Affiliations of authors: F. Laden, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; G. Collman, National Institute of Environmental Health Sciences, Research Triangle Park, NC; K. Iwamoto, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD; A. J. Alberg, K. J. Helzlsouer, H.-Y. Huang, School of Hygiene and Public Health, Department of Epidemiology, The Johns Hopkins University, Baltimore, MD; G. S. Berkowitz, M. S. Wolff, Division of Environmental and Occupational Medicine, Mount Sinai Medical Center, New York, NY; J. L. Freudenheim, Department of Social and Preventive Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo; S. E. Hankinson, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, Boston; T. R. Holford, T. Zheng, Yale University School of Medicine, New Haven, CT; K. B. Moysich, Cancer Control and Epidemiology, Roswell Park Cancer Institute, Buffalo; J. D. Tessari, Department of Environmental Health, Colorado State University, Fort Collins; 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.
Correspondence to: Francine Laden, Sc.D., Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: francine.laden{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Before 1993, six small casecontrol studies (fewer than 50 case subjects) evaluated levels of organochlorines in adipose tissue (49). Although results were inconclusive, combined evidence from these studies suggested a modest association of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the major metabolite of DDT, and PCBs with an increased risk of breast cancer. In 1993, a casecontrol study of serum concentrations of DDE and PCBs collected 16 months before diagnosis of breast cancer (58 case patients and 171 control subjects) found a statistically significant fourfold increase in risk in the 10th decile of DDE and a statistically nonsignificant twofold risk with PCBs (10).
In September 1993, five studies were funded by the National Cancer Institute (Bethesda, MD) and the National Institute of Environmental Health Sciences (Research Triangle Park, NC)1 to more rigorously evaluate whether the risk of breast cancer was associated with exposure to organochlorines. Results of individual studies have been published elsewhere (1116); all five studies concluded that there was no evidence of an association overall. However, suggestions of effects in specific subgroups were observed, and even though all of the studies are considered to be large, they had limited power to perform these subgroup analyses. Therefore, we undertook to reanalyze the primary data by use of a standardized approach to control for confounding and to assess effect modification. The combined results were evaluated in a parallel analysis. These five studies were selected for this report for the following reasons: similarities in regional location of the subjects, the relatively large population sizes (more than 150 case patients per study), the ability to control for confounding factors, and the standardization of methodologies to the extent possible by having the investigators meet early in the conduct of the studies. This analysis is not designed to be an evaluation of the entire body of literature.
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METHODS |
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The five studies included in this analysis have been described in detail individually (1116). They consist of 1400 case patients with breast cancer and 1642 control subjects. The study design, the dates of blood draw and of follow-up, descriptions of the study participants, and the definitions of PCBs and DDE are presented in Table 1. The Western New York (Western NY) and Mount Sinai (Mount Sinai Medical Center, New York, NY) studies selected study subjects from New York state, the participants in the Yale study resided in Connecticut, and the participants in the Campaign Against Cancer and Stroke (CLUE I) study came from Maryland. The Nurses' Health Study (NHS) is a national sample, with at least one participant in each of 31 states. However, 54% resided in a northeastern state or in Maryland in 1986. The majority of the study participants in all of the studies were postmenopausal.
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The NHS is an ongoing study of 121 701 U.S. nurses, and the source population for this study was the 32 826 women who gave blood samples in 1989 and 1990. Incident cases of breast cancer were identified 1 month to 4 years after blood collection. Women who had donated blood and were cancer free (with the exception of nonmelanoma skin cancer) at the time of the diagnosis of the case patient were eligible as control subjects. They were matched to each case patient on year of birth, menopausal status, month and time of blood collection, fasting status when blood was drawn, and use of hormone replacement therapy.
From 1974 through 1994, the CLUE I study identified incident cases of breast cancer among the 20 305 women who donated blood in 1974 and who resided in Washington County, MD. Control subjects were selected from those participants who were not diagnosed with cancer (with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix) at the time of the diagnosis of the case patient. Case patients and control subjects were matched one to one on year of birth, menopausal status, and date of blood donation.
