Warner, M, B Eskenazi, P Mocarelli, PM Gerthoux, S Samuels and L Needham. 2002. Serum Dioxin Concentrations and Breast Cancer Risk in the Seveso Womens Health Study.Environmental Health Perspectives 110:625628.
Previous work in the aftermath of the 1976 Seveso, Italy, pesticide factory accident failed to establish links between dioxin exposure and breast cancer incidence. This new study of Seveso residents by Warner et al. finds that breast cancer risk increases significantly with higher dioxin exposures. The authors suggest that an earlier study, covering only the first decade after the accident, had not allowed sufficient time to pass since exposure for dioxin's impacts to be manifest.
Their findings highlight the reality that the consequences of exposure may not be manifest for decades, and that to understand the causes of breast cancer you must know about chemical exposures years before diagnosis. This study reinforces the argument that epidemiological work examining contamination levels at the time of diagnosis (for example,the Long Island Breast Cancer Study) are of limited value for establishing (or refuting) the causes of breast cancer.
What did they do?Warner et al. measured dioxin (specifically 2,3,7,8-tetrachlorodibenzo-p- dioxin, or TCDD) levels in blood samples that had been taken shortly after the accident and stored. They used data from the Seveso Womens Health Study (SWHS), "a historical cohort study of the female population residing around Seveso at the time of the explosion in 1976." "Women eligible for the SWHS were infants to 40 years old in 1976, had resided in one of the most highly contaminated zones, A or B, and had adequate stored sera collected soon after the explosion."
They used health records to identify women within the cohort who had developed breast cancer by mid-1998 and then performed a series of statistical analyses comparing dioxin levels in women with vs. those without a cancer diagnosis. Their analysis included extensive work to control for the effects of factors known to affect the risk of breast cancer, including: age at first pregnancy, age at last pregnancy, lactation, family history of breast cancer, age at menarche, smoking, and alcohol consumption, etc.
What did they find?Warner et al. identified 981 women in the SWHS cohort who met the criteria of the study. Of them, 232, 279, 241 and 229 were 0-10, 11-20, 21-30 and 31-40 years old, respectively, at the time of the explosion. Among them, 15 women had been diagnosed with breast cancer (1.5%).
The average age of women at the time of the explosion who by 2001 had been diagnosed with breast cancer was 30.1 years (ranging from 14-39 years). Their average age at the time of diagnosis was 45.2 years. The average timelag between the explosion and breast cancer diagnosis was 15.2 years (range 8-21 years).
Warner et al. found that a 10-fold increase in dioxin levels was associated with a 2.1 increase in risk for breast cancer. Despite the small number of cases, the increase was statistically significant.
Warner et al. acknowledge that the small number of breast cancer cases in their cohort limits the strength of their conclusions.
What does it mean?This paper reinforces previous other studies finding statistical links between dioxin exposure and breast cancer risk, for example, women working in contaminated chemical plants. And because of the stored blood samples and the increasing duration of the study (i.e., length of time over which the effects of exposure might be manifest), Warner et al. had significant advantages over other studies.
"An advantage of the SWHS is that we were able to examine the relationship between serum TCDD concentration and breast cancer incidence, thus eliminating potential bias associated with disease survival. In addition, we were able to collect information during the interview, allowing consideration of potential confounding by known risk factors in the analysis. Finally, we were able to measure individual serum TCDD concentrations near the time of exposure, thus minimizing exposure misclassification."
Warner et al. discuss two other studies of breast cancer in Seveso-exposed women:
Warner et al. comment that the women in the SWHS cohort are only now, on average, entering the age of maximum risk to breast cancer.
"Breast cancer incidence increases steadily with age, with the most rapid increase between ages 40 and 55 years. Moreover, the youngest women in the SWHS cohort were, in general, the most highly exposed. Of women who were 2030 years of age at interview, 68% had serum TCDD levels > 100 ppt. Many of these women may not have had sufficient time for the effects of TCDD, if any, to become clinically manifest. Thus, it will be important to continue to follow the SWHS cohort."
They also discuss animal experiments indicating the most sensitive stages to disruption of mammary gland development by dioxin occur in the womb and post-natally through to sexual maturity. As Warner et al.'s research only covered the first 18 years post-explosion, girls exposed in Seveso to dioxin before puberty have not yet reached the age of highest incidence of breast cancer. This would suggest that the SWHS study has not yet observed the effect of dioxin on those in the most vulnerable stages of development when exposure took place.
The unstated implication of these two observations is that, if the link that they observed between dioxin and breast cancer risk is not a statistical fluke, then the association should become stronger as the cohort ages, making it imperative to continue this research.
In the meantime, this result adds additional weight to the urgency for the US EPA to release itsdioxin reassessment and initiate stronger protective standards on dioxin exposure.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), a widespread environmental contaminant, has been shown to disrupt multiple endocrine pathways. The International Agency for Research on Cancer classified TCDD as a known human carcinogen, primarily based on occupational studies of increased mortality from all cancers combined. Using data from the Seveso Women's Health Study (SWHS), we examined the association between individual serum TCDD levels and breast cancer risk in women residing around Seveso, Italy, in 1976, at the time of an industrial explosion that resulted in the highest known population exposure to TCDD. The SWHS cohort comprises 981 women who were infants to 40 years old in 1976, resided in the most contaminated areas at the time of the explosion, and had archived sera that was collected soon after the explosion. For each woman, serum TCDD exposure was measured by high-resolution mass spectrometry. Cancer cases were identified during interview and confirmed by medical record. At interview, 15 women (1.5%) had been diagnosed with breast cancer and serum TCDD levels for cases ranged from 13 to 1,960 ppt. Cox proportional hazards modeling showed that the hazard ratio for breast cancer associated with a 10-fold increase in serum TCDD levels (log10 TCDD) was significantly increased to 2.1 (95% confidence interval, 1.0-4.6). Covariate-adjusted results were not different. Individual serum TCDD is significantly related with breast cancer incidence among women in the SWHS cohort. Continued follow-up of the cohort will help shed light on the possible role of TCDD in the pathogenesis of breast cancer. Key words: breast neoplasms, dioxin, epidemiology, tetrachlorodibenzo-p-dioxin. Environ Health Perspect 110:625-628 (2002). [Online 15 May 2002]
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