Breast Cancer May Be Caused by PCBs

Studies of Breast Cancer, PCBs and Dioxin

Study #65

statistically significant predictors of PCB levels included age, serum lipids, parity, and fish consumption

BACKGROUND: Organochlorines, such as 2,2-bis (4-chlorophenyl)-1,1-dichloroethylene (DDE), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) are lipophilic compounds that are ubiquitous in the environment and may cause adverse health effects in humans. METHODS: We examined the correlation between epidemiological exposure variables and serum DDE, PCB, and HCB levels in a sample of 192 healthy, female postmenopausal western New York residents; a subset of the control group from a case-control study on breast cancer risk. Usual diet, reproductive and medical histories, and other lifestyle information were obtained by an extensive in person interview. Serum levels (ng/g) of DDE, HCB, and 69 PCB congeners were determined by gas chromatography with electron capture detection. Statistical analyses included computations of crude and age and lipid adjusted correlation coefficients, as well as multiple linear regression analysis. RESULTS: Results indicated that the strongest predictors for serum DDE levels were age, serum lipids, parity, and fruit and dairy consumption. Statistically significant predictors of PCB levels included age, serum lipids, parity, and fish consumption. Serum HCB levels were related to age, serum lipids, and fruit and red meat consumption. CONCLUSIONS: Our findings are consistent with previous investigations that reported strong associations between organochlorine levels and age and serum lipids. The absence of other data showing an association between fruit intake and organochlorine levels make the importance of this finding unclear. (Moysich et al, 2002)

Study #66

grouping with respect to degree of chlorination, enzyme induction, occurrence, and other toxicological aspects were useful for reducing PCB congeners into meaningful analytic units

BACKGROUND: Polychlorinated biphenyls (PCBs) have been associated with a variety of health outcomes. Enhanced laboratory techniques can provide a relatively large number of individual PCB congeners for investigation. However, to date there are no established frameworks for grouping a large number of PCB congeners into meaningful analytic units. METHODS: In a case-control study of serum PCB levels on breast cancer risk, measured levels of 56 PCB congener peaks were available for analysis. We considered several approaches for grouping these compounds based on 1) chlorination, 2) factor analysis, 3) enzyme induction, 4) enzyme induction and occurrence, and 5) enzyme induction, occurrence, and other toxicological aspects. The utility of a framework was based on the mechanism of biologic actions within each framework, lack of collinearity among congener groups, and frequency of detection of PCB congener groups in measured serum levels of 192 healthy postmenopausal women. RESULTS: Most participants had detectable levels for the proposed PCB congeners groups, using degree of chlorination as a grouping framework. In addition, the previously proposed grouping approach based on enzyme induction, occurrence, and other toxicological aspects was an applicable alternative to the crude approach of grouping by degree of chlorination. Grouping these congeners with respect to P450 enzyme induction activity, and the previously proposed framework based on enzyme induction and occurrence, did not fit these data as well, because only a small proportion of participants had detectable levels for the congener groups with the greatest toxicological potential. Statistical grouping did not result in an interpretable and meaningful clustering of these exposures. CONCLUSIONS: In these data, grouping with respect to degree of chlorination and the previously proposed framework based on enzyme induction, occurrence, and other toxicological aspects were the most useful approaches to reducing a large number of PCB congeners into meaningful analytic units. Factors affecting the utility of the proposed grouping frameworks are discussed. (Moysich et al, 1999)

Study #67

Congener specific analysis of PCBs showed that some individual congeners were preferentially excluded from or concentrated in the breast cyst fluid

The organochlorines, dichloro-diphenyl-trichloroethane and polychlorinated biphenyl (PCB) are pervasive environmental contaminants. Results from previous studies have been conflicting regarding the relationship between the internal dose of these organochlorine residues and breast cancer risk. To determine whether these compounds are present in breast cyst fluids and whether cyst fluid and plasma concentrations are correlated, we analyzed organochlorines in paired cyst fluid and plasma samples from 24 subjects using gas chromatography and electron capture detection. All but one of the women had a history of multiple cysts, suggesting that they were at elevated risk for future breast cancer. DDE (a metabolite of dichloro-diphenyl-trichloroethane) was present in 22 of the cyst samples and PCB was detected in 19 of the cyst samples. Organochlorine levels were more concentrated in the plasma than in breast cyst fluids. Levels of DDE in plasma were significantly correlated with those in cyst fluid (r = 0.73; P < 0.001); in contrast to PCB levels in cyst and plasma (r = 0.37; P = 0.12). Congener specific analysis of the PCBs showed that some individual congeners were preferentially excluded from or concentrated in the cyst fluid. To our knowledge, this study is the first to demonstrate that PCB and DDE are present in cyst fluids and thus in contact with the ductal epithelium of the breast. These results support the use of plasma DDE as a proxy for DDE in the target tissue in research on the role of environmental factors in breast cancer. (Blackwood et al, 1998)

Study #68

levels of most congeners of PCBs were similar whether measured in fat or blood samples
PCB congener patterns were similar in most human and wildlife samples, but different from PCB patterns found in people exposed to PCBs occupationally
di-ortho PCBs 153 and 137 were found in all fat and over 98% of blood samples

Some organochlorine pesticides (OCPs) and PCBs are under investigation as possible risk factors for breast cancer because of their estrogenic properties and widespread presence in the environment. It is important to know whether adipose tissue used by some investigators and serum assays used by others can provide comparable information on body burden. Concentrations of seven OCPs or their breakdown products as well as 14 PCB congeners were measured in the adipose tissue and serum of 293 women enrolled as controls in a case-control study of environmental factors for breast cancer in Long Island, New York, a high-risk region. Adipose OCP/PCB levels were measured using a supercritical fluid extraction method developed by the authors. 1,1-Dichloro-2,2-di(4-chlorophenyl)ethylene (p,p'-DDE) was detected in all adipose and serum samples; two chlordane derivatives, beta-hexachlorocyclohexane (a lindane isomer) and hexachlorobenzene, were detected in at least 92% of adipose samples. The di-ortho hexachlorinated PCB congeners 2,4,5,2',4',5'-hexachlorobiphenyl and 2,3,4,2',4',5'-hexachlorobiphenyl were detected in all adipose and over 98% of serum samples. 1,1-Dichloro-2,2-di(4-chlorophenyl)ethylene comprised 77% of total pesticide residues in adipose and 71% in serum. 2,4,5,2',4',5'-Hexachlorobiphenyl comprised 24% of adipose and 21% of serum PCBs. The relative concentration patterns of the 14 PCB congeners were similar to those reported in other human studies and were also typical of patterns reported in environmental samples from various biota, including mammals and birds, but differed substantially from patterns reported in occupationally exposed workers. All adipose-serum correlations for pesticides and most PCBs were statistically significant. Either serum or adipose OCP/PCB levels of a variety of environmental organochlorine compounds may serve as useful biomarkers of body burden. (Stellman et al, 1999)

Study #69

PCB 77 (dioxin-like) enhanced breast tumor development after the tumors were initiated by another toxic chemical
PCB congeners can influence breast cancers

Polychlorinated biphenyls (PCBs) are fat-soluble environmental pollutants which can be stored in the fatty tissue of breast and secreted in milk. Previous studies have shown that PCBs can influence liver carcinogenesis in animal models but no such studies have been reported in breast. These experiments aimed to determine whether a PCB congener could influence mammary carcinogenesis using the rat DMBA-induced mammary tumour model system. 3,3',4,4'-Tetrachlorobiphenyl (TCB) enhanced the development of DMBA-induced mammary tumours in young female rats and did so in animals fed either a low-fat (5% w/w corn oil) or a high-fat (20% w/w corn oil) diet. The combination of TCB and high-fat diet resulted in tumours growing so fast that the experiment had to be terminated at 10.5 weeks for humane reasons. At termination the total numbers of tumours in each group of 20 rats were: 4 in the low-fat group, 22 in the low-fat plus TCB group, 25 in the high-fat group and 50 in the high-fat plus TCB group. Histopathological analysis confirmed that 98% of the tumours were mammary carcinomas, predominantly in situ ductal carcinomas, but, in addition, revealed that 13 of the tumours had an invasive phenotype of which 12/13 had all arisen in TCB-treated animals. This demonstrates, for the first time, that a PCB congener can influence mammary carcinogenesis. (Nesaretnam et al, 1998)

Study #70

PCB 80 is weakly estrogenic
PCB 52 revealed no estrogenic properties

Polychlorinated biphenyls (PCBs) are widespread, persistent environmental contaminants of which some congeners can act as endocrine disrupters. Previous work has shown that 3,4,3',4'-tetrachlorobiphenyl (PCB77) can act as an oestrogen with actions mediated through the oestrogen receptor. Here, oestrogenic actions have been assessed for two further tetrachlorobiphenyl isomers. Assays of oestrogenic action have involved (1) ligand regulation of oestrogen-sensitive gene expression; (2) ligand regulation of cell growth in oestrogen-dependent human breast cancer cell lines MCF7 McGrath and ZR-75-1; and (3) ligand activity in the immature mouse uterine weight bioassay in vivo. These results demonstrate that 3,5,3',5'-tetrachlorobiphenyl (PCB 80) can be considered to be a weak oestrogen agonist, but the 2,5,2',5'-congener (PCB 52) revealed no oestrogenic properties in any of these assays. Implications of these results are discussed in relation to structure-activity predictions for environmental oestrogens. (Nesaretnam et al, 1997)

Study #71

PCB 77 (dioxin-like) is estrogenic, highly toxic and bioaccumulates significantly
one PCB congener can act as both an agonist and antagonist of estrogen and the magnitude of these effects can alter according to molecular environment
studied levels of PCB 77 are similar to levels found in humans, so these results may be relevant

Polychlorinated biphenyls (PCBs) are one of the most widespread, persistent man-made products in the ecosystem giving rise to serious environmental contamination and potential hazard to health. The PCBs, in common with other compounds such as the dioxins, have been shown to exert some biological actions mediated through the aryl hydrocarbon receptor. Evidence for interaction of PCBs with other nuclear receptors has been sparse. Here we present evidence that 3,4,3',4'-tetrachlorobiphenyl (TCB) (PCB77), a PCB with high toxicity and significant bioaccumulation, can act as an estrogen with actions mediated through the estrogen receptor. Evidence is presented from multiple assay systems including 1) ligand binding to estrogen receptor in a competitive binding assay, 2) ligand ability to induce estrogen receptor binding to DNA, 3) ligand regulation of gene expression from a transfected exogenous (ERE-tk-CAT) or an endogenous (pS2) estrogen-regulated gene, 4) ligand regulation of cell growth in estrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1, and 5) ligand activity in the immature mouse uterine weight bioassay in vivo. These results demonstrate that TCB (PCB77) can be included in the increasing list of environmental pollutants that possess the ability to mimic estrogen action and be termed an environmental estrogen. Since the concentrations of TCB used here (10(-9) M; 292 ng/liter) are not incompatible with levels of PCB/TCB found in human tissues, these results may have physiological relevance. Use of multiple approaches to study estrogenic action demonstrates that one congener can act as both an agonist and antagonist of estrogen action and that the magnitude of these effects can alter according to the molecular environment. (Nesaretnam et al, 1996)

Study #72

A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260. (Study was funded by General Electric Corp, a major PCB polluter.)

A comprehensive chronic toxicity and carcinogenicity study was conducted on a series of Aroclors (1016, 1242, 1254, and 1260). Each Aroclor was assessed at multiple dietary concentrations, ranging from 25 to 200 ppm, for 24 months in male and female Sprague-Dawley rats. Liver toxicity was indicated by elevated serum enzyme activity (AST, ALT, and GGT), elevated serum cholesterol concentration, decreases in hematologic parameters (RBC, Hb, and Hct), hepatocellular hypertrophy, an increased incidence of altered hepatocellular foci, and an increased incidence of hepatocellular neoplasms (primarily adenomas). Liver toxicity was distinctly more severe in females than in males. The incidence of hepatocellular neoplasms was highly sex-dependent (females >> males), differed between Aroclor mixtures and, for females, increased with dose and followed the general incidence pattern of Aroclor 1254 > Aroclor 1260 approximately Aroclor 1242 > Aroclor 1016. A significant response (p < 0.05) in males was seen only for the high dose of Aroclor 1260. A small increase in the incidence of thyroid gland follicular cell adenomas was noted in males for Aroclors 1242, 1254, and 1260, with the incidence being uniform across dose groups and Aroclor mixtures. For females, increased survival relative to controls was observed for all Aroclor treatment groups. A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260. (Mayes et al, 1998) (This study was funded by General Electric Corp.)

