Search the Database

Breast Cancer

• Pesticide exposure and increased breast cancer risk in women population studies
  Pesticide exposure is emerging as a risk factor for various human diseases. Breast cancer (BC) is a multifactorial disease with known genetic and non-genetic risk factors. Most BC cases are attibutable to non-genetic risk factors, with a history of adverse environmental exposures playing a significant role. Pesticide exposure can occur at higher levels in female populations participating in rural activities such as spraying of pesticides in the field, unprotected handling of pesticides at home, and washing of contaminated clothes. Exposure can also be significant in the drinking water of certain populations. Here, we reviewed the literature on women's exposure to pesticides and the risk of BC. We summarize the main links between pesticide exposure and BC and discuss the role of dose and exposure context, as well as potential mechanisms of toxicity. Overall, reports reviewed here have documented stronger associations between higher levels of exposure and BC risk, including documenting direct and acute pesticide exposure in certain female populations. However, discrepancies among studies regarding dose and mode of exposure may result in misunderstandings about the risks posed by pesticide exposure. Plausible mechanisms linking pesticides to breast cancer risk include their impacts as endocrine disruptors, as well as their roles as genotoxic agents, and modulators of the epigenome. Besides establishing links between pesticide exposure and breast cancer, the literature also highlights the critical need to understand the routes and doses of women's exposure to pesticides and the specific associations and mechanisms that are determinants of disease etiology and prognosis.
  [Panis, C. and Lemos, B. (2024) Pesticide exposure and increased breast cancer risk in women population studies, Science of The Total Environment. Available at: https://www.sciencedirect.com/science/article/pii/S0048969724031358?via%3Dihub. ]
• Atrazine promotes breast cancer development by suppressing immune function and upregulating MMP expression
  There is evidence that the triazine herbicide atrazine, which is used extensively, is present in both surface water and groundwater, and its interfering effect on immune systems, endocrine systems, and tumours has been reported by laboratory and epidemiological studies. This study explored how atrazine affected 4T1 breast cancer cell development in vitro and in vivo. The obtained results showed that after exposure to atrazine, the cell proliferation and tumour volume were significantly increased and the expression of MMP2, MMP7, and MMP9 was upregulated. The thymus and spleen indices, the CD4 + and CD3 + lymphocyte percentages which from the spleen and inguinal lymph nodes, and the CD4 + /CD8 + ratio were noticeably lower than they were in the control group. Importantly, tumour-infiltrating lymphocytes such as CD4 + , CD8 + , and NK cells were decreased while Treg cells were increased. Moreover, IL-4 was increased and IFN-γ and TNF-α were decreased in the serum and tumour microenvironment. These results suggested that atrazine can suppress systemic as well as local tumour immune function and upregulate MMPs to promote breast tumour development.
  [Wang, M., Chen, J., Zhao, S., Zheng, J., He, K., Liu, W., Zhao, W., Li, J., Wang, K., Wang, Y. and Liu, J., 2023. Ecotoxicology and Environmental Safety, 253, p.114691.]
• Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship
  Environmental endocrine-disrupting chemicals (EDCs) are a mixture of chemical compounds capable to interfere with endocrine axis at different levels and to which population is daily exposed. This paper aims to review the relationship between EDCs and breast, prostate, testicle, ovary, and thyroid cancer, discussing carcinogenic activity of known EDCs, while evaluating the impact on public health. A literature review regarding EDCs and cancer was carried out with particular interest on meta-analysis and human studies. The definition of EDCs has been changed through years, and currently there are no common criteria to test new chemicals to clarify their possible carcinogenic activity. Moreover, it is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at different ages, even if preclinical and clinical evidence suggest that developing fetus and neonates are most vulnerable to endocrine disruption. EDCs represent a major environmental and health issue that has a role in cancer development. There are currently some EDCs that can be considered as carcinogenic, like dioxin and cadmium for breast and thyroid cancer; arsenic, asbestos, and dioxin for prostate cancer; and organochlorines/organohalogens for testicular cancer. New evidence supports the role of other EDCs as possible carcinogenic and pregnant women should avoid risk area and exposure. The relationship between EDCs and cancer supports the need for effective prevention policies increasing public awareness.
  [Modica, R., Benevento, E. and Colao, A., 2023. Journal of Endocrinological Investigation, 46(4), pp.667-677.]
• Exposome epidemiology for suspect environmental chemical exposures during pregnancy linked to subsequent breast cancer diagnosis.
  Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.
  [Go, Y.M., Weinberg, J., Teeny, S., Cirillo, P.M., Krigbaum, N.Y., Singer, G., Tran, V., Cohn, B.A. and Jones, D.P., 2023. Environment International, 178, p.108112.]
• Risk of breast cancer in daughters of agricultural workers in Denmark.
  Agricultural workers face unique occupational hazards such as pesticide exposure, which has been associated with breast cancer. However, research considering the association between parental agricultural work and breast cancer in female offspring is lacking. Therefore, the aim of the present nested case-control study was to explore this association. The Danish Cancer Registry was utilized to identify women diagnosed with primary breast cancer. A total of 5587 cases were included in the study, and for each case, 20 cancer-free female controls were selected, matched on year of birth. It was a requisition that both cases and controls were born in Denmark and that either maternal or paternal employment history was available. Adverse associations were consistently noted for different time windows of maternal employment in "Horticulture" and breast cancer. Inverse associations were observed for paternal employment in most of the examined agricultural industries, although a small increased risk was indicated for perinatal employment in "Horticulture". Furthermore, maternal preconceptional employment in "Horticulture" was observed to increase the risk of ER + tumors (odds ratio [OR] = 1.79, 95% confidence interval [CI]: 1.13-2.85, whereas parental perinatal employment was linked to an elevated risk of ER-tumors (maternal employment: OR = 2.48, 95% CI: 1.18-5.21; paternal employment: OR = 1.62, 95% CI: 0.70-3.77). The present study indicates that maternal horticultural employment in different potential susceptible time windows may elevate the risk of breast cancer subtypes. These findings need to be reproduced in future prospective cohort studies, including information on e.g., pesticide exposure withing job categories and lifestyle factors.
  [Pedersen, J.E. and Hansen, J., 2023. Environmental Research, p.117374.]
• Breast carcinogenesis induced by organophosphorous pesticides
  Breast cancer is a major health threat to women worldwide and the leading cause of cancer-related death. The use of organophosphorous pesticides has increased in agricultural environments and urban settings, and there is evidence that estrogen may increase breast cancer risk in women. The mammary gland is an excellent model for examining its susceptibility to different carcinogenic agents due to its high cell proliferation capabilities associated with the topography of the mammary parenchyma and specific stages of gland development. Several experimental cellular models are presented here, in which the animals were exposed to chemical compounds such as pesticides, and endogenous substances such as estrogens that exert a significant effect on normal breast cell processes at different levels. Such models were developed by the effect of malathion, parathion, and eserine, influenced by estrogen demonstrating features of cancer initiation in vivo as tumor formation in rodents; and in vitro in the immortalized normal breast cell line MCF-10F, that when transformed showed signs of carcinogenesis such as increased cell proliferation, anchorage independence, invasive capabilities, modulation of receptors and genomic instability. The role of acetylcholine was also demonstrated in the MCF-10F, suggesting a role not only as a neurotransmitter but also with other functions, such as induction of cell proliferation, playing an important role in cancer. Of note, this is a unique experimental approach that identifies mechanistic signs that link organophosphorous pesticides with breast carcinogenesis.
  [Calaf, G.M., 2022. Advances in Pharmacology (San Diego, Calif.), 96, pp.71-117.]
• Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies
  Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs might exert estrogenic disruption and promote breast cancer progression, but the molecular mechanism is unclear, especially the molecular initiating event. G protein-coupled estrogen receptor (GPER), as a candidate therapeutic target, plays vital roles in the development of breast cancer. This work aimed to reveal the potential mechanism through GPER pathway. Firstly, we screened the activities of seven most common NIs on GPER signal pathway by calcium mobilization assay. Clothianidin, acetamiprid (ACE), and dinotefuran activated GPER most potently and ACE displayed the highest agonistic activity with the lowest observed effective concentration (LOEC) of 1 μM. The molecular docking and dynamics simulation showed favored interaction trend between the NIs and GPER. The three NIs with GPER activity induced 4T1 breast cancer cells migration and ACE showed the highest potency with LOEC of 100 nM. ACE also induced 4T1 cells proliferation at high concentration of 50 μM and up-regulated GPER expression in a dose-dependent manner. We speculated that both the induction effects of ACE on 4T1 cells proliferation and migration might be owing to the activation and up-regulation of GPER. By using 4T1-Luc cells injected orthotopic tumor model, we found that ACE also promoted in-situ breast cancer growth and lung metastasis in normal mouse dependent on GPER. However, ACE only promoted in-situ breast cancer growth through GPER but not lung metastasis in ovariectomized mice, implying that the ACE-induced lung metastasis should be related to endogenous estrogen from ovary. Overall, we demonstrated that NIs promoted breast cancer progression via GPER pathway at human related exposure levels and their female health risks need urgent concerns.
  [Li, X., He, S., Xiao, H., He, T.T., Zhang, J.D., Luo, Z.R., Ma, J.Z., Yin, Y.L., Luo, L. and Cao, L.Y., 2022. Environment International, 170, p.107568.]
• Cancer and occupational exposure to pesticides: an umbrella review
  Purpose
  The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.