Exposure Measurements and Laboratory Methods
PCBs refer to a sum of PCB congeners, although the specific congeners included differ between studies. The number of congeners measured by each study are presented in Table 1 (see individual study publications for details). Congeners 118, 138, 153, and 180 were detected in all five studies and make up the majority of the total sums. The DDE measure discussed in this report refers to the sum of the concentrations of DDT and DDE in the CLUE I study and DDE in the other four studies. Measures of PCBs and DDE were adjusted for plasma or serum lipids with the formula described by Phillips et al. (18) in all of the studies, with the exception of the Yale study where gravimetric lipid determination was used (15). Lipid-adjusted levels are presented in units of micrograms of organochlorine per gram of lipid.
With the exception of Mount Sinai and the NHS, where both studies were analyzed at Mount Sinai, each study used a different laboratory. Full laboratory methods are described in the previous publications (1116). A series of quality-control samples were exchanged among the four laboratories involved in these studies over the course of the grant period. Three sets of standards and two sets of blood serum were exchanged. The first set of blood serum was not prepared as a single uniform pool, and data are not reported. Standards and sera contained several PCB congeners and organochlorine pesticides. Laboratories were not aware of the concentrations of the analytes or the exact composition of the solutions. The three sets of standards, using DDE as an example, had an overall average recovery across all four laboratories of 98.8%, with coefficients of variation of 8.7% (20 parts per billion [ppb]), 18% (500 ppb), and 17% (50 ppb). The serum pool (10.0 ppb) results were 101% ± 5.1% (mean ± standard deviation) among the four laboratories (triplicate analyses by each laboratory). Comparable results were obtained for the other analytes.
Statistical Methods
Study-specific quintile cutoffs for lipid-adjusted and unadjusted DDE and PCBs were determined from the control distributions. The odds ratios (ORs), which estimate the relative risk, and the 95% confidence intervals (CIs) for each quintile relative to the lowest quintile were estimated for each study separately. Because case and control subjects in the NHS and CLUE I studies were individually matched, conditional logistic regression was used to estimate the ORs; unconditional logistic regression was used in the other studies, controlling for race (where appropriate), menopausal status, and continuous variables for age and age squared in minimally adjusted models. Multivariate models included the variables in the minimal models as well as body mass index (BMI) (24.9, 2529.9, or
30 kg/m2), use of hormone replacement therapy (never or ever), and combined variables for parity and lactation (nulliparous, one or two children, and never lactated; one or two children and lactated; three or more children and never lactated; or three or more children and lactated). These variables were chosen because they were available in all studies, and they are potentially related to organochlorine levels (1922) and/or breast cancer risk (23). Lactation is the major route of excretion of organochlorine residues, and it has been shown to lower the risk of breast cancer. One study (24) has reported results indicating that high levels of DDE might inhibit a woman's ability to breast-feed. Therefore, lactation might actually be on the causal pathway, as opposed to a confounder. However, because this relationship is unclear, we decided to evaluate lactation as a confounder in this analysis. Furthermore, in the analyses of lactation as a potential effect modifier (see Table 4
), results were similar in the nulliparous and never-lactated groups, as in the previous results.
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To examine whether the associations between organochlorines were modified by conventional risk factors for breast cancer, unconditional analyses within strata of age (<40, 4049, 5059, or 60 years old), menopausal status (premenopausal or postmenopausal), use of hormone replacement therapy (never or ever), BMI (
24.9, 2529.9, or
30 kg/m2), and lactation (nulliparous, parous and never lactated, or parous and ever lactated) were conducted, controlling for age, age squared, menopausal status, and matching factors, as appropriate. Tests of trend were performed for each study across the entire dataset and within each stratum in the stratified analyses by use of the natural logarithm of the organochlorine as a continuous independent variable. All statistical tests were two-sided.
Variation in the effect size across studies was quantified with the 2 test for heterogeneity (25). Pooled ORs and 95% CIs were calculated by use of the random-effects model developed by DerSimonian and Laird (26).
