkers the specific source of exposure is often unclear, so associations are difficult to translate into risk reduction strategies.

Full Report
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Julia Green Brody, PhD
Kirsten B. Moysich, PhD
Olivier Humblet, MS
Kathleen R. Attfield, BS
Gregory P. Beehler, MA
Ruthann A. Rudel, MS

Silent Spring Institute, Newton, Massachusetts.
Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York.