Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world. Involvement of organochlorines has been proposed in disease etiology. No study has investigated organochlorine exposure in relation to survival after a NHL diagnosis.

Methods: In a survivor cohort consisting of 232 NHL cases from the Danish Diet, Cancer and Health cohort, we examined the association between adipose tissue organochlorine concentrations [polychlorinated biphenyls (PCBs) and pesticides] and subsequent survival, using Cox proportional hazards models.

Results: We found no statistically significant association between organochlorine concentrations and subsequent survival. If anything, there was a nonsignificant tendency toward an inverse association with PCBs, but not pesticides.

Conclusions: In conclusion, the current study does not support an increased risk of death among NHL patients with high tissue concentrations of organochlorines.

Impact: This is the first study to investigate adipose organochlorine concentrations and survival after a NHL diagnosis. Cancer Epidemiol Biomarkers Prev; 27(2); 224–6. ©2017 AACR.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide, and incidence rates have increased over the past 40 years (1, 2), suggesting that environmental factors may play a role in disease etiology (2). A number of occupations have been found at increased risk, including farmers and pesticide applicators (2).

Many organochlorines have been banned in the Western world for decades, but are still ubiquitously present in the environment due to their persistent nature (3). A recent leveling-off of the NHL incidence has been proposed to coincide with the more strict legislation regarding pesticide use and handling (4). A meta-analysis of organochlorine pesticides and NHL found a strong association (5), whereas a meta-analysis of polychlorinated biphenyls (PCBs) found no association with occupational exposure, but did find an association between blood concentrations and NHL (6).

We have not identified any studies investigating the association between organochlorine concentrations and survival after NHL. This study aimed to investigate the association between organochlorine concentrations in adipose tissue and survival after NHL diagnosis, among middle-aged Danes.

A detailed description of the Diet, Cancer and Health cohort is published previously (7). A total of 57,053 Danes were included from 1993 to 1997, where they filled in a lifestyle questionnaire, were subjected to anthropometrical measurements, and provided an adipose tissue biopsy from the buttock. Participants have been followed in Danish registries on cancer and mortality ever since.

The study was approved by the local ethical committees of Copenhagen and Frederiksberg Municipalities. All participants provided written informed consent, and the study was conducted according to the Helsinki Declaration.

Organochlorines measured in adipose tissue were 10 PCB congeners (International Union of Pure and Applied Chemistry nos. 99, 118, 128, 138, 153, 156, 170, 180, 183, 187, and 201), and p,p-DDT, p,p-DDE, β-hexachlorocyclohexane, dieldrin, hexachlorobenzene, cis-nonachlor, trans-nonachlor, and oxychlordane. Samples were analyzed at Le Centre de Toxicologie, Institut national de santé publique du Quebec (Quebec, Canada). Details are described in ref. 8.

Cox proportional hazards models estimating mortality rate ratios (MRR) and 95% confidence intervals (CI) were used to investigate the association between organochlorine concentrations and survival. Time since diagnosis was used as underlying time scale. Follow-up started at date of diagnosis and continued until death, emigration, or February 1, 2016, whichever came first.

MRRs were calculated as crude: stratified by sex and age at diagnosis, and adjusted for calendar year of diagnosis, and with additional adjustment for smoking status, alcohol consumption, waist circumference, recreational sports, education, and area-level socioeconomic status. Adjustment for smoking duration and intensity had no effect on estimates and were therefore not included. Stratified analyses were conducted for sex to explore effect modification. P values for heterogeneity across strata were calculated using χ2 tests. The procedure PHREG in SAS 9.3 was used for all analyses (SAS Institute Inc.).

A total of 271 persons were diagnosed with NHL in the Danish Cancer Registry until July 31, 2008. We excluded 22 with no adipose tissue sample, and 17 with insufficient adipose tissue available, or because of laboratory analysis errors. This left 232 persons for the study. Of these, 123 died during follow-up.

Several potential confounders were unevenly distributed among deceased and nondeceased: Deceased participants were more likely to be male, have a long education, be current smokers, have a higher median alcohol intake, but also to abstain at baseline. They were less likely to participate in leisure-time sports and live in areas with low socioeconomic status (Table 1). Median follow-up time for all participants was 8.5 years (95% CI, 0.4–16.3). For deceased, it was 4.0 years (95% CI, 0.2–12.3).

Table 1.

