Organohalogen and EBV response

Case-control study on concentrations of organohalogen compounds and titers of antibodies to Epstein-Barr virus antigens in the etiology of non-Hodgkin lymphoma
Lennart Hardell* 1 MD, PhD; Mikael Eriksson 2 MD, PhD; Gunilla Lindström 3 PhD;

Bert van Bavel 3 PhD; Annika Linde 4 MD, PhD, Michael Carlberg 1 MSc, Göran
Liljegren 5 MD, PhD

1 Department of Oncology, Örebro Medical Centre, S-701 85 Örebro, SWEDEN
2 Department of Oncology, University Hospital, S-221 85 Lund
3 Department of Environmental Chemistry, Umeå University, S-901 87 Umeå
4 Department of Virology, Swedish Institute for Infectious Disease Control and Microbiology Tumour Biology Center, Karolinska Institute, S-171 82 Stockholm
5 Department of Surgery, Örebro Medical Center, S-701 85 Örebro, Sweden

Contract grant sponsors: Cancer-och Allergifonden,  Örebro County Council Research Committee, Örebro Medical Centre Foundation, Gunnar Nilsson Foundation, IngaBritt och Arne Lundbergs forskningsstiftelse, and Lions Research Foundation

*Correspondence to: Department of Oncology, Örebro Medical Centre, S-701 85
Örebro, Sweden. Fax:+46 19 101768

Key words: Non-Hodgkin lymphoma, PCB, DDE, hexachlorobenzene, chlordane, tetrabrominated diphenyl ether, Epstein-Barr virus, etiology


A rapid increase in incidence of non-Hodgkin lymphoma (NHL) has been reported from many countries. Exposure to certain pesticides and organochlorines has been shown to be risk factors. Epstein-Barr virus (EBV) is a human herpesvirus that has been associated with some subgroups of NHL, such as Burkitt lymphoma and lymphomas related to severe immunosuppression. In this study, we measured lipid adjusted blood concentrations of 36 congeners of polychlorinated biphenyls (PCBs), p,p´-dichloro-diphenyl-dichloroethylene (p,p´-DDE), hexachlorobenzene (HCB), four different subgroups of chlordanes (trans-nonachlordane, cis-nonachlordane, MC6 and oxychlordane) and 2,2',4,4'-tetrabrominated diphenyl ether (TBDE) in incident cases of NHL and controls from the general population. Titers of antibodies to the Epstein-Barr early antigen (EA) were correlated to concentrations of organochlorines. We found a significant difference in lipid adjusted blood concentrations of total PCBs and TBDE between cases and controls. Titers of antibodies to EA IgG > 80 were correlated to an increased risk for NHL with odds ratio (OR) = 1.9, 95% confidence interval (CI) =0.94-3.8. This risk was further increased in those with a level above the median value of “sum of PCBs� (OR=4.0, CI=1.2-14), HCB (OR=5.3, CI=1.6-19), sum of chlordanes (OR=4.0, CI=1.2-14) and TBDE (OR=21, CI=4.6-124), suggesting an interaction between EBV and a higher concentration of these chemicals. Also for the “sum of immunotoxic PCBs� increased risk was found in that group (OR=6.4, CI=1.9-24). Subdivision of NHL in histological types yielded highest risks for low-grade B-cell NHL.


A rapid increase in incidence of non-Hodgkin lymphoma (NHL) during the last 20-30 years has been reported in many Western countries.(1-3) Several studies have shown pesticide exposure to be a risk factor for NHL.(4,5)  Conditions characterized by immunosuppression such as immunosuppressive treatment after organ transplantation, severe inborn immunodeficiencies and HIV-infection have been reported to increase the risk for NHL. (4,6,7) Some factors evaluated as possible risk factors for NHL, such as exposure to organochlorines, have been reported to induce immunological changes.(8-10) Epstein-Barr virus (EBV) is a human herpesvirus with a tropism for B-lymphocytes, and the virus is found worldwide. The majority of the world's adult population has antibodies to EBV antigens. The primary infection usually occurs during childhood and is often subclinical. After the primary infection, a latent infection is established, which is balanced by the immune response by the host, and among others antibodies to the Epstein-Barr Early antigen (EA), Viral Capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) may be detected.(11)

