1 Department of Preventive Oncology and Epidemiology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.
2 Unité de Recherche en Santé Publique, Centre de Recherche du CHUQ (CHUL), Beauport, Québec, Canada.
3 Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Ste-Foy, Canada.
4 Unité de Recherche en Santé des Populations et Centre des Maladies du Sein Deschênes-Fabia, Hôpital Saint-Sacrement, Centre Hospitalier Affilié Universitaire de Québec, Québec, Canada.
5 Unité de Recherche en Endocrinologie de la Reproduction, Centre de Recherche du Pavillon Saint-François-d'Assise, Québec, Canada.
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ABSTRACT |
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breast neoplasms;; case-control studies;; estrogens;; polychlorinated biphenyls
Abbreviations: CI, confidence interval;; odds ratio;; PCB, polychlorinated biphenyl;; TEQ, 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents.
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INTRODUCTION |
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PCBs constitute a family of 209 possible congeners that were extensively used in industrial and commercial products from 1930 to 1980. PCBs were commercialized as mixtures (Aroclor 1254 (Monsanto Chemical Company, St. Louis, Missouri), Clophen 60 (Farbenfabricken Bayer GmbH, Leverkusen, Germany), and so on) usually composed of 5070 different congeners (21). A total of 132 congeners have been identified in commercial products, some of them being present in only one mixture and others in all of them (22
). Although their use was banned 20 years ago in Canada and the United States, they are still found in the environment and in the food chain, especially in fatty foods (23
). This results from their great stability and continued release into the environment, because of improper storage, disposal, and ongoing use in some parts of the world. Biologic half-lives of several years have been documented in humans for the most persistent congeners (24
), resulting in their accumulation with age in body fat, including adipose tissue (25
), plasma lipids (26
), and milk fat (27
).
Several mechanisms might be involved in the modulation of breast cancer risk by specific PCB congeners. First, PCBs (lower chlorinated) and some hydroxylated metabolites display estrogenic properties (2830
). Second, mono- and non-ortho-substituted congeners share some structural similarities with 2,3,7,8-tetrachlorodibenzo-p-dioxin and can bind the aryl hydrocarbon receptor (31
). The consequences of activation of the aryl hydrocarbon receptor pathway on breast cancer risk are, however, not clear. On the one hand, dioxin-like compounds elicit a broad spectrum of antiestrogenic activities (32
36
) and may reduce breast cancer risk. On the other hand, activation of the aryl hydrocarbon receptor leads to induction of CYP1A1/A2 and CYP1B1 expression, which in turn could increase the biotransformation of estradiol to catechol estrogens (37
42
), the latter exhibiting genotoxic properties (43
). Di-ortho-substituted congeners induce a different profile of biotransformation enzymes (CYP2B1/B2 and CYP3A), similar to that induced by phenobarbital (37
, 44
, 45
), and these enzymes are also involved in the metabolism of estradiol (39
, 45
, 46
). Mono-ortho PCBs are both phenobarbital- and dioxin-like inducers and are therefore referred to as mixed inducers (37
). A recent case-control study reported that concentrations of two mono-ortho PCBs in breast adipose tissue were associated with breast cancer risk (17
).
We previously reported that exposure to total PCBs, as estimated by the concentration of the most abundant and persistent congener in plasma lipids (PCB 153), was not associated with breast cancer risk (47). To test the hypothesis that exposure to specific PCB congeners may be related to breast cancer, we examined the relation between the disease risk and the plasma lipid concentrations of 14 individual PCB congeners, with a special focus on mono-ortho PCB congeners that display dioxin-like activity. The risk was examined separately in premenopausal and postmenopausal women in view of recent results suggesting that the menopausal status may modify the effect of PCBs on breast cancer risk (17
).
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MATERIALS AND METHODS |
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Blood samples were obtained from cases and hospital controls after surgery and for cases prior to the initiation of chemotherapy or radiotherapy. A research nurse visited population controls at their residence, and blood sampling was performed during this visit. Information on lifestyle, dietary habits, and reproductive history was obtained by telephone interview. Women were categorized as menopausal if they had no menses during the last 6 months. Review boards from Université Laval and the participating hospitals have approved the study proposal, and informed consent was obtained from all women prior to their enrollment.
Laboratory analyses
Fourteen PCB congeners (International Union for Pure and Applied Chemistry (IUPAC) numbers 28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183, 187) were quantified in plasma samples by high-resolution gas chromatography with electron-capture detection (47). The detection limit for each congener was 0.02 µg/liter. The average percentage of recovery for all congeners was greater than 95 percent, and the between-day precision ranged from 3.3 percent to 7.0 percent. The total plasma lipid content was determined by enzymatic methods, and concentrations of PCBs are reported in µg/kg of plasma lipids.