Characteristics of persons diagnosed with NHL in the Danish Diet, Cancer and Health cohort

AllDeceased
N = 232N = 123
Baseline variables 
Male, % 52.6 56.9 
Education, % 
 <7 years 37.9 36.6 
 8–10 years 44.4 44.7 
 >10 years 17.7 18.7 
Smoking status, % 
 Never 31.9 26.0 
 Former 32.3 27.6 
 Current 35.8 46.3 
Alcohol, g/daya 14.0 (0.8–62.6) 15.4 (1.4–69.7) 
 Abstainers 2.6 3.3 
Waist circumference, cm 91 (70–112) 91 (71–111) 
Recreational physical activity, %b 54.7 52.0 
Area-level socioeconomic status, % 
 Low 22.8 20.3 
 Medium 58.6 58.5 
 High 16.4 20.3 
 Missing 2.2 0.8 
Characteristics at time of diagnosis 
Age at diagnosis 64.1 (55.0–73.6) 64.1 (54.5–73.6) 
AllDeceased
N = 232N = 123
Baseline variables 
Male, % 52.6 56.9 
Education, % 
 <7 years 37.9 36.6 
 8–10 years 44.4 44.7 
 >10 years 17.7 18.7 
Smoking status, % 
 Never 31.9 26.0 
 Former 32.3 27.6 
 Current 35.8 46.3 
Alcohol, g/daya 14.0 (0.8–62.6) 15.4 (1.4–69.7) 
 Abstainers 2.6 3.3 
Waist circumference, cm 91 (70–112) 91 (71–111) 
Recreational physical activity, %b 54.7 52.0 
Area-level socioeconomic status, % 
 Low 22.8 20.3 
 Medium 58.6 58.5 
 High 16.4 20.3 
 Missing 2.2 0.8 
Characteristics at time of diagnosis 
Age at diagnosis 64.1 (55.0–73.6) 64.1 (54.5–73.6) 

NOTE: All NHL cases (all), and those who died during follow-up (deceased). Median and 5–95 percentile, unless otherwise stated.

aAmong those drinking alcohol.

bPercentage of persons who answered “yes” that they participated in a recreational physical activity.

View Large

None of the included organochlorines were significantly associated with mortality. However, there was a consistent tendency toward a nonsignificant, inverse association with PCBs, for example, ΣPCB: MRR 0.85 (0.64–1.11) per interquartile range. For pesticides, the same pattern was not seen, for example, DDE: MRR 1.03 (0.88–1.21; Table 2).

Table 2.

Adjusted MRRs and 95% CI in association with adipose PCB and pesticide concentrations in NHL cases

