Authors:
Eskenazi, B., Macarelli, P., Warner, M., Samuels, S., Vercellini, P., Olive, D., Needham, LL., Paterson, D.B., Brambilla, P., Gavoni, N., Casalni, S., Panazza, S., Turner, W., Gerthoux, PM.

Title:
Serum Dioxin Concentrations and Endometriosis: A cohort study in Seveso, Italy

Journal:
Environmental Health Perspectives: 110(7); 629-634, 2002

Summary:
Chlorinated dibenzo-p-dioxins (CDDs) are a class of related chlorinated hydrocarbons that are structurally similar. CDDs are divided into groups based on the number of chlorine atoms attached at one of eight positions on the dioxin molecule. The CDD with 4 chlorine atoms at the 2, 3, 7 and 8 positions (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD) is one of the most toxic CDDs and serves as a prototype. Other CDDs with similar toxic properties to TCDD are known as 'dioxin-like'. CDDs are produced through incomplete combustion of organic material in events such as forest fires or volcanic activity. As well, they are produced unintentionally through industrial and municipal incineration and combustion processes. Experimental studies have shown that although dioxin has been shown to block the action of estrogen under certain conditions it has also been demonstrated to promote the growth and survival of endometriotic implants in mice and monkeys. Consequently, it has been proposed that dioxins may play a role in the pathobiology of endometriosis. Endometriosis is a disease of the female reproductive system that involves the growth and function of endometrial glands and stroma outside of the uterus.

In July 1976, an explosion occurred at the OCMESA chemical plant located close to Seveso, Italy. An 18 km2 area had approximately 30kg of dioxin deposited on it resulting in the highest levels of TCDD in any human residential population. The exposed area was later divided up into zones based on exposure levels. Zone A was the most heavily contaminated area and housed 736 residents who were evacuated within 2 weeks after the accident. Zone B, was the area with the next highest contamination and housed nearly 4500 residents who were warned about consuming locally grown food but were not evacuated from their residences. Zone R, was the least contaminated and housed close to 35 000 residents. A non-exposed area, known as Zone non-ABR, was composed of residents in the surrounding region (n=180 000). Blood samples had been collected as part of a health assessment of the residents.

The current study was conducted to investigate whether there was an association between TCDD exposure and endometriosis among women of reproductive age who had resided in the exposed area. Women were eligible if they were 30 years of age or younger in 1976, had adequate stored sera collected between 1976 and 1980, and resided in Zones A or B during the time of the accident. Women who had never been sexually active were excluded from the study due to cultural reasons. In total, there were 601 participants of which 19 cases of endometriosis were diagnosed. Endometriosis was confirmed by laparoscopy or laparotomy, or if she had a positive ultrasound in which a cyst or mass characteristic of endometriosis was identified. Non-diseased women (n=277) were defined by surgery without a finding of endometriosis, a negative ultrasound, exam and symptom history. A woman was considered uncertain (n=305) for the disease if she had a negative surgery and ultrasound but she had reported symptoms or signs on an exam. The earliest serum sample for each woman was sent for TCDD analysis by lipid-weight bases in parts per trillion at the U.S. Centers for Disease Control and Prevention.

The authors found that serum levels were higher in women that were less than 10 years old and living in Zone A at the time of the accident, women who were premenarcheal at the time of the accident, women who were never married, and women who had never had children. Eskenazi et al. did not find a significant difference in TCDD exposure levels between endometriosis cases and non-diseased women. A dose-response relationship was also not established.

The results of this study do not suggest that endometriosis is related to dioxin exposure. The small number of cases of endometriosis severely limits this study's power to detect an association. The authors found the prevalence of endometriosis to be only 3.2% in this population. Over 300 women were classified as "uncertain for the disease" with 273 having either signs or symptoms. The difficulties in diagnosing and confirming the presence of this disease make it likely that misclassification error occurred. However, the extensive follow-up period was an important aspect of this study as it allowed for time to pick up delayed effects.