EBV has been associated with certain types of NHL such as Burkitt lymphoma and lymphomas occurring in immunologically compromised or HIV-infected subjects.(12)

Polychlorinated biphenyls (PCBs) are aromatic chemicals that are very stable in the environment. They do not occur naturally but have been widely used in electrical equipment and building constructions because of their physical properties. Theoretically, 209 congeners are possible, but only about 130 of these are likely to occur in commercial products.

Humans are exposed to PCB mainly through the food chain by consumption of contaminated fish, meat and dairy products. In humans, PCB is stored mainly in the adipose tissue.(13) PCB was used in Sweden until 1973 when use was prohibited by law.

Exposure to PCB has been suggested to induce measurable changes in the immune system,(8,14) although in doses higher than background exposure. Increased concentrations of some specific PCBs in patients with NHL compared with controls has been shown.(15) In another study, a dose-response relation between lipid-corrected concentrations of total PCB (quartiles) and risk of NHL overall was found.(16)

Flame-retardants such as polybrominated diphenyl ethers (PBDEs) have been increasingly used since the 1970's and are environmental hazards identified more recently.(17,18) They are halogenated aromatic compounds just as PCBs and may exert similar toxicological effects.(19,20)  In our previous study we reported increased concentrations of  2,2',4,4'-tetrabrominated diphenyl ether (TBDE), one congener of PBDE, in patients with NHL.(21)

DDT is an insecticide that has been widely used because of its chemical stability. DDT and its metabolites p,p'-dichlorodiphenyldichloroethyelene (p,p´-DDE) and DDD are lipid soluble and bioaccumlate. No association has been found between exposure to DDT or concentrations of p,p´-DDE and NHL in epidemiological studies.(5,15-17,22,23)

Hexachlorobenzene (HCB) has been used in agriculture as a fungicide and occurs also in industry as an intermediate in chemical processes. HCB has been found as a contaminant in pesticides.(24) In a previous study, no association between HCB and NHL was found.(15)

Chlordanes are substances originating from synthesis of cyklodienes and have been described to be distributed throughout the biosphere. Technical chlordane has been used both in agriculture and in the control of termites. Production of chlordane started in USA in 1947 and chlordanes were registered in Sweden until 1969. Also these compounds are stored mainly in adipose tissue. Exposure to chlordane has been suggested to induce immunological changes measured in lymphocyte functions in vitro.(9) An association between chlordanes and NHL has been suggested(25)

The purpose of this investigation was to determine concentrations of these organohalogen compounds in a larger sample of patients with NHL and population based controls. We also wanted to correlate concentrations of these substances to titers of antibodies to EBV. Ethical committee approved the study.

Material and Methods

Case and control ascertainment

In the first phase of this study adipose tissue samples were obtained from the abdominal wall of incident NHL patients. Approximately 2-10 g adipose tissue was taken in local anesthesia. As controls, patients operated for a benign lesion at the Department of Surgery at the Örebro Medical Center Hospital were used. During that procedure an adipose tissue sample was taken from the abdominal wall. They were in the same age group (within 5 year interval) and of the same sex as the NHL patients and without a cancer diagnosis. This part of the study consisted of 50 cases and 47 controls. All these cases and controls were recruited during the same time period, 1994-97.

They were all living in the catchment area of the Örebro-Uppsala medical region. The first results of this part of the study have been previously reported.(15,21,25)

In the second part of the study, blood samples were taken from 32 incident patients with NHL during the time period 1997-99. Of them 16 were derived from the Department of Oncology at the Örebro Medical Center and 16 from the Department of Oncology at the University Hospital in Lund. After informed consent approximately 50 ml of blood was drawn in glass tubes with heparin. The blood was centrifuged and plasma was frozen in glass bottles for later analysis. One control in the same age group as the case (5-year interval) and same sex was recruited to each case from the Population Register. They were sent a letter asking for participation in the study. Glass tubes were then sent for blood sampling at the nearest medical department. In total 21 controls from the Örebro region and 15 from the Lund region were included.