PCBsPesticides
NMRR (95% CI)aMRR (95% CI)bNMRR (95% CI)aMRR (95% CI)b
PCB 187 (Group 1B) p,p′-DDE 
Per IQR (24) 231 1.00 (0.78–1.30) 0.96 (0.74–1.26) Per IQR (720) 231 1.03 (0.88–1.20) 1.03 (0.88–1.21) 
 Below median 115 1.00 (ref) 1.00 (ref)  Below median 115 1.00 (ref) 1.00 (ref) 
 Above median 116 0.75 (0.51–1.09) 0.72 (0.48–1.07)  Above median 116 1.12 (0.77–1.63) 1.22 (0.81–1.82) 
PCB 201 (Group 1B) p,p′-DDT 
Per IQR (8) 218 0.90 (0.69–1.17) 0.79 (0.57–1.10) Per IQR (22) 134 0.93 (0.75–1.16) 0.93 (0.74–1.17) 
 Below median 104 1.00 (ref) 1.00 (ref)  Below median 65 1.00 (ref) 1.00 (ref) 
 Above median 114 1.01 (0.66–1.53) 0.91 (0.57–1.46)  Above median 69 0.89 (0.51–1.55) 0.83 (0.46–1.51) 
PCB 118 (Group 2A) β-Hexachlorocyclohexane 
Per IQR (22) 226 0.79 (0.62–1.01) 0.83 (0.63–1.10) Per IQR (33) 218 0.91 (0.70–1.17) 0.88 (0.67–1.16) 
 Below median 107 1.00 (ref) 1.00 (ref)  Below median 107 1.00 (ref) 1.00 (ref) 
 Above median 119 0.76 (0.51–1.12) 0.94 (0.61–1.46)  Above median 111 0.96 (0.62–1.47) 0.96 (0.61–1.52) 
PCB 156 (Group 2A) Oxychlordane 
Per IQR (14) 229 0.97 (0.78–1.22) 0.87 (0.67–1.13) Per IQR (14) 165 0.99 (0.701-.43) 0.99 (0.67–1.46) 
 Below median 112 1.00 (ref) 1.00 (ref)  Below median 79 1.00 (ref) 1.00 (ref) 
 Above median 117 0.95 (0.64–1.41) 0.80 (0.52–1.24)  Above median 86 1.37 (0.82–2.29) 1.42 (0.81–2.49) 
PCB 138 (Group 2B) Cis-Nonachlor 
Per IQR (90) 231 0.90 (0.67–1.20) 0.91 (0.68–1.22) Per IQR (5.4) 151 1.00 (0.71–1.39) 1.05 (0.73–1.51) 
 Below median 95 1.00 (ref) 1.00 (ref)  Below median 73 1.00 (ref) 1.00 (ref) 
 Above median 136 0.79 (0.54–1.16) 0.85 (0.57–1.21)  Above median 78 0.79 (0.46–1.34) 0.78 (0.44–1.38) 
PCB 170 (Group 2B) Trans-Nonachlor 
Per IQR (42) 231 0.97 (0.74–1.27) 0.81 (0.59–1.12) Per IQR (22.5) 228 0.85 (0.65–1.11) 0.84 (0.63–1.12) 
 Below median 102 1.00 (ref) 1.00 (ref)  Below median 111 1.00 (ref) 1.00 (ref) 
 Above median 129 0.92 (0.61–1.38) 0.82 (0.53–1.26)  Above median 117 0.83 (0.56–1.23) 0.80 (0.52–1.23) 
PCB 99 (Group 3) Dieldrin 
Per IQR (16) 166 0.92 (0.69–1.21) 0.87 (0.62–1.23) Per IQR (18) 137 0.87 (0.67–1.14) 0.94 (0.70–1.28) 
 Below median 79 1.00 (ref) 1.00 (ref)  Below median 67 1.00 (ref) 1.00 (ref) 
 Above median 87 0.95 (0.59–1.52) 0.85 (0.51–1.43)  Above median 70 0.97 (0.56–1.70) 1.09 (0.58–2.05) 
PCB 153 (Group 3) Hexachlorobenzene 
Per IQR (130) 232 0.95 (0.74–1.23) 0.92 (0.71–1.19) Per IQR (38) 198 0.81 (0.59–1.11) 0.78 (0.55–1.12) 
 Below median 111 1.00 (ref) 1.00 (ref)  Below median 99 1.00 (ref) 1.00 (ref) 
 Above median 121 0.89 (0.61–1.31) 0.91 (0.62–1.35)  Above median 99 0.85 (0.55–1.32) 0.84 (0.51–1.38) 
PCB 180 (Group 3) ΣChloradanes 
Per IQR (70) 232 1.01 (0.81–1.27) 0.86 (0.66–1.13) Per IQR (48.8) 228 0.87 (0.64–1.18) 0.89 (0.65–1.21) 
 Below median 106 1.00 (ref) 1.00 (ref)  Below median 114 1.00 (ref) 1.00 (ref) 
 Above median 126 0.98 (0.65–1.47) 0.83 (0.53–1.30)  Above median 114 0.78 (0.52–1.17) 0.87 (0.57–1.32) 
PCB 183 (Group 3) ΣDDT + DDE 
Per IQR (13) 219 0.94 (0.70–1.26) 0.98 (0.73–1.32) Per IQR (743) 231 1.02 (0.88–1.19) 1.02 (0.87–1.20) 
 Below median 104 1.00 (ref) 1.00 (ref)  Below median 115 1.00 (ref) 1.00 (ref) 
 Above median 115 0.84 (0.57–1.25) 0.85 (0.56–1.28)  Above median 116 1.12 (0.77–1.63) 1.22 (0.81–1.83) 
ΣPCB 
Per IQR (387.5) 232 0.90 (0.69–1.17) 0.85 (0.64–1.11)     
 Below median 116 1.00 (ref) 1.00 (ref)     
 Above median 116 0.81 (0.56–1.19) 0.80 (0.54–1.19)     
ΣPCBs suggested immunotoxic     
Per IQR (285) 232 0.94 (0.72–1.25) 0.88 (0.66–1.17)     
 Below median 113 1.00 (ref) 1.00 (ref)     
 Above median 119 0.84 (0.57–1.25) 0.79 (0.53–1.20)     