Mono-ortho-substituted congeners display some affinity for the aryl hydrocarbon receptor, and a toxicity scale relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin, the most potent aryl hydrocarbon receptor agonist, was established to calculate the total concentration of dioxin-like compounds in a mixture. A total concentration of mono-ortho congeners, expressed as 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQ), was computed by adding up the weighed concentration of each congener according to its respective toxic equivalency factor, which was 0.0001 for PCB 105 and PCB 118 and 0.0005 for PCB 156 (48).
Statistical analysis
An analysis of variance was conducted to compare the mean concentrations of PCB congeners between cases and controls. The PCB concentrations in plasma lipids displayed lognormal distributions, and therefore all statistical analyses were performed using the natural logarithm of PCB concentrations. A concentration equal to half of the detection limit was assumed for samples with organochlorine levels below the detection limit. Statistical analyses were not performed for congeners that were detected in less than 70 percent of the women.
Point and interval estimation of the odds ratio was based on unconditional logistic regression analysis. Quantile limits of PCB plasma concentrations were based on the distribution observed among controls. Risks were always calculated in relation to the lowest category. Age (30<40, 40<50, 50<60, 60 years) and region of residence (rural/urban) were included in all multivariate models because cases and controls were frequency matched for these variables. The other variables evaluated as confounders were as follows: body mass index (weight (kg)/height (m)2), total energy consumed, alcohol consumption, age at first cigarette, number of reproductive years, age at first child, total breastfeeding duration, use of oral contraceptive, use of hormone therapy, first degree family history of breast cancer, and history of benign breast disease. A variable was considered as a confounder when its inclusion in the model modified the odds ratio (adjusted for age and region of residence) by more than 10 percent. Characteristics of cases and controls were compared using Student's t tests for continuous variables or chi-squared tests for categorical variables. All statistical analyses were performed using SAS version 6.12 software (SAS Institute, Inc., Cary, North Carolina).
RESULTS
Population and hospital controls exhibited similar characteristics, with the exception that population controls showed more fertile years (p = 0.003) and a smaller body mass index (p = 0.0001). Furthermore, the concentrations of organochlorines were comparable in both groups, and the associations between organochlorine exposure and breast cancer risk were comparable, regardless of the control group used for risk calculation (47). Consequently, both control groups were combined for the present statistical analyses. Cases and controls did not differ with regard to most characteristics presented in table 1. Family history of breast cancer and history of benign breast disease were reported more frequently by cases than controls (p = 0.002 and p = 0.001, respectively).
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DISCUSSION
Results of the present study suggest that exposure to dioxin-like mono-ortho PCB congeners increases the risk of breast cancer. Weighed total concentrations of three mono-ortho congeners (PCB 105, PCB 118, PCB 156), expressed in TEQ, were associated with breast cancer risk. PCB 118 and PCB 156 were also individually related to risk, but the most abundant and persistent PCB congeners (PCB 138, PCB 153, PCB 180) were not linked to breast cancer risk.
The relation between PCBs and breast cancer has been addressed using different measures of exposure in previous studies. Most studies that used the total PCB concentration as the measure of exposure reported no association with breast cancer risk (17
,
,
). Recent studies investigated the relations between breast cancer risk and PCB congeners either considered individually or grouped according to common characteristics. Zheng et al. (13
) conducted a case-control study involving 475 cases and 502 controls, who were either randomly selected from residents living in the same county or patients from the same hospital (cases with newly diagnosed breast diseases or normal tissue). Neither total PCB serum concentrations (nine congeners) nor groups of congeners were associated with breast cancer risk. More specifically, the total concentrations of "potentially anti-estrogenic and dioxin-like" congeners (PCB 74, PCB 118, PCB 138, PCB 156, PCB 170) were not associated with breast cancer risk. Using a comparable grouping scheme (congeners 118, 138, 156, 170), we found no association in our data set either (OR = 1.31, 95 percent CI: 0.72, 2.34; fourth vs. first quartile). Zheng et al. (14
) did not find any association in a second study involving breast adipose tissue instead of serum for PCB analysis. However, the authors reanalyzed their data using logistic ridge regression analysis and demonstrated a protective effect on breast cancer risk for PCB 156, while PCB 180 and PCB 183 were associated with an increased risk (16
).
In contrast, Aronson et al. (17) reported an association between the concentration of either PCB 105 (OR = 3.17, 95 percent CI: 1.51, 6.68; fourth vs. first quartile) or PCB 118 (OR = 2.31, 95 percent CI: 1.11, 4.78; fourth vs. first quartile) measured in breast adipose tissue and breast cancer risk, in a case-control study involving 217 cases and 213 controls with benign breast disease. However, no association between PCB 118 in breast adipose tissue and breast cancer risk was observed in a study from Long Island, New York, involving 232 cases and 323 hospital controls admitted to surgery for benign breast disease or other diseases (18
). In a Norwegian study with 150 cases and 150 controls, Ward et al. (19
) also did not note an association between breast cancer risk and the concentration of PCB 118 measured in serum samples that were collected 2 years or more prior to diagnosis.
