Breast Cancer and Exposure to Organochlorines in the CECILE Study: Associations with Plasma Levels Measured at the Time of Diagnosis and Estimated during Adolescence

Exposure to environmental chemicals with hormonal effects, such as organochlorine compounds (OCs), during developmental periods of breast cells may have an impact on the incidence of breast cancer later in life. However, the assessment of exposure to these chemicals that occurred in early life at the time of breast cancer development in adult women is a difficult challenge in epidemiological studies. Plasma levels of the OCs p,p’-dichlorodiphenyl dichloroethene (DDE) and polychlorinated biphenyl congener 153 (PCB153) were measured in 695 cases and 1055 controls of a population-based case-control study conducted in France (CECILE study). Based on these values, we used a physiologically-based pharmacokinetic (PBPK) model to estimate PCB153 levels at age 11–20 years when the women were adolescents. Overall, there was no clear association between breast cancer risk and measured levels of DDE and PCB153 at the time of diagnosis, but there was a trend of decreasing odds ratios of breast cancer with increasing DDE and PCB153 levels in women aged 50 years and over. The PBPK model revealed that PCB153 concentrations estimated during adolescence were highest in the youngest women born after 1960 who reached adolescence at a time when environmental contamination was maximum, and very low in the oldest women who attained adolescence before the contamination peak. Negative associations between breast cancer and PCB153 estimates during adolescence were also found. The negative associations between DDE and PCB153 levels measured at the time of diagnosis or estimated during adolescence in our study were unexplained. Further investigations are needed to clarify whether this finding is real or related to study artifacts. However, this study suggests that using PBPK models in epidemiological studies to back-estimate OC exposures during early life stages may be useful to address critical questions on cancer development.

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title: A Case Study Addressing the Reliability of Polychlorinated Biphenyl Levels Measured at the Time of Breast Cancer Diagnosis in Representing Early-Life Exposure
abstract: To date, breast cancer epidemiologic studies have relied on blood or tissue specimens sampled at the time of diagnosis or a few years prior to assess lifetime exposure to polychlorinated biphenyls (PCB). In this study, we evaluated whether such PCB measurements are indicative of early-life levels by reconstructing lifetime toxicokinetic profiles for women included in the CECILE case–control study, using a physiologically based pharmacokinetic (PBPK) model.  We simulated lifetime toxicokinetic profiles of PCB-153 for 2,134 French women by incorporating information on body weight history, height, pregnancies, and breast-feeding in the PBPK model. Oral dose was calculated by considering measured blood PCB-153 and the temporal trend of environmental contamination. Area under the concentration versus time curve (AUC) for each decade of life and maximum blood concentration (Cmax) were compiled and compared with measured levels, using Pearson partial correlation analyses adjusting for age at diagnosis.  When considering all individuals, simulated AUCs correlated with measured PCBs, with coefficients ranging from 0.735 to 0.981. The weakest correlations were obtained with AUCs for the first decades of life. Stratified analyses suggested that breast-feeding reduces the reliability of late-life blood levels in representing lifetime exposure.  Results of this study suggest that PCB levels measured at the time of diagnosis do not fully represent early-life exposures.  PBPK-derived estimates of early-life levels circumvent the limitations of current approaches in assessing PCB lifetime exposure and may be used to address hypothesized windows of breast vulnerability (e.g., puberty) in this population. Cancer Epidemiol Biomarkers Prev; 20(2); 281–6.

