Molecular Epidemiology of Dioxin-Related Illness in Seveso
Condition: 2,3,7,8-Tetrachlorodibenzo-Para-Dioxin (TCDD) Exposure
Study type: Observational

Summary: 
      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-terachlorodibenzo-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 proceeding in three phases. The first is a pilot/validation study that is
      complete (field activities) and involved 126 subjects. The second is a case-control study of
      about 100 individuals with chloracne and 100 controls. The field components of phase one and
      two are complete, and analyses of results are underway. The third and final phase is a
      planned case-control study of TCDD-related cancers that will include approximately 125 cases
      and 125 controls.

      The study includes a questionnaire/interview and a biospecimen collection; 73 ml of blood are
      obtained from each participant.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        The study included subjects who were exposed to dioxin and controls not exposed to dioxin.
      
Keywords: Molecular Epidemiology; Cross-Sectional; Gene-Enviroment Interaction