In 1976 an accidental explosion in a chemical plant in Seveso, Italy resulted in contamination of the local population with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD). There is evidence that TCDD and related phenoxy herbicides act as teratogens, tumor promoters, and carcinogens in experimental animals. In humans, TCDD causes chloracne but the precise role in immune and reproductive dysfunction, and cancer is controversial. Approximately 20 years after the Seveso, Italy accident, NCI investigators designed a population-based study to evaluate the impact of TCDD exposure on chloracne and cancer using mechanistically-based biomarkers of dioxin response in humans. They measured current lipid-adjusted plasma TCDD conCentreations in these subjects, and found they were still elevated in exposed subjects, particularly in women, and were inversely associated with plasma IgG. Subjects who developed chloracne after the accident had no evidence of dioxin-related long-term toxicity. Using improved methods to estimate dioxin levels, investigators identified several changes in gene expression in lymphocytes and increased frequency of t(14;18) translocation-positive cells with increasing plasma dioxin. They also found that maternal dioxin exposure affects neonatal thyroid function.