Study #73

Among PCBs, Heptachlor is estrogenic, whereas Aroclor 1221 and Aroclor 1254, both individually and in combination, are only weakly estrogenic

DDT and polychlorinated biphenyls (PCBs), which are widespread in the ecosystem, can mimic estrogen-mediated cell activities. Thus, they can potentially interfere with many physiologic processes. We compared the effects of organochlorines belonging to the DDT and PCB families, alone and in combination, for their ability to influence the estrogen receptor-mediated activities in preneoplastic breast epithelial cells and breast cancer cells. Multiple assay systems requiring functional estrogen receptor were employed to test estrogen-like activity of organochlorine ligands. Two-sided statistical tests were used to compare the data. p,p'-DDT, the predominant form of DDT in the environment, is a more potent estrogen than o,p'-DDT (P<.001), although it is less effective than o,p'-DDT in inhibiting the binding of estradiol (natural estrogen) to estrogen receptor. Among the PCBs, Heptachlor is estrogenic (in transient reporter assays; P< or =.001), whereas Aroclor 1221 and Aroclor 1254, both individually and in combination, are only weakly estrogenic. p,p'-DDT is the most effective organochlorine in regulating estrogen receptor-mediated cellular responses. In estrogen receptor-positive breast cancer cells, p,p'-DDT evokes responses by itself and enhances the responses in collaboration with estradiol or o,p'-DDT. (Shekhar et al, 1997)

Study #74

adipose (fat) tissue levels of PCBs should be analyzed in addition to blood serum to fully understand the relationship of PCBs to breast cancer
no significant relationship was found between serum concentrations and tissue residues for 15 of the 17 compounds analyzed

The presence of organochlorine pesticides, such as p,p'-DDT[2,2-bis(p-chlorophenyl)-1,1,1-trichloroethanel, and of polychlorinated biphenyls (PCBs) in human serum and adipose tissue has been reported in many studies over the last four decades. Recently, debate has heightened concerning the link of these compounds to breast cancer. To clarify and resolve this issue, accurate analytical residue data must be obtained. Separation of the organochlorine pesticides from the PCBs in breast tissue is critical to obtaining valid residue data. Based on methods refined in the Analytical Laboratory at Colorado State University, accurate residue levels were established for nine individual PCB congeners and eight organochlorine pesticides. The breast adipose tissue method used was a modification of the Mills et al. and de Faubert Maunder et al. methods. The serum method employed was a modification of the Burse et al. method. Both breast adipose tissue and serum from 36 women were analyzed, and correlations of the residues from the two substrates were evaluated. Serum concentrations of p,p'-DDE, the primary metabolite of p,p'-DDT, were correlated (alpha = .05) with the concentrations of p,p'-DDE in human breast adipose tissue (r = .808). Serum concentrations of the PCB congener BZ 153 were also significantly correlated to the human breast adipose tissue concentrations of BZ 153 (r = .377). No significant relationship was found between serum concentrations and tissue residues for 15 of the 17 compounds analyzed. This lack of correlation between breast adipose tissue and serum, as well as an absence of the compound residues in serum, emphasized that adipose tissue should be analyzed in addition to serum to fully understand the relationship of the organochlorine compounds to breast cancer. (Archibeque-Engle et al, 1997)

Study #75

sample PCB levels can vary up to 20% depending on sampling methods

Extensive literature exists supporting the accumulation of organochlorine pesticides such as DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane], and polychlorinated biphenyls (PCBs) in human adipose tissue. Debate has surfaced concerning the link between these environmental contaminants and human breast cancer. Accurate residue analysis and proper analytical procedures are critical in determining the extent to which these compounds play a role in human breast cancer. Further, adequate quality assessment/quality control (QA/QC) is critical for reliable residue analysis. The purpose of this research was twofold: (1) to find an appropriate surrogate for human breast adipose tissue for spiking purposes, as human samples are difficult to obtain, and (2) to develop a human breast adipose tissue pool that yields adequate reproducibility with low coefficients of variation (CVs) for each compound of interest. Using a previously validated method developed in the Analytical Laboratory at Colorado State University, rendered ovine adipose tissue was found to be a suitable spiking material, as it was free of interfering compounds and behaved in a manner similar to human breast adipose tissue throughout the analytical method. Further, this analytical method was used to produce data on three control pool preparations: (A) blended human breast adipose tissue (n = 26), (B) blended and partially rendered human breast adipose tissue (n = 12), and (C) fully blended and rendered human breast adipose tissue (n = 15). The CVs between control pools vary up to 20% for a single compound. The most reproducible preparation procedure requires full blending and rendering. (Archibeque-Engle et al, 1996)

Study #76

Study does not support the hypothesis that exposure to PCBs increases the risk of breast cancer

Exposure to "environmental estrogens" such as organochlorines in pesticides and industrial chemicals has been proposed as a cause of increasing rates of breast cancer. Several studies have reported higher blood levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and polychlorinated biphenyls (PCBs) in patients with breast cancer than in controls. We measured plasma levels of DDE and PCBs prospectively among 240 women who gave a blood sample in 1989 or 1990 and who were subsequently given a diagnosis of breast cancer before June 1, 1992. We compared these levels with those measured in matched control women in whom breast cancer did not develop. Data on DDE were available for 236 pairs, and data on PCBs were available for 230 pairs. The median level of DDE was lower among case patients than among controls (4.71 vs. 5.35 parts per billion, P=0.14), as was the median level of PCBs (4.49 vs. 4.68 parts per billion, P=0.72). The multivariate relative risk of breast cancer for women in the highest quintile of exposure as compared with women in the lowest quintile was 0.72 for DDE (95 percent confidence interval, 0.37 to 1.40) and 0.66 for PCBs (95 percent confidence interval, 0.32 to 1.37). Exposure to high levels of both DDE and PCBs was associated with a nonsignificantly lower risk of breast cancer (relative risk for women in the highest quintiles of both DDE and PCBs as compared with women in the lowest, 0.43; 95 percent confidence interval, 0.13 to 1.44). Our data do not support the hypothesis that exposure to DDT and PCBs increases the risk of breast cancer. (Hunter et al, 1997)

Study #77

eleven of 13 hydroxylated metabolites of PCBs were anti-estrogenic, while 2 were estrogenic
human metabolites of PCBs were not estrogenic in human breast cancer cells (industry consultants)

Hydroxylated metabolites of polychlorinated biphenyls (OHCBs) have been identified in blood of marine mammals, fish-eating birds, and humans at concentrations in some cases exceeding those of the unmetabolized polychlorinated biphenyls (PCBs). OHCBs have been associated with inhibition of vitamin A and thyroxin transport, estrogenicity in a mouse uterotrophic assay, and feminization of male turtle sexual development. OHCBs, representing both environmentally derived and laboratory exposure-derived metabolites, were tested in an in vitro bioassay utilizing an estrogen-responsive human breast adenocarcinoma cell line (MCF7-LUC) stably transfected with a luciferase reporter gene linked to estrogen responsive elements. OHCB activity was tested at three different media concentrations of 17beta-estradiol (E2), comparing the concentration-response curves using charcoal-stripped medium (0.0009 nM E2), and two physiologically relevant E2 concentrations (0.1 and 1.0 nM E2). Eleven of 13 OHCBs tested were anti-estrogenic. Evidence for an estrogen receptor mediated mechanism of action was apparent for only two OHCBs: -4-OH-2',3,3',4',5,5'-Cl6-biphenyl and 4,4'-(OH)2-3,3',5,5'-Cl4-biphenyl. These two have not been identified in environmental samples. The remaining OHCBs exhibited "anti-estrogenicity" that was related to their effect on cell viability and, therefore, cannot be described as exhibiting "hormone disruption" solely by an estrogen receptor mediated mechanism. OHCB anti-estrogenic activity was eliminated in the presence of E2 concentrations normally found in humans, except for 4,4'(OH)2-3,3',5,5'-Cl4-biphenyl. 4-OH-2',3',4',5'-Cl4-biphenyl and 4-OH-2',4',6'-Cl3-biphenyl were partial estrogen agonists, exhibiting weak estrogenicity in the presence of 0.0009 nM E2 and weak anti-estrogenicity in the presence of 0.1 and 1 nM E2. Human metabolites of PCBs were not estrogenic in MCF7 cells. (Kramer et al, 1997)

Study #78

changes in PCB levels within a 1 to 3-month period are minimal for noncancer patients and a single measure for estimating exposure is highly reliable for PCB

Chlorinated hydrocarbons may increase breast cancer risk. Most epidemiological studies addressing this possibility have used one biological sample to measure a subject's cumulative exposure to these compounds. Little is known about short-term temporal variation in organochlorines, particularly in individuals with low levels. Thus, the reliability of using one sample to assess blood levels of chlorinated hydrocarbons in an epidemiological study is unknown. To better understand the temporal changes in blood measures among women with nonoccupational exposures to these compounds, we collected two 5-ml blood samples, an average of 2 months apart, from each of 31 nonfasting healthy women, ages 45-81 years. Samples were assayed for 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), polychlorinated biphenyls (PCBs), and trans-nonachlor in blinded, matched pairs. Results were adjusted for estimated total plasma lipids. The correlations between the two blood samples were high for DDE and PCBs (lipid-adjusted, r = 0.96 and r = 0.89, respectively). For trans-nonachlor, the correlation was relatively poor (lipid-adjusted r = 0.57); however, with the removal of one outlier, the correlation improved substantially (lipid-adjusted, r = 0.90). The mean difference between the two blood samples in unadjusted [-0.36 ng/ml, 95% confidence interval (CI), -0.97, 0.24 ng/ml, P = 0.23] and lipid-adjusted (-0.035 microgram/g lipid; 95% CI, -0.124, 0.055; P = 0.44) DDE levels was small. Similarly, there was little change in the mean difference for unadjusted (-0.14 ng/ml; 95% CI, -0.53, 0.25 ng/ml; P = 0.47) and lipid-adjusted (0.006 microgram/g lipid; 95% CI, -0.050, 0.062; P = 0.82) PCB levels. The mean differences in trans-nonachlor levels between the two blood draws were also small: unadjusted (-0.03 ng/ml; 95% CI, -0.07, 0.02 ng/ml; P = 0.20) and lipid-adjusted (-0.003 microgram/g lipid; 95% CI, -0.010, 0.004; P = 0.33). These data suggest that temporal changes in organochlorine levels within a 1 to 3-month period are minimal for noncancer patients and that a single measure for estimating exposure is highly reliable for DDE and PCB. For trans-nonachlor, however, where the correlation between blood draws was lower, three samples would be needed for estimating exposure; if an outlier is removed from our data, however, then we can conclude that only a single measure is sufficient. These data, therefore, offer no clear conclusion for the use of a single measurement for trans-nonachlor. (Gammon et al, 1997)

Study #79

PCB 126 (dioxin-like) significantly increased hydroxylation of estradiol in female rat livers
Hydroxylation has been suggested as responsible for development of estrogen-dependent tumors

The four environmental pollutants studied (3,3',4,4',5-pentachlorobiphenyl, 2,2',4,4'-tetrabromodiphenyl ether, Tris-(p-chlorophenyl)methanol, and 3,4,5-trichloroguaiacol) were all found to induce a significant increase in 4-hydroxylation of estradiol activity in male rat liver microsomes. However, only 3,3',4,4',5-pentachlorobiphenyl was found to significantly increase 4- and 2-hydroxylation of estradiol in female rat liver microsomes. 4-Hydroxylation has been suggested to be responsible for the development of estrogen-dependent tumors and, therefore, it cannot be excluded that these pollutants can be a risk for the development of estrogen-dependent tumors in humans and wildlife. (Segura et al, 1997)

Study #80

Lower chlorinated, ortho substituted, non coplanar PCBs are weakly estrogenic

Lower chlorinated, ortho substituted, non coplanar polychlorinated biphenyls (PCBs) are weakly estrogenic in rodents and in some in vitro assays. The estrogenic potency of six PCB congeners and one of their para-hydroxylated metabolites have been tested in an estrogen-responsive MCF-7 human breast-cancer cell-culture system, to evaluate the utility of this system for assessment of PCB and hydroxylated PCB estrogenic activity. This assay is based on the estrogen receptor-mediated induction of postconfluent cell proliferation. The results of the limited test series were generally consistent with, but not absolute in the requirement for ortho-chlorine substitution and para-hydroxylation for estrogenic potency, demonstrating the usefulness of the MCF-7 focus assay for estrogenic structure-activity evaluation of PCBs. (Gierthy et al, 1997)

Study #81

free radicals and oxidative DNA damage are produced during oxidation of lower chlorinated PCBs
increased oxidative DNA damage is detected in human breast tumor tissue

