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Total Effective Xenoestrogen Burden in Serum Samples and Risk for Breast Cancer in a Population-Based Multicase-Control Study in Spain
Pastor-Barriuso, R., Fernandez, M. F., Castano-Vinyals, G., Whelan, D., Perez-Gomez, B., Llorca, J., Villanueva, C. M., Guevara, M., Molina, J. M., Artacho-Cordon, F., Barriuso-Lapresa, L., Tusquets, I., Dierssen-Sotos, T., Aragones, N., Olea, N., Kogevinas, M., Pollan, M. Environ Health Perspect. 2016. .
Topic area
Environmental pollutant - PCBs Xenoestrogens OCPs
Study design
Population-based case-control
Funding agency
Acción Transversal del Cancer Carlos III Institut
Study Participants
Menopausal Status
The menopausal status of women included in this study is listed here.
No analysis based on menopausal status
Number of Controls
Controls: 196
Participant selection: Inclusion and exclusion criteria
Criteria used to select participants in the study.
Participants were recruited for the Multi Case-control Study (MCC-Spain) of breast, prostate, colorectal and stomach cancers and chronic lymphocytic leukemia between 2008 to 2013 in twelve Spanish provinces. The MCC-Spain includes 1,750 histologically confirmed incident breast cancer cases aged 20-85 years. 4,101 population controls were selected at random from administrative records of primary care centers within the catchment areas of the hospitals from which the cases were recruited. In the present study, 204 cases and 204 controls matched on province, 5-year age interval and 2-unit BMI category were randomly selected from among those who agreed to donate blood samples in the provinces of Madrid, Barcelona, Navarra, and Cantabria. Cases that had prevalent or recurrent breast cancer at baseline or initiated HRT or chemotherapy before blood extraction were excluded. Cases and controls with insufficient serum were also excluded, resulting in the numbers reported above.
Comment about participation selection
Blood samples were collected from 76% of participants in MCC-Spain. It is not stated whether those who provided blood samples differed from those who did not.
Exposure Investigated
Exposures investigated
Serum concentrations of total effective xenoestrogen burden (TEXB-α and TEXB-β), PCB-138, PCB-153, PCB-180, HCB, and p,p'-DDE. TEXB-α fraction captures organohalogenated lipophilic xenoestrogens (OCPs, PCBs, halogenated bisphenols, etc.). TEXB-β fract
Exposure assessment comment
Serum samples collected at enrollment (pre-treatment). Samples taken after breast cancer diagnosis may not capture the relevant etiological period for breast cancer development.
Breast cancer outcome investigated
Primary incident breast cancer
Confounders considered
Other breast cancer risk factors, such as family history, age at first birth, and hormone replacement therapy use, that were taken into account in the study.
Province, age, BMI, education level, smoking status, number of births, age at first birth, menopausal status, HRT use, previous breast biopsy, family history of breast cancer, serum lipid levels, mutual adjustment of TEXB-α and TEXB-β.
Genetic characterization included
If the study analyzed relationships between environmental factors and inherited genetic variations, this field will be marked Yes. No, if not.
Strength of associations reported
Serum concentration (ng/mL), compared to tertile 1:

PCB-138 tertile 2 (0.81-1.59): aOR 1.34 (95% CI 0.64-2.81)
PCB-138 tertile 3 (≥1.60): aOR 1.64 (95% CI 0.78-3.46)

PCB-153 tertile 2 (0.91-2.07): aOR 0.90 (95% CI 0.45-1.82)
PCB-153 tertile 3 (≥ 2.08): aOR 1.33 (95% CI 0.64-2.75)

PCB-180 tertile 2 (0.53-1.17): aOR 0.96 (95% CI 0.47-1.98)
PCB-180 tertile 3 (≥ 1.18): aOR 1.09 (95% CI 0.49-2.43)

HCB tertile 2 (0.44-1.25): aOR 0.63 (95% CI 0.32-1.24)
HCB tertile 3 (≥1.26): aOR 0.64 (95% CI 0.27-1.50)

p,p'-DDE tertile 2 (1.38-6.76): aOR 1.61 (95% CI 0.81-3.21)
p,p'-DDE tertile 3 (≥ 6.77): aOR 0.63 (95% CI 0.27-1.46)

Serum TEXB concentration (Eeq pM/mL), compared to tertile 1:

TEXB-α tertile 2 (2.63-8.75): aOR 1.50 (95% CI 0.55-4.08)
TEXB-α tertile 3 ≥ 8.76): aOR 1.80 (95% CI 0.63-5.09)
TEXB-α tertile 3, among premenopausal women: aOR 4.06 (95% CI 0.41-40.7)
TEXB-α tertile 3, among postmenopausal women: aOR 2.62 (95% CI 1.07-6.46)

TEXB-β tertile 2 (4.57-11.27): aOR 1.75 (95% CI 0.65-4.71)
TEXB-β tertile 3 (≥ 11.28): aOR 3.53 (95% CI 1.24-10.0)
TEXB-β tertile 3, among premenopausal women: aOR 1.92 (95% CI 0.19-19.1)
TEXB-β tertile 3, among postmenopausal women: aOR 4.53 (95% CI 2.00-10.3)
Results Comments
OR for TEXB-alpha was higher among women with BMI < 25 (OR: 6.37; 95% CI: 1.69-24.0) than among women with BMI ≥ 25 (OR: 2.44; 95% CI: 0.88-6.76). P for interaction was 0.24 The association for TEXB-α was attenuated in a model that mutually adjusted for the fraction containing endogenous hormones and polar xenoestrogens (TEXB-β) (OR, 1.80; 95% CI: 0.63–5.09), but as the authors discuss, adjusting for the TEXB-β fraction could introduce rather than reduce bias by creating a negative association between the TEXB-α fraction and endogenous hormones.
BACKGROUND: Most studies on endocrine disrupting chemicals and breast cancer have focused on single compounds with inconclusive findings. OBJECTIVES: We assessed the combined estrogenic effect of mixtures of xenoestrogens in serum and its relation 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-alpha) and endogenous hormones and more polar xenoestrogens (TEXB-beta) were determined in serum samples by using high-performance liquid chromatography separation and E-Screen bioassay. Odds ratios for breast cancer comparing tertiles of serum TEXB-alpha and TEXB-beta were estimated using logistic models, and smooth risk trends using spline models. RESULTS: Cases had higher geometric mean TEXB-alpha and TEXB-beta levels (8.32 and 9.94 Eeq pM/mL) 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-alpha with the first tertile were 1.77 (0.76, 4.10) and 3.45 (1.50, 7.97), and those for TEXB-beta were 2.35 (1.10, 5.03) and 4.01 (1.88, 8.56). A steady increase in risk was evident across all detected TEXB-alpha levels and a sigmoidal trend for TEXB-beta. Individual xenoestrogens showed weak and opposed 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, thus highlighting the importance of evaluating xenoestrogen mixtures, rather than single compounds, when studying hormone-related cancers.
Author address
National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain. Biosanitary Institute of Granada (ibs.GRANADA), University of Granada, Granada
Reviewers Comments
This study is one of the first to investigate mixtures of chemicals and breast cancer using a functional assay (E-screen) to obtain an integrated measure of activity from known and unknown estrogenic substances in blood.
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