title: Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs: occurrence and dietary intake in The Netherlands.
abstract: Data on occurrence of dioxins (polychlorinated dibenzo-p-dioxins [PCDDs] and dibenzofurans [PCDFs]), dioxin-like PCBs (polychlorinated non-ortho and mono-ortho biphenyls) and non-dioxin-like PCBs (as represented by the so-called indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) in food products consumed in The Netherlands that were collected in measurement programs carried out during 1998 and 1999, and combined with food consumption data to assess the dietary intake of these persistent food contaminants. The estimated median life-long-averaged intake of the sum of dioxins and dioxin-like PCBs in the population is 1.2 pg WHO-TEQ (toxic equivalents) per kg body weight (bw) per day, while the estimated median life-long-averaged intake of indicator-PCBs is 5.6 ng per kg bw per day. The contribution of different food groups to the total intake of both dioxins + dioxin-like PCBs and non-dioxin-like PCBs is fairly uniformly distributed over the foods consumed: meat products (23% and 27%, respectively), dairy products (27% and 17%, respectively), fish (16% and 26%, respectively), eggs (4% and 5%, respectively), vegetable products (13% and 7%, respectively), and industrial oils and fats (17% and 18%, respectively). Compared with earlier intake estimations the present estimation shows a continued reduction in the intake of dioxins as well as PCBs. This reduction is related to the decrease in the concentration of these substances in the majority of foodstuffs. Nevertheless, a small part of the population still has a rather high life-long averaged intake: 8% of the population is exposed to intake levels above the tolerable weekly intake for dioxins and dioxin-like PCBs of 14 pg WHO-TEQ per kg bw per week, as recently derived by the Scientific Committee on Food of the European Commission. For the non-dioxin-like PCBs an internationally accepted maximum intake level is still lacking. However, to provide risk managers with a health-based guideline to prevent health effects of exposure to non-dioxin-like PCBs, the (international) derivation of a tolerable daily intake is recommended. Monitoring the dietary intake of PCBs is just as important as monitoring the intake of dioxins and dioxin-like PCBs, and attempts to decrease the exposure to both compound classes need continuous attention.

title: Serum polychlorinated biphenyl and organochlorine insecticide concentrations in a Faroese birth cohort.
abstract: A prospective birth cohort of 1022 participants was established in the Faroe Islands over a 21-month period during 1986-1987. We collected questionnaire data on potential persistent organic pollutant (POP) concentration predictors, such as duration of breastfeeding and blubber consumption. To assess the participants' exposure from in utero to 14 years of age to polychlorinated biphenyls (PCBs) and the insecticide p,p'-DDT and its primary degradate p,p'-DDE, we measured 37 PCB congeners and pesticides in 316 umbilical cord samples taken from participants at birth, in 124 serum samples collected from participants at approximately 7 years of age, and in 795 serum samples collected from participants at 14 years of age. Measurements of higher chlorination PCB congeners made on individuals' serum samples collected at 7 years and 14 years were highly correlated (typically r > 0.5, p > 0.01), although their concentrations at 7 years were generally two to three times higher than at 14 years. Similarly, umbilical cord PCB concentrations were correlated with PCB concentrations in both 7- and 14-year serum samples. Sex-specific differences in higher chlorination PCB and p,p'-DDE concentrations were found at 14 years but not at 7 years, although a sex interaction with blubber consumption and nursing duration was observed at both ages. Both duration of breastfeeding and consumption of blubber were significant predictors of serum summationPCB concentrations at 7 and 14 years. Multivariate analyses showed that breastfeeding duration was the primary contributor to serum summationPCB concentrations at 7 years, and blubber consumption was the primary contributor at 14 years. These data suggest that infant exposures from breastfeeding were sufficiently large so that continued exposures to PCBs, p,p'-DDT, and p,p'-DDE through the diet have not fully diluted their contribution to the summationPCB and p,p'-DDE body burden of the children.

title: Temporal trends in concentrations and total serum burdens of organochlorine compounds from birth until adolescence and the role of breastfeeding.
abstract: The aims of the present study are to assess the temporal trends of organochlorine compounds (OCs) concentrations and total serum burdens from birth until adolescence and the influence of breastfeeding in these temporal trends.



In 1997 two birth cohort studies were set up in Ribera d'Ebre (N=102) and the island of Menorca (N=482), Spain. Concentrations (ng/mL) of OCs [pentachlorobenzene (PeCB), four isomers of hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (4,4'-DDT), dichlorodiphenyldichloroethylene (4,4'-DDE) and seven polychlorobiphenyl congeners (Σ7PCBs)] were measured in cord blood and at the age of 4 and 14years. The total serum burdens (ng) of these compounds were estimated based on the total blood volume (mL) of children at the different ages. We compared median concentrations and total serum burdens of these OCs at the different time-points of follow-up between children of Ribera d'Ebre and Menorca and between breastfed and non-breastfed children.