  Methods
  Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.

  Results
  Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.

  Conclusions
  Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
  [Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ]

• Endocrine disrupting chemicals and breast cancer: a systematic review of epidemiological studies
  

  Abstract

  Background: Endocrine-disrupting compounds (EDCs) are ubiquitous substances that are found in our everyday lives, including pesticides, plasticizers, pharmaceutical agents, personal care products, and also in food products and food packaging. Increasing epidemiological evidence suggest that EDCs may affect the development or progression of breast cancer and consequently lead to lifelong harmful health consequences, especially when exposure occurs during early life in humans. Yet so far no appraisal of the available evidence has been conducted on this topic.

  Objective: To systematically review all the available epidemiological studies about the association of the levels of environmental exposures of EDCs with breast cancer risk.

  Methods: The search was performed in accordance with the PRISMA guidelines. We retrieved articles from PubMed (MEDLINE) until 10 March 2021. The key words used in this research were: "Endocrine disruptor(s)" OR "Endocrine disrupting chemical(s)" OR any of the EDCs mentioned below AND "Breast cancer" to locate all relevant articles published. We included only cohort studies and case-control studies. All relevant articles were accessed in full text and were evaluated and summarized in tables.

  Results: We identified 131 studies that met the search criteria and were included in this systematic review. EDCs reviewed herein included pesticides (e.g. p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), atrazine, 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD or dioxin)), synthetic chemicals (e.g. bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), parabens, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), contraceptive pills), phytoestrogens (e.g. genistein, resveratrol), and certain mycotoxins (e.g. zearalenone). Most studies assessed environmental EDCs exposure via biomarker measurements.

  Conclusion: We identified certain EDC exposures could potentially elevate the risk of breast cancer. As majority of EDCs are highly persistent in the environment and bio-accumulative, it is essential to assess the long-term impacts of EDC exposures, especially multi-generational and transgenerational. Also, since food is often a major route of exposure to EDCs, well-designed exposure assessments of potential EDCs in food and food packing are necessary and their potential link to breast cancer development need to be carefully evaluated for subsequent EDC policy making and regulations.

  Keywords: Breast cancer; dietary; endocrine-disrupting chemicals; environmental; epidemiological studies; systematic review.
  [Wan, M.L., Co, V.A. and El-Nezami, H. (2021) ‘Endocrine disrupting chemicals and breast cancer: A systematic review of Epidemiological Studies’, Critical Reviews in Food Science and Nutrition, 62(24), pp. 6549–6576. doi:10.1080/10408398.2021.1903382. ]

• Grandmaternal Perinatal Serum DDT in Relation to Granddaughter Early Menarche and Adult Obesity: Three Generations in the Child Health and Development Studies Cohort
  

  Serum DDTs during or just after pregnancy were associated with breast cancer in mothers (F0), and with breast cancer, mammographic density, and obesity in adult daughters (F1) in the Child Health and Development Studies multi-generational cohort in prior publications. Here, we investigate F0 perinatal serum DDT associations with granddaughters'(F2) measured obesity at a median age of 26 and self-reported age at menarche. F2 weight, height and waist circumference were measured by trained examiners. o,p'-DDT, p,p'-DDT and p,p'-DDE were measured in archived F0 perinatal serum. F0 DDT associations with F2 outcomes, accounting for F1 characteristics, were estimated in log-linear models adjusted for F0 and F1 body mass index (BMI), race, and menarche timing (N = 258 triads for obesity; N = 235 triads for early menarche). Interactions between F0 BMI and DDTs were estimated. F0 o,p'-DDT was associated with F2 obesity [Odds ratio (OR), 2.6; 95% confidence interval (CI), 1.3–6.7; tertile 3 vs. 1), among normal weight F0 (70%), but not among overweight and obese F0 (Pinteraction = 0.03), independent of other DDTs. F0 o,p'-DDT was also associated with F2 early menarche (OR, 2.1; 95% CI, 1.1–3.9, tertile 3 vs. 1) and this association was not modified by F0 BMI. Ancestral exposure to environmental chemicals, banned decades ago, may influence the development of earlier menarche and obesity, which are established risk factors for breast cancer and cardiometabolic diseases. Discovery of actionable biomarkers of response to ancestral environmental exposures in young women may provide opportunities for breast cancer prevention.

  
  [Cirillo, P.M., La Merrill, M.A., Krigbaum, N.Y. and Cohn, B.A. Cancer Epidemiology and Prevention Biomarkers.]
• Exposure to organophosphorus insecticides and increased risks of health and cancer in US women
  Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, OD = 3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (OD = 2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant.
  [Sun, H., Sun, M.L. and Barr, D.B., 2020. Environmental Toxicology and Pharmacology, 80, p.103474.]
• Incidence of male breast cancer in Scotland over a twenty-five-year period (1992–2017)
  Male breast cancer (MBC) accounts for around 1% of all breast cancers diagnosed. There are inconsistent reports on the incidence of MBC which some propose may be rising. Here, for the first time, the incidence of MBC in Scotland over 25 years from 1992 to 2017 was examined through interrogating the Information Services Division Scotland database. Results showed MBC incidence rose with age, peaking in the 65–70 and 75–79 age groups. Both the total number and the age-adjusted incidence of MBC increased in Scotland since 1992. This rising trend was most clear in the North of Scotland. Interestingly a higher MBC incidence in some rural areas was also observed. Our findings emphasise the need for a better understanding of MBC risk factors so that improved prevention policies can be applied for patient benefit.
  [Reddington, R., Galer, M., Hagedorn, A., Liu, P., Barrack, S., Husain, E., Sharma, R., Speirs, V. and Masannat, Y., 2020. European Journal of Surgical Oncology.]
• US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects
  Breast cancer risk from pesticides may be missed if effects on mammary gland are not assessed in toxicology studies required for registration. Using US EPA's registration documents, we identified pesticides that cause mammary tumors or alter development, and evaluated how those findings were considered in risk assessment. Of 28 pesticides that produced mammary tumors, EPA's risk assessment acknowledges those tumors for nine and dismisses the remaining cases. For five pesticides that alter mammary gland development, the implications for lactation and cancer risk are not assessed. Many of the mammary-active pesticides activate pathways related to endocrine disruption: altering steroid synthesis in H295R cells, activating nuclear receptors, or affecting xenobiotic metabolizing enzymes. Clearer guidelines based on breast cancer biology would strengthen assessment of mammary gland effects, including sensitive histology and hormone measures. Potential cancer risks from several common pesticides should be re-evaluated, including: malathion, triclopyr, atrazine, propylene oxide, and 3-iodo-2-propynyl butylcarbamate (IPBC).
  [Cardona, B. and Rudel, R.A., 2020. Molecular and Cellular Endocrinology, p.110927.]
• DDT and Breast Cancer: Prospective Study of Induction Time and Susceptibility Windows
  In a previous Child Health and Development Studies report, p, p’-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50–54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure. We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50–54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31–49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1–3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p’-DDT, o, p’-DDT, and p, p’-DDE. Odds ratios (ORs) below are given for doubling of serum p, p’-DDT. All statistical tests were two-sided. For early postmenopausal breast cancer, p, p’-DDT was associated with risk for all women (OR_{DDT 50–54} = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (OR_{DDT 50–54 for first exposure after infancy} = 2.83, 95% CI = 1.96 to 4.10 vs OR_{DDT 50–54 for first exposure during infancy} = 0.56, 95% CI = 0.26 to 1.19; P_{interaction DDT x age at first exposure} = .01). In contrast, for premenopausal breast cancer, p, p’-DDT was associated with risk among women first exposed during infancy through puberty, but not after (OR_{DDT = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03). p, p’-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause.}
  [Cohn, B.A., Cirillo, P.M. and Terry, M.B., 2019. 111(8), pp.803-810.]
• Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway
  Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression.We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved.Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay. To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways. We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer.
  
