The Molecular Epidemiology of Dioxin Exposure in Former Chemical Workers

Background: Dioxins, a class of toxic and persistent chemical compounds, are ubiquitous in the environment. This dissertation presents the results of three studies that share the major aim of characterizing some of the mechanistic factors through which dioxins exert their toxic effects in humans, using observational data. The first investigated the association with a chromosomal aberration that may mediate development of Non-Hodgkin’s Lymphoma (NHL). The second evaluated the potential antagonistic behavior of non-dioxin-like polychlorinated biphenyls on dioxin activity. The third was designed to better understand chloracne susceptibility in exposed persons. Methods: A large international multidisciplinary research team enrolled, surveyed, and examined two cohorts of Eastern European subjects. One was composed of chemical factory workers occupationally exposed to dioxins. The other was composed of residents from a nearby city without known dioxin exposure. Additionally, the relationship between dioxin exposure and gene expression in a subsample of the two cohorts was investigated. Results: The first study demonstrated a significant association between background serum levels of dioxin-like polychlorinated biphenyl 126 and chromosomal translocation t(14;18) frequency in the population-based cohort, and this relationship was modified by smoking habit. In the second study, expression of the aryl hydrocarbon receptor was significantly associated with serum dioxin levels, and non-dioxin-like polychlorinated biphenyl 153 was shown to have an antagonistic effect on this dioxin-induced expression. The third study showed a much higher prevalence of smoking in those who developed chloracne versus those who did not in the occupationally exposed cohort. Conclusions: These findings suggest a biologically plausible mechanism for increased risk of NHL. Additionally, this is the first time that the interaction between dioxin-like and non-dioxin-like compounds has been reported in a human observational study. Finally, these findings may help to explain why only some of those with dioxin exposure seem more likely to develop chloracne. Taken together, the results of these studies have important implications for risk assessment of exposure to dioxins and dioxin-like compounds. Furthermore, these findings suggest that dioxin toxicity in humans may be significantly altered by avoidance or cessation of smoking, a modifiable behavior.