From birth until adolescence concentrations of all OCs drastically reduced. These reductions were mainly derived from the dilution of OCs, associated to an increase in total blood volume of children at the age of 4 and 14years. Despite the reduction in OCs concentrations, the total serum burdens of 4,4'-DDE and Σ7PCBs, were higher in adolescents than at birth. Increases in OCs total serum burden occurred both in breastfed and non-breastfed children, but were significantly higher in the first.



Even after decades of banning OCs production and use, current young generations in westernized countries are still bioaccumulating these compounds. Given the potential health effects of OCs, especial attention should be paid in the control of secondary emissions in the environment and in the control of food production and contamination. In countries with endemic malaria it is important to work towards effective alternatives to the use of DDT.

title: DDT/DDE and breast cancer: a meta-analysis.
abstract: The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. We searched PubMed and Web of Science for studies published through June 2012 assessing DDT/DDE exposure and breast cancer.  Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE (1.05; 95% CI: 0.93-1.18) and DDT (1.02; 95% CI: 0.92-1.13). Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls (11.30 ng/g lipid; p=0.01). No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.

title: Exposure to Dichlorodiphenyltrichloroethane and the Risk of Breast Cancer: A Systematic Review and Meta-analysis
abstract: This study extended and updated a meta-analysis of the association between exposure to dichlorodiphenyltrichloroethane (DDT) and the risk of breast cancer.  We reviewed the published literature on exposure to DDE and breast cancer risk to update a meta-analysis from 2004. The total of 35 studies included 16 hospital-based case–control studies, 11 population-based case–control studies, and 10 nested case–control studies identified through keyword searches in the PubMed and EMBASE databases.  The summary odds ratio (OR) for the identified studies was 1.03 (95% confidence interval 0.95–1.12) and the overall heterogeneity in the OR was observed (I2 = 40.9; p = 0.006). Subgroup meta-analyses indicated no significant association between exposure to DDE and breast cancer risk by the type of design, study years, biological specimen, and geographical region of the study, except from population-based case–control studies with estimated DDE levels in serum published in 1990s.  Existing studies do not support the view that DDE increases the risk of breast cancer in humans. However, further studies incorporating more detailed information on DDT exposure and other potential risk factors for breast cancer are needed.

title: Polychlorinated biphenyls and breast cancer: A congener-specific meta-analysis.
abstract: The incidence of breast cancer is related to various risk factors, especially that the environmental and lifestyle factors account for major contribution at the rate of 70% to 95% over all. However, there still remains some controversy over the epidemiological evidence regarding the effects of environmental carcinogens on the risk of breast cancer. We conducted a quantitative meta-analysis aiming at full evaluation of the effects of polychlorinated biphenyls (PCBs) on breast cancer in a congener-specific fashion. Four online literature databases were systematically searched before 1st January 2015, for studies stating correlation between PCB congeners and breast cancer. The Newcastle-Ottawa Scale was used to evaluate the quality of the studies that were included in our analysis. Sixteen studies were included in our final meta-analysis after screening based on the priori inclusion criteria. Nine PCB congeners were reported by more than two studies and they were presented in detail. The pooled Odds Ratios (ORs) showed a significant increase in the risk of breast cancer in individuals with higher plasma/fat levels of PCB 99 (OR: 1.36; 95% CI: 1.02 to 1.80), PCB 183 (OR: 1.56; 95% CI: 1.25 to 1.95) and PCB 187 (OR: 1.18; 95% CI: 1.01 to 1.39). Besides, the outcomes did not support a relationship between dioxin-like PCB congeners and the risk of breast cancer. The results of our meta-analysis imply that PCB 99, PCB 183 and PCB 187 would increase the risk of breast cancer. The mechanism of this increased risk may be by the induction of the CYP2B family in cytochrome P450 enzymes.