  [Caron-Beaudoin, É., Viau, R. and Sanderson, J.T., 2018. Environmental health perspectives, 126(4), p.047014.]
• Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer.
  Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues-2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and mirex-assayed by high resolution gas chromatography were abundant in breast tissue. p,p'-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p'-DDE and HCB were significantly correlated (P < .001) with patient age at mastectomy, and levels of p,p'-DDE were correlated (P < .05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.
  [Ellsworth RE1, Kostyniak PJ2, Chi LH, et al. 2018. Environ Toxicol. doi: 10.1002/tox.22573.]
• Comparison of Weibull and Lognormal Cure Models with Cox in the Survival Analysis Of Breast Cancer Patients in Rafsanjan.
  The current study retrospective cohort study was conducted on 140 patients referred to Ali Ibn Abitaleb Hospital, Rafsanjan southeastern Iran from 2001 to 2015 suffering from breast cancer. According to AIC, log-normal model was more consistent than Weibull. In the multivariable Lognormal model, the effective factors like smoking, second -hand smoking, drinking herbal tea and the last breast-feeding period were included. In addition, using Cox regression factors of significant were the disease grade, size of tumor and its metastasis (p-value<0.05). As Rafsanjan is surrounded by pistachio orchards and pesticides applied by farmers, people of this city are exposed to agricultural pesticides and its harmful consequences. The effect of the pesticide on breast cancer was studied and the results showed that the effect of pesticides on breast cancer was not in agreement with the models used in this study. Based on different methods for survival analysis, researchers can decide how they can reach a better conclusion. This comparison indicates the result of semi-parametric Cox method is closer to clinical experiences evidences.
  [Hoseini M, Bahrampour A, Mirzaee M. 2017. J Res Health Sci. 17(1):E1-6.]
• Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents.
  The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. Authors evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (≥10,000 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα predicts a weak and unstable interaction (-4.10 kcal mol-1) compared to estradiol (-25.79 kcal mol-1), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Study reveals that glyphosate, but not other components present in GBHs, can activate ERα in vitro, albeit at relatively high concentrations.
  [Mesnage R, Phedonos A, Biserni M, et al. 2017. Food Chem Toxicol. 108(Pt A):30-42.]
• Levels of persistent organic pollutants in breast milk of Maya women in Yucatan, Mexico.
  In this study, 24 breast milk samples, obtained from rural Maya women, from municipalities of Yucatan, Mexico, were analyzed for organochlorine pesticide (OCP) residues by gas chromatography. Recent studies have shown that Maya communities have a poor perception about the proper usage and handling of OCP. The karstic soil in this area has a high vulnerability to groundwater pollution by the use of OCP in agriculture and livestock activities. The impact of the ecosystem on human health is much more critical due to the prevailing poverty and a very low educational level of these communities. About 30% of the Maya population consumes water directly from contaminated wells and sinkholes, resulting in a chronic exposure to OCP. The samples served to identify and quantify high levels of OCP residues (18.43 mg/kg of heptachlor epoxide and 1.92 mg/kg of endrin in the metropolitan zone; 2.10 mg/kg of dieldrin, 0.117 mg/kg of endosulfan II, 0.103 mg/kg of heptachlor, 0.178 mg/kg of endrin, and 0.127 mg/kg of endrin aldehyde in the main agricultural zone and on the west coast). The detected levels of OCP residues are a major concern and represent a potential risk to women and children in the region. This could be associated with the high rates of cervical uterine and breast cancer mortality in Yucatan. Thus, regulations on the usage of OCP and their enforcement are necessary, and it is important to establish a yearly monitoring program for OCP residues in breast milk and groundwater, as well as to implement health promotion programs for women in particular and the general population in general.
  [Polanco Rodríguez ÁG, Inmaculada Riba López M, Angel DelValls Casillas T, et al. 2017. Environ Monit Assess. 189(2):59]
• Occupational exposures and genetic susceptibility to urinary tract cancers: a systematic review and meta-analysis.
  This study aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and urinary tract cancers. Authors searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. A meta-analysis was performed to provide summary estimates for the association between a certain genetic polymorphism, occupational exposure and bladder cancer (BC) or kidney cancer (KC), when appropriate. Fifteen studies on BC and six on KC were deemed eligible for the review. With regard to BC, an overall odds ratio (OR) of 2.07 [95% confidence interval (CI): 1.38-3.09] for those with GSTM1 and an OR of 2.07 (95% CI: 1.38-3.09) for those with GSTT1 null genotype were reported when exposed to polycyclic aromatic hydrocarbons (PAHs). NAT2 slow genotype carriers had an OR of 3.59 (95% CI: 2.62-4.93) for BC when exposed to aromatic amines and an OR of 2.07 (95% CI: 1.36-3.15) when exposed to PAHs. With regard to KC and pesticide exposure, the meta-analysis reported an OR of 4.38 (95% CI: 2.28-8.41) for GSTM1 present genotype, an OR of 2.59 (95% CI: 1.62-4.15) for GSTT1-present genotype and an OR of 6.51 (95% CI: 2.85-14.89) for combined effects of GSTM1 and GSTT1 active genotypes. This meta-analysis indicates a possible association between the variant genotypes of GSTM1, GSTT1, NAT2 and SULT1A1, occupational exposure to aromatic amines or PAHs, and development of BC. Our results suggest that polymorphisms in GSTM1 and GSTT1 genes could influence the risk for developing KC in individuals occupationally exposed to pesticides.
  [Stojanovic J, Milovanovic S, Pastorino R, et al. 2017. Eur J Cancer Prev. doi: 10.1097/CEJ.0000000000000364]
• Organochlorine pesticides accumulation and breast cancer: A hospital-based case-control study.
  The aim of this study is to detect the accumulation status of organochlorine pesticides in breast cancer patients and to explore the relationship between organochlorine pesticides contamination and breast cancer development. A hospital-based case-control study in 56 patients with breast cancer and 46 patients with benign breast disease was conducted. The accumulation level of several organochlorine pesticides products (β-hexachlorocyclohexane, γ-hexachlorocyclohexane, polychlorinated biphenyls-28, polychlorinated biphenyls-52, pentachlorothioanisole, and pp'-dichlorodiphenyldichloroethane) in breast adipose tissues of all 102 patients was detected. Thereafter, authors examined the expression status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER2), and Ki-67 in 56 breast cancer cases by immunohistochemistry. In addition, they analyzed the risk of breast cancer in those patients with organochlorine pesticides contamination using a logistic regression model. Data showed that breast cancer patients suffered high accumulation levels of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52. However, the concentrations of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52 were not related to clinicopathologic parameters of breast cancer. Further logistic regression analysis showed polychlorinated biphenyls-52 and pp'-dichlorodiphenyldichloroethane were risk factors for breast cancer. Results provide new evidence on etiology of breast cancer.
  [He TT, Zuo AJ, Wang JG, Zhao P. 2017. Tumour Biol. 39(5):1010428317699114]
• Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer
  Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
  [Di Donato M, Cernera G, Giovannelli P, et al. 2017. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ]
• Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study.
  The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of Persistent Organic Pollutants (POPs) and breast cancer with focus on the highly exposed Greenlandic Inuit population.The study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000-2003 and 2011-2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs).The study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 - 2003 to 2011-2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference. For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) were associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk. Significant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.
  [Wielsøe M, Kern P, Bonefeld-Jørgensen EC. 2017. Environ Health. 16(1):56. ]
• Childhood and Adolescent Pesticide Exposure and Breast Cancer Risk.
