NORA Manufacturing Sector Strategic Goals
R018976 - 021H: t(14:18) Translocations in Dioxin Exposed Workers from Ufa (8976)Start Date: 8/1/2008
End Date: 7/31/2012
Principal Investigator (PI)Name: Joan Karr
Funded By: NIOSH
Primary Goals Addressed5.06.0
Secondary Goal Addressed
Attributed to Manufacturing
This study will investigate dose-response relationships between frequency of t(14;18) chromosomal translocation in periperal blood lymphocytes and body burdens of dioxin biproducts in a Russian worker population (Ufa, Russia) exposed to dioxin at the workplace. The PI will investigate how increasing blood levels of one of the dioxin biproducts (TCDD) effects expression of two genes and proteins and how these effects may correlate to increased genetic changes (t(14;18) chromosomal translocations) in this population.
The results of this study will have significant value for dioxin risk assessment. Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer in the United States. There is increasing epidemiologic evidence that exposure to TCDD increases risk of NHL. The recent molecular epidemiology study by Baccarelli et al (2006) suggests that the mechanism may be through dioxin promoting the expansion of t(14;18) clones which then increases the numbers of cells at risk for cumulative DMA damage. A recent NHL case control study found that NHL risk was related to blood TEQ and blood levels of dibenzofurans (de Roos et al, 2005). The Ufa Khimprom cohort offers a unique, highly-exposed population in which to investigate the effects of blood TCDD, TEQ, and other dioxin and dibenzofuran congeners on the frequency of t(14;18) translocations. Of particular interest for risk assessment, is whether increases in risk will be observed at blood dioxin levels which overlap background levels in the U.S. general population.
The specific aim of this study is to investigate the dose-response relationships between the frequency of t(14;18) translocations in peripheral blood lymphocytes and body burdens of TCDD, other dioxin congeners, and dioxin total toxic equivalent (TEQ) in a population of workers with occupational exposure to dioxin. Dioxin exposure has been associated with an increased risk of non-Hodgkin's lymphoma (NHL) in previous epidemiologic investigations. The t(14;18) translocation is the most frequent chromosomal translocation in human lymphoid malignancies. It is assumed to be an early event occurring in a pre-B stage cell which is a necessary, but not sufficient, step in the carcinogenesis pathway for follicular lymphoma. The overall frequency of t(14;18) cells in an individual gives an indication of the number of cells at risk for this additional DNA damage, and t(14;18) translocation has been proposed as a biomarker of environmental carcinogen exposure for NHL. We observed a significant dose-response relationship between current blood levels of TCDD and frequency of t(14;18) translocations in the population of individuals who had been environmentally exposed to 2,3,7,8-TCDD in Seveso, Italy in 1976. The current study will compare the frequency of t(14;18) translocations in 200 former TCP and 2,4,5-T workers and 200 former 2,4-D workers from the Khimprom chemical plant in Ufa, Russia to a referent population of 200 unexposed workers and retirees from the city of Beloretsk, Russia. The dioxin-exposed workers will be recruited from among workers who are currently participating in a study of reproductive outcomes among Khimprom workers. The referent population will be randomly selected from the population of residents of Beloretsk, Russia (minimal dioxin exposure) who are enrolled in the Territorial Insurance Fund. Referents will be frequency matched to the exposed on age, gender, ethnicity, employment status, and smoking. We will administer a health questionnaire, dermatologic examination and measure dioxin levels (congener- specific and TEQ) in blood and t(14;18) translocations in peripheral blood lymphocytes. We will back extrapolate peak dioxin levels using occupational histories and the best fitting pharmacokinetic models for TCDD and other congeners. We will investigate the dose-response relationship between t(14;18) translocation-positive cells and current blood TCDD, back-extrapolated blood TCDD, other dioxin congeners, and total dioxin TEQ. We will investigate the effect of increasing blood TCDD on BCL2 and KLF4 expression and how these effects are associated with increased frequency of t(14;18) translocations. We will also establish a repository of DNA and RNA from study participants for future molecular and gene expression profiling studies.
The specific aims of this research are to:
- Recruit 400 former dioxin-exposed Khimprom workers from the city of Ufa (200 who had been engaged in the production of TCP, TCP-Cu, or 2,4,5-T and 200 who had been engaged in the production of 2,4-D) and 200 unexposed referents from the city of Beloretsk, frequency matched to the exposed on age, gender, ethnicity (Bashkir, Tatar or ethnic Russian), smoking (never, former, current), and employment status (active, retired).
- Ascertain past and current health status (in particular history of lymphoma and potential confounders such as age, smoking, UV light exposure, ionizing radiation exposure, hepatitis C infection, and family history of NHL) through questionnaire, medical record review, and physical examination (for chloracne, hair and skin color).
- Ascertain past and current occupational and environmental dioxin exposure through questionnaire and occupational personnel record review.
- Measure dioxin blood levels (congener specific and dioxin total toxin equivalent (TEQ)) in these 600 participants.
- Evaluate the fit of one and two compartment toxicokinetic models to blood dioxin data and use the best fitting model to back extrapolate dioxin levels in the 400 Khimprom workers.
- Measure the prevalence and frequency of t(14;18) translocation-positive cells in the 600 participants.
- Measure the expression of BCL2 and KLF4 in lymphocytes from the 600 participants
- Investigate the dose-response relationship between the prevalence and frequency of t(14;18) translocation-positive cells and current blood TCDD, back-extrapolated blood TCDD, blood levels of other dioxin congeners, and TEQ.
- Investigate the effect of increasing blood TCDD on 8CL2 and KLF4 expression and how these effects are associated with increased frequency of t(14;18).
- Establish a repository of DMA and RNA for future molecular and gene expression profiling studies.
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