title: Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study
abstract: BackgroundEnvironmental Persistent Organic Pollutants (POPs) can alter the hormone homeostasis by mimicking, interfering or blocking the function of hormones; moreover POPs are hypothesized to modify the risk of breast cancer. The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of POPs and breast cancer with focus on the highly exposed Greenlandic Inuit population.MethodsThe study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000–2003 and 2011–2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs). Independent samples t-test was used to compare differences between cases and controls and odds ratios (OR) adjusted for identified confounders were obtained using logistic regression.ResultsThe study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 – 2003 to 2011–2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference was maintained for ∑OCP, dichlorodiphenyldichloroethylene (p,p′-DDE), ∑PFAA, ∑perfluorinated sulfonic acids (PFSA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS). For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) of ∑PCB, ∑estrgoenicPCB, PCB99, PCB138, PCB153, PCB170, PCB170, and PCB183 was associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk.ConclusionSignificant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.

title: Correlations among polychlorinated biphenyls, dioxins, and furans in humans.
abstract: Correlations among human levels of polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans potentially complicate interpretation of studies of their individual health effects. Outcomes attributed to one may, in fact, be due to another.



We present correlations among dioxins, furans, and PCBs in blood collected in 1991-1992 from 44 American Vietnam veterans from Michigan.



Correlations among specific dioxins and furans ranged from 0.26 to 0.80, with the higher-chlorinated congeners being more highly correlated. Correlations among PCBs ranged from 0.06 to 0.94, with those occurring at highest concentrations being more highly correlated. Correlations of PCBs with dioxins and furans ranged from -0.09 to 0.59. Correlations of individual chemicals with total dioxin toxic equivalents ranged from 0.31 to 0.76.



If confirmed in other populations, such correlations may allow the use of simpler assays but may also raise issues of confounding and calibration.

title: Serum organochlorines and breast cancer risk in Japanese women: a case–control study
abstract: ObjectiveMost epidemiological studies of the association between breast cancer risk and exposure to organochlorine pesticides or polychlorinated biphenyls (PCBs), which are suspected endocrine disrupters and potential risk factors for human breast cancer, have been conducted in western countries, and the majority of results have been null and the rest inconsistent. Here, we examined these associations in Japanese women in the largest study in Asian women to date.MethodsThe study was a matched case–control study of breast cancer with 403 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan.MeasurementsSerum samples were measured for PCBs and nine pesticide-related organochlorines, including dichlorodiphenyltrichloroethane (DDT). Odds ratios of breast cancer or its hormone-receptor-defined subtypes according to serum organochlorines were calculated.ResultsNo increase in the risk of breast cancer was seen among women with higher serum concentrations of any organochlorine: o,p′-DDT, p,p′-DDT, p,p′-dichlorodiphenyldichloroethylene, hexachlorobenzene, β-hexachlorocyclohexane, trans-nonachlor, cis-nonachlor, oxychlordane, mirex, or PCBs. Rather, higher serum levels of cis-nonachlor, mirex, or total PCBs were associated with a decreased risk of breast cancerConclusionsOverall, these results suggest that breast cancer risk in Japan, a low-incidence country, is similar to that in western countries in terms of organochlorine exposure.

title: Risk of female breast cancer and serum concentrations of organochlorine pesticides and polychlorinated biphenyls: a case-control study in Tunisia.
abstract: The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of breast cancer in a female population from Tunisia. The relationship between serum levels of the pollutants and the risk of cancer was assessed using logistic regression analyses. In the unadjusted models, β-hexachlorocyclohexane (β-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only β-HCH and p,p'-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose-response relationship that was significant for p,p'-DDE (p-trend=0.020) and borderline significant for heptachlor (p-trend=0.078). A similar trend was also confirmed for β-HCH, in which concentrations≥limit of detection were positively associated with breast cancer risk (vs. concentrations<limit of detection, OR=3.44, p<0.05). Finally, the relative influence of each chemical in the presence of the others was assessed by entering the three chemicals in a single model with all covariates, and only β-HCH remained positively associated with the risk of cancer (OR:1.18, 95%CI: 1.05-1.34). Our findings suggest a potential association between exposure to at least one organochlorine pesticide and breast cancer risk. However, our results should be interpreted with caution, and further research is warranted to confirm these findings.

