Research A Prospective Study of Organochlorines in Adipose Tissue and Risk of Non‑Hodgkin Lymphoma Elvira Vaclavik Bräuner,1 Mette Sørensen,1 Eric Gaudreau,2 Alain LeBlanc,2 Kirsten Thorup Eriksen,1 Anne Tjønneland,1 Kim Overvad,3 and Ole Raaschou-Nielsen1 1Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 2Centre de toxicologie du Québec, Institut National de Santé Publique du Québec, Quebec City, Quebec, Canada; 3Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark Background : Exposure to organochlorines has been examined as a potential risk factor for non-Hodgkin lymphoma (NHL), with inconsistent results that may be related to limited statistical power or to imprecise exposure measurements. o Bjectiv : Our purpose was to examine associations between organochlorine concentrations in prediagnostic adipose tissue samples and the risk of NHL. Methods : We conducted a case–cohort study using a prospective Danish cohort of 57,053 persons enrolled between 1993 and 1997. Within the cohort we identified 256 persons diagnosed with NHL in the population-based nationwide Danish Cancer Registry and randomly selected 256 sub- cohort persons. We measured concentrations of 8 pesticides and 10 polychlorinated biphenyl (PCB) congeners in adipose tissue collected upon enrollment. Associations between the 18 organochlorines and NHL were analyzed in Cox regression models, adjusting for body mass index. r esult : Incidence rate ratios and confidence intervals (CIs) for interquartile range increases in concentrations of dichlorodiphenyltrichlorethane (DDT), cis-nonachlor, and oxychlordane were 1.35 (95% CI: 1.10, 1.66), 1.13 (95% CI: 0.94, 1.36), and 1.11 (95% CI: 0.89, 1.38), respectively, with monotonic dose–response trends for DDT and cis-nonachlor based on categorical models. The relative risk estimates were higher for men than for women. In contrast, no clear association was found between NHL and PCBs. c onclusi : We found a higher risk of NHL in association with higher adipose tissue levels of DDT, cis-nonachlor, and oxychlordane, but no association with PCBs. This is the first study of organochlorines and NHL using prediagnostic adipose tissue samples in the exposure assessment and provides new environmental health evidence that these organochlorines contribute to NHL risk. k ey words : adipose tissue, case–cohort, non-Hodgkin lymphoma, organochlorines. Environ Health Perspect 120:105–111 (2012). http://dx.doi.org/10.1289/ehp.1103573 [Online 26 August 2011] Non-Hodgkin lymphomas (NHLs) are a het- erogeneous group of B- and T-cell neoplasms arising primarily in the lymph nodes. Incidence rates have nearly doubled in Western countries since the 1970s, although no further rise has been observed since the mid-1990s (Dreiher and Kordysh 2006). Established risk factors include genetic susceptibility and previous his- tory of malignant disease (Wang et al. 2007). Immunological conditions are also related to this group of cancers, as evidenced by a more than 100-fold increased risk of NHL among organ transplant recipients receiving immuno- suppressive therapy (Fisher and Fisher 2004) and an increased incidence among subjects with primary immunodeficiency and autoimmune diseases (Vineis et al. 2000). However, these factors, in combination with longer life spans and changes in diagnostic patterns, cannot explain all cases, and many researchers specu- late that the increase is partly due to exposure to environmental agents, including organo- chlorines (Hardell and Axelson 1998). Dichlorodiphenyltrichlorethane (DDT) and other organochlorines are carcinogenic in animals (International Agency for Research on Cancer 1987), and the production and environmental release of these compounds with subsequent bioaccumulation accelerated during the decades after 1945 (World Resources Institute 1990), coinciding with increasing incidence rates for NHL in Western populations. Organochlorines are ubiquitously present as a mixture of mother compounds and metabolites in the environment and are characterized by high lipid solubility, environ- mental persistence, bioaccumulation (Agency for Toxic Substances and Disease Registry 1993), and long biological half-lives in human tissue (Wolff et al. 2000). Several studies have described immunotoxicity of selected organo- chlorines (Heilmann et al. 2006; Reed et al. 2004; Tryphonas et al. 2003). The evidence relating organochlorines to NHL risk has been reviewed (Dreiher and Kordysh 2006) and the association remains unclear, with some studies reporting associa- tions and others finding none. Reasons for these discrepancies may include low statis- tical power or imprecise exposure measure- ments, such as surrogate measures including occupation or self-reported questionnaires gathered after diagnosis. More recent studies have evaluated biological exposure measure- ments and have more consistently reported associations between NHL risk and various organochlorine pesticides and polychlorinated biphenyl (PCB) congeners (Bertrand et al. Environmental Health Perspectives • volume 120 | number 1 | January 2012 2010; Cantor et al. 2003; De Roos et al. 2005; Engel et al. 2007; Laden et al. 2010; Quintana et al. 2004; Spinelli et al. 2007). However, the specific compounds identified were not con- sistent among the studies, and different bio- logical media were used. Questions pertaining to the best quantification of biological expo- sure have been raised (Aronson et al. 2000; Whitcomb et al. 2005), and adipose tissue samples have been regarded by various authors (Allam and Lucena 2001; Hardell et al. 1996; Quintana et al. 2004) as the preferred indica- tor of human exposure because organochlorine levels are known to be higher in adipose tissue and more representative of the cumulative internal exposure. However, only two studies have previously measured organochlorines in adipose tissue (Hardell et al. 1996; Quintana et al. 2004), and in both studies the adipose tissue was sampled after the diagnosis, render- ing results difficult to interpret because treat- ment may affect subsequent organochlorine concentrations (Gammon et al. 1996; Morgan and Roan 1971). In the present study, we investigated the hypothesis that organochlorines are related to an increased NHL risk, and we are the first to use adipose tissue sampled before the NHL diagnosis to assess organochlorine exposures in a population-based setting. Materials and Methods Between December 1993 and May 1997, 160,725 persons 50–64 years of age were invited to participate in the prospective Diet, Cancer and Health study. The participants had to be born in Denmark, live in Copenhagen Address correspondence to O. Raaschou-Nielsen, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen 2100, Denmark. Telephone: 45 35257617. Fax: 0045 35257731. E-mail:ole@ cancer.dk Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1103573). E.V.B. was supported by the Danish Medical Research Council, Danish Cancer Society, Aase and Ejnar Danielsens, King Christian the 10th, A.P. Møller, the Hartmann Brothers, the Foundation of 1870, Snedker Jacobsen and hustru Astrid Jacobsen, Architect Holger Hjortenberg and hustru Dagmar Hjortenberg, Civil Engineer Frode V. Nyegaard, and Simon Spies. The authors declare they have no actual or potential competing financial interests. Received 14 February 2011; accepted 26 August 2011. 105