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RESULTS |
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There was some evidence of an increased risk with elevated levels of PCBs among women in the middle category of BMI (2529.9 kg/m2), with a pooled OR for the third tertile of 1.57 (95% CI = 1.11 to 2.22), but not among other women (Table 4). Among the heavier women, there was a suggestion of an inverse association of breast cancer with PCBs in four of the five studies. If Yale is not included in the pooled OR, then the point estimate and CIs for the third tertile appear to be protective (pooled OR = 0.27; 95% CI = 0.15 to 0.49). The risk of breast cancer was not positively associated with PCBs when all of the study populations were restricted to postmenopausal women or were stratified by 10-year age groups or use of hormone replacement therapy. In similar subgroup analyses of DDE, there was no evidence of effect modification (data not shown).
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DISCUSSION |
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The ranges of DDE and PCBs in the five studies were comparable. PCBs were the greatest in the Mount Sinai population, possibly because of its racial makeup. In this study, African-Americans had the highest levels of PCBs, and African-Americans and Hispanics had the highest levels of DDE (16). The other study populations were not as racially mixed (see Table 1). Levels of DDE (unadjusted and lipid adjusted) were highest in CLUE I. The timing of when blood was drawn is the most likely explanation. These samples were donated closest to the period when DDT was still in use in the United States. It is unclear why the DDE levels in the Yale study are low compared with the other studies.
These research groups are not the only groups exploring the relationship between exposure to organochlorines and the risk of breast cancer, and this combined analysis is not designed to be an evaluation of the whole body of literature. From 1993, when funding for these studies began, through December 2000, 17 additional studies have been published. These include three U.S. studies, where risk of breast cancer and concentrations of DDE and PCBs in blood were evaluated prospectively. In none of them was a positive association observed overall (2729), although there was some evidence for statistically nonsignificant increases in risk for Caucasian and African-American women with higher DDE levels in the study by Krieger et al. (27). A recent case control study (30) in North Carolina observed a large statistically significant association among African-American women but only in specific body mass subgroups: the leanest subgroup for DDE and the heaviest subgroup for PCBs. A prospective study from Denmark (31) observed elevated levels of the pesticides dieldrin and -hexachlorocyclohexane but not of DDE and PCBs among case patients with breast cancer. There was no evidence of an association of any of the above organochlorines and breast cancer in a prospective study of 150 case patients from Norway (32). Five non-U.S. retrospective casecontrol studies (3337) focused on concentrations of DDE in blood samples. An elevated risk of breast cancer was associated with high exposures to DDE in Colombia and in one (37) of the two studies from Mexico (33,37). A Canadian case-control study evaluated associations of many organochlorines with breast cancer risk (38). An overall association with risk was not observed for any of the organochlorines; however, women with more aggressive cancers had the highest levels of DDE. Five studies (3943) evaluated organochlorine concentrations in adipose tissue. Again, there was no evidence to support an association of total PCBs with overall risk of breast cancer, although some congeners were elevated in case patients compared with control subjects in the three studies (39,40,43) that examined these associations. Only one study (39) of the five studies observed an association with DDE. Thus, the majority of the studies published to date do not support the hypothesis that elevated exposure to DDT and PCBs increases the risk of breast cancer. The source of the discrepancy between the conclusions from these studies and the earlier studies (before 1995) is not clear. Sample size and chance are possible explanations.
Some of the research groups included in this parallel analysis also evaluated exposure to specific congeners of PCBs, different groupings of the PCB congeners, and exposure to other organochlorine pesticides. Western NY reported null results for mirex, hexachlorobenzene, and different groupings of PCBs on the basis of degree of chlorination (11). Yale evaluated adipose tissue and observed no association of exposure to PCBs (44), DDE (45), hexachlorobenzene (46), or -benzene hexachloride (47) with an increased risk of breast cancer.
Because there are only five studies in this analysis, we grouped them regardless of study design. Treatment of breast cancer has been shown to affect plasma concentrations of PCBs but not of DDE (48). However, in the retrospective casecontrol studies, blood was collected from the case patients close to diagnosis and before treatment. There were no clear patterns of results associated with type of study.