title: Joint effects of nine polychlorinated biphenyl (PCB) congeners on breast cancer risk.
abstract: Polychlorinated biphenyls (PCB) have been a major environmental health concern because of their wide distribution and persistence in the environment. Estimating joint effects of all congeners in a single analysis is complicated by correlation among exposure levels, and the resulting collinearity makes the results difficult to interpret.



Patients with breast-related surgery at Yale-New Haven Hospital were interviewed using a standardized questionnaire, and breast adipose tissue samples were analysed for nine PCB congeners (74, 118, 138, 153, 156, 170, 180, 183, 187). The study recruited 490 women (304 cases and 186 controls) between 1994 and 1997. Logistic ridge regression was used to analyse the instability caused by collinearity.



Although total PCB did not appear to be associated with breast cancer risk, significant differences in effect were observed among the nine congeners. Logistic ridge regression demonstrated a protective effect on breast cancer risk for a potentially anti-oestrogenic and dioxin-like congener, 156, while two phenobarbital, CYP1A and CYP2B inducers had an adverse effect, 180 and 183. This analysis also suggested that a protective effect for another phenobarbital congener, 153, was largely explained by instability caused by collinearity.



These results indicate that studies of PCB congeners and health require an in-depth statistical analysis in order to better understand the complex issues related to their collinearity.

title: Breast cancer risk associated with congeners of polychlorinated biphenyls.
abstract: Experimental studies show that hormonal and nonhormonal activities of polychlorinated biphenyls (PCBs) are structure dependent, suggesting that the breast cancer risk associated with PCBs may vary according to specific PCB congeners. In 1994-1997, the authors conducted a case-control study of Connecticut women to investigate whether breast cancer risk is associated with body burden of PCBs and varies by PCB congeners. A total of 304 breast cancer cases and 186 controls aged 40-79 years were recruited into the study. Fresh breast adipose tissue was analyzed for PCBs. The age- and lipid-adjusted geometric mean tissue levels of total PCBs were not significantly different (p = 0.46) for the cases (478.6 parts per billion) and controls (494.1 parts per billion). The covariate-adjusted odds ratio was 0.7 (95% confidence interval: 0.4, 1.1) for all study participants when the third tertile was compared with the lowest tertile. No individual congeners or groups of congeners were associated with a significantly increased risk of breast cancer. Further stratification by type of breast disease; menopausal, parity, and lactation status; and body size also showed no significant association with body levels of PCBs. These results suggest that environmental exposure to PCBs may not substantially affect breast cancer risk.

title: Polychlorinated biphenyls and risk of testicular germ cell tumors.
abstract: Exposure to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCB), may alter hormonal balance and thereby increase risk of testicular germ cell tumors (TGCT). To study the relationship of PCBs to TGCT, prediagnostic serum samples from 736 cases and 913 controls in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Adjusted odds ratios and 95% confidence intervals were estimated using logistic regression. PCB levels were examined in association with all TGCT and, separately, with each histologic type (seminoma and nonseminoma). Risks associated with seven functional groupings of PCBs, as well as sum of PCBs, were also examined. There were significantly decreased risks of TGCT in association with eight PCBs (PCB-118, PCB-138, PCB-153, PCB-156, PCB-163, PCB-170, PCB-180, and PCB-187) and no association with the remaining three (PCB-99, PCB-101, and PCB-183). The same eight congeners were significantly associated with decreased risk of nonseminoma, whereas five (PCB-138, PCB-153, PCB-156, PCB-163, and PCB-170) were associated with decreased risk of seminoma. All functional groupings of PCBs were also associated with decreased risk of TGCT and of nonseminoma, whereas six of the seven functional groups were associated with decreased risk of seminoma. Sum of PCBs was significantly associated with decreased risk of TGCT (P(trend) = 0.006), nonseminoma (P(trend) = 0.007), and seminoma (P(trend) = 0.05). Overall, these data do not support the hypothesis that PCB exposure increases the risk of TGCT.