Altogether, both parts of this study encompassed 82 cases and 83 controls. For technical reasons results were not available for included persons. From the majority of these subjects, blood was also drawn for analysis of antibodies to EBV-antigens. In total, this was done for 145 subjects, 67 cases and 78 controls.

All samples were assigned a unique id-number, which did not show if it was from a case or a control. Case or control identity was disclosed during the statistical analysis of the results.

The participants were sent a questionnaire, asking detailed questions about previous occupations and exposure to potential risk factors, such as pesticides. Also length and weight at the time of sampling of adipose tissue or blood was assessed. Additionally the weight one-year before the time when blood was drawn was asked for since weight might be changed during the development of NHL. The questionnaire was answered by all cases and all but one control. Body Mass Index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters.

All cases were recruited by two of us (LH and ME) from our clinics. No case with NHL refused to participate. Controls for adipose tissue sampling at the surgical department were included on a consecutive basis by one of us (GL) when a control patient fulfilling the inclusion criteria was identified. No control subject refused to participate.

EBV antigens

Antibodies to different EBV antigens were analyzed as earlier described.(26) In brief, indirect immunofluorescence (IF) was used for IgG and IgM antibodies to the virus capsid antigen (VCA) and the combined restricted and diffuse components of early antigens (EA R+D). The VCA IgG antibodies were end-point titrated in four-fold dilutions from 1/20, while EA IgG was analyzed in one dilution, allowing for detection of antibodies in serum dilution ³1/40 (titre ³1/40). Positive samples were end-titrated. EBNA-1 IgG antibodies were screened in a peptide ELISA with the alanine-glycine repeat as antigen. The EA and VCA IgG titres found in healthy Swedes with the used methods have been published previously.(26) The samples were coded at examination, and blinded for if they were derived from a case or a control person. The completed results were uncoded by the clinicians, and titers and seroprevalences in cases and controls were compared statistically.

Analysis of organohalogen compounds

Approximately 20 ml of blood plasma was used for analyses of 36 PCB congeners, p,p´-DDE, HCB, four chlordane congeners and TBDE. The plasma samples and blank samples were fortified with 13C-labelled internal standards. The lipid fraction, including the organochlorines, was first removed from the plasma by use of a Hydromatrix column.(27) The lipid content was then determined gravimetrically and further cleaned up by multi-layer silica chromatography. Congener specific analyses and quantification of the organochlorines were done by high-resolution gas chromatography and mass spectrometry, HRGC-MS, running in EI and SIM mode. The methods detection level, MDL, was in the range of 0.3-1 pg/g for the various analytes and samples. All results are expressed in ng/g lipid.

Statistical methods

Unconditional logistic regression was performed using the SAS system (SAS Institute, Cary, NC) for calculation of odds ratio (OR) and 95% confidence interval (CI). In the analyses adjustments were made for age, sex, Body Mass Index (BMI) at the time of sampling, and specimen analyzed (adipose tissue sample or blood). Antibody variables and organohalogen variables were dichotomized using the median concentration of the controls. The SAS System was also used for descriptive statistics and Wilcoxon rank sum tests. In one of the analyses, PCBs were grouped according to immunotoxic properties for the detected PCBs (PCBs #66, 110, 105, 118, 74, 128/167, 156, 138, 170/190) as suggested by Moysich et al.(27)


Results for the sum of PCBs (36 congeners), sum of chlordanes (oxychlordane, MC6, trans- and cis-nonachlordane), p,p'-DDE, HCB, TBDE and antibody titers to EBV antigens are presented for 165 subjects, 82 