Association between Cumulative Airborne Dioxin Exposure and Chronic Lymphocytic Leukemia/Non-Hodgkin's Lymphoma Risk in a Nested Case-Control Study within the French E3N Cohort

Background: Dioxins are a family of lipophilic, bio-accumulative chemical compounds belonging to persistent organic pollutants groups. The TCDD (2, 3, 7, 8 tetrachlorodibenzo-para-dioxin) which is the most toxic congener of dioxins is classified as carcinogen to humans by the International Agency for Research on Cancer. Airborne dioxins exposure is suspected to increase the risk of Chronic Lymphocytic Leukemia (CLL) and non-Hodgkin's lymphoma (NHL) in some studies. Although dioxins are bio-accumulative in the human body, no epidemiological study had assessed the relationship between cumulative airborne dioxin exposure and CLL/NHL risk.

Objective: The relationship between cumulative airborne dioxin exposure and CLL or NHL risk was assessed in a case-control study nested within the French E3N cohort (cohort of 98 995 women covered by the health insurance provider of the national education system).

Materials and methods: All incident cases of CLL/NHL diagnosed between 1990 and 2008 were selected. They were identified by self-administered questionnaires as well as through reports from family members and from the national cause of death registries. All cases were validated with medical reports. Subtypes of NHL were classified according to the International Lymphoma Epidemiology Consortium working group classification of lymphoid neoplasms for epidemiologic research. 368 incident cases of CLL and NHL were matched to 368 controls on age (± 1 year) and on the department of residence reported at inclusion in 1990.

Cumulative exposure to airborne dioxins was estimated for each participant at the individual address level using a Geographic Information System (GIS) based exposure index including residence-to-source distance, wind direction, annual dioxin emission intensity, length of operation and meteorological parameters (1). Airborne dioxin exposure was summarized into a cumulative exposure index from the latest inclusion date (i.e., the date of return of the first questionnaire) of the case-control pair, to the index date (i.e., the date of diagnosis of the case). Multivariate conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). The main model was adjusted on education level used as a proxy for socioeconomic status, place of residence, body mass index (kg/m²), physical activity (metabolic equivalent activity task-hour per week (MET-h/w)) and smoking status.

Results: The mean follow-up time was 11.7 years ranging from 0.2 to 19.4 years and the cumulative exposure index averaged was 3.6 µg-TEQ/m². The mean age of women at diagnosis of CLL/NHL was 63.3 years. The subtype distribution was 23% of Diffuse Large B-cell Lymphoma (DLBCL), 19% of Follicular Lymphoma (FL), 27% of CLL & small lymphocytic lymphoma (SLL), 11% of Marginal Zone Lymphoma (MZL) and 20% of other NHL. We observed a statistically significant positive association between the cumulative dioxin exposure index and the CLL/NHL risk (OR and 95% CI: 1.2 (1.0,1.4) for a 4.4 log µg-TEQ/m² increase corresponding to a standard deviation). Analysis by subtypes showed a significant association between the CLL/SLL subtypes and the cumulative continuous exposure index (OR and 95% CI: 1.6 (1.1,2.3)) (Table 1).

Discussion/Conclusion: The present study supports a positive significant association between cumulative airborne dioxin exposure and CLL/NHL risk, and, more specifically, a positive significant association for CLL & SLL. Our findings are consistent with publications that found positive associations between dioxin exposure and CLL/NHL risk. This is the first epidemiological study investigating the relationship between cumulative airborne dioxins exposure and CLL/NHL risk using a GIS-based cumulative exposure index and a multi-source approach. These findings contribute to justify the efforts to decrease the airborne exposition to dioxins. Additional studies evaluating the association between cumulative dioxin exposure and other hematologic malignancies are required.

Reference 1. Coudon, T., Danjou, A.M.N., Faure, E. et al. Development and performance evaluation of a GIS-based metric to assess exposure to airborne pollutant emissions from industrial sources. Environ Health18, 8 (2019). https://doi.org/10.1186/s12940-019-0446-x

No relevant conflicts of interest to declare.