title: Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.
abstract: Polychlorinated biphenyls (PCBs) are ubiquitous environmental persistent contaminants giving rise to potential health hazard. Some PCBs exert dioxin-like activities mediated through the aryl hydrocarbon receptor. Although reports on interaction with other nuclear receptors are sparce, some congeners are hypothesized to possess endocrine disruptive potential. Here we present evidence that the three PCBs most abundant in biological extracts, 2,2',3'4,4',5-hexachlorobiphenyl (PCB#138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB#153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB#180) have pleiotropic effects on the estrogen- and androgen-receptor. In MCF-7 cells a slightly increased cell proliferation was observed at low concentrations (1-10 nM) in cells co-treated with 0.01 nM 17beta-Estradiol, whereas the compounds inhibited cell growth significantly at 1 and 10 microM. In reporter gene (ERE-tk-CAT) analysis the three congeners exhibited a significantly estrogen receptor-ligand mediated decrease of the chloramphenicol transferase activity in both control and 10 nM 17beta-estradiol induced MCF-7 cells. In addition, PCB#138 elicited a dose-dependent antagonistic effect on androgen receptor activity in transiently co-transfected Chinese Hamster Ovary cells with an IC(50), of 6.2 microM. In summary, this study indicate that the di-ortho, multiple-chloro substituted biphenyls, PCB#138, PCB#153 and PCB#180, can compete with the binding of the natural ligand to two nuclear receptors and thus possess the ability to interfere with sexual hormone regulated processes.

title: Antiestrogenic potentials of ortho-PCB congeners by single or complex exposure
abstract: Di-ortho PCB congeners 52, 138, 153 and 180, and the mono-ortho coplanar congener 118 have been detected as a complex mixture in human tissue in Korea. This study examined the antiestrogenic effects of samples exposed to single or combination treatment of the ortho-PCB congeners. In order to determined the combined toxicity, a sample mixture (M1, M2, M3, M4, and M5) was designed based on the ortho-PCB congeners found in Korean human tissue. With the exception of PCB 52, the ortho-PCB congeners (PCB 118, 138, 153, and 180) showed weak antiestrogenic activity. The antiestrogenic activity of di-ortho PCB congeners (PCB 138, 153, and 180) was induced by the depletion of endogenous E2 as well as through the ER-dependent pathway, whereas the antiestrogenic activity of mono-ortho PCB 118 was only induced through the depletion of endogenous E2. When the MCF7-BUS cells were treated with mixtures containing the no effective concentration (10-6 M) of the PCB congeners, M3 (PCB 118 + PCB 138 + PCB 180) and M4 (PCB 118 + PCB 138) had an antiestrogenic effect but the other mixtures (M1; PCB 52 + PCB 118 + PCB 138 + PCB 180, M2; PCB 118 + PCB 138 + PCB 153 + PCB 180, M5; PCB 118 + PCB 180) did not. Although the mechanism for the interaction between the PCB congeners is not completely understood, it was presumed that exposure to a mixture of the PCB congeners might have synergistic effects on their antiestrogenicity through the ER-independent pathway.

title: Impact of Polychlorinated Biphenyls Contamination on Estrogenic Activity in Human Male Serum
abstract: Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lower-chlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as anti-estrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17β-Estradiol (E2) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of anti-estrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent non-dioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects.

