Molecular Epidemiology of Dioxin-Related Illness in Seveso

In 1976 an accidental explosion in a chemical plant 16 miles north of Milan 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 human, TCDD causes chloracne in those exposed. Associations with various cancers have been reported, but the precise role in human toxicity, immune and reproductive dysfunction, and cancer is controversial.

The Seveso accident provides a unique opportunity for an epidemiological investigation in that the exposures are the highest recorded in humans, the exposure involves TCDD without other contaminants, and a cohort in the involved and surrounding area has been enumerated.

There is inter-individual variation in the action of genes involved in TCDD effect in human cells. The quality of human AH receptor, and the CYP1A1 and arnt genotypes are examples of susceptibility markers that may identify subjects at high risk for TCDD-related disease. A hypothesis that could explain the inconsistent association of TCDD exposure with cancer is that genetic susceptibility may influence which individuals are adversely affected by TCDD exposure.

The study is in three phases. The first is a pilot/validation study of 126 highly exposed and not exposed subjects. The second is a case-control study of 100 individuals with chloracne and 100 controls. The field components of phase one and two are complete. The third and final phase is a planned case-control study of TCDD-related cancers that will include approximately 125 cases and 125 controls.

Using different methods to estimate TCDD levels below the detection limit, we found that, approximately 20 years after the accident, plasma TCDD was still elevated in subjects from the exposed areas, particularly in women, and was negatively associated with IgG plasma levels. Subjects who developed chloracne after the accident had high TCDD levels, and no evidence of TCDD-related long-term toxicity.