We have previously reported that mono- and dichlorinated biphenyls (PCBs) can be metabolized to dihydroxy compounds and further oxidized to reactive metabolites which form adducts with nitrogen and sulfur nucleophiles including DNA [Amaro et al. (1966) Chem. Res. Toxicol. 9, 623-629; Oakley et al. (1996) Carcinogenesis 17, 109-114]. The former studies also demonstrated that during the metabolism of PCBs superoxide may be produced. We have therefore examined the abilities of PCB metabolites to induce free radical-mediated oxidative DNA damage using a newly developed, highly sensitive, 32P-postlabeling assay for 8-oxode-oxyguanosine (8-oxodG) [Devanaboyina, U., and Gupta, R. (1996) Carcinogenesis 17, 917-924]. The incubation of 3,4-dichloro-2'5'-dihydroxybiphenyl (100 microM) with calf thymus DNA (300 micrograms/microL) in the presence of the breast tissue and milk-associated enzyme, lactoperoxidase (10 mU/mL), and H2O2 (0.5 mM) resulted in a significant increase in free radical-induced DNA damage (253 8-oxodG/10(6) nucleotides) as compared to vehicle-treated DNA (118 8-oxodG/10(6) nucleotides). Substituting CuCl(2) (100 microM) for lactoperoxidase/H2O2, however, resulted in a substantial increase in 8-oxodG content (2669 8-oxodG/10(6) nucleotides). FeCl(3) was ineffective, suggesting that CuCl(2) but not FeCl(3) mediates oxidation of PCB dihydroxy metabolites, resulting in oxidative DNA damage. The addition of catalase (100 U/mL) and sodium azide (0.1 M) reduced the effect of CuCl(2) (849 and 896 8-oxodG/10(6) nucleotides, respectively), while superoxide dismutase (600 U/mL) moderately stimulated and glutathione (100 microM) substantially stimulated 8-oxodG formation (3014 and 4415 8-oxodG/10(6) nucleotides, respectively). The effect of various buffers as well as the effects of PCB structure on Cu(II)-mediated oxidative DNA damage were examined. These results demonstrate that free radicals and oxidative DNA damage are produced during oxidation of lower chlorinated biphenyls. The relevance of the results is discussed in view of the recent report that increased oxidative DNA base damage is detected in the DNA of human breast tumor tissue. (Oakley et al, 1996)

Study #82

study provided guidelines for PCB half-lives

Most studies on the half-lives of environmental contaminants have been based on small sample sizes and a limited number of repeated measurements. In this paper, we address issues of study design and sample size for half-life studies. Useful guidelines are provided for choosing the number of repeats and the optimal time interval between repeats for estimating an individual's half-life with a given level of precision, while minimizing the cost of the study. In addition, sample size and power considerations for studies comparing two population half-lives are investigated. An example is presented using data from a study on polychlorinated biphenyls and breast cancer. (Kim et al, 1996)

Study #83

two PCB congeners (2,3,4-HCB, 2,4,5-HCB) inhibit gap junctional intercellular communication (GJIC) in normal human breast epithelial cells, which could have tumor-promoting potential

Chemical pollutants in the Great Lakes have found their way through the food chain into humans because of their environmental persistence and lipophilicity. Some epidemiological studies have claimed an association between metabolites of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), polychlorinated biphenyls (PCBs), and polybrominated biphenyls (PBBs) and breast cancer, but others have reported no such association. We examined various halogenated hydrocarbons for their capacity to inhibit gap junctional intercellular communication (GJIC) in normal human breast epithelial cells (HBEC) when given as single compounds or as mixtures. The scrape-loading/dye transfer and fluorescent redistribution after photobleaching techniques were used to measure GJIC; immunostaining and Western and Northern analyses were performed on connexin 43 (Cx43) gap junction protein and message to determine how halogenated hydrocarbons might affect GJIC. DDT, dieldrin, and toxaphene inhibited GJIC in a dose-responsive manner after 90 min treatments. Dieldrin suppressed GJIC within 30 min with no recovery after 24 hr. Inhibition of GJIC by DDT and toxaphene was partially restored after 12 hr and fully restored after 24 hr. Several PCB and PBB congeners inhibited GJIC in a dose-responsive and time-dependent manner, but GJIC was almost restored to control values 24 hr after exposure. The highest concentrations of the individual chemicals that did not inhibit GJIC was determined, and mixtures containing two of these chemicals were tested for their ability to inhibit GJIC. Significant inhibition of GJIC was observed when cells were treated with a mixture of DDT and 2,4,5-hexachlorobiphenyl (2,4,5-HCB), dieldrin and 2,4,5-HCB, or dieldrin and 2,4,5-hexabromobiphenyl (2,4,5-HBB). These results indicate that halogenated hydrocarbons, alone or in specific combinations, can alter GJIC at the post-translational level. These results are consistent with the hypothesis that DDT, dieldrin, toxaphene, 2,3,4-HCB, 2,4,5-HCB, and 2,4,5-HBB could have tumor-promoting potential in human breast tissue. (Kang et al, 1996)

Study #84

since the breast appears to be most susceptible to the carcinogenic effects of ionizing radiation during the first decade of life, exposure to other carcinogens during early breast development may be important in determining breast cancer risk
It is not known whether exposure to PCBs in the womb or though breast milk can affect breast cancer rates in female offspring

Although estrogens have been identified as key endocrine hormones in the control of early mitogenesis and development in the mammary gland, local control of cell proliferation during ductal morphogenesis may be regulated by polypeptides such as TGF-alpha or TGF-beta. Many breast tumors are estrogen dependent, and some breast tumor cell lines are known to produce TGF-alpha, suggesting that the mitogenic pathways controlling early normal mammary growth and the growth of some breast tumors may be similar. While progesterone does not appear to be important in the early program of ductal growth, progesterone and estrogen are necessary for the cyclic proliferation of mammary ductal cells that occurs during the menstrual cycle, and for lobuloalveolar growth during pregnancy. Since increased cell division enhances the chances for the formation of a malignant phenotype in the breast, exogenous hormones containing estrogen alone or estrogen and progesterone may increase breast cancer risk. While DES is no longer prescribed to prevent abortions, it demonstrates that high doses of an estrogen during a period of mammary proliferation can affect breast cancer risk. Whether the addition of progestogens to estrogen replacement therapy enhances breast cancer risk in postmenopausal women remains an unanswered question because of the lack of large, well-controlled prospective studies. There currently is no evidence to indicate that the progestogen-containing subdermal contraceptive Norplant increases breast cancer risk. However, it has not been determined if the elevation of serum estrogens reported in some Norplant users affects breast cancer risk. There is little evidence that combined OCAs enhance breast cancer risk in most women. More research is needed to substantiate the findings that OCA use in young women, especially before a first full-term pregnancy, may enhance breast cancer risk. Animal studies indicate that there are critical periods of susceptibility to chemical carcinogens, since the number and malignancy of tumors are increased when carcinogens are administered to young virgin animals during the proliferative period of ductal morphogenesis. Since the breast appears to be most susceptible to the carcinogenic effects of ionizing radiation during the first decade of life, exposure to other carcinogenic agents during the period of early breast development may be important in determining breast cancer risk. Therefore, more studies are needed to confirm the observation that heavy drinkers and heavy smokers are at higher risk for developing breast cancer when they start smoking or drinking at an early age. The observation that serum and urinary estrogen levels increase with alcohol consumption may provide a basis for the higher risk of developing breast cancer in heavy drinkers. While the restriction of methyxanthine intake may alleviate the symptoms associated with fibrocystic breast disease in some women, there is not enough evidence to suggest that a reduction in caffeine intake will reduce breast cancer risk. Evidence for an association between electromagnetic radiation and breast cancer is limited. Electromagnetic radiation may only pose a risk in certain occupations with exposure to very high levels for extended periods of time. It is not known whether exposure to PCBs transplacentally or though the lipid fraction of human milk can affect breast cancer rates in female offspring. The higher risk of breast cancer in women with elevated DDE levels in their blood underscores the importance of determining the extent to which environmental contaminants affect breast cancer risk. (Snedeker et al, 1996)

Study #85

in addition to occupational exposures, environmental estrogens may have played a role in breast cancer in women and men in industrialized countries

The deleterious, disruptive effects of estrogen mimics on the endocrine system were discovered after the compounds were released into the environment. Their chemical structure does not obviously resemble that of steroid hormones; hence, their estrogenic effects were totally unexpected. In addition to occupational exposures, environmental estrogens may have played a role in decreasing the quantity and quality of human semen during the last 50 years and in increasing the incidences of testicular cancer and cryptorchidism in men and breast cancer in women and men in industrialized countries. Testing the environmental estrogen hypothesis will require developing appropriate biomarkers of exposure and measuring these biomarkers at developmental points where exposure is critical. We report the ongoing development of a method to extract and separate xenoestrogens from ovarian estrogens with human serum as a source, followed by determination of xenoestrogen concentration by a bioassay. We also critically assess bioassays currently available to measure the cumulative effect of xenoestrogens, e.g., (a) the E-SCREEN assay, which measures the proliferative effect of estrogens on their target cells, and (b) the induction by estrogens of specific gene products, such as progesterone receptor and pS2. (Sonnenschein et al, 1995)

Study #86

available data do not indicate PCBs will affect the risk of breast cancer in any but the most unusual situation
Some congeners of PCB elicit very weak estrogenic responses in animals, while dioxin and related compounds have anti-estrogenic properties.

The organochlorines, a diverse group of some 15,000 compounds, have been implicated increasingly as being harmful to humans. Some congeners of DDT and PCB elicit very weak estrogenic responses in animals, while the dioxin TCDD and related compounds have antiestrogenic properties. This review summarizes the evidence regarding whether certain organochlorine compounds, usually as persistent food-chain contaminants, increase the risk of breast and endometrial cancers through their estrogenic potential. In humans, neither ecologic data nor occupational studies provide clear support for an association between organochlorine exposure and the occurrence of these cancers. In our summary analysis of occupational exposure, the rate ratio of breast cancer for exposed cf unexposed women was 0.84 (95 percent confidence interval [CI] = 0.50-1.33) for PCBs and 1.08 (CI = 0.68-1.58) for TCDD. Similarly, effect estimates close to unity were found in summary analysis of breast cancer case-control studies regarding levels of DDE and PCB in adipose tissue or serum. In two recent nested case-control studies using stored specimens, the odds ratio per standard deviation increase in serum p,p'-DDE was 1.27 (CI = 0.95-1.69). Although estrogenic effects of certain organochlorine compounds should be easier to detect on the endometrium, we know of no analytic epidemiologic studies of endometrial cancer published to data. We conclude that available data do not indicate that organochlorines will affect the risk of these two cancers in any but the most unusual situation. (Adami et al, 1995)

Study #87

coplanar PCBs significantly increase the ratio of 16 alpha-OHE1/2-OHE1 metabolites to values comparable to or greater than those observed after DMBA (a known breast carcinogen)

Xenobiotic estrogens are external compounds with estrogenic activity that may thereby affect the risk of breast cancer. This paper describes a mechanism by which xeno-estrogens may affect the development of breast cancer. Estradiol metabolism proceeds by hydroxylation at one of two mutually exclusive sites at C-2 and C-16 alpha. The catechol pathway yields the weakly estrogenic 2-hydroxyestrone (2-OHE1), which inhibits breast cell proliferation. In contrast, the alternative pathway yields the genotoxic 16 alpha-hydroxyestrone (16 alpha-OHE1), which enhances breast cell growth, increases unscheduled DNA synthesis, and oncogene and virus expression, and increases anchorage-independent growth. Using a radiometric assay that measures the relative formation of 16 alpha-OHE1 versus 2-OHE1 from specifically tritiated estradiol in (ER+) MCF-7 cells, we compared the ratio of 16 alpha-OHE1/2-OHE1 observed after treatment with the known rodent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) with the ratios after treatment with DDT, atrazine, gamma-benzene hexachloride, kepone, coplanar PCBs, endosulfans I and II, linoleic and eicosapentenoic acids, and indole-3-carbinol (I3C). These pesticides significantly increase the ratio of 16 alpha-OHE1/2-OHE1 metabolites to values comparable to or greater than those observed after DMBA. In contrast, the antitumor agent I3C increased 2-OHE1 formation and yielded ratios that are 1/3 of those found in unexposed control cells and 1/10th of those found in DMBA-treated cells. Thus the ratio of 16 alpha-OHE1/2-OHE1 may provide a marker for the risk of breast cancer. Assays of this ratio, which can be measured in spot urines, may prove useful for a variety of in vitro and in vivo studies bearing on breast cancer risk. (Bradlow et al, 1995)

Study #88

the most abundant compounds found in fat tissue in both breast cancer cases and controls were p, p-DDE and PCB

