Bräuner et al. Two studies have estimated associa- tions between organochlorines measured in adipose tissue and NHL risk. The first was a small study that examined only summed chlordanes (Hardell et al. 1996) in samples obtained after diagnosis (in cases), whereas the other used adipose samples taken post mortem (Quintana et al. 2004). Prospective studies are advantageous when investigating carcinogenic effects exerted years before clini- cal presentation, whereas organochlorine lev- els in adipose samples collected after diagnosis have been shown to be affected by treatment (Gammon et al. 1996) and weight loss (Glynn et al. 2003; Jandacek et al. 2005) and to pos- sibly alter metabolic function (Morgan and Roan 1971; Mullerova and Kopecky 2007), which could be related to weight fluctuations, ultimately affecting organochlorine levels. We sampled adipose tissue up to 15 years before the NHL diagnosis, and given the relatively long half-lives of DDT, cis-nonachlor, and oxychlordane (up to 6 years), our prospective measures represent a relatively stable internal dose that is likely to reflect exposures several years before follow-up for cancer started. We are the first group to report associa- tions between NHL and DDT, cis-nonachlor, and oxychlordane mainly (or possibly only) among men. Eight previous studies consid- ered both sexes, but only one investigated sex- specific effects of DDT on NHL (Miligi et al. 2003) and reported no association for either sex. The stronger associations among men in our study population may be due to differ- ences in metabolism and elimination of the compounds (e.g., women can excrete these compounds via breast-feeding). Some studies have suggested that BMI could confound associations between organo- chlorine concentrations and NHL, although this is controversial (Cox et al. 1999). A positive association between high BMI and organochlorines may be expected in relation to prolonged consumption of fatty foods, which are often associated with overweight and pos- sibly a high intake of lipophilic compounds; conversely, however, a high BMI and body fat content could result in a dilution effect. We investigated whether persons with a high BMI had greater risk of NHL than persons with low BMI, analyzing data both with and without adjusting for BMI, and found no evidence of effect modification or confounding. BMI was measured at the time of enrollment/adipose sampling, which is relevant for assessing the effect of BMI on the adipose sample but does not reflect effects of BMI over time. The timing of diagnosis relative to the organochlorine measurement has been inves- tigated in only one previous study (Engel et al. 2007), which reported a stronger exposure– response association among subjects diagnosed within the years before median follow-up (early follow-up) compared with subjects diag- nosed in the years after median follow-up (late follow-up). We observed no significant differ- ences related to the duration of follow-up and thus could not confirm this result. The major strength of this study is the pro- spective collection of adipose tissue samples in a general population setting. Follow-up was virtually complete, and reliable nationwide registries provided information on vital status and cancer. Selection bias is unlikely because cases and subcohort participants came from Table 4. IRRs for NHL and 95% CI in association with adipose concentrations of p,p´-DDT, cis-nonachlor, and oxychlordane within strata of sex. n (cases/subcohort) IRR (95% CI) Women Men the same cohort and fulfilled the same eligibil- ity criteria. Further, recall bias was avoided by the objective exposure assessment method, and disease status could not have biased exposure assessment because adipose tissue was obtained and frozen before cancer diagnosis. The exact mechanisms by which organo- chlorines might increase NHL risk remain to be elucidated but the involvement of immuno- suppression is suspected. Evidence of