Smaller studies also provided some evidence of a link between dioxin-like congeners and breast cancer risk. Liljegren et al. (8) reported an increased risk of breast cancer among women with the highest breast adipose tissue levels of non-ortho coplanar congeners PCB 77 (OR = 2.9, 95 percent CI: 0.5, 15) and PCB 169 (OR = 3.4, 95 percent CI: 0.5, 18). Güttes et al. (9
) reported significantly higher concentrations of PCB 118 in breast adipose tissue of cases than in that of controls. Finally, concentrations of PCB 28 and PCB 52 in breast fat were associated with malignant lesions in a study involving 69 women with breast cancer and 65 women with benign breast disease (20
).
Our study is therefore the second large case-control study to note a positive association between mono-ortho PCBs and breast cancer risk. It is worthwhile mentioning that the same laboratory conducted PCB analyses in our study and those of Aronson et al. (17). This laboratory has a large amount of experience in conducting congener-specific PCB analyses and has repeatedly obtained excellent results in interlaboratory quality assurance and control programs. Furthermore, this laboratory reaches detection limits of 0.02 µg/liter in plasma for most PCB congeners, including mono-ortho PCBs, whereas higher detection limits are often reported by other laboratories conducting these analyses (5
, 10
, 13
). Hence, we might speculate that the random error associated with the determination of mono-ortho congeners may be lower for this laboratory compared with others involved in similar studies, which had allowed us and Aronson's group to observe these associations.
Our results may indicate a relation between dioxin-like compounds and breast cancer risk. Although only three dioxin-like compounds (mono-ortho-substituted PCBs) were analyzed in this study, we previously showed that PCB 105, PCB 118, and PCB 156 represent a major fraction of the total TEQ concentration in milk samples from the southern Quebec population (49). Furthermore, the total dioxin-like compound concentrations (including 2,3,7,8-polychlorodibenzo-p-dioxins, 2,3,7,8-polychlorodibenzofurans, and non- and mono-ortho PCB congeners, expressed in TEQ) were highly correlated to the total concentrations of the three mono-ortho congeners also expressed in TEQ (Spearman's r = 0.91, p < 0.0001) in 25 breast milk samples from southern Quebec (É. Dewailly, unpublished data). Hence, mono-ortho PCBs constitute a good indicator of all dioxin-like compounds in our population, and the latter may constitute a risk factor for breast cancer.
One mechanism by which dioxin-like compounds might increase breast cancer risk is through the induction of biotransformation enzymes that may in turn affect estradiol metabolism (39). For example, non-ortho congener PCB 169 was shown to induce CYP1A1 and CYP1B1 but not estradiol metabolism when tested in MCF-7 or HepG2 cells, whereas non-ortho congener PCB 126 induced both enzymes and estradiol metabolism (42
). Other studies showed that CYP1A, CYP3A, and CYP1B1 enzyme induction increases the formation of 4-hydroxy-estradiol, a catechol estrogen that produces DNA damage through the formation of reactive free radicals (43
).
Alternatively, plasma lipid levels of mono-ortho PCB congeners may not be causally related to the disease but may be an indicator of women metabolically predisposed to breast cancer. In contrast to PCB 153 that is highly refractory to metabolism (50), plasma lipid concentrations of more easily metabolized congeners such as PCB 105 or PCB 118 reflect in part the activities of enzymes involved in their biotransformation (24
). The higher the activities of biotransformation enzymes in a person (due to genetic polymorphisms or dietary/lifestyle habits), the lower are the concentrations of these congeners. Further supporting this statement, we previously reported in a group of fish eaters environmentally exposed to PCBs that plasma lipid concentrations of mono-ortho congeners PCB 105 and PCB 118 were inversely correlated to liver CYP1A2 activity, which was itself induced by smoking (51
). In this study, the mean plasma concentration of PCB 118 was 40 percent lower in heavy smokers compared with that in nonsmokers (13.1 vs. 21.5 µg/kg of lipids; p < 0.05). Perhaps plasma lipid concentrations of PCB 105 and PCB 118 indicate a particular profile of biotransformation enzyme, mainly defined by elevated CYP1A/1B1 activities, which could affect circulating levels of estrogens, a known risk factor for breast cancer (52
). Further studies are needed to identify which cytochrome P450 enzymes are involved in mono-ortho PCB metabolism and how these enzymes may modulate circulating levels of estrogens and their metabolites in women.
In conclusion, our results and those obtained in a previous Canadian study suggest a relation between plasma concentrations of mono-ortho PCB congeners and breast cancer risk. Although levels of these dioxin-like compounds may represent a risk factor for the disease, additional studies are needed before concluding that these compounds are causally involved in the etiology of breast cancer.
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ACKNOWLEDGMENTS |
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The authors are indebted to the nurses who participated in this study, to Andrée Christen who supervised the data collection, and to Dr. Jean-Philippe Weber, Dr. Liliane A. Ferron, and Évelyne Pelletier for organochlorine analyses.
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NOTES |
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REFERENCES |
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