Affiliations of authors: F. Laden, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; D. J. Hunter, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department of Epidemiology and the Center for Cancer Prevention, Harvard School of Public Health, Boston; M. S. Wolff, Division of Environmental and Occupational Medicine, Mount Sinai Medical Center, New York, NY.
Correspondence to: Francine Laden, Sc.D., Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: francine.laden{at}channing.harvard.edu).
Glustrom and colleagues question whether residual 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE) and polychlorinated biphenyl (PCB) levels constitute an appropriate biomarker for determining the estrogenic component of organochlorine exposures. They suggest that hydroxylated metabolites of aromatic organochlorines would be more appropriate measures of exposure to estrogenic compounds. Our article and a host of epidemiologic studies have addressed the association of body burdens of DDE, PCB, and similar neutral, persistent organochlorines with risk for breast cancer, a chronic disease with long latency. In this context, researchers have been concerned principally with a valid marker for lifelong organochlorine exposure, not with identifying the presence of hormonally active metabolites. DDE, a major degradation product of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), has been shown to have a long half-life and to reflect long-term exposure to DDT (1). PCBs that are measured in epidemiologic studies include mainly the long-lived congeners, although hormonally active, less persistent subgroups have also been considered (2). It is also relevant to etiologic research that specific organochlorine body burdens are directly associated with consumption of contaminated foods and that body burdens are highest in geographic areas of high contamination, e.g., near waterways where organochlorines contaminate sport fish (3).
We agree that the idea of studying risk of breast cancer with organochlorine metabolites may have merit. Indeed, the argument has long been advanced that the phenolic metabolites of PCBs are biologically active and that their distribution in the body may be relevant to target organ toxicity (4). Furthermore, hormonal potential is comparable to potent compounds such as bisphenol A and nonylphenol that are the focus of much current research (5). However, it is not clear exactly how to incorporate direct measurements into epidemiologic research. Polar phenolic metabolites are not persistent, and thus as biomarkers, they may have limited applicability in epidemiologic studies of breast cancer. Furthermore, neutral organochlorines may be less active and have a lower binding capacity than their phenolic counterparts, but they do bind to hormone receptors (6). In addition, their long persistence in the body may magnify their lower hormonal activity relative to the phenolic metabolites. Hydroxylated organochlorines are likely to be highly correlated with neutral parent residues (7), just as the neutral organochlorine residues are intercorrelated in most nonoccupationally exposed populations. Thus, the neutral organochlorines, such as the ones in our study, are useful biomarkers regardless of whether their biologic potential arises from innate hormonal activity or through their metabolites.
As we know, the choice of biomarkers in epidemiology requires a careful match between the temporal qualities of both the exposure metric and the disease outcome and their relationship to the biologic mechanism. Keeping this in mind, our poor understanding of environmental risk factors leaves much room for further investigation of chemical exposures, including their biologically active metabolites. For hydroxylated organochlorines, more experimental data are clearly required before embarking on etiologic studies of chronic disease. For neutral organochlorines, at least under current low-level circumstances of exposure, our article and the predominance of the recent literature suggest that there is not a strong association with breast cancer risk.
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