Trial Information

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.

The analyses of the expression of key genes in the aryl hydrocarbon receptor (AhR) pathway,
which is necessary for most TCDD effects, showed a significant reduction in AhR expression
by increasing plasma dioxin levels. Cytochrome P450 gene SNPs and haplotypes were
associated with variable TCDD-related gene inducibility.

On-going studies are examining the proteomics and gene expression pattern (by microarray) in
exposed subjects compared with not exposed individuals, and the frerquency of t(14;18)
translocations in lymphocytes from the same subjects.

The study includes a questionnaire/interview and a biospecimen collection; 73 ml of blood
were obtained from each participant.