Over the last few decades, concern has heightened over the potential hormone-like effects of environmental chemicals on the reproductive health of fish, wildlife, and humans. The compound 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, produced by various chemical reactions and combustion processes, and in animals is a potent endocrine disrupter. On July 10, 1976, a chemical explosion near Seveso, Italy exposed the residents to the highest levels of TCDD exposure in a human population. We followed up the women 20 years after the accident to determine whether they were at higher risk for reproductive disease. Women aged 0 to 40 years at the time of the explosion, and who lived in Zones A or B were interviewed and examined, and serum specimens stored from the time of the explosion were analyzed to determine individual levels of TCDD exposure. The Seveso Women's Health Study, originally funded in 1996 (R01 ES07171) aimed to examine the relationship of serum TCDD levels and endometriosis. Continued funding in 1999 and 2001 allowed the analysis of additional serum specimens for TCDD and examination of the relation to other reproductive endpoints: menstrual cycle characteristics, age of menarche, fetal loss and birth weight, age at menopause, breast cancer incidence, length of lactation, ovarian disease and fibroids. We found that the youngest women (< 10 years in 1976) were the highest exposed, but they were also the least likely to have experienced reproduction at follow-up (25 percent nulliparous in 1996). Among other findings, we observed a significant increased risk for breast cancer, but the cohort averaged only 40 years old in 1996. In this proposal, we aim to follow-up this unique cohort approximately 30 years after the explosion, when the women have aged and longer-term sequelae of exposure to TCDD may emerge. We expand our health assessment to include non-reproductive health outcomes likely affected by endocrine disruption. Specifically, we aim to study the relation of serum TCDD to breast cancer, diabetes and metabolic syndrome, bone density, and women and neonatal thyroid hormone. The proposed study takes advantage of previously collected data and specimens, including the 1976 serum TCDD levels and 1996 archived bloods. We propose to interview the women about their health and obtain medical records, and on a subsample, perform a bone density evaluation, and measure thyroid hormone and TCDD/TEQ in archived 1996 blood. We will acquire from registry records the neonatal TSH levels of all children born after 1994. The Seveso Women's Health Study is the only comprehensive study to date of the health of women exposed to TCDD. This study has the benefit of being a large cohort study with a wide range of TCDD exposure, documented by individual-level TCDD measured in sera collected soon after the explosion. ExpandCollapse Abstract