A precise and highly reproducible analytical method was developed for the assessment of organochlorinated pesticide and polychlorinated biphenyl residues in adipose tissue (> or = 50 mg). The method can be utilized for epidemiological studies on the significance of these environmental pollutants in the etiology of breast cancer. Supercritical fluid extraction (SFE) with CO2 and modified CO2 (addition of 5% dichloromethane) is employed to remove incurred pesticide residues from adipose tissues that have been surgically removed from breast cancer patients and controls. An alumina sorbent, placed in the extracting vessel together with a specimen, removes the bulk of co-extracted lipids; a subsequent purification of the SFE extracts by column chromatography on alumina removes the remaining traces of lipids that would interfere with the gas chromatographic analysis with electron capture detection. The method was tested by analyzing a Certified Reference Material 430 pork fat with known amounts of pesticide residues that are commonly found in fat or in foods with a high fat content. The recoveries of analytes ranged from 73.4% for endrin to 115% for alpha-, beta- and gamma-hexachlorocyclohexane, hexachlorobenzene and dieldrin, with standard deviations of 4-12% for individual analytes. The analysis of adipose tissue for organochlorinated compounds on the basis of this new method suggested that the pesticide levels were higher in breast cancer patients than in controls. However, the small number of samples analyzed in this study (n = 5, both groups) precludes definitive conclusions. The most abundant compounds in both cases and controls were p, p-DDE (379 +/- 286 and 160 +/- 149 p.p.b.) and PCB (223 +/- 145 and 124 +/- 65.7 p.p.b.), followed by the termiticide chlordane residues oxychlordane and transnonachlor. (Djordjevic et al, 1994)

Study #89

the data do not support the hypothesis that exposure to DDE and PCBs increases risk of breast cancer
PCBs were lower among white breast cancer patients compared with white controls

Five small case-control studies have examined the relationship between exposure to organochlorines and the risk of breast cancer and have found inconsistent results. In these studies, organochlorine levels in breast cancer patients were measured after (or at most 6 months before) diagnosis. We tested the hypothesis that organochlorines are a risk factor for breast cancer, using prospectively gathered data on serum levels of DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] (the main metabolite of the pesticide DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane]) and polychlorinated biphenyls (PCBs). Study subjects belonged to a cohort of 57,040 women (46,629 white, 8123 black, and 2288 Asian) from the San Francisco Bay Area who took a multiphasic health examination, independent of concern about risk of breast cancer, in the late 1960s. At that time, a sample of blood was obtained, then frozen and stored. Follow-up was through December 31, 1990. We conducted a nested case-control study of 150 case patients and 150 matched control subjects. A random sample of 50 women per racial/ethnic group who had been diagnosed with breast cancer more than 6 months after the multiphasic examination (mean follow-up = 14.2 years) was selected, and each case patient was matched to a cancer-free control subject. Matched analyses found no differences in the case patients' and control subjects' serum levels of DDE (mean difference = 0.2 parts per billion [ppb]; 95% confidence interval [CI] = -6.7, 7.2) or PCBs (mean difference = -0.4 ppb; 95% CI = -0.8, 0.1). DDE levels, however, tended to be higher among black case patients compared with black controls (mean difference = 5.7 ppb; 95% CI = -3.3, 14.8), and PCBs were lower among white case patients compared with white controls (mean difference = -0.6 ppb; 95% CI = -1.2, -0.1). Organochlorine levels were significantly higher among black and Asian women compared with white women. The mean difference for DDE was 11.0 ppb for black women (95% CI = 4.3, 17.6) and 12.6 ppb for Asian women (95% CI = 6.0, 19.2); for PCBs, the respective differences were 0.8 ppb for black women (95% CI = 0.2, 1.4) and 1.4 ppb for Asian women (95% CI = 0.8, 1.9). The results were not altered by adjusting for relevant confounders, and the lack of association between exposure to organochlorines and breast cancer was present regardless of length of follow-up, year of diagnosis, or the case patient's menopausal and estrogen-receptor status. The data do not support the hypothesis that exposure to DDE and PCBs increases risk of breast cancer. Future investigations must consider the biologic mechanisms involved and variations in exposure to chemical pollutants and of breast cancer incidence rates among diverse groups of women. (Krieger et al, 1994)

Study #90

PCB 77 (dioxin-like) does not exhibit ER agonist activity but exhibits a broad spectrum of anti-estrogenic responses consistent with ligand-mediated AhR-ER crosstalk

3,3',4,4'-Tetrachlorobiphenyl (tetraCB) binds to the aryl hydrocarbon receptor (AhR), and several reports have demonstrated that AhR agonists exhibit antiestrogenic and antitumorigenic activities in human breast cancer cells, the rodent uterus and breast. In contrast, a recent study showed that 3,3',4,4'-tetraCB bound the estrogen receptor (ER) and exhibited ER agonist activities, and we therefore have reinvestigated the estrogenic and antiestrogenic activities of 3,3',4,4'-tetraCB. Our results showed that 3,3',4,4'tetraCB and a structurally related analog, 3,3',4,4',5-pentaCB, did not bind the mouse uterine or human ER, did not induce proliferation of MCF-7 or T47D human breast cancer cells or induce reporter gene activity in cells transfected with E2-responsive constructs derived from the creatine kinase B (pCKB) or cathepsin D (pCD) gene promoters. Moreover, 3,3',4,4'-tetraCB and 3,3',4,4',5-pentaCB did not induce an increase in uterine wet weight, peroxidase activity or progesterone receptor binding in the 21-25-day-old female B6C3F1 mouse uterus. In contrast, both compounds inhibited 17beta-estradiol (E2)-induced cell proliferation and transactivation in MCF-7/T47D cells and uterine responses in B6C3F1 mice; surprisingly inhibition of E2-induced reporter gene activity was not observed in T47D cells transfected with pCKB, and this was observed as a cell-specific response with other AhR agonists. Additionally, 3,3',4,4'-tetraCB significantly inhibited mammary tumor growth in female Sprague-Dawley rats initiated with 7,12-dimethylbenzanthracene. Our results indicate that 3,3',4,4'-tetraCB does not exhibit ER agonist activity but exhibits a broad spectrum of antiestrogenic responses consistent with ligand-mediated AhR-ER crosstalk. (Ramamoorthy et al, 1999)

Study #91

two hydroxylated metabolites of PCBs exhibited estrogenic activity, which was additive at high and low levels of estrogen receptor expression

The estrogenic activity of 2',4',6'-trichloro-4-biphenylol (HO-PCB3), 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB4), and an equimolar mixture of both compounds (HO-PCB3/HO-PCB4) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 cells, and in a yeast-based reporter gene assay. Treatment of the animals with 17beta-estradiol (E2) (0.02 microg/kg/day x3) resulted in increased uterine wet weight, peroxidase activity and progesterone receptor binding. Treatment with 18, 73, 183 or 366 micromol/kg (x3) doses of HO-PCB3, HO-PCB4, or HO-PCB3/HO-PCB4 (equimolar) caused a dose-dependent increase in estrogenic activity; a maximal-induced response was not observed at any dose and the activity of the mixture was additive. Binding of E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 to the mouse uterine estrogen receptor (ER) was determined in a competitive binding assay using [3H]E2 as the radioligand. The IC50 values were 1.1 x 10(-8), 3.4 x 10(-6), 9.9 x 10(-7), and 4.25 x 10(-6) m, respectively. HO-PCB3 and HO-PCB4 maximally induced MCF-7 cell proliferation, rat creatine kinase, and human complement C3 (C3-LUC) reporter gene activity at concentrations of 10(-5) to 10(-6) m, and these compounds were 10(3) to 10(4) less potent than E2. The HO-PCB3/HO-PCB4 mixture was active at the high concentration (10(-5) m) and was additive for these responses. HO-PCB3 and HO-PCB4 also exhibited estrogenic activity in human HepG2 cells cotransfected with C3-LUC and an ER expression plasmid, and the estrogenic activity of the HO-PCB mixture was additive. Similar results were obtained in yeast transformed with the human ER and a double estrogen responsive element upstream of the beta-gal reporter gene. The effects of variable ER expression on the potential synergistic interactions of HO-PCB3/HO-PCB4 were investigated in HepG2 cells cotransfected with C3-LUC (405 ng/well) and variable amounts of ER expression plasmid (270, 27, 2.7, or 0.27 ng/well). The results show that as ER levels decreased, the magnitude of the induction response by E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 also decreased. However, the activities of the HO-PCB mixture were additive at high and low levels of ER. Similar results were obtained in MDA-MB-231 cells cotransfected with C3-LUC and variable amounts of ER expression plasmid. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus; MCF-7, HepG2, and MDA-MBA-231 human cancer cells; and a yeast based-reporter gene assay, both HO-PCB3 and HO-PCB4 exhibited estrogenic activity. The estrogenic activity of an equimolar mixture of these compounds was additive at high and low levels of ER expression. (Ramamoorthy et al, 1997)

Study #92

in addition to the hydroxylated metabolites, selected parent PCB congeners may also exhibit estrogenic and anti-estrogenic activities

Several studies have reported that polychlorinated biphenyls (PCBs) exhibit estrogenic activity; however, it is not clear if these responses are associated with the polychlorinated hydrocarbon or its hydroxylated metabolite. In order to further test this hypothesis, a battery of in vitro and in vivo assays were used to investigate the estrogenic and antiestrogenic activities of 2,4,6,2',6'-pentachlorobiphenyl (PCB 104), its para-hydroxylated derivative 2,4,6,2',6'-pentachloro-4-biphenylol (HO-PCB 104), and its para-chlorinated derivative 2,4,6,2',4',6'-hexachlorobiphenyl (PCB 155). PCB 104 was found to 1) compete with tritiated 17beta-estradiol (E2) for binding to the mouse uterine estrogen receptor (ER); 2) induce gene expression in MCF-7 human breast cancer cells transiently transfected with the Gal4-human ER chimeric construct (Gal4-HEGO) and the Gal4-regulated luciferase reporter gene (17m5-G-Luc); and 3) increase MCF-7 cell proliferation in a dose-dependent manner. HO-PCB 104 exhibited greater estrogenic activity than PCB 104 in the in vitro assays examined. However, gas chromatographic-mass spectrophotometric analysis of extracts prepared from MCF-7 cells incubated with PCB 104 failed to detect the presence of the expected major metabolite HO-PCB 104. The estrogenic activity of the para-chlorinated derivative, PCB 155, was minimal compared to PCB 104 and HO-PCB 104, but it did exhibit significant antiestrogenic activity following co-treatment with 1 nM E2. Co-treatment of PCB 104 with 1 nM E2 had no effect on reporter gene expression compared to E2 alone, while 10 microM HO-PCB 104 exhibited additivity with 1 nM E2. At a dose of 202 mg/kg,PCB 104 increased uterine wet weight in ovariectomized CD-1 mice and induced vaginal epithelial cell cornification at 202, 16, and 1.7 mg/kg in a dose-dependent manner. These studies demonstrate that in addition to the hydroxylated metabolites, selected parent PCB congeners may also exhibit estrogenic and antiestrogenic activities. (Fielden et al, 1997)

Study #93

all but one of the tested hydroxylated PCBs competitively bound to the mouse and rat estrogen receptors
structure and estrogen receptor binding relationships were different in the rat and mouse
estrogenic activities were not dose-dependent
several hydroxy-PCB congeners exhibited antiestrogenic activity
two hydroxy-PCB congeners induced CAT activity in breast cancer cells transiently transfected with the Vit-CAT plasmid
structure-estrogenicity/anti-estrogenicity relationships for these hydroxy-PCBs were complex and response-specific

