Environment and Breast Cancer: Science Review

Evidence From Humans
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Dioxin exposure and cancer risk in the Seveso Women's Health Study
Warner, M., Mocarelli, P., Samuels, S., Needham, L., Brambilla, P., Eskenazi, B. Environ Health Perspect. 2011. 119:12, 1700-5.
Topic area
Environmental pollutant - Dioxin TCDD
Study design
Retrospective cohort
Funding agency
NIH EPA Endometriosis Association NIEHS Regione Lo
Study Participants
Menopausal Status
The menopausal status of women included in this study is listed here.
No analyses based on menopausal status
Number in Cohort
Cohort: 981 women in study I in 1996; 833 women followed up in study II in 2008
Participant selection: Inclusion and exclusion criteria
Criteria used to select participants in the study.
In the Seveso Women's Health Study, women 0-40 years of age in 1976 who had resided in one of the most highly contaminated zones at the time of the Seveso accident, and had adequate stored sera collected soon after the explosion were asked to participate. Enrollment began in March 1996 and was completed in July 1998; a total of 981 (80%) participated in this first follow-up. For the second follow-up, enrollment began April 2008 and ended December 2009. Of the 981 women, 833 (84.9%) agreed to participate, 16 were deceased (14 from cancer), 36 could not be located or contacted.
Exposure Investigated
Exposures investigated
TCDD in serum collected between 1976 and 1985. For women with post-1977 TCCD measurements greater than 10 ppt, the TCDD exposure level was back-extrapolated to 1976 (n=70). For non-detect values (n=96), half the LOD was assigned. Serum measurements were l
Exposure assessment comment
Women were age 0-40 at exposure.
Early life exposures considered
Yes, n=232 were less than 10 years of age and n=284 were premenarcheal at the time of explosion.
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.
parity, family history of breast cancer
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
Per 10-fold increase in TCDD (ppt) exposure:
1976-2009 follow-up: aHR 1.44 (95% CI 0.89-2.33)
0-10 year follow-up: HR 2.91 (95% CI 0.90-9.44)
11-20 year follow-up: HR 2.23 (95% CI 1.09-4.56)
21-32 year follow-up: HR 1.06 (95% CI 0.58-1.93)
Results Comments
HRs by follow up period are unadjusted. Of all the SWHS cancer cases, half were breast cancer; 55% of those cases were diagnosed premenopause.
BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), a widespread environmental contaminant, disrupts multiple endocrine pathways. The International Agency for Research on Cancer classified TCDD as a known human carcinogen, based on predominantly male occupational studies of increased mortality from all cancers combined. OBJECTIVES: After a chemical explosion on 10 July 1976 in Seveso, Italy, residents experienced some of the highest levels of TCDD exposure in a human population. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort study of the reproductive health of the women. We previously reported a significant increased risk for breast cancer and a nonsignificant increased risk for all cancers combined with individual serum TCDD, but the cohort averaged only 40 years of age in 1996. Herein we report results for risk of cancer from a subsequent follow-up of the cohort in 2008. METHODS: In 1996, we enrolled 981 women who were 0-40 years of age in 1976, lived in the most contaminated areas, and had archived sera collected near the explosion. Individual TCDD concentration was measured in archived serum by high-resolution mass spectrometry. A total of 833 women participated in the 2008 follow-up study. We examined the relation of serum TCDD with cancer incidence using Cox proportional hazards models. RESULTS: In total, 66 (6.7%) women had been diagnosed with cancer. The adjusted hazard ratio (HR) associated with a 10-fold increase in serum TCDD for all cancers combined was significantly increased [adjusted HR = 1.80; 95% confidence interval (CI): 1.29, 2.52]. For breast cancer, the HR was increased, but not significantly (adjusted HR = 1.44; 95% CI: 0.89, 2.33). CONCLUSIONS: Individual serum TCDD is significantly positively related with all cancer incidence in the SWHS cohort, more than 30 years later. This all-female study adds to the epidemiologic evidence that TCDD is a multisite carcinogen.
Author address
Center for Environmental Research and Children's Health, School of Public Health, University of California at Berkeley, Berkeley, California 94720, USA. mwarner@berkeley.edu
Reviewers Comments
Authors note that increased risk during earlier years of follow up may reflect dioxin’s action as a tumor promotor. Many of these women are still young for breast cancer diagnosis, so follow up will be important.