PCBsPesticides
NMRR (95% CI)aMRR (95% CI)bNMRR (95% CI)aMRR (95% CI)b
PCB 187 (Group 1B) p,p′-DDE 
Per IQR (24) 231 1.00 (0.78–1.30) 0.96 (0.74–1.26) Per IQR (720) 231 1.03 (0.88–1.20) 1.03 (0.88–1.21) 
 Below median 115 1.00 (ref) 1.00 (ref)  Below median 115 1.00 (ref) 1.00 (ref) 
 Above median 116 0.75 (0.51–1.09) 0.72 (0.48–1.07)  Above median 116 1.12 (0.77–1.63) 1.22 (0.81–1.82) 
PCB 201 (Group 1B) p,p′-DDT 
Per IQR (8) 218 0.90 (0.69–1.17) 0.79 (0.57–1.10) Per IQR (22) 134 0.93 (0.75–1.16) 0.93 (0.74–1.17) 
 Below median 104 1.00 (ref) 1.00 (ref)  Below median 65 1.00 (ref) 1.00 (ref) 
 Above median 114 1.01 (0.66–1.53) 0.91 (0.57–1.46)  Above median 69 0.89 (0.51–1.55) 0.83 (0.46–1.51) 
PCB 118 (Group 2A) β-Hexachlorocyclohexane 
Per IQR (22) 226 0.79 (0.62–1.01) 0.83 (0.63–1.10) Per IQR (33) 218 0.91 (0.70–1.17) 0.88 (0.67–1.16) 
 Below median 107 1.00 (ref) 1.00 (ref)  Below median 107 1.00 (ref) 1.00 (ref) 
 Above median 119 0.76 (0.51–1.12) 0.94 (0.61–1.46)  Above median 111 0.96 (0.62–1.47) 0.96 (0.61–1.52) 
PCB 156 (Group 2A) Oxychlordane 
Per IQR (14) 229 0.97 (0.78–1.22) 0.87 (0.67–1.13) Per IQR (14) 165 0.99 (0.701-.43) 0.99 (0.67–1.46) 
 Below median 112 1.00 (ref) 1.00 (ref)  Below median 79 1.00 (ref) 1.00 (ref) 
 Above median 117 0.95 (0.64–1.41) 0.80 (0.52–1.24)  Above median 86 1.37 (0.82–2.29) 1.42 (0.81–2.49) 
PCB 138 (Group 2B) Cis-Nonachlor 
Per IQR (90) 231 0.90 (0.67–1.20) 0.91 (0.68–1.22) Per IQR (5.4) 151 1.00 (0.71–1.39) 1.05 (0.73–1.51) 
 Below median 95 1.00 (ref) 1.00 (ref)  Below median 73 1.00 (ref) 1.00 (ref) 
 Above median 136 0.79 (0.54–1.16) 0.85 (0.57–1.21)  Above median 78 0.79 (0.46–1.34) 0.78 (0.44–1.38) 
PCB 170 (Group 2B) Trans-Nonachlor 
Per IQR (42) 231 0.97 (0.74–1.27) 0.81 (0.59–1.12) Per IQR (22.5) 228 0.85 (0.65–1.11) 0.84 (0.63–1.12) 
 Below median 102 1.00 (ref) 1.00 (ref)  Below median 111 1.00 (ref) 1.00 (ref) 
 Above median 129 0.92 (0.61–1.38) 0.82 (0.53–1.26)  Above median 117 0.83 (0.56–1.23) 0.80 (0.52–1.23) 
PCB 99 (Group 3) Dieldrin 
Per IQR (16) 166 0.92 (0.69–1.21) 0.87 (0.62–1.23) Per IQR (18) 137 0.87 (0.67–1.14) 0.94 (0.70–1.28) 
 Below median 79 1.00 (ref) 1.00 (ref)  Below median 67 1.00 (ref) 1.00 (ref) 
 Above median 87 0.95 (0.59–1.52) 0.85 (0.51–1.43)  Above median 70 0.97 (0.56–1.70) 1.09 (0.58–2.05) 
PCB 153 (Group 3) Hexachlorobenzene 
Per IQR (130) 232 0.95 (0.74–1.23) 0.92 (0.71–1.19) Per IQR (38) 198 0.81 (0.59–1.11) 0.78 (0.55–1.12) 
 Below median 111 1.00 (ref) 1.00 (ref)  Below median 99 1.00 (ref) 1.00 (ref) 
 Above median 121 0.89 (0.61–1.31) 0.91 (0.62–1.35)  Above median 99 0.85 (0.55–1.32) 0.84 (0.51–1.38) 
PCB 180 (Group 3) ΣChloradanes 
Per IQR (70) 232 1.01 (0.81–1.27) 0.86 (0.66–1.13) Per IQR (48.8) 228 0.87 (0.64–1.18) 0.89 (0.65–1.21) 
 Below median 106 1.00 (ref) 1.00 (ref)  Below median 114 1.00 (ref) 1.00 (ref) 
 Above median 126 0.98 (0.65–1.47) 0.83 (0.53–1.30)  Above median 114 0.78 (0.52–1.17) 0.87 (0.57–1.32) 
PCB 183 (Group 3) ΣDDT + DDE 
Per IQR (13) 219 0.94 (0.70–1.26) 0.98 (0.73–1.32) Per IQR (743) 231 1.02 (0.88–1.19) 1.02 (0.87–1.20) 
 Below median 104 1.00 (ref) 1.00 (ref)  Below median 115 1.00 (ref) 1.00 (ref) 
 Above median 115 0.84 (0.57–1.25) 0.85 (0.56–1.28)  Above median 116 1.12 (0.77–1.63) 1.22 (0.81–1.83) 
ΣPCB 
Per IQR (387.5) 232 0.90 (0.69–1.17) 0.85 (0.64–1.11)     
 Below median 116 1.00 (ref) 1.00 (ref)     
 Above median 116 0.81 (0.56–1.19) 0.80 (0.54–1.19)     
ΣPCBs suggested immunotoxic     
Per IQR (285) 232 0.94 (0.72–1.25) 0.88 (0.66–1.17)     
 Below median 113 1.00 (ref) 1.00 (ref)     
 Above median 119 0.84 (0.57–1.25) 0.79 (0.53–1.20)     