The effects of structure on the estrogenicity and antiestrogenicity of hydroxylated polychlorinated biphenyls were investigated using the following estrogen-sensitive assays: competitive binding to the rat and mouse cytosolic estrogen receptor (ER); immature rat and mouse uterine wet weight, peroxidase and progesterone receptor (PR) levels; induction of luciferase activity in HeLa cells stably transfected with a Gal4:human ER chimera and a 17mer-regulated luciferase reporter gene; proliferation of MCF-7 human breast cancer cells; induction of chloramphenicol acetyl transferase (CAT) activity in MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a CAT reporter gene. The chemicals synthesized for this study contained a 4-hydroxy group in one ring, a 2- or 3-chloro substituent meta or ortho to the hydroxyl group, and variable substitution (2',3',4',5'-, 2',3',4',6'-, 2',3',5',6'-tetrachloro and 2',4',6'-trichloro) in the chlorophenyl ring. The compounds included: 2,2',3',4',5'- (A), 2,2',3',4',6'- (B), and 2,2',3',5',6'-pentachloro- (C); 2,2',4',6'-tetrachloro-4-biphenylol (D); 2',3,3',4',5'- (E), 2',3,3',4',6'- (F), and 2',3,3',5',6'-pentachloro (G); and 2',3,4',6'-tetrachloro-4-biphenylol (H). With the exception of 2',3,4',6'-tetrachloro-4-biphenylol (H), all of the compounds competitively bound to the mouse and rat ER with relative binding affinities [compared to 17beta-estradiol (E2)] varying from 1.4 x 10(-3) to 5.3 x 10(-5). The structure-ER binding relationships for the hydroxy-PCB congeners were different in the rat and mouse, and no dose-dependent estrogenic activities were observed in the mouse or rat uterus. Several hydroxy-PCB congeners exhibited antiestrogenic activity (primarily in the mouse uterus) and two compounds, 2,2',3',5',6- and 2,2',3',4',6'-pentachloro-4-biphenylol, inhibited E2-induced uterine wet weight, PR binding, and peroxidase activity in the mouse uterus. 2,2',3',4',5'- and 2,2',3',4',6'-Pentachloro-4-biphenylol induced CAT activity in MCF-7 cells transiently transfected with the Vit-CAT plasmid; the remaining congeners did not induce CAT activity but exhibited antiestrogenic activity in MCF-7 cells cotreated with 10(-9) E2 plus 10(-5) M hydroxy-PCBs. Complementary structure-estrogenicity relationships were observed utilizing the HeLa cell luciferase induction and MCF-7 cell proliferation assays. The placement of the 2- or 3-chloro groups in the phenolic ring had minimal effects on estrogenic activity, whereas 2,4,6-trichloro- and 2,3,4,6-tetrachloro substitution in the chlorophenyl ring (B, D, F, and H) were required for this response. Substitution in the phenolic ring was also not important for structure-antiestrogenicity relationships, and the most active compounds (A, C, E, and G) contained 2',3',4',5'- and 2',3',5',6'-tetrachlorophenyl groups. Thus, structure-estrogenicity/antiestrogenicity relationships for this series of hydroxy-PCBs were complex and response-specific. (Conner et al, 1997)

Study #94

occupational exposure to relatively high levels of PCBs are not associated with an increased incidence of breast cancer
E2 2-hydroxylase activity and the 16alpha-hydroxyestrone/2-hydroxyestrone metabolite ratio in breast cancer cells does not predict xenoestrogens or mammary carcinogens

It was initially reported that levels of polychlorinated biphenyls (PCBs) or p,p'-DDE were elevated in breast cancer patients (serum or tissue) versus controls. These results, coupled with reports that selected environmental estrogens decreased 17beta-estradiol (E2) 2-hydroxylase activity and increased the ratio of 16alpha-hydroxyestrone/2-hydroxyestrone metabolites in MCF-7 human breast cancer cells, have led to the hypothesis that xenoestrogens are a preventable cause of breast cancer. More recent studies and analysis of organochlorine levels in breast cancer patients versus controls show that these contaminants are not elevated in the latter group. Moreover, occupational exposure to relatively high levels of PCBs and DDT/DDE are not associated with an increased incidence of breast cancer. A reexamination of the radiometric E2 2-hydroxylase assay in MCF-7 cells with diverse estrogens, antiestrogens, and carcinogens showed that the mammary carcinogen benzo[a]pyrene induced this response and the antiestrogen ICI 164,384 decreased E2 2-hydroxylase activity. Thus, E2 2-hydroxylase activity and the 16alpha-hydroxyestrone/2-hydroxyestrone metabolite ratio in MCF-7 cells does not predict xenoestrogens or mammary carcinogens. (Safe, 1997) (Industry consultant)

Study #95

levels of PCBs are not consistently elevated in breast cancer patients
there is no evidence that women occupationally-exposed to relatively high levels of PCBs exhibit an increased incidence of breast cancer (industry consultant)

Organochlorine industrial compounds, combustion products and pesticides have been widely identified in the environment and residues have been detected in extracts prepared from fish, wildlife, human tissues as well as human milk and serum. Many of these compounds possess sex steroid activities and therefore have the potential to disrupt endocrine-regulated homeostasis. Organochlorines which exhibit hormonal activity include: (i) polychlorinated biphenyls (PCBs), hydroxylated PCBs, o,p'-DDT, and other organochlorine insecticides which exhibit estrogen receptor (ER) agonist activities; (ii) p,p'-DDE, a ligand for the androgen receptor which exhibits antiandrogen activity; (iii) PCBs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related aromatic hydrocarbons which bind the aryl hydrocarbon (Ah) receptor and exhibit tissue-specific antiestrogenic activity; and (iv) hydroxylated aromatics which bind transthyretin, a thyroid hormone binding protein. Although, it has been suggested that the estrogenic activity of PCBs and DDE may be a contributing factor for development of breast cancer in women, levels of these compounds are not consistently elevated in breast cancer patients and there is no evidence that women occupationally-exposed to relatively high levels of PCBs or DDE exhibit an increased incidence of breast cancer. In contrast, epidemiology studies suggest that women exposed to high levels of TCDD during an industrial accident in Seveso, Italy, have a decreased incidence of both breast and endometrial cancer. Based on the dietary intake of hormone or antihormone mimics derived from natural compounds in food, the estrogenic contribution of organochlorine compounds is small and their role in development of breast cancer is questionable. (Safe et al, 1997) (Industry consultant)

Study #96

all of the hydroxy-PCB congeners inhibited one or more estrogenic responses
one congener inhibited 17beta-estradiol-induced cell proliferation and CAT activity in breast cancer cells

Several hydroxylated polychlorinated biphenyls (PCBs) identified in human serum have been synthesized and these include 2,2',3,4',5,5'-hexachloro-4-biphenylol; 2,3,3',4',5-pentachloro-4-biphenylol; 2',3,3',4',5-pentachloro-4-biphenylol; 2,2',3,3',4',5-hexachloro-4-biphenylol; 2,2',3,3',4',5,5'-heptachloro-4-biphenylol; 2,2',3,4',5,5',6-heptachloro-4-biphenylol; and 2,2',3',4,4',5,5'-heptachloro-3-biphenylol. The hydroxy-PCBs exhibited minimal binding to the rat uterine cytosolic estrogen receptor (ER) and did not induce proliferation of estrogen-responsive MCF-7 human breast cancer cells at concentrations ranging from 10(-5) to 10(-8) M. The estrogenic activity of these compounds was further investigated utilizing two estrogen-responsive in vitro bioassays, namely, (i) HeLa cells stably transfected with a Gal4:human ER chimera and a 17-mer-regulated luciferase reporter gene, and (ii) MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a chloramphenicol acetyl transferase (CAT) reporter gene. None of the hydroxy-PCBs significantly induced luciferase activity in the stably transfected HeLa cells or CAT activity in MCF-7 cells at concentrations as high as 10(-5) M. The antiestrogenic effects of the hydroxy-PCBs were also investigated using the same bioassays in which the cells were cotreated with 17beta-estradiol plus the hydroxy-PCBs. All of the hydroxy-PCB congeners inhibited one or more estrogenic response, and one congener, 2,2',3,4',5,5',6-heptachloro-4-biphenylol, inhibited 17beta-estradiol-induced cell proliferation and CAT activity in MCF-7 cells and luciferase activity in HeLa cells. (Moore et al, 1997)

Study #97

the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of natural estrogenic flavonoids in the diet (Industry consultant)

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet. (Safe, 1995) (Industry consultant)

Study #98

dioxin-like PCB congeners (numbers 81, 169, 77, 157, 105, and 114) were anti-estrogenic, in descending order of potency
PCB commercial mixtures (Aroclors 1221, 1232, 1248, 1254 and 1260) were inactive as anti-estrogens at the highest concentrations used in this study (10(-6)M)
several dioxins and furans were also anti-estrogens

The concentration-dependent effects of several PCB, PCDD, and PCDF congeners and several commercial PCB preparations as antiestrogens were determined in the aryl hydrocarbon (Ah)-responsive MCF-7 human breast cancer cell lines. The inhibition of the 17 beta-estradiol-induced secretion of the 52-kDa protein (procathepsin D) was measured using a combination of polyacrylamide gel electrophoresis, double-staining of the protein bands with ISS ProBlue and silver stain, and quantitation by densitometric analysis. For the PCBs, the order of antiestrogenic potency was 3,3',4,4',5-pentachlorobiphenyl > 3,3',4,4',5,5'-hexachlorobiphenyl approximately 3,3',4,4'-tetrachlorobiphenyl > 2,3,3',4,4',5'-hexa, 2,3,3',4,4'- and 2,3,4,4',5-pentachlorobiphenyl > Aroclors 1221, 1232, 1248, 1254, and 1260 were inactive as antiestrogens at the highest concentrations used in this study (10(-6) M). For the PCDDs and PCDFs, the order of antiestrogenic potency was 2,3,7,8-tetrachlorodibenzo-p-dioxin > 2,3,7,8-tetrachlorodibenzofuran > 2,3,4,7,8-pentachlorodibenzofuran > 1,2,3,7,9-pentachlorodibenzofuran > 1,3,6,8-tetrachlorodibenzofuran. With few exceptions, the order of potency for all these congeners and mixtures paralleled their relative activities as agonists for other Ah receptor-mediated responses and their competitive binding affinities for the Ah receptor. The results of this study support the role for the Ah receptor in mediating the inhibition of the 17 beta-estradiol-induced secretion of the 52-kDa protein in MCF-7 cells and also points out the utility of this technique as a bioassay for this class of compounds. (Krishnan et al, 1993)

Study #99

PCBs and Dioxin induced enzymes which in turn can activate many potential mutagens and carcinogens in the mammary gland

Sprague-Dawley rat mammary gland is extremely sensitive to tumorigenesis by single or multiple doses of several polycyclic aromatic hydrocarbons. We obtained quantitative data on the in vitro mutagenic activation of several procarcinogens by 9000 g supernatant fraction (S9) from rat mammary gland using the Ames test. Mutagenic activation was shown to be dependent on a nicotinamide adenine dinucleotide phosphate (NADPH) generating system. An S9 preparation from mammary tissue of lactating Sprague-Dawley rats was shown to activate 2-aminoanthracene (2-AA). A polychlorinated biphenyl mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given to rats greatly raised the specific activity (revertant TA98 colonies/mg S9 protein) of the mammary tissue using 2-AA as a test carcinogen, and permitted detection of 2,4-diaminoanisole (DAA) and 2,7-diaminofluorene (DAF) activation. Procarcinogens 2-aminofluorine (2-AF), benzo[a]pyrene (BP) and aflatoxin (AFL) B1 were not detectably activated by mammary gland. Mutagenesis produced in mammary S9 activation of 2-AA, DAA or DAF was significantly inhibited by alpha-naphthoflavone (alpha NF) but was inhibited minimally by metyrapone (MP). Human mammary tumor cell lines (734B, SkBr3, MDA-MD-330) possessed inducible procarcinogen metabolizing activities similar to those found in S9 of rat mammary tissue. We demonstrated a simple and convenient use of the Ames test to characterize activation of many potential mutagens and carcinogens for mammary gland. When a test compound such as 2-AA was used, selective enzyme induction and inhibition was demonstrated. (Maack et al, 1986)

Study #100

the accumulation of PCBs measured in breast fat tissue do not relate to the occurrence of mammary cancer

Epidemiological studies have related the incidence of mammary cancer to the dietary intake of fat and/or meat. Since organochlorine compounds (e.g., polychlorinated biphenyls (PCB) and DDT (and its metabolite DDE] are accumulated in the adipose tissue it was tempting to suggest a relationship between levels of PCB and "DDT" (i.e., DDT + DDE) in breast fat tissue and the occurrence of mammary cancer. To elucidate this theory, the organochlorine levels of 14 breast fat tissue samples from breast cancer patients and similar samples from 18 deceased mammary cancer patients were compared to that of 21 similar samples from noncancer patients and finally to adipose tissue samples from 35 non-cancer autopsy specimens. No significant differences were traced. Thus it seems that the accumulation of PCB and DDT measured in breast fat tissue do not relate to the occurrence of mammary cancer. (Unger et al 1984)

Study #101

PCBs have been detected in human milk samples. Their possible contribution to breast cancer has never been seriously studied (1983)

Organochlorine insecticides and polychlorinated biphenyls (PCBs) have been found to be carcinogenic in animal studies. Eight of these insecticides and PCBs have been detected in human milk samples. Their possible contribution to breast cancer has never been seriously studied. Substances which cause scarring or provide anchorage when embedded in tissue can contribute to carcinogenesis. Sharp outer fragments of popcorn kernels may contribute to the type of tissue fibrosis associated with colorectal cancer. Lack of innovation in dietary cancer epidemiology is discussed. (Blondell, 1983)