  To date, epidemiologic studies have not strongly supported an association between pesticide exposure and breast cancer. However, few previous studies had the ability to assess specific time periods of exposure. Studies that relied on adult serum levels of metabolites of organochlorine pesticides may not accurately reflect exposure during developmental periods. Furthermore, exposure assessment often occurred after diagnosis and key tumor characteristics, such as hormone receptor status, have rarely been available to evaluate tumor subtype-specific associations. We examined the association between pesticide exposure during childhood and adolescence and breast cancer risk in the prospective Sister Study cohort (N = 50,884 women) to assess this relation by tumor subtype. During an average 5-year follow-up, 2,134 incident invasive and in situ breast cancer diagnoses were identified. Residential and farm exposure to pesticides were self-reported at study enrollment during standardized interviews. Multivariable hazard ratios and 95% confidence intervals for breast cancer risk were calculated with Cox proportional hazards regression. HRs were near null for the association between childhood/adolescent pesticide exposure and breast cancer risk overall or among ER+/PR+ invasive tumors. However, among women who were ages 0-18 before the ban of dichlordiphenyltrichloroethane in the US, exposure to fogger trucks or planes was associated with a hazard ratio = 1.3 for premenopausal breast cancer (95% confidence interval: 0.92, 1.7). These findings do not support an overall association between childhood and adolescent pesticide exposure and breast cancer risk. However, modest increases in breast cancer risk were associated with acute events in a subgroup of young women.
  [Niehoff NM, Nichols HB, White AJ, 2016. Epidemiology. 27(3):326-33. ]
• Correlation between toxic organochlorine pesticides and breast cancer.
  Organochlorines (OCs) are common environmental pollutants that have been linked to cancer. This work aims to assess the role of OCs as a risk factor for breast cancer and to evaluate the cellular changes induced by exposure to such environmental contaminants. The study included 70 cancer patients subjected to thorough history taking and routine investigations. Samples from tumor and normal adjacent tissue were taken to measure OCs' levels and to perform molecular analysis (some oncogenic and apoptotic markers) by flow cytometry. There were significantly higher concentrations of methoxychlor, dichloro-diphenyl-trichloroethane (DDT), hexa-chlorobenzene (HCB), and chlordane in tumor tissue samples compared to the surrounding normal tissue. There was a positive statistically significant correlation between G2m and dichloro-diphenyl-dichloroethane, DDT, and methoxychlor. There was also a negative correlation between propidium iodide (PI) and heptachlor as well as between PI, B-cell lymphoma 2, and methoxychlor. Annexin showed a negative correlation with HCB and methoxychlor. In conclusion, the higher level of organochlorine pesticides in the tissue specimens of breast cancer and the resultant molecular dysfunction highlight a possible association. Further research is warranted to elucidate the other possible mechanisms involved in the process of carcinogenesis.
  [Eldakroory SA, Morsi DE, Abdel-Rahman RH, et al. 2016. Hum Exp Toxicol.:960327116685887]
• Differences in GPR30 Regulation by Chlorotriazine Herbicides in Human Breast Cells
  Over 200,000 cases of invasive breast cancer are diagnosed annually; herbicide contaminants in local water sources may contribute to the growth of these cancers. GPR30, a G protein coupled receptor, was identified as a potential orphan receptor that may interact with triazine herbicides such as atrazine, one of the most commonly utilized chlorotriazines in agricultural practices in the United States. Our goal was to identify whether chlorotriazines affected the expression of GPR30. Two breast cancer cell lines, MDA-MB-231 and MCF-7, as well as one normal breast cell line, MCF-10A, were treated with a 100-fold range of atrazine, cyanazine, or simazine, with levels flanking the EPA safe level for each compound. Using real-time PCR, we assessed changes in GPR30 mRNA compared to a GAPDH control. Our results indicate that GPR30 expression increased in breast cancer cells at levels lower than the US EPA drinking water contamination limit. During this treatment, the viability of cells was unaltered. In contrast, treatment with chlorotriazines reduced the expression of GPR30 in noncancerous MCF-10A cells. Thus, our results indicate that cell milieu and potential to metastasize may play a role in the extent of GPR30 response to pesticide exposure.
  [Florian CP, Mansfield SR, Schroeder JR. Biochem Res Int. 2016:2984081]
• Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer.
  Organochlorine pesticides (OCs) have been associated with breast cancer development and progression, but the mechanisms underlying this phenomenon are not well known. In this work, we evaluated the effects exerted on normal human mammary epithelial cells (HMEC) by the OC mixtures most frequently detected in healthy women (H-mixture) and in women diagnosed with breast cancer (BC-mixture), as identified in a previous case-control study developed in Spain. Cytotoxicity and gene expression profile of human kinases (n=68) and non-kinases (n=26) were tested at concentrations similar to those described in the serum of those cases and controls. Although both mixtures caused a down-regulation of genes involved in the ATP binding process, our results clearly indicate that both mixtures may exert a very different effect on the gene expression profile of HMEC. Thus, while BC-mixture up-regulated the expression of oncogenes associated to breast cancer (GFRA1 and BHLHB8), the H-mixture down-regulated the expression of tumor suppressor genes (EPHA4 and EPHB2). Our results indicate that the composition of the OC mixture could play a role in the initiation processes of breast cancer. In addition, the present results suggest that subtle changes in the composition and levels of pollutants involved in environmentally relevant mixtures might induce very different biological effects, which explain, at least partially, why some mixtures seem to be more carcinogenic than others. Nonetheless, our findings confirm that environmentally relevant pollutants may modulate the expression of genes closely related to carcinogenic processes in the breast, reinforcing the role exerted by environment in the regulation of genes involved in breast carcinogenesis.
  [Rivero J, Henríquez-Hernández LA, Luzardo OP, et al. Toxicol Lett. 246:42-8. ]
• Epidemiological trends of hormone-related cancers in Slovenia.
  The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
  [Zadnik V, Krajc M. 2016. Arh Hig Rada Toksikol. 67(2):83-92. ]
• Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review
  Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes.
  [Giulivo M, Lopez de Alda M, Capri E, Barceló D. 2016. Environ Res. 151:251-264.]
• Occupational exposure and risk of breast cancer
  Breast cancer is a multifactorial disease and the most commonly diagnosed cancer in women. Traditional risk factors for breast cancer include reproductive status, genetic mutations, family history and lifestyle. However, increasing evidence has identified an association between breast cancer and occupational factors, including environmental stimuli. Epidemiological and experimental studies demonstrated that ionizing and non-ionizing radiation exposure, night-shift work, pesticides, polycyclic aromatic hydrocarbons and metals are defined environmental factors for breast cancer, particularly at young ages. However, the mechanisms by which occupational factors can promote breast cancer initiation and progression remains to be elucidated. Furthermore, the evaluation of occupational factors for breast cancer, particularly in the workplace, also remains to be explained. The present review summarizes the occupational risk factors and the associated mechanisms involved in breast cancer development, in order to highlight new environmental exposures that could be correlated to breast cancer and to provide new insights for breast cancer prevention in the occupational settings. Furthermore, this review suggests that there is a requirement to include, through multidisciplinary approaches, different occupational exposure risks among those associated with breast cancer development. Finally, the design of new epigenetic biomarkers may be useful to identify the workers that are more susceptible to develop breast cancer.
  [Fenga C. Biomed Rep. 4(3):282-292.]
• Chlorpyrifos inhibits cell proliferation through ERK1/2 phosphorylation in breast cancer cell lines.
  It has been reported that oxidative stress may be induced by pesticides and it could be the cause of health alteration mediated by pollutants exposure. The present investigation was designed to identify the pathway involved in chlorpyrifos (CPF)-inhibited cell proliferation in MCF-7 and MDA-MB-231 breast cancer cell lines. In addition, authors determined if CPF-induced oxidative stress is related to alterations in antioxidant defense system. The molecular mechanisms underlying in the cell proliferation inhibition produced by the pesticide were also looked at. Study demonstrates that CPF (50 μM) induces redox imbalance altering the antioxidant defense system in breast cancer cells. The main mechanism involved in the inhibition of cell proliferation induced by CPF is an increment of p-ERK1/2 levels mediated by H2O2 in breast cancer cells. Study concluded that ERK1/2 phosphorylation is subsequent to ROS production induced by CPF but not the inverse.
  [Ventura C, Venturino A, Miret N, et al. 2015. Chemosphere. 120:343-50.]
• DDT Exposure in Utero and Breast Cancer
  Context: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation.