NOTE: Linear estimates per interquartile range (IQR) and categorical estimates above/below median.

aStratified by sex and age at diagnosis in 5-year age groups and adjusted for calendar year of diagnosis.

bStratified by sex and age at diagnosis in 5-year age groups and adjusted for calendar year of diagnosis, smoking status (never/former/current), alcohol consumption (g/day, linear), abstainer (yes/no), waist circumference (cm, linear), recreational physical activity (yes/no), education (≤7/8–10/>10 years), and area-level socioeconomic status (low/medium/high/missing).

View Large

There was no interaction between any organochlorine and sex (all P ≥ 0.08).

In this study of adipose tissue organochlorine concentrations and NHL survival, we found no association.

The study strengths include the prospective design and long and complete follow-up of participants through the well-validated Danish Civil Registration System. The precision of the organochlorine concentration analyses has been validated and found sound (8). We do thus not expect substantial measurement error of the exposure. Finally, we were able to thoroughly adjust for lifestyle factors and socioeconomic parameters known to be associated with mortality.

The study is limited by the number of cases, which restricted the statistical power. Sixty-four persons died from NHL, but we did not have power to investigate cause-specific mortality. We only had one sample for each participant, which was taken at cohort entry. The study included cases diagnosed until 2008, who were followed up until 2016; thus, for some participants, the sample was taken decades before the outcome of interest. As organochlorine concentrations might vary over time, the samples may not have been taken at the most clinically relevant time period.

In conclusion, we did not find that organochlorine concentrations were associated with subsequent mortality among NHL patients.

No potential conflicts of interest were disclosed.

Conception and design: N. Roswall, A. Tjønneland, O. Raaschou-Nielsen

Development of methodology: N. Roswall, O. Raaschou-Nielsen

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): E.V. Bräuner, A. Tjønneland, O. Raaschou-Nielsen

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): N. Roswall, M. Sørensen, O. Raaschou-Nielsen

Writing, review, and/or revision of the manuscript: N. Roswall, M. Sørensen, E.V. Bräuner, A. Tjønneland, O. Raaschou-Nielsen

Study supervision: O. Raaschou-Nielsen

This work was supported by The Danish Research Center for Environmental Health.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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2017
American Association for Cancer Research.