The Molecular Epidemiology of Dioxin Exposure in Former Chemical Workers

Details

• Personal Author:
  Ruestow P
• Description:
  The major aim of the studies described in detail herein was to further characterize the mechanisms through which dioxins exert their toxic effects in humans. 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. Preliminary analyses revealed relatively high levels of dioxin-like (DL) and non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) in this population-based group. An association between dioxin exposure and Non-Hodgkin's Lymphoma (NHL) has been demonstrated in other occupationally and environmentally exposed cohorts, though the molecular mechanisms explaining this relationship are debated. A potential link between dioxin exposure and the presence of t(14;18) chromosomal translocations in lymphocytes, a likely intermediate step in the causal pathway for two NHL subtypes, has also been established. Our study of risk factors for t(14;18) expansion demonstrated a significant association between closer-to-background serum levels of DL PCB 126 and t(14;18) frequency in the environmentally exposed cohort, and this relationship was modified by smoking habit. Risk was increased in current (RR=1.51, 95%CI: 1.17-1.94) and former (RR=1.13, 95%CI: 1.03-1.24) smokers, but not in never smokers (RR=.99, 95%CI: 0.95-1.03). These findings suggest a biologically plausible mechanism for increased risk of NHL. Dioxin toxicity is believed to occur as a result of persistent activation of the aryl hydrocarbon receptor (AhR), a transcription factor that regulates several drug-metabolizing genes, among others. We investigated the relationship between dioxin exposure and gene expression in a subsample of the two cohorts. Expression of the AhR itself was found to be significantly associated with serum dioxin levels, with expression in the highest tertile of dioxin dose 1.4-fold higher than that in the lowest tertile. We further demonstrated the antagonist activity of NDL-PCB 153 on dioxin-induced AhR gene expression. This is the first time that this chemical interaction has been reported in a human observational study. One of the well-established health effects of dioxin exposure (and subsequent AhR activation) is chloracne, a condition characterized by skin lesions resembling acne vulgaris. In an attempt to identify risk factors that might explain inter-individual differences in chloracne development after dioxin exposure, we found a much higher prevalence of smoking in those who developed chloracne versus those who did not in the occupationally exposed cohort. Given recent findings regarding the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in chloracne development, we suggest possible mechanisms through which risk of chloracne may be modified by concurrent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and cigarette constituent exposures. The results of these studies have important implications for risk assessment when it comes to dioxin and PCB exposure. Highlighted are exciting areas for future research into the molecular toxicity of these chemicals. Furthermore, our findings suggest that risks associated with dioxin toxicity may be significantly altered by avoidance or cessation of smoking, a modifiable behavior. [Description provided by NIOSH]
• Subjects:
  Cohort Studies Dioxins Environmental Exposure Genetics Manufacturing And Industrial Facilities Neoplasms Occupational Exposure Occupational Health Safety
• Keywords:
  Chemical Industry Workers Cohort Studies Environmental Exposure Gene Expression Gene Regulation Genes Lymphatic Cancer Occupational Exposure
• Publisher:
  University of Illinois at Chicago
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Thesis
• Place as Subject:
  Illinois ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-123
• NIOSHTIC Number:
  nn:20056795
• Citation:
  Chicago. IL: University of Illinois at Chicago, 2015 Aug; :1-123
• Federal Fiscal Year:
  2015
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Illinois at Chicago
• Peer Reviewed:
  False
• Start Date:
  20080801
• Source Full Name:
  The molecular epidemiology of dioxin exposure in former chemical workers
• End Date:
  20130731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:54d5513fd1957ce6de4365003ccd164933187e1ac7945d7d6a349cafb97bd9dd1abde27a7f325e69902e44a9c79142c4e72856d8a5ce51e4b4d8c0bed6cb8281
• Download URL:
  https://stacks.cdc.gov/view/cdc/214314/cdc_214314_DS1.pdf
• File Type:
  [PDF - 894.94 KB ]