We focused our analysis on lipid-adjusted levels of DDE and PCBs in micrograms per gram of lipid. Organochlorines are stored in the lipid component of the blood; therefore, these measures take into account lipid concentrations and potentially influential factors, such as fasting status at the time that blood was drawn. Yale used gravimetric lipid determination, whereas the other studies calculated total lipids from total cholesterol and triglycerides. These two methods might yield different absolute values. However, the unadjusted and lipid-adjusted distribution of PCBs from Yale were comparable to the distributions obtained in the other studies, and unadjusted as well as lipid-adjusted DDE levels were low.
With the exception of Mount Sinai and the NHS, each study used a different laboratory for organochlorine analyses. Absolute values may vary between laboratories because of many factors, including differences in analytic techniques and the number of different congeners included in the sum of PCBs. The NHS measured concentrations in plasma, whereas the other studies measured serum. This difference was unlikely to limit our ability to pool the data because levels of DDE and PCBs from the NHS were comparable to those in the other studies. In addition, dates of blood collection and location of residence of the participants differed between studies; these factors might influence the range of observed values. Because of these expected disparities in organochlorine values and other uncontrolled differences in the study populations, categories were formed from study-specific control distributions. The ORs were estimated separately, and then category-specific results were pooled. Therefore, the ORs for each category were compared among studies, regardless of the actual range of values. Continuous analyses within each study also supported the conclusion of no association of lipid-adjusted plasma/serum PCBs or DDE with breast cancer risk.
A strength of our analysis is that, unlike traditional meta-analyses from published data, each study was analyzed similarly. All values are presented in the same units. The same covariates were included in the logistic models, and effect modification was assessed in identical categories. Even so, because of differences between the studies, the specific numbers from the pooled results should be used with caution. They are only a guide to the qualitative observations.
The combined evidence from these five U.S. studies does not support an association of breast cancer risk with plasma or serum concentrations of PCBs and DDE. However, even though we have combined data from five different populations, the scope of our findings is somewhat limited. With the exception of CLUE I, all blood measurements were obtained more than 10 years after these chemicals were banned in the United States. Current levels are predicted to be indicative of past exposures because of the long half-lives of the compounds, but the evaluations of risks associated with low levels from a general population sample, years after exposure, could be biased to the null from nondifferential measurement error. Furthermore, we cannot generalize our conclusions to exposures experienced occupationally, in utero, or during adolescence. We focused on DDE and total PCBs because they are the most persistent organochlorines and the most easily detectable in biologic specimens. They are not necessarily the most toxic. The absence of an association with DDE and total PCBs does not rule out the possibility that specific PCB congeners, other pesticides, or environmental contaminants may be associated with breast cancer. All that being said, exposure to DDE and PCBs, as measured in adult women, is unlikely to explain the high and increasing rates of breast cancer experienced in the northeastern United States.
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NOTES |
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Supported by PHS grants U01CA11535, CA40356, and CA49449 (NCI) and CA/ES62995, CA/ES62984, CA/ES62988, CA/ES62951, and CA/ES62986 (NCI and NIEHS) from the NIH, DHHS. Additional funding to perform the combined analysis was cosponsored by the NIEHS and the Federal Coordinating Committee on Breast Cancer coordinated by the U.S. PHS's Office on Women's Health, DHHS. F. Laden was supported in part by an Institutional National Research Service Award T32HL07427.
We acknowledge the dedication of the participants of these studies, as well as the help of the following people: Sandra C. Hoffman, John W. Brock, Virlyn W. Burse, George W. Comstock, and Larry L. Needham (for CLUE I); Steven Brower, Ruby Senie, Ira J. Bleiweiss, Paul Tartter, Karen Ireland, Benjamin Pace, Noah Roy, Sylvan Wallenstein, and Ainsley Weston (for the Mount Sinai Study); Graham Colditz, Frank Speizer, Sherry Yaun, Sue Wei Chang, and Jaime Hart (for the Nurses' Health Study); and Paul Kostyniak, Hebe Greizerstein, Peter G. Shields, Christine B. Ambrosone, John E. Vena, James R. Marshall, and Saxon Graham. (for the Western New York Study).
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Manuscript received October 11, 2000; revised February 22, 2001; accepted March 14, 2001.
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