Study #102

The long-term and pernicious impacts of endocrine disruptors show our poor understanding of the complexities of life's mechanisms
the collective exercise of wisdom, prudence and responsibility towards the essence and integrity of humanity has become, more than ever, an ethical, and perhaps even a survival, imperative

Considering the worldwide threat to health and reproduction related to endocrine disruptors (by-products of the chemical industry); considering the untrammelled development of the industrialization and engineering of the living, ethics and gynaecology/obstetrics itself is at a crossroads. Endocrine disruptors (derived from organochlorines and persistent organic pollutants such as PCBs, dioxins and furans, and pesticides such as aldrin, chlordane and DDT), are prime suspects in the deterioration of fertility and intellectual faculties and possibly a key factor in endometriosis, breast cancer and prostate cancer. The long-term and pernicious impacts of endocrine disruptors show our poor understanding of the complexities of life's mechanisms. Paradoxically, with our short-term perspectives and predilection for a technological fix, the problem posed by endocrine disruptors may accelerate the use of reproductive technologies such as ICSI and even cloning, as well as the dissemination of genetically modified organisms. The cure could be worse than the disease. Given the gravity of the challenge to humanity related to the chemical erosion of human health, the mutation of human conception introduced by reproductive technologies and by the drive to genetically modify nature and even human nature, we must urgently re-evaluate the direction in which our societies are headed and the reliance on profit-oriented technology to save us from ourselves. In these circumstances, the collective exercise of wisdom, prudence and responsibility towards the essence and integrity of humanity has become, more than ever, an ethical, and perhaps even a survival, imperative. (Vandelac et al, 1999)

Study #103

epidemiologic studies assessing the link between exposure to pesticides or PCBs and breast cancer have generally not shown enhanced breast cancer risk with higher levels of xenoestrogen exposure

Controversy exists over the role that environmental estrogens, such as pesticides or polychlorinated biphenyls (PCBs), might play as risk factors for breast cancer. Several laboratory studies have suggested that these chemicals function as weak estrogens, binding to the estrogen receptor and inducing various measures of estrogen response. However, epidemiologic studies assessing the link between exposure to pesticides or PCBs and breast cancer have generally not shown enhanced breast cancer risk with higher levels of xenoestrogen exposure. These findings heighten our uncertainty about the relevance of the preclinical findings to human breast cancer risk. (Davidson, 1998)

Study #104

No indication emerged of a relationship between PCB content in extractable breast fat tissue and the occurrence of breast cancer

A. Evidence for carcinogenicity to humans (limited) Information on the possible carcinogenic risk of human exposure to polychlorinated biphenyls (PCBs) comes from studies of occupational populations and of populations exposed to the compounds accidentally. PCB mixtures may be contaminated with polychlorinated dibenzofurans and polychlorinated dibenzodioxins (see, e.g, p. 350). A slight increase in the incidence of cancer, particularly melanoma of the skin, was reported in a small group of men exposed to Aroclor 1254, a mixture of PCBs. In a study of over 2500 US workers exposed to a similar mixture of PCBs during the manufacture of electrical capacitors, five deaths due to cancer of the liver and biliary passages were observed, where as 1.9 would have been expected. This increase was sustained mainly by female workers in one of the two plants in the study (four of the five deaths), and all five workers had first been employed before the early 1950s. Another study of workers in a capacitor plant was conducted in Italy. Exposure in the early years of production (until 1964) was to PCB mixtures containing 54% chlorine (mainly Aroclor 1254 and Pyralene 1476), which were later replaced by mixtures containing 42% chlorine (mainly Pyralene 3010 and 3011). Early results showed a significant excess of all cancers among male workers, which was due mainly to cancers of the digestive system and of the lymphatic and haematopoietic tissues. Among female workers, a slight increase in mortality from cancer of the lymphatic and haematopoietic tissues was reported. The study was later enlarged and extended to include 2100 workers and to cover the period 1946-1982. Both male and female workers exhibited significantly increased cancer mortality in comparison with rates for the local population (14 observed, 7.6 expected; and 12 and 5.3, respectively, for men and women). Among male workers, cancers of the gastrointestinal tract (two stomach, two pancreas, one liver and one biliary passages) taken together were significantly increased (6 observed, 2.2 expected). Female workers showed a significant increase in deaths from haematological neoplasms (4 observed, 1.1 expected). In Sweden, among 142 male workers employed between 1965 and 1978 in a capacitor manufacturing plant when PCB mixtures containing up to 42% chlorine had been used, no significant excess of cancer deaths was noted. Cancer incidence was also examined: the number of cases observed corresponded well to that expected. One individual in a subgroup with higher exposure developed two relatively rare tumours, both of which occurred ten years after the start of exposure: a slow-growing mesenchymal tumour (desmoid) and a malignant lymphoma. After contamination of cooking oil with a mixture of PCBs (Kanechlor 400) in Japan in 1968, a large population was intoxicated ('Yusho' disease). An early report on mortality from 1963-1983 showed a significantly increased risk of all cancers, and an almost five-fold significantly elevated risk of primary liver cancer. The edible rice oil had also been contaminated by polychlorinated quaterphenyls and polychlorinated dibenzofurans. Dose response relationships were not clarified. A further comprehensive study of 887 male 'Yusho' patients showed statistically significantly increased mortality from all malignancies (33 observed, 15.5 expected), from liver cancer (9 observed, 1.6 expected) and from lung cancer (8 observed, 2.5 expected). Use of local rather than national rates in calculating expected number of deaths decreased the observed:expected ratio for liver cancer from 5.6 to 3.9, which was still statistically significant. A closer look at the geographical distribution of liver cancer cases did not allow exclusion of factors other than PCB poisoning as a possible explanation for this finding. For the 874 female patients examined, none of the noted observed:expected ratios was significant. In a series of ten autopsies of 'Yusho' patients, two adenocarcinomas of the liver were found, with no indication of a direct association with exposure to PCBs. Ultrasonic and tumour marker examination of two series of 79 and 125 patients with 'Yusho' disease in 1983 and 1984, respectively, did not reveal any case of hepatic-cell carcinoma. Two studies of the PCB content of fat tissues and cancer occurrence were available. An association was suggested between PCB concentrations in subcutaneous abdominal adipose tissue and the occurrence of cancers of the stomach, colon, pancreas, ovaries and prostate. No indication emerged of a relationship between PCB content in extractable breast fat tissue and the occurrence of breast cancer. The available studies suggest an association between cancer and exposure to PCBs.The increased risk from hepatobiliary cancer emerged consistently in different studies. Since, however, the numbers were small, dose-response relationships could not be evaluated, and the role of compounds other than PCBs could not be excluded, the evidence was considered to be limited. B. Evidence for carcinogenicity to animals (sufficient) Certain PCBs (particularly with greater than 50% chlorination) produced benign and malignant liver neoplasms in mice and rats after their oral administration. Oral administration of Aroclor 1254 to rats yielded hepatocellular adenomas and carcinomas as well as intestinal metaplasia and a low, statistically nonsignificant incidence of stomach adenocarcinomas. PCBs were inadequately tested in mice for induction of skin tumours. In several studies, oral or intraperitoneal administration of PCBs enhanced the incidences of preneoplastic lesions and of neoplasms of the liver induced in rats by N-nitrosodiethylamine or 2-acetylaminofluorene. In one study, intragastric administration of PCBs to mice increased the incidence of lung tumours induced by intraperitoneal administration of N-nitrosodimethylamine. C. Other relevant data No data were available on the genetic and related effects of PCBs in humans. Dominant lethal effects were not induced in rats administered PCBs orally, but were produced in rats nursed by females that had received PCBs orally. PCBs did not induce chromosomal aberrations in bone-marrow cells or spermatagonia of rats treated in vivo; micronuclei were not induced in bone-marrow cells of mice in one study, while equivocal results were obtained in a second study in which the PCBs were administered in corn oil. They did not transform Syrian hamster embryo cells in vitro. PCBs induced DNA strand breaks and unscheduled DNA synthesis in rat hepatocytes in vitro. Neither chromosomal breakage nor aneuploidy was induced in Drosophila. PCB mixtures did not induce SOS repair and were not mutagenic to bacteria. 2,2',5,5'-Tetrachlorobiphenyl induced DNA strand breaks in mouse cells in vitro. 2,4,5,2',4',5'-Hexachlorobiphenyl but not 3,4,5,3',4',5'-hexachlorobiphenyl inhibited intercellular communication in Chinese hamster V79 cells. Purified 2,4,2',4'-, 2,5,2',5'- and 3,4,3',4'-tetrachloro- and 2,4,6,2',4',6'-hexachlorobiphenyl were not mutagenic to bacteria. (IARC, 1987)

Study #105

most breast cancer risk factors can be linked to cumulative lifetime exposures to bioavailable estrogens
the steep increase in breast cancers in high social strata is thought to reflect different cumulative exposures to endogenous or exogenous estrogens and proestrogens
exogenous risk factors for breast cancer include exposure to PCBs

A review of environmental risk factors for female breast cancer summarized the epidemiologic aspects of female breast cancer and discussed various environmental and occupational risk factors for female breast cancer. Breast cancer is the most common malignancy found in female populations, with more than 910,000 new cases being diagnosed on a worldwide basis annually. Incidence varies widely, however, showing a more than 10 fold variation across populations. Incidence has increased markedly throughout the world during the past 20 years. Most of the risk factors can be linked to cumulative lifetime exposures to bioavailable estrogens. Early menarche and late menopause increase the lifelong estrogen load and are considered to be recognized risk factors. Postmenopausal obesity is a risk factor, probably due to estrogen forming in adipose tissue depots. Genetic factors probably account for less than 10% of all known cases. The risk for breast cancer shows a clear socioeconomic trend, with a steep increase in high social strata. This trend is thought to at least partially reflect the different cumulative exposures to endogenous or exogenous estrogens and proestrogens that exist in different socioeconomic strata. Exogenous risk factors for breast cancer include exposure to ionizing radiation, chlorinated hydrocarbon pesticides, chlorinated solvents, polychlorinated biphenyls (PCBs), tobacco smoke, and low frequency electromagnetic fields (EMFs). Limited evidence exists that employment in the pharmaceuticals industry and as a cosmetologist or beautician are occupational risk factors. Recommendations for future research on the etiology of breast cancer were summarized. (Welp et al, 1998)

Study #106

study found no evidence of an adverse effect associated with serum levels of several PCB exposure measures: total PCBs, total number of detected PCB congener peaks, and PCB congener groups

This report includes results from a case-control study examining the relation of serum levels of DDE, hexachlorbenzene (HCB), and poly chlorinated biphenyls (PCBs) to risk of postmenopausal breast cancer. The study sample included 154 primary, incident, histologically confirmed, breast cancer cases and 192 community controls. In the entire sample there was no evidence of an adverse effect associated with serum levels of DDE, HCB, and several PCB exposure measures: total PCBs, total number of detected PCB congener peaks, and PCB congener groups. We consistently observed effect modification by history of lactation with respect to all exposures. (Moysich et al, 1998)

Study #107

higher halogenated PCBs (especially, tetra-, penta-, and hexa- chlorinated biphenyls) act as promoters of carcinogenesis
lower halogenated PCBs may be activated by hepatic and breast (milk) enzymes to oxygenated species that are electrophilic and bind to DNA

Our research is aimed at the investigation of the effects of polychlorinated biphenyls (PCBs) in breast cancer. PCBs are industrial chemicals which persist in our environment. The lipophilicity of PCBs and their tendency to bioaccumulate in adipose tissue and breast milk raise concern about the health risks associated with exposure to PCBs and related compounds. Commercial PCB mixtures are complete carcinogens, producing hepatocellular carcinomas in rats and mice, but the mechanisms by which they do so have not been determined. We and others have shown that higher halogenated PCBs (especially, tetra-, penta-, and hexa- chlorinated biphenyls) act as promoters of carcinogenesis, but their initiating or DNA damaging activity has not been conclusively demonstrated. In our original proposal we presented considerable data to support the concept that the lower halogenated biphenyls may be activated by hepatic and breast (milk) enzymes to oxygenated species that are electrophilic and bind to DNA. Of par (incomplete abstract) (Robertson, 1998)

Study #108

PCBs have weak estrogenic activity and may enhance breast cancer formation by an estrogenic effect on breast epithelial cell growth
PCBs inhibit gap junctional intercellular communication (GJIC) which may be involved in enhanced growth and breast cancer formation