  Hypothesis: In utero exposure to DDT is associated with an increased risk of breast cancer.

  Design: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year).

  Setting and participants: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study.

  Main outcome measure: Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured.

  Results: Maternal o,p'-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings.

  Conclusions: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.
  [Cohn, B. et al. (2015) DDT exposure in utero and breast cancer, The Journal of Clinical Endocrinology and Metabolism. Available at: https://pubmed.ncbi.nlm.nih.gov/26079774/. ]

• Effects of environmental organochlorine pesticides on human breast cancer: putative involvement on invasive cell ability
  POPs are known to be particularly toxic and have been associated with endocrine-disrupting effects in several mammals, including humans even at very low doses. As environmental estrogens, they could play a critical role in carcinogenesis, such as in breast cancer. With the purpose of evaluating their effect on breast cancer biology, o,p'-DDT, p,p'-DDE, and p,p'-DDD (50-1000 nM) were tested on two human breast adenocarcinoma cell lines: MCF-7 expressing estrogen receptor (ER) α and MDA-MB-231 negative for ERα, regarding cell proliferation and viability in addition to their invasive potential. Cell proliferation and viability were not equally affected by these compounds. In MCF-7 cells, the compounds were able to decrease cell proliferation and viability. On the other hand, no evident response was observed in treated MDA-MB-231 cells. Concerning the invasive potential, the less invasive cell line, MCF-7, had its invasion potential significantly induced, while the more invasive cell line MDA-MB-231, had its invasion potential dramatically reduced in the presence of the tested compounds. Altogether, the results showed that these compounds were able to modulate several cancer-related processes, namely in breast cancer cell lines, and underline the relevance of POP exposure to the risk of cancer development and progression, unraveling distinct pathways of action of these compounds on tumor cell biology.
  [Pestana D, Teixeira D, Faria A, Domingues V, et al. 2015. Environ Toxicol. 30(2):168-76.]
• In vitro evaluation of oestrogenic/androgenic activity of the serum organochlorine pesticide mixtures previously described in a breast cancer case-control study.
  Some organochlorine pesticides (OCs) have been individually linked to breast cancer (BC) because they exert oestrogenic effects on mammary cells. In this work authors evaluated the in vitro effects exerted on human BC cells by the OC mixtures that were most frequently detected in two groups of women who participated in a BC case-control study developed in Spain: healthy women and women diagnosed with BC. The cytotoxicity, oestrogenicity, and androgenicity of the most prevalent OC mixtures found in healthy women (H-mixture) and in BC patients (BC-mixture) were tested at concentrations that resembled those found in the serum of the evaluated women. Our results showed that both OC mixtures presented a similar oestrogenic activity and effect on cell viability, but BC-mixture showed an additional anti-androgenic effect. These results indicate that although the proliferative effect exerted by these mixtures on human breast cells seems to depend mainly on their oestrogenic action, the BC-mixture might additionally induce cell proliferation due to its anti-androgenic activity, therefore increasing the carcinogenic potential of this mixture. The findings of this study demonstrate that subtle variations in the composition of a mixture may induce relevant changes in its biological action.
  [Rivero J, Luzardo OP, Henríquez-Hernández LA, Machín RP, et al. 2015. Sci Total Environ. 537:197-202]
• Organochlorine insecticides DDT and chlordane in relation to survival following breast cancer.
  Study examined associations between organochlorine insecticides p,p'-DDT , its primary metabolite, p,p'-DDE, and chlordane assessed shortly after diagnosis and survival among women with breast cancer. A population-based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow-up of 5 and 15 years, authors identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer-related. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all-cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer-specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all-cause and breast cancer-specific mortality. Third tertile DDE concentrations were inversely associated with 15-year all-cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population-based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.
  [Parada H Jr, Wolff MS, Engel LS, White AJ, et al. 2015. Int J Cancer. doi: 10.1002/ijc.29806]
• Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study
  Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. This study evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. Among 30 003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43).Authors observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation.
  [Lerro CC, Koutros S, Andreotti G, Friesen MC, et al. 2015. Occup Environ Med. 72(10):736-44]
• Risk of female breast cancer and serum concentrations of organochlorine pesticides and polychlorinated biphenyls: a case-control study in Tunisia
  The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of breast cancer in a female population from Tunisia. β-hexachlorocyclohexane (β-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only β-HCH and p,p'-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose-response relationship that was significant for p,p'-DDE. A similar trend was also confirmed for β-HCH, in which concentrations≥limit of detection were positively associated with breast cancer risk (vs. concentrations<limit of detection, OR=3.44, p<0.05). Finally, the relative influence of each chemical in the presence of the others was assessed by entering the three chemicals in a single model with all covariates, and only β-HCH remained positively associated with the risk of cancer. Findings suggest a potential association between exposure to at least one organochlorine pesticide and breast cancer risk. However, our results should be interpreted with caution, and further research is warranted to confirm these findings.
  [Arrebola JP, Belhassen H, Artacho-Cordón F, Ghali R, Ghorbel H, et al. 2015. Sci Total Environ. 520:106-13]
• The organochlorine pesticides residues in the invasive ductal breast cancer patients.
  75 invasive ductal carcinoma (IDC) patients were enrolled with control of 79 benign breast diseases patients and control of 80 healthy women. Morning fasting blood specimens and adipose tissue specimens beside the primary lesion were detected with gas chromatograph. In blood specimens, both levels of β-HCH and PCTA were higher in IDC than those in both controls, and increasingly higher among the three IDC degrees. In adipose tissue specimens, all levels of β-HCH, PCTA and pp'-DDE were higher in IDC than those in control (all p<0.05) and increasingly higher among three IDC degrees. The levels of β-HCH, PCTA in both blood specimens and adipose tissue specimens were higher in estrogen receptor (ER) positive IDC than those in ER negative IDC. The higher level of organochlorine pesticides residues in blood and adipose tissue specimens of IDC infers its association with IDC, but the details remains to reveal, and this study may helpful in this field.
  [Yang JZ, Wang ZX, Ma LH, Shen XB, et al. 2015. Environ Toxicol Pharmacol. 40(3):698-703]
• Timing of Environmental Exposures as a Critical Element in Breast Cancer Risk
  Literature was reviewed and evidence gathered on the effects of the environment on risk of breast cancer or mammary tumor development in animal research models as it pertained to the influence of timing of exposure on later-life outcomes.Evidence has accumulated for several chemicals that environmental factors have a stronger effect on breast cancer risk when exposure occurred early in life. The insecticide, dichlorodiphenyltrichloroethane, is an excellent example and is just one of several chemicals for which there seems to be both animal and human evidence for the developmental basis of adult disease. The developing breast undergoes many changes in early life, leaving it vulnerable to the effects of epigenetic marks, endocrine disruption, and carcinogens. More research is needed in the area of early beginnings of breast cancer, with prevention of the disease as the ultimate goal.