the immunotoxicity of organochlorines (includ- ing DDT and chlordane) has been reviewed, and both human and toxicological evidence suggests immunotoxicity (Repetto and Baliga 1997). More recent animal and in vitro stud- ies confirm this for DDT and individual chlordanes (Reed et al. 2004; Tryphonas et al. 2003); however, this evidence is com- posed mainly of acute high-dose studies, and the relevance to typical human exposure levels may be questioned. It remains unclear which specific compounds are related to NHL risk and whether this association is causal. We can- not rule out confounding from unaccounted risk factors, for example, other more toxic agents such as furans, dioxins, or coplanar PCBs that are bioaccumulated in parallel with DDT, cis-nonachlor, and oxychlordane. More research is needed to clarify possible interac- tions with organochlorines and other agents such as viruses and genetic polymorphisms to further elucidate biological mechanisms behind this association. Conclusion Our results add new evidence of an association between exposure to DDT and chlordanes and NHL at prospectively measured exposure levels experienced by a general population but do not contribute to the evidence that exposure to PCB congeners may increase the risk of NHL. Ref Rencs Agency for Toxic Substances and Disease Registry. 1993. Selected PCBs (Acrochlor-1260, -1254, -1248, -1242, -1232, -1221 and -1016). Atlanta, GA:Agency for Toxic Substances and Disease Registry. Allam MF, Lucena RA. 2001. Breast cancer and PCBs: true or false association? Eur J Cancer Prev 10:539–540. Anderson HA. 1985. Utilization of adipose tissue biopsy in char- acterizing human halogenated hydrocarbon exposure. Environ Health Perspect 60:127–131. Archibeque-Engle SL, Tessari JD, Winn DT, Keefe TJ, Nett TM, Zheng T. 1997. Comparison of organochlorine pesticide and polychlorinated biphenyl residues in human breast adipose tissue and serum. J Toxicol Environ Health 52:285–293. Aronson KJ, Miller AB, Woolcott CG, Sterns EE, McCready DR, Lickley LA, et al. 2000. Breast adipose tissue concentrations of polychlorinated biphenyls and other organochlorines and breast cancer risk. Cancer Epidemiol Biomarkers Prev 9:55–63. Baris D, Zahm SH, Cantor KP, Blair A. 1998. Agricultural use of DDT and risk of non-Hodgkin’s lymphoma: pooled analysis of three case-control studies in the United States. Occup Environ Med 55:522–527. Barlow WE. 1994. Robust variance estimation for the case– cohort design. Biometrics 50:1064–1072. Bertrand KA, Spiegelman D, Aster JC, Altshul LM, Korrick SA, Rodig SJ, et al. 2010. Plasma organochlorine levels and risk ovlume 120 | number 1 | January 2012 • Environmental Health Perspectives Men 8/16 16/13 20/11 10/7 9/7 63/54 7/14 10/21 19/20 17/11 19/8 72/74 21/21 16/19 15/27 13/12 9/4 74/83 23/31 25/21 23/17 10/10 2/3 83/82 1.00 1.90 (0.60, 6.02) 3.36 (1.06, 10.64) 2.05 (0.53, 7.87) 2.30 (0.60, 8.77) 1.50 (1.14, 1.98) 1.00 1.02 (0.30, 3.47) 2.00 (0.61, 6.51) 3.00 (0.86, 10.51) 4.42 (1.21, 16.09) 1.39 (1.00, 1.93) Women 1.00 0.77 (0.31, 1.89) 0.48 (0.20, 1.17) 0.88 (0.31, 2.47) 1.69 (0.47, 6.08) 1.15 (0.72, 1.86) 1.00 1.37 (0.60, 3.12) 1.41 (0.59, 3.34) 1.24 (0.45, 3.44) 0.67 (0.10, 4.46) 0.94 (0.73, 1.20) p-Value for differenceb 0.35 0.06 Compound/concentrationa (μg/kg lipids) p,p´-DDT Linear estimate per IQRc cis-Nonachlor Linear estimate per IQRc Oxychlordane 6–15 15–22 22–36 36–49 49–460 3–5 5–7 7–10 10–15 15–39 110 8–19 14/24 16/28 1.00 1.00 19–25 17/23 21/23 1.29 (0.52, 3.22) 1.44 (0.62, 3.37) 25–33 18/15 28/24 2.05 (0.78, 5.35) 1.74 (0.76, 3.97) 33–41 13/3 21/15 6.15 (1.46, 25.93) 1.81 (0.71, 4.66) 41–354 12/6 9/10 3.45 (0.97, 12.20) 1.18 (0.39, 3.52) Linear estimate per IQRc 74/71 95/100 1.27 (0.90, 1.79) 0.97 (0.73, 1.29) 0.23 aThe cutoffs between exposure groups were 25th, 50th, 75th, and 90th percentiles. bFor Wald test for interaction. cLinear estimate per IQR based on pesticide concentrations analyzed as continuous variables.