The incidence of breast cancer is increasing dramatically in the United States. Man-made environmental agents such as pesticides, polychlorinated biphenyls (PCBs), phthalate esters, and dioxin have been implicated in this increase. Many xenobiotics such as DDT and PCBs have weak estrogenic activity and may enhance breast cancer formation by an estrogenic effect on breast epithelial cell growth. These agents can also inhibit gap junctional intercellular communication (GJIC); this reduction may also be involved in enhanced growth and breast cancer formation by these agents. The studies outlined in this proposal will determine whether there is a link between xenobiotic inhibition of human mammary epithelial cell GJIC, growth, and estrogenicity. These studies are highly relevant to the prevention of breast cancer. An understanding of the relationship between xenobiotic inhibition of GJIC, estrogenic activity, and the enhancement of growth in human breast epithelial cells will lead to more widely acc (incomplete abstract) (Ruch, 1998)

Study #109

Studies of breast cancer risk from organochlorine exposure have shown increased levels of PCBs

The association between increased risk of nonHodgkin's lymphoma (NHL) or breast cancer and exposure to organochlorine compounds (OCs) was reviewed. Several organochlorines have been reported to adversely affect the human immune system, providing a mechanism whereby immunological defense against early cancer stages and immune cells themselves may be influenced by this class of chemicals. In addition, some of these compounds have been reported to have estrogenic effects contributing additional evidence for their role in the induction of breast cancer. Epidemiological studies on the risk of NHL from OC exposure have consistently demonstrated an increased risk for NHL associated with exposure to pesticides, particularly herbicides. Studies of breast cancer risk from OC exposure have shown increased levels of polychlorinated biphenyl, DDT (50293) and DDE (3547044) in breast tissue samples obtained from breast cancer cases. Methodological issues complicating the interpretation of such studies were discussed. The author presents several recommendations regarding the control and use of OCs. (Hoffmann, 1996)

Study #110

PCBs exhibit endocrine-disrupting hormonal activity, and can interfere with the reproductive systems of human and other animals
Organochlorines appeared to be biphasic (at lower concentrations they stimulated breast cancer growth, and at higher levels they inhibited growth.)

Certain environmental pollutants exhibit endocrine-disrupting hormonal activity. They can interfere with the reproduction systems of human and other animals. These chemicals include pesticides, the plastics ingredient bisphenol-A, non-ionic surfactants (alkylphenol-polyethoxylates orAPnEO, n=9-90) and some polychlorinated biphenyls (PCBs). In this study, the influences of these pesticide, namely chlordane, endosulfan and dieldrin on the growth of human breast cancer cells were examined to evaluate their impacts on human. Results showed that these chemicals exhibited significant effects on the growth of human breast cancer cells and their effects appeared to be biphasic. At concentrations of 1.75 muM, chlordane induced the growth proliferation of MCF-7 cells which contained estrogen receptors, while no stimulation effect was observed in SK-BR-3 cells, an estrogen receptor negative cell line. At concentrations above 87.5 muM, these chemicals showed inhibitory effects on t (incomplete abstract) (HSU et al, 1998)

Study #111

few studies provide information about long term exposure to low doses of PCBs that would parallel exposure in young women
laboratory data do not provide compelling evidence for PCB-dependent, estrogen mediated effects on breast cancer, although they do not exclude the possibility
PCBs were estrogenic in animal studies, binding to estrogen receptors leading to increased uterine weights and blocking ovulation
when hydroxylated, PCB congeners structurally resemble estradiol

The chemical and experimental data linking organochlorine compounds to cancer of the breast, endometriosis, and endometrial cancer through an estrogenic effect were reviewed. Estrogenicity was defined as producing biological responses comparable to endogenous estrogen, such as increased uterine weight. Surveys found that organochlorine compounds accumulate in adipose tissue. Human exposure resulted from eating contaminated foods, particularly those high in fat. Body burden increased with increasing age. Geographical variation in body burden varied with local use and environmental burden. DDT (50293) mimicked the effects of estrogen in several animal studies, elevating uterine weights, enzymes, and glycogen content, and stimulating cell division in the uterus. Polychlorinated biphenyls (PCB) also showed estrogenic properties in animal studies, including binding to estrogen receptors leading to increased uterine weights and blocking ovulation. When hydroxylated, PCB congeners structurally resembled estradiol. Other organochlorine compounds, such as chlorinated dioxins, showed antiestrogenic properties in-vivo. Most available data regarding estrogenic effects of various organochlorinated compounds were based on either in-vitro testing or short term, single exposure in-vivo tests. Few studies provided information about long term exposure to low doses of potentially estrogenic compounds that would parallel exposure in young women. Data concerning endometrial cancer and endometriosis were especially limited. The authors conclude that laboratory data do not provide compelling evidence for an organochlorine dependent, estrogen mediated effect on cancer of the breast, endometrial cancer, or endometriosis, although they do not exclude the possibility of such an effect. (Ahlborg et al, 1995)

Study #112

a woman's lifetime exposure to endogenous hormones and breast cancer are strongly related
PCBs mimic biological activity of estrogen and may contribute to an increased risk
PCBs in breast tissue may influence formation of hydroxyl radicals in cells effecting oxidative DNA damage

We hypothesize that organochlorine xenobiotics may promote or modulate the formation of DNA-adducts that influence initial stages of carcinogenesis. This links three distinct observations regarding breast cancer risk. The first is the strong relationship between a woman's lifetime exposure to endogenous hormones and breast cancer; the second is that some environmental organochlorines mimic the biological activity of estrogen and may contribute to an increased risk; and the third is that environmental contaminants in breast tissue may influence the formation of hydroxyl radicals in cells effecting oxidative DNA damage. The specific aims and work to date for each aim are: (1) to measure isomers of DDT, DDE and PCBs by specialized techniques of gas chromatography/mass spectrometry (GC) and GC/electron-capture detection (ECD). (incomplete abstract) (Graham, 1998)

Study #113

human milk can contain components [including PCBs] capable of causing genotoxic damage in human breast cells, which may be significant in breast cancer initiation

Genotoxic agents of environmental or dietary origin may play a role in breast cancer initiation. The ability of extracts of human milk to cause mutations in S. typhimurium TA1538 and YG1019 and to induce micronuclei and DNA strand breaks in MCL-5 cells was investigated. Twenty samples from different donors were analysed and of these, 6 were adjudged to produce a positive mutagenic response in one or both bacterial strains. The same samples also induced significant micronucleus formation in MCL-5 cells. In the comet assay, 13/20 samples caused DNA strand breaks in MCL-5 cells. Viable exfoliated breast cells were recovered from fresh milk samples and the ability of milk extracts to cause DNA damage in these cells was demonstrated. The results show that human milk can contain components capable of causing genotoxic damage in test systems and in human breast cells, events that may be significant in the initiation of breast cancer. Keywords include: PCBs. (Martin et al, 1999)

Study #114

(earlier version of study above)

We tested the proposition that human mammary lipid contains mutagenic/genotoxic agents that could cause DNA damage in adjacent epithelial cells. Lipid samples from breast tissue surgically removed from 40 women undergoing elective reduction mammoplasty were extracted by a solid-phase procedure. Mutagenicity was observed in Salmonella typhimurium TA98 and TA1538 in 16 of 40 (40%) extracts assayed with rat-liver S9, but not in its absence. No mutagenicity was seen in S. typhimurium TA100 or Escherichia coli WP2uvrA(pKM101). Bacterial mutagenicity correlated with micronucleus-forming activity in a metabolically competent mammalian cell line (MCL-5). This genotoxic activity merits further investigation in relation to the etiology of breast cancer. Keywords include: PCBs (Martin et al, 1996)

Study #115

Increases in male breast cancers may be part of larger trend of increasing male reproductive disorders, possibly linked to estrogenic environmental chemicals

A comprehensive review of declining male reproductive health was presented. The review was undertaken at the request of the Danish Environmental Protection Agency with its final content and form decided by a panel of international experts. Trends in male reproductive disorders were discussed, including significant declines in semen quality and volume, and increases in testicular cancer, cryptorchidism, hypospadias and male breast cancer from the 1930s to the present day. African American men had lower rates of testicular cancer than white American men, while Finnish men were less likely to develop testicular or breast cancer than Danish men. The effects of estrogenic pollutants on male reproduction in gastropods, reptiles, fish, birds, porpoises, seals and Florida panthers were described. Reproductive disorders in wildlife were associated with interference of normal prenatal sexual development by estrogenic or other endocrine disrupting environmental pollutants. The function of estrogen in the sexual differentiation in humans and resulting genital development disorders and malignancies was described. The effects of estrogen resistance in mice and man were cited and the effects of overexpression of the estrogen receptor in transgenic mice was described. Structural abnormalities, lower semen quality and incidence of testicular cancer in men prenatally exposed to diethylstilbestrol (56531) were reviewed. Neonatal and prenatal effects of synthetic estrogens in animal models, including effects on Mullerian ducts and developing testis were considered to be dependent on the point in fetal development that exposure occurred. The occurrence and effects of estrogenic environmental chemicals, including organochlorine pesticides, polychlorinated biphenyls, alkylphenol polyethoxylates and phytoestrogens, on male reproductive health were discussed. Existing models and assays for evaluating exposure to estrogenic substances were debated. An appendix describing the reproductive toxicology of numerous pesticides and environmental chemicals was provided. (Toppari et al, 1996)

Study #116

some studies have found higher breast tissue levels of organochlorines among breast cancer patients, but the findings are inconsistent.

The majority of endocrine disrupter chemicals alter biological functions by binding with estrogen receptors and showing estrogen-like effects. This hypothesis is strongly supported by studies in animal models and cell cultures. However, it remains unclear whether these chemicals have clinical effects. Diethylstilbestrol, used in the past for the prevention of spontaneous abortions, has been demonstrated to cause uterine, vaginal, and uterine tube anomalies, as well as uterine cancer in young women. The incidence of endometriosis has increased markedly in recent years. Rhesus monkeys exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, had a progressed stage of endometriosis. Some studies have found higher breast tissue levels of synthetic contraceptives and organochlorines among breast cancer patients, but the findings are inconsistent. Abnormalities in thyroid hormones have been suggested among patients exposed to PCBs in the Kanemi Yusho accident. This review summarizes the results of recent studies of endocrine disrupter chemicals in relation to endocrine and reproductive disorders in the human female. (Sone, 1999)

Study #117

most studies on half-lives of PCBs, linked with increased risk of breast cancer, have been based on small sample sizes and a limited number of repeated measurements
researchers need to adjust hormone measurements for systematic fluctuations over the menstrual cycle

Failure to account for errors-in-measurement of exposure and confounder variables can result in biased estimates of relative risk. We have developed a technique for correcting for measurement error when subjects have a variable number of repeated measurements and the average of the measurements is used as the subject's measure of exposure in the analysis. A bootstrap method for obtaining confidence intervals of the relative risk estimates, which takes into account the variability in the estimates of the correction factors, has also been devised. In addition, we have considered a model for adjusting hormone measurements for systematic fluctuations over the menstrual cycle, which will allow more valid comparisons of hormone levels between premenopausal cases and controls. Finally, most studies on the half-lives of environmental contaminants such as PCBs, which have been linked with an increased risk of breast cancer, have been based on small sample sizes and a limited number of repeated measurmen (incomplete abstract) (Kim, 1996)

Study #118

Certain dioxins and dioxin-like PCBs are anti-estrogenic and suppress tumors, which may make them useful in treating breast cancer

The interaction between chlorinated hydrocarbons and endocrine pathways resulting from the binding of such compounds to the aryl hydrocarbon (Ah) receptor was reviewed. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin (1746016) (TCDD) has been reported to decrease the incidence of mammary and uterine tumors in-vivo, to inhibit 17beta-estradiol (E2) induced responses in rodent mammary glands and uteri as well as in human breast cancer lines, to inhibit age dependent and carcinogen induced formation of mammary tumors in mice, and to inhibit E2 regulated responses in rats. Studies have suggested that the formation of the nuclear Ah receptor was required for TCDD induced antiestrogenicity. Several possible mechanisms have been proposed to be associated with the antiestrogenic effects of Ah receptor agonists. Recent investigations conducted by the authors on one of these possible mechanisms, the inhibition of E2 induced cathepsin-D gene transcription by TCDD, were described and discussed. Based on the observed antiestrogenic and antitumorigenic activity of Ah receptor agonists, a series of nontoxic alkyl polychlorinated dibenzofurans with potential application for the clinical treatment of breast cancer has been prepared. (Safe et al, 1995) (industry consultant)