  [Fenton S and Birnbaum, L. 2015. Endocrine Soc. http://dx.doi.org/10.1210/jc.2015-2848]
• Assessing the underlying breast cancer risk of Chinese females contributed by dietary intake of residual DDT from agricultural soils.
  The greatest concern over DDT exposure in China arose since the early 1990s for the rising breast cancer incidence, and the cause still remains to be elucidated. An extensive survey of DDT background in agricultural soils, covered the entire region of China, was conducted. Considering the geographical differences with diverse DDT contributions and different diet products and habits, the average daily dietary intake was modeled and estimated to be 0.34 μg/kg p,p'-DDE (the main bioactive constituent in DDT). Population attributable fraction derived from a case-control study from 78 women with breast cancer and 72 controls was used to assess the DDT exposure risk to breast cancer. Based on the estimated population attributable fraction with a median value of 0.6% (IQR 0.23-2.11%), the excess annual breast cancer incidence rate attributable to p,p'-DDE exposure averaged 0.06×10(-5) with significant spatial variations varying from 0.00021×10(-5) to 11.05×10(-5) in Chinese females. Exposure to DDT is a contributor to breast cancer, but the overall limited relative risk and population attributable fraction imply confounding factors for breast cancer in Chinese females.
  [Tang M, Zhao M, Zhou S, et al. 2014. Environ Int. 73:208-15]
• Case-control study of breast cancer and exposure to synthetic environmental chemicals among Alaska Native women.
  Exposure to environmental chemicals may impair endocrine system function. Alaska Native (AN) women may be at higher risk of exposure to these endocrine disrupting chemicals, which may contribute to breast cancer in this population. To measure the association between exposure to select environmental chemicals and breast cancer among AN women. A case-control study of 170 women (75 cases, 95 controls) recruited from the AN Medical Center from 1999 to 2002. Participants provided urine and serum samples. Serum was analyzed for 9 persistent pesticides, 34 polychlorinated biphenyl (PCB) congeners, and 8 polybrominated diethyl ether (PBDE) congeners. Urine was analyzed for 10 phthalate metabolites. We calculated geometric means (GM) and compared cases and controls using logistic regression. Serum concentrations of most pesticides and 3 indicator PCB congeners (PCB-138/158; PCB-153, PCB-180) were lower in case women than controls. BDE-47 was significantly higher in case women (GM=38.8 ng/g lipid) than controls (GM=25.1 ng/g lipid) (p=0.04). Persistent pesticides, PCBs, and most phthalate metabolites were not associated with case status in univariate logistic regression. The odds of being a case were higher for those with urinary mono-(2-ethylhexyl) phthalate (MEHP) concentrations that were above the median; this relationship was seen in both univariate (OR 2.16, 95% CI 1.16-4.05, p=0.02) and multivariable (OR 2.43, 95% CI 1.13-5.25, p=0.02) logistic regression. Women with oestrogen receptor (ER)-/progesterone receptor (PR)-tumour types tended to have higher concentrations of persistent pesticides than did ER+/PR+ women, although these differences were not statistically significant. Exposure to the parent compound of the phthalate metabolite MEHP may be associated with breast cancer. However, our study is limited by small sample size and an inability to control for the confounding effects of body mass index. The association between BDE-47 and breast cancer warrants further investigation.
  [Holmes AK, Koller KR, Kieszak SM, Sjodin A, et al. 2014. Int J Circumpolar Health. 73:25760.]
• Effect of nonpersistent pesticides on estrogen receptor, androgen receptor, and aryl hydrocarbon receptor.
  Nonpersistent pesticides are considered less harmful for the environment, but their impact as endocrine disruptors has not been fully explored. The pesticide Switch was applied to grape vines, and the maximum residue concentration of its active ingredients was quantified. The transactivation potential of the pesticides Acorit, Frupica, Steward, Reldan, Switch, Cantus, Teldor, and Scala and their active compounds (hexythiazox, mepanipyrim, indoxacarb, chlorpyrifos-methyl, cyprodinil, fludioxonil, boscalid, fenhexamid, and pyrimethanil) were tested on human estrogen receptor α (ERα), androgen receptor (AR) and arylhydrocarbon receptor (AhR) in vitro. Relative binding affinities of the pure pesticide constituents for AR and their effect on human breast cancer and prostate cancer cell lines were evaluated. Residue concentrations of Switch's ingredients were below maximum residue limits. Fludioxonil and fenhexamid were ERα agonists (EC50 -values of 3.7 and 9.0 μM, respectively) and had time-dependent effects on endogenous ERα-target gene expression (cyclin D1, progesterone receptor, and nuclear respiratory factor 1) in MCF-7 human breast cancer cells. Fludioxonil, mepanipyrim, cyprodinil, pyrimethanil, and chlorpyrifos-methyl were AhR-agonists (EC50 s of 0.42, 0.77, 1.4, 4.6, and 5.1 μM, respectively). Weak AR binding was shown for chlorpyrifos-methyl, cyprodinil, fenhexamid, and fludioxonil. Assuming a total uptake which does not take metabolism and clearance rates into account, in vitro evidence suggests that pesticides could activate pathways affecting hormonal balance, even within permitted limits, thus potentially acting as endocrine disruptors.
  [Medjakovic S, Zoechling A, Gerster P, et al. 2014. Environ Toxicol. 29(10):1201-16]
• Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors.
  Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor
  [Albini A, Rosano C, Angelini G, Amaro A, et al.2014. Curr Med Chem. 21(9):1129-45.]
• Household and occupational exposure to pesticides and risk of breast cancer.
  The association between breast cancer in women and the use of household or occupational pesticides was examined in a population-based case-control study. This study was conducted in Western Australia in 2009-2011 and included 1,789 controls and 1,205 cases. Information on household pesticide exposure was collected from questionnaires. For occupational pesticide exposure, job-specific modules (JSMs) were used. Women's exposures to pesticides in households and workplaces were not related to increased risk of breast cancer. The prevalence of occupational exposure to pesticides among women in our study was low. In the stratified analyses, the odd ratios associated with household pesticide use were similar among participants who believed pesticides increased breast cancer risk and those who did not. The results of our study did not show associations between breast cancer and household or occupational exposure to pesticides.
  [El-Zaemey S, Heyworth J, Glass DC, 2014. Int J Environ Health Res. 24(2):91-102]
• Progression of Breast Cancer Cells Was Enhanced by Endocrine-Disrupting Chemicals, Triclosan and Octylphenol, via an Estrogen Receptor-Dependent Signaling Pathway in Cellular and Mouse Xenograft Models
  In the present study, we determined whether two endocrine-disrupting chemicals (EDCs), triclosan (TCS) and octylphenol (OP), are able to alter the expression of two cell cycle regulators, cyclin D1 and p21, in both in vitro and mouse breast cancer models. In addition, we determined whether the stimulatory effects of OP or TCS on breast cancer progression may be associated with an estrogen receptor (ER)-mediated signaling pathway. Altered expressions of cyclin D1 and p21 were observed in MCF-7 human breast cancer cells treated with TCS and OP, which is linked to the G1/S transition of cell cycle, leading to cell proliferation. In a xenograft mouse model, breast tumor masses were established following exposure to TCS and OP for 8 weeks. In these animals, the tumor cells with BrdU-positive nuclei were increased by treatment with 17β-estradiol (E2), OP, and TCS compared to that of a control (corn oil), suggesting that TCS and OP increase DNA synthesis during the S phase in tumor cells. Increased level of cyclin D1 protein by TCS and OP was also observed in vivo, implying that the effects of these EDCs possessing estrogenic activity alter the expression of genes related to cancer progression. It was of interest that the effects of TCS and OP were reversed by ICI 182,780, an ER antagonist, indicating that EDC-induced activities are mediated by an ER-dependent signaling pathway. Taken together, these results suggest that TCS and OP may promote breast cancer progression, via an ER-mediated signaling cascade.
  [Lee, HR et al. 2014. Chemical Research in Toxicology doi: 10.1021/tx5000156. ]
• DDT/DDE and breast cancer: a meta-analysis.
  The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. Summary Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE. Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls. No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.
  [Ingber SZ, Buser MC, Pohl HR, et al. 2013. Regul Toxicol Pharmacol. 67(3):421-33]
• Glyphosate induces human breast cancer cells growth via estrogen receptors.
  This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
  [Thongprakaisang S, Thiantanawat A, Rangkadilok N, et al. 2013. Food Chem Toxicol.59:129-36]
• Noticing pesticide spray drift from agricultural pesticide application areas and breast cancer: a case-control study.
  Study examined the relationship between self-reported noticing of pesticide spray drift from agricultural areas and breast cancer. A case-control study of breast cancer was conducted in Western Australia from 2009 to 2011. Awareness of pesticide spray drift from agricultural areas was assessed by a self-report of whether the participant had noticed spray drift. This analysis included 1,743 controls and 1,169 cases. Among women who reported 'ever noticed' pesticide spray drift from agricultural areas, an increased risk of breast cancer was also observed. A dose response relationship between lifetime exposure to noticing pesticide spray drift and risk of breast cancer was observed. An increased risk of breast cancer was observed among women who noticed pesticide spray drift: initially at the age of 20 or younger; at least 20 years before diagnosis; and for 10 years or more. These findings support the hypothesis that women who ever noticed spray drift or who first noticed spray drift at a younger age had increased risk of breast cancer.
  [El-Zaemey S, Heyworth J, Fritschi L. 2013. Aust N Z J Public Health.37(6):547-55.]
• Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain)
  This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk.The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024).This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk.
  [Boada LD, Zumbado M, Henríquez-Hernández LA, et al. 2012. Environ Health. 11:28]
• In vitro effects of herbicides and insecticides on human breast cells.
  Authors examined the cytotoxicity of more environmentally relevant concentrations of four herbicides, acetochlor, atrazine, cyanazine, and simazine, and two insecticides, chlorpyrifos and resmethrin, in three human breast cell lines. Interestingly, cytotoxicity was not observed in the estrogen-dependent MCF-7 mammary epithelial carcinoma cells; rather increases in cell viability were seen for some of the compounds at select concentrations. These results vary greatly from what was observed in the estrogen independent MDA-MB-231 breast cancer cells and the non-cancerous MCF-10A breast cells. This gives insight into how different tumors may respond to pesticide exposure and allows us to make more accurate conclusions about the potential cytotoxicity or, at times, stimulatory actions of these pesticides.
  [Rich JD, Gabriel SM, Schultz-Norton JR. 2012. ISRN Toxicol. 2012:232461]
• Synergistic effect of malathion and estrogen on mammary gland carcinogenesis.
  Breast cancer is the most frequent malignancy diagnosed in women and is a classical model of hormone-dependent malignancy. Over the past 15-20 years, epidemiological studies have pointed to an increased breast cancer risk associated with prolonged exposure to female hormones. On the other hand, environmental chemicals such as malathion, an organophosphorous pesticide used to control a wide range of sucking and chewing pests of field crops, may be involved in the etiology of breast cancers. Results indicated that estrogen alone increased average number of lobules per mm2 of rat mammary glands in comparison to control and malathion alone at 30, 124, 240 and 400 days after 5-day treatments. On the other hand, malathion alone significantly increased the number of ducts in stage of proliferation at 10-240 days after 5-day treatments. Furthermore, markers for cancer detection such as mutant p53, c-myc, c-fos and CYPs proteins were overexpressed after treatments. Atropine, an anticholinergic drug, counteracted these effects when it was combined with malathion under similar conditions. The combination of malathion and estrogen synergistically increased number of lobules and ducts per mm2 of rat mammary glands after treatments and inducing mammary cancer. It can be concluded that combination of an environmental substance such as the pesticide malathion and an endogenous substance such as estrogen can enhance the deleterious effects in human mammary glands inducing cancer and atropine is able to diminish these effects.
  [Calaf GM and Echiburú-Chau C. 2012. Oncol Rep. 28(2):640-6.]
• Environmental exposure and breast cancer among young women in Rio de Janeiro, Brazil
  Increasing breast cancer rates among young women (less than 40 years old) have been reported by the population-based cancer registries in Brazil. A case series study was carried out in Rio de Janeiro aiming to obtain epidemiological information allowing the generation of hypotheses to be further evaluated in analytical studies. One hundred and ten women 20-35 years old diagnosed with breast cancer were interviewed to determine the role environment plays in patients cased upon residential location. A comprehensive questionnaire including personal information (medical and lifestyle antecedents, reproductive history, family history of cancer, chemical and radiation exposure) was employed, and the obtained data were further compared with data provided by controls (women without cancer). An unconditional logistic regression was further employed to ascertain the respective odds ratios (OR) and their 95% confidence intervals (CI). Seventy-one percent of cancer cases were sporadic breast cancer, and familial aggregation (first degree relatives) was observed in just 3.5% (5.5% including second-degree relatives). Forty (51.3%) of the cancer cases were reported to have resided at a distance of less than 20 m from an electrical power transformer. Bivariate analysis revealed OR = 5.62 (95% CI 2.63-12) for residential use of pesticides during adulthood, OR = 2.15 (95% CI 1.22-3.77) for dental diagnostic x-rays, and OR= 1.53 (95% 0.77-3.04) for living nearby an electrical power transformer. Further multivariate analysis showed an adjusted OR = 3.5 (95% CI 1.11-11.0) for residential use of pesticides, and an adjusted OR = 2 (95% CI 1.24-3.23) for dental diagnostic x-rays during adulthood. The observed results highlight the importance of exploring the contribution of selected environmental agents possibly involved in breast carcinogenesis among young women.
  [Ortega Jacome, G.P., et al. 2010. J Toxicol Environ Health A. 73(13-14):858-65.]
• Environmental Oestrogens and Breast Cancer: Evidence for Combined Involvement of Dietary, Household and Cosmetic Xenoestrogens
  Many environmental compounds with oestrogenic activity are measurable in the human breast and oestrogen is a known factor in breast cancer development. Exposure to environmental oestrogens occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable oestrogenic responses. Results presented here and elsewhere demonstrate that in combination, chemicals can give oestrogenic responses at lower concentrations, which suggests that in the breast, low doses of many compounds could sum to give a significant oestrogenic stimulus. Updated incidence figures show a continued disproportionate incidence of breast cancer in Britain in the upper outer quadrant of the breast which is also the region to which multiple cosmetic chemicals are applied. If exposure to complex mixtures of oestrogenic chemicals in consumer products is a factor in breast cancer development, then a strategy for breast cancer prevention could become possible.
  [Darbre, P and Charles, A. 2010. Anticancer Research. 30(3): 815-827]
• Pesticides and breast cancer risk: a comparison between developed and developing countries
  Literature review links DDT to breat cancer in the developing world. According to the authors, there is a dearth of studies in developing countries, which cannot be made up for generalizing the results from developed countries to the developing and third world.
  [Shakeel MK, George PS, Jose J, Jose J, Mathew A. 2010. Asian Pac J Cancer Prev. 2010;11(1):173-80.]
• Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats
  Atrazine (ATR), a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw)/day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND)4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing.
  [Enoch R.R., et al. 2007. Environmental Health Perspectives, 115(4).]
• Reported residential pesticide use and breast cancer risk on Long Island, New York
  A population based, case control study of Long Island, New York breast cancer cases finds an increased risk associated with: (a) lifetime residential pesticide use (OR 1.39); (b) application of lawn insecticides themselves (OR 1.56) and is higher if it is in liquid form (OR 1.77) or a combination of product type for outdoor plants (OR 1.83); (c) professional application of pesticides in a vegetable and fruit garden more than doubled (OR 2.29); and, (d) application of pesticides for insects or diseases on outdoor plants by self (OR 1.58) or by professional (OR 1.79).
  [Teitelbaum, S.L., et al. 2007. American Journal of Epidemiology 165(6):643-651.]
• Breast cancer risk in Hispanic agricultural workers in California
  In a registry-based case-control study of breast cancer in farm labor union members in California, 128 breast cancer (BC) cases newly diagnosed in 1988--2001 and 640 cancer-free controls were investigated. Stage and grade of disease at diagnosis were about the same as in the California Hispanic population. Risk of breast cancer was not associated with work with any specific crops or commodities except mushrooms, where the adjusted odds ratio (OR) was 6.00 (95% CI 2.01-18.0). Controlling for covariates, adjusted ORs (and 95% CIs) for breast cancer in quartiles of pesticide use were 1.00, 1.30 (0.73-2.30), 1.23 (0.67-2.27), and 1.41 (0.66-3.02). Chlordane, malathion, and 2,4-D were associated with increased risk. Risk associated with chemical use was stronger in younger women, those with early-onset breast cancer, and those diagnosed earlier (1988--1994).
  [Mills, P.K. and Yang, R., 2005. Breast cancer risk in Hispanic agricultural workers in California. International journal of occupational and environmental health, 11(2), pp.123-131.]
• Pesticide Use and Breast Cancer Risk among Farmers’ Wives in the Agricultural Health Study
  The authors examined the association between pesticide use and breast cancer incidence among farmers’ wives in a large prospective cohort study in Iowa and North Carolina. Participants were 30,454 women with no history of breast cancer prior to cohort enrollment in 1993–1997. Through 2000, 309 incident breast cancer cases were identified via population-based cancer registries. Rate ratios were calculated for individual pesticides using Poisson regression, controlling for confounding factors. Breast cancer standardized incidence ratios were 0.87 (95% confidence interval: 0.74, 1.02) for women who reported ever applying pesticides and 1.05 (95% confidence interval: 0.89, 1.24) for women who reported never applying pesticides. There was some evidence of increased risk associated with use of 2,4,5-trichloro-phenoxypropionic acid (2,4,5-TP) and possibly use of dieldrin, captan, and 2,4,5-trichlorophenoxyacetic acid (2,4,5-TP), but small numbers of cases among those who had personally used the pesticides precluded firm conclusions. The authors found no clear association of breast cancer risk with farm size or washing of clothes worn during pesticide application, but risk was modestly elevated among women whose homes were closest to areas of pesticide application. Further follow-up of this cohort should help clarify the relation between pesticide exposure and breast cancer risk.
  [Engel, L, Hill, D, Hoppin, J, et al. 2005. Am. J. Epidemiol. 161 (2): 121-135.]
• Breast cancer and serum organochlorine residues.
  The aim of this study was to compare the blood levels of total dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB) in samples collected at the time of breast cancer discovery, in order to avoid the potential consequences of body weight change (after chemotherapy or radiotherapy) on the pesticide residue levels. Blood levels of HCB and total DDT were compared in 159 women with breast cancer and 250 presumably healthy controls. Risk of breast cancer associated with organochlorine concentration was evaluated. Mean levels of total DDT and HCB were significantly higher for breast cancer patients than for controls. No differences in serum levels of total DDT or HCB were found between oestrogen receptor positive and oestrogen receptor negative patients with breast cancer. These results add to the growing evidence that certain persistent pollutants may occur in higher concentrations in blood samples from breast cancer patients than controls.
  [Charlier C, Albert A, Herman P, et al.2003. Occup Environ Med. 60(5):348-51.]
• Occupational histories of cancer patients in a Canadian cancer treatment center and the generated hypothesis regarding breast cancer and farming
  Occupational exposures increase cancer risks. The Windsor Regional Cancer Centre in Windsor, Ontario, was the first Canadian cancer treatment center to collect the work histories of its patients, which were recorded using a computer-based questionnaire. Breast cancer cases represented the largest respondent group. The lifetime occupational histories of 299 women with newly diagnosed breast cancers were compared with those of 237 women with other cancers. Odds ratios (ORs) were calculated using logistic regression, adjusting for age, social class, and education. The OR for women < or = 55 years of age with breast cancer who had ever farmed, compared with women of the same age with other cancers, was 9.05 (95% CI 1.06, 77.43). Patients' occupational histories can help to inform understanding of cancer etiology and prevention. This effort points to a need for investigation of the possible association between breast cancer and agricultural hazards such as pesticides.
  [Brophy, J.T., Keith, M.M., Gorey, K.M., Laukkanen, E., Hellyer, D., Watterson, A., Reinhartz, A. and Gilberston, M., 2002. International journal of occupational and environmental health, 8(4), pp.346-353.]
• Mammographic findings and occupational exposure to pesticides currently in use on Crete
  Women occupationally exposed to pesticides in Crete greenhouses have higher risks of incidence for number of breast tissue legions, which are risk markers for subsequent invasive breast cancer.
  [Dolapsakis, G., et al. 2001. Eur J Cancer 37(12):1531-1536.]
• A population-based case-control study of farming and breast cancer in North Carolina
  A population based, case control study of North Carolina female farmers finds that while farmers in general tend to have lower breast cancer risk, for those women who reported being present in fields during or shortly after a pesticide application (OR 1.8) and for those who reported not using protective clothing while applying pesticides (OR 2.0) are at increased risk for breast cancer.
  [Duell, E.J., et al. 2000. Epidemiology 11(5):523-531.]
• Identification of occupational cancer risks in British Columbia
  Lifetime occupational histories as well as information on known and suspected breast cancer risk factors were collected by means of a self-administered questionnaire from 1018 women with incident breast cancer ascertained from the British Columbia Cancer Registry, and from 1020 population controls. A matched case-control study design was used. Conditional logistic regression for matched sets data and the likelihood ratio were used in a two-step procedure and were performed separately for pre-menopausal women, post-menopausal women, and for all cases combined. Excess risk was noted for several white-collar occupations. Significantly increased risk was observed: (1) among pre-menopausal women: in electronic data-processing operators; barbers and hairdressers; in sales and material processing occupations; and in the food, clothing, chemical and transportation industries; (2) among post-menopausal women: in schoolteaching; in medicine, health, and nursing occupations; in laundry and dry-cleaning occupations; and in the aircraft and automotive, including gasoline service station, industries. Several significant associations were also seen in the combined group of pre- and post-menopausal women, particularly in crop farmers and in the fruit and vegetable, publishing and printing, and motor vehicle repair industries. The results of this study suggest excess breast cancer risk in a number of occupations and industries, notably those that entail exposure to solvents and pesticides.
  [Band, P.R., et al. 2000. J Occup Environ Med 42(3):284-310.]