title: Activation of the aryl hydrocarbon receptor by TCDD inhibits mammary tumor metastasis in a syngeneic mouse model of breast cancer.
abstract: Treatment with aryl hydrocarbon receptor (AhR) agonists can slow or reverse the growth of primary mammary tumors in rodents, which has fostered interest in developing selective AhR modulators for treatment of breast cancer. However, the major goal of breast cancer therapy is to inhibit metastasis, the primary cause of mortality in women with this disease. Studies conducted using breast cancer cell lines have demonstrated that AhR agonists suppress proliferation, invasiveness, and colony formation in vitro; however, further exploration using in vivo models of metastasis is warranted. To test the effect of AhR activation on metastasis, 4T1.2 mammary tumor cells were injected into the mammary gland fat pad of syngeneic Balb/c mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Primary tumor growth was monitored for 4 weeks, at which time metastasis was determined. TCDD treatment suppressed metastasis by approximately 50%, as measured both in the lung and in mammary glands at sites distant from the primary tumor. Primary tumor growth was not suppressed by TCDD exposure nor was proliferation of 4T1.2 cells affected by TCDD treatment in vitro. Taken together, these results suggest that the protective effect of AhR activation was selective for the metastatic process and not simply the result of a direct decrease in tumor cell proliferation or survival at the primary site. These observations in immunologically intact animals warrant further investigation into the mechanism of the protective effects of AhR activation and support the promise for use of AhR modulators to treat breast cancer.

title: Dioxin emissions from a municipal solid waste incinerator and risk of invasive breast cancer: a population-based case-control study with GIS-derived exposure
abstract: BackgroundTo date, few epidemiologic studies have examined the relationship between environmental PCDD/F exposure and breast cancer in human populations. Dioxin emissions from municipal solid waste incinerators (MSWIs) are one of the major sources of environmental dioxins and are therefore an exposure source of public concern. The purpose of this study was to examine the association between dioxins emitted from a polluting MSWI and invasive breast cancer risk among women residing in the area under direct influence of the facility.MethodsWe compared 434 incident cases of invasive breast cancer diagnosed between 1996 and 2002, and 2170 controls randomly selected from the 1999 population census. A validated dispersion model was used as a proxy for dioxin exposure, yielding four exposure categories. The latter were linked to individual places of residence, using Geographic Information System technology.ResultsThe age distribution at diagnosis for all cases combined showed a bimodal pattern with incidence peaks near 50 and 70 years old. This prompted us to run models separately for women aged 20–59 years, and women aged 60 years or older. Among women younger than 60 years old, no increased or decreased risk was found for any dioxin exposure category. Conversely, women over 60 years old living in the highest exposed zone were 0.31 time less likely (95% confidence interval, 0.08–0.89) to develop invasive breast cancer.ConclusionBefore speculating that this decreased risk reflects a dioxin anti-estrogenic activity with greater effect on late-onset acquired breast cancer, some residual confounding must be envisaged.

title: Body weight loss increases plasma and adipose tissue concentrations of potentially toxic pollutants in obese individuals
abstract: While there appears to be a consensus among scientists and clinicians that body weight loss reduces the risk of several chronic diseases, these apparently favourable effects should be balanced against any potentially harmful side effect of weight loss. In this regard, weight loss has been shown to produce an increase in blood concentration of potentially toxic organochlorine pollutants in animals that can cause prejudice to health, but human data are lacking. Thirty-nine obese individuals were subjected to a hypocaloric diet during 15 weeks. Blood and subcutaneous adipose tissue samples were analysed before and after treatment for 26 organochlorine compounds. A control group consisting of 57 women of similar mean age was also formed in order to compare plasma concentrations. Organochlorine pollutants were found in every subject and all 19 compounds detected had their plasma concentration increased following treatment (mean body weight loss 9.5 kg), 15 of which were statistically significant. When compared with a control group, five compounds increased significantly. These observations persisted after an 18 week low-fat diet/exercise program follow-up. Increases were correlated with body weight loss (−0.3 ≥ r ≥−0.6, P<0.05) and adipose tissue analyses yielded similar results, as their concentration of organochlorine compounds increased following treatment. Body weight loss increases plasma and subcutaneous adipose tissue concentrations of organochlorine pesticides and PCBs in obese subjects. These results raise concerns about an undesired and potentially harmful side effect of weight loss in some obese patients who seem to be at greater risk of health problems than leaner subjects since they show higher organochlorine body burden.