Total Effective Xenoestrogen Burden in Serum Samples and Risk for Breast Cancer in a Population-Based Multicase–Control Study in Spain

Background: Most studies on endocrine-disrupting chemicals and breast cancer have focused on single compounds and have produced inconclusive findings. Objectives: We assessed the combined estrogenic effects of mixtures of xenoestrogens in serum and their relationship to breast cancer risk. Methods: A total of 186 incident pretreatment breast cancer cases and 196 frequency-matched controls were randomly sampled from a large population-based multicase–control study in Spain. The total effective xenoestrogen burden attributable to organohalogenated xenoestrogens (TEXB-α) and endogenous hormones and more polar xenoestrogens (TEXB-β) was determined in serum samples using high-performance liquid chromatography and E-Screen bioassay. Odds ratios for breast cancer comparing tertiles of serum TEXB-α and TEXB-β were estimated using logistic models, and smooth risk trends were obtained using spline models. Results: Cases had higher geometric mean TEXB-α and TEXB-β levels (8.32 and 9.94 Eeq pM/mL, respectively) than controls (2.99 and 5.96 Eeq pM/mL, respectively). The fully adjusted odds ratios for breast cancer (95% confidence intervals) comparing the second and third tertiles of TEXB-α with the first tertile were 1.77 (0.76, 4.10) and 3.45 (1.50, 7.97), respectively, and those for TEXB-β were 2.35 (1.10, 5.03) and 4.01 (1.88, 8.56), respectively. A steady increase in risk was evident across all detected TEXB-α levels and a sigmoidal trend was observed for TEXB-β. Individual xenoestrogens showed weak and opposing associations with breast cancer risk. Conclusions: This is the first study to show a strong positive association between serum total xenoestrogen burden and breast cancer risk, highlighting the importance of evaluating xenoestrogen mixtures, rather than single compounds, when studying hormone-related cancers. Citation: Pastor-Barriuso R, Fernández MF, Castaño-Vinyals G, Whelan D, Pérez-Gómez B, Llorca J, Villanueva CM, Guevara M, Molina-Molina JM, Artacho-Cordón F, Barriuso-Lapresa L, Tusquets I, Dierssen-Sotos T, Aragonés N, Olea N, Kogevinas M, Pollán M. 2016. Total effective xenoestrogen burden in serum samples and risk for breast cancer in a population-based multicase–control study in Spain. Environ Health Perspect 124:1575–1582; http://dx.doi.org/10.1289/EHP157

[1]  N. Olea,et al.  Development of a marker of estrogenic exposure in human serum. , 1995, Clinical chemistry.

[2]  Ruthann A Rudel,et al.  Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention , 2006, Cancer.

[3]  R. Rudel,et al.  New Exposure Biomarkers as Tools for Breast Cancer Epidemiology, Biomonitoring, and Prevention: A Systematic Approach Based on Animal Evidence , 2014, Environmental health perspectives.

[4]  C. Vidal,et al.  Use of hormone therapy and isoflavones and mammographic density in Spain , 2016, Menopause.

[5]  C Sonnenschein,et al.  The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. , 1995, Environmental health perspectives.

[6]  Åke Bergman,et al.  State of the Science of Endocrine Disrupting Chemicals - 2012 , 2012 .

[7]  T. Shioda,et al.  Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development , 2014, PloS one.

[8]  S. Hankinson,et al.  Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers , 2015, Steroids.

[9]  S. Greenland.  Quantifying Biases in Causal Models: Classical Confounding vs Collider-Stratification Bias , 2003, Epidemiology.

[10]  A. Kortenkamp,et al.  Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. , 2002, Environmental health perspectives.

[11]  Stephen W Duffy,et al.  Risk determination and prevention of breast cancer , 2014, Breast Cancer Research.

[12]  Laura N. Vandenberg,et al.  Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. , 2012, Endocrine reviews.

[13]  A. Castaño,et al.  Serum PCB levels in a representative sample of the Spanish adult population: the BIOAMBIENT.ES project. , 2014, The Science of the total environment.

[14]  C. González,et al.  Polychlorinated biphenyls in Spanish adults: determinants of serum concentrations. , 2009, Environmental research.

[15]  B. Macmahon.  Epidemiology and the causes of breast cancer , 2006, International journal of cancer.

[16]  Mariana F. Fernández,et al.  Analysis of population characteristics related to the total effective xenoestrogen burden: a biomarker of xenoestrogen exposure in breast cancer. , 2007, European journal of cancer.

[17]  D. Gibson,et al.  Endocrine disruption of oestrogen action and female reproductive tract cancers. , 2014, Endocrine-related cancer.

[18]  A. Kortenkamp,et al.  Assessment of the total effective xenoestrogen burden in extracts of human placentas , 2009, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[19]  A. Trentham-Dietz,et al.  Proportion of invasive breast cancer attributable to risk factors modifiable after menopause. , 2008, American journal of epidemiology.

[20]  A. Kortenkamp,et al.  Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles , 2012, PloS one.

[21]  William H. Bisson,et al.  The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. , 2015, Carcinogenesis.

[22]  A. Sasco,et al.  Breast Cancer Risk and the Combined Effect of Environmental Estrogens , 2004, Cancer Causes & Control.

[23]  L. Hilakivi-Clarke,et al.  Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk , 2013, Journal of Mammary Gland Biology and Neoplasia.

[24]  Ana Rivas,et al.  Assessment of total effective xenoestrogen burden in adipose tissue and identification of chemicals responsible for the combined estrogenic effect , 2004, Analytical and bioanalytical chemistry.

[25]  Vicente Martín,et al.  Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design. , 2015, Gaceta sanitaria.

[26]  S. Greenland.  Dose‐Response and Trend Analysis in Epidemiology: Alternatives to Categorical Analysis , 1995, Epidemiology.

[27]  C. González,et al.  Serum levels of organochlorine pesticides in healthy adults from five regions of Spain. , 2009, Chemosphere.

[28]  A. Kortenkamp.  Ten Years of Mixing Cocktails: A Review of Combination Effects of Endocrine-Disrupting Chemicals , 2007, Environmental health perspectives.

[29]  D. Phillips,et al.  Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding , 1989, Archives of environmental contamination and toxicology.

[30]  M. Zwahlen,et al.  Adiposity and cancer risk: new mechanistic insights from epidemiology , 2015, Nature Reviews Cancer.

[31]  C. la Vecchia,et al.  Epidemiology and pathophysiology of alcohol and breast cancer: Update 2012. , 2012, Alcohol and alcoholism.

[32]  G. Meijer.  GLOBOCAN 1: Cancer Incidence and Mortality Worldwide. , 2000 .

[33]  Mariana F. Fernández,et al.  Endocrine Disruptors: Time to Act , 2014, Current Environmental Health Reports.

[34]  J. Chang-Claude,et al.  Population attributable risk of invasive postmenopausal breast cancer and breast cancer subtypes for modifiable and non-modifiable risk factors. , 2011, Cancer epidemiology.

[35]  A. Kortenkamp,et al.  Extending the Applicability of the Dose Addition Model to the Assessment of Chemical Mixtures of Partial Agonists by Using a Novel Toxic Unit Extrapolation Method , 2014, PloS one.