Study #119

incomplete abstract

Long-term exposure to fat-soluble xenobiotics is assessed by the concentration of DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), the persistent metabolite of DDT, in subcutaneous fat, aspirated from the buttocks of breast cancer patients and age-matched controls, from five European centers collaborating in a case-control study on breast cancer. In such studies using sample material of living subjects only small amounts of samples can be made available for analysis. In this particular study the only sample material available for the analysis of DDE were aliquots of the aspirates that were originally analyzed for fatty acids. Due to the small sample quantities available, e.g. aliquots of 200-800 mul, on-line LC-GC is most convenient because a major part of the sample can be used in the analytical procedure. In the LC-GC procedure 50 mul of sample was injected on the LC column resulting in a 180 mul fraction containing the analytes of interest. The LC fraction was tra (incomplete abstract – also measured PCBs) (Gort et al, 1997)

Study #120

increased incidences of breast cancer were found due to airborne pollutants [including PCBs]

Epidemiological techniques were used to investigate cancer risks to a population surrounding a large military facility, the Massachusetts Military Reservation (MMR). Population based case/control studies of cancer were conducted in the Upper Cape region of Massachusetts from 1988 through 1991. The towns in this area have a combined population of 40,000. MMR rests on the sole source aquifer that supplies Cape residents with their drinking water. The contamination at MMR was in general a result of the maintenance and fueling of aircraft and ground vehicles, along with certain other ancillary activities. Fuels, oils, lubricants, and halogenated and nonhalogenated solvents were spilled at the site. Several miscellaneous chemicals were also present at the site including pesticides, polychlorinated biphenyls, paints, lead acid batteries, chemicals for film developing, corrosion control materials, and engine repair materials. A landfill operation had been opened at the base in 1944. A high benzene (71432) content of 1,100 parts per billion was found in a monitoring well in the Forestdale neighborhood of Sandwich. The major positive findings were related to exposures from the gun and mortar positions and the base runways. The major exposures were not through the water, but through the air. Increased incidences of lung and breast cancer were found due to the exposure to airborne pollutants. The exposures arose from artillery firing and open air burning of unused propellants. (Ozonoff et al, 1994)

Study #121

incomplete abstract

Lately, a theory on possible oestrogenic effects of environmental contaminants like PCB, dioxin and some pesticides, has caused much concern. The "oestrogen theory" states that persistent, bioaccumulating chemicals affect foetal development by acting like oestrogens. This results in permanent changes, of the reproductive organs in particular, and leads to reduced reproductive success. The theory is based to a large degree on reports on animals from the Great Lakes region in North America, alligators from Florida and fish from rivers in Great Britain. Now that a decline in human semen quality over the last 50 years has been reported, the question has been raised as to whether this too may be a result of environmental oestrogens. The higher incidence of other diseases like hypospadia, cryptorchidism and testicular cancer also indicates that something may be affecting the reproductive health of the male. Whether the higher incidence of endometriosis and breast cancer can b (incomplete abstract) (Ringvold et al, 1997)

Study #122

breast cancer rates have increased, and the increase may be due to natural and synthetic chemical exposures which mimic hormones

In recent years, evidence from disparate observations has indicated adverse changes in the reproductive health and fecundity of animals and humans. In humans, there is strong evidence for such trends in the incidences of testicular and female breast cancer, and concern has also been expressed regarding semen quality, cryptorchidism, hypospadias and polycystic ovaries. Laboratory studies have indicated that some chemicals in the environment, both natural and synthetic, have the potential to disrupt the endocrine system and that these could, at least theoretically, be partly responsible for the observed changes. Chemicals thus identified include the naturally occurring steroid hormones, phyto- and myco-estrogens, and anthropogenic chemicals such as synthetic hormones, organotins, organochlorine pesticides, polychlorinated biphenyls, dioxins, alkylphenol polyethoxylates, phthalates and bisphenol-A. While there is no direct evidence from human studies to confirm a causal li (incomplete abstract) (Harrison et al, 1997)

Study #123

Dioxin exposure may have implications in toxicity pathways other than the AhR signaling pathway [certain PCBs are dioxin-like, or are frequently contaminated with dioxin]

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals causes a variety of tissue- and species-specific biological and toxicological effects, most of which are mediated by the aryl hydrocarbon receptor (AhR). The AhR complex is a ligand-dependent transcription factor that binds to its specific DNA recognition site as a dimer with the AhR nuclear translocator (ARNT) and activates gene transcription. Here, we have examined the ability of a nuclear corepressor, the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), to interact with and modulate AhR-dependent gene expression. Using glutathione S-transferase (GST) "pull-down" binding assays, we have mapped a major interaction between these factors to the silencing domain of SMRT and the PAS B ligand binding domain of AhR, and this interaction is unaffected by the addition of an AhR ligand. Association of SMRT with the AhR:ARNT:DNA complex was not detected by GST pull-down or gel retardation assays. Transient cotransfections of mammalian cells (Hepa1c1c7, MCF-7, and BG-1) with SMRT and a TCDD-inducible luciferase reporter containing the dioxin-responsive domain from the mouse CYP1A1 regulatory region revealed that SMRT does not repress, but enhances, AhR signaling. However, when a reporter containing a human CYP1A1 upstream region was cotransfected with SMRT into human MCF-7 cells, AhR-driven reporter activity was decreased by half, suggesting that SMRT acts on the human CYP1A1 promoter via a factor other than the AhR in MCF-7 cells. Furthermore, the interaction between SMRT and the AhR may have implications in pathways other than the AhR signaling pathway. (Rushing et al, 2002)

Study #124

manmade estrogen disruptors [such as dioxin] may redirect estrogen metabolism in a more toxic pathway in breast cancer cells by altering the enzyme ratio
few studies have addressed the molecular consequences of a combination of contaminants

Dioxin and pesticides with xenoestrogenic activity are environmental contaminants that are suspected of promoting human diseases such as cancers. However, few studies have addressed the molecular consequences of a combination of these contaminants, a situation that is likely to occur in the environment. We investigated the effects of natural and xenoestrogens on basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 (CYP) 1A1 and 1B1. The CYP1B1/1A1 ratio is a critical determinant of the metabolism and toxicity of estradiol in mammary cells. Here we show that in MCF-7 cells, 17beta-estradiol and alpha-endosulfan can repress whole cell ethoxyresorufin-O-deethylase activity, lowering CYP1A1 mRNA levels as well as promoter activity as assessed by transient transfection assays. These negative effects are observed at both the basal and tetrachlorodibenzo-p-dioxin-induced levels. Under the same conditions, CYP1B1 mRNA levels and promoter activity are not affected. The effects on mRNA-induced levels are also observed in another mammary cell line, T47D, but not in mammary cell lines that do not express aryl hydrocarbon receptor and estrogen receptor (ER). Moreover, the use of ER antagonists shows that these effects are ER dependent in MCF-7 cells. In human hepatoma HepG2 cells, which lack functional ER, alpha-endosulfan, but not 17beta-estradiol, displays a repressive effect on CYP1A1 through a different mechanism. These results show that xenoestrogens, by altering the ratio of CYP1B1/CYP1A1, could redirect estradiol metabolism in a more toxic pathway in the breast cell line MCF-7. (Coumoul et al, 2001)

Study #125

Dioxin exposure of baby female rats in the womb increased the total proliferative compartment in terminal end buds (breast tissue) of the resulting adult female rats
Alteration of breast tissue differentiation (increased number of terminal end buds) is correlated with increased susceptibility to breast cancer from prenatal exposure to dioxin
Dioxin treatment resulted in an increased number of chemically-induced breast cancers in rats

Prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated for its potential to predispose to breast cancer. Analysis of mammary gland differentiation and cell proliferation were used as biomarkers. Timed pregnant Sprague-Dawley CD rats were gavaged with 1 microg TCDD/kg on day 15 post-conception. Control animals were treated with the same volume of vehicle (sesame oil) on the same schedule. Mammary gland differentiation studies revealed that prenatal TCDD treatment, as compared with sesame oil treatment, resulted in significantly more terminal end buds and fewer lobules II in 50-day-old offspring, but no significant alterations to mammary gland differentiation in 21-day-old offspring. Terminal end buds are the most susceptible terminal ductal structures and lobules the least susceptible to carcinogenesis. Prenatal TCDD treatment did not alter labeling index in the mammary terminal ductal structures of 21- and 50-day-old rats, but the total proliferative compartment in terminal end buds of 50-day-old rats was larger. Prenatal TCDD treatment resulted in an increased number of chemically induced mammary adenocarcinomas in rats. TCDD delayed time of vaginal opening and caused disruption to the estrous cycle. Alteration to mammary gland differentiation (increased number of terminal end buds) is correlated with increased susceptibility to mammary cancer from prenatal exposure to TCDD. (Brown et al, 1998)

Study #126

prevention of breast cancer may require intervention at an early age
investigation of chemical exposures as possible etiologic factors for breast cancer has not been a research priority in the United States
because breast cancer risk is strongly associated with reproductive hormones, environmental chemicals which mimic hormones should be investigated

Investigation of chemical exposures as possible etiologic factors for breast cancer has not been a research priority in the United States, which is surprising given the evidence from animal studies that environmental chemicals cause cancer and reproductive dysfunction. Study of environmental chemicals has also been indicated by the failure of traditional epidemiologic methods to account for significant proportions of breast cancer incidence with other risk factors. The fact that breast cancer risk is strongly associated with reproductive hormones is a further clue that environmental chemicals should be investigated. In addition to cancer, specific outcomes that need to be explored are reproductive dysfunction, immunotoxicity and neurotoxicity. Policy guiding our research should encourage toxicologic investigations of exposures to environmental chemicals that use state-of-the-art methods to determine exposure and human health effects. Using the approach suggested by John McLachlan, functional toxicology should be used to assess the activity of chemicals with regard to these outcomes. Just as dioxin toxicity can be expressed as toxic equivalents, estrogenic activity, for example, can be characterized in terms of estrogenic equivalents. In addition to the need to undertake this kind of research, needs for methods development and creative research funding mechanisms are discussed. Prevention of breast cancer may require intervention at an early age. Better understanding of breast cancer etiology, and especially its environmental components, may lead us toward that goal. (Wolff, 1995)

Study #127

tamoxifen alone did not produce toxicity
dioxin and tamoxifen together produced toxicity (elevated liver dioxin retention and enhanced severity of liver pathology)

Tamoxifen, an antiestrogen commonly used in breast cancer therapy, potentiated the lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when coadministered to female CD1 mice, despite the virtual lack of toxicity associated with the administration of tamoxifen alone. The 58-day ip LD50 of TCDD was reduced from 330 to 185 micrograms/kg by sc administration of 1 mg/kg/day tamoxifen. A significant dose-response relationship was observed for the potentiating effect of tamoxifen on TCDD lethality. All mice receiving TCDD developed a centrilobular pattern of hepatocellular degeneration and necrosis with perivascular infiltration of inflammatory cells. Clinical chemistry parameters were indicative of liver disease. Abnormalities in mice receiving tamoxifen plus TCDD were similar to, but more severe than, those in mice receiving TCDD only. Seven days after administration of [14C]TCDD, liver retention of radioactivity was increased 80-100% by coadministration of tamoxifen. This elevated retention was associated with a 50 and 37% decrease in excretion of radioactivity by the urinary and fecal routes, respectively. Our results suggest that the potentiation of TCDD toxicity by tamoxifen is associated with decreased excretion of TCDD, leading to elevated liver retention and enhanced severity of liver pathology. (MacKenzie et al, 1992)

Study #128

answers to mechanistic questions have not been and should not be the driving force behind public health policy
cancer activists embrace a form of conservatism that advocates prudence in the face of exposure to estrogenic and other endocrine-disrupting chemicals
unmet needs for cancer activists refer not so much to data gaps as to the failure to eliminate ongoing cancer hazards

Cancer activists who participate with cancer researchers in shaping public health policy provide a different perspective on the question of breast cancer etiology. We place a higher priority on reducing women's exposure to suspected breast carcinogens than in debating the specific biochemical mechanisms by which these agents may operate. As the fruits of AIDS activism and antismoking campaigns illustrate, answers to mechanistic questions have not been and should not be the driving force behind public health policy. As such, cancer activists embrace a form of conservatism that advocates prudence in the face of exposure to estrogenic and other endocrine-disrupting chemicals. This perspective stands in contrast to scientific conservatism, which directs its caution toward the issue of proof. Unmet needs for cancer activists refer not so much to data gaps as to the failure to eliminate ongoing cancer hazards. For this author and activist, unmet needs include ending women's continued exposure to such common estrogenic compounds as detergents, triazine herbicides, plastics, and polychlorinated biphenyls. (Steingraber, 1997)

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Table of Contents

Introduction

Summary of Study Results

Studies of Breast Cancer, PCBs and Dioxin (128 studies in 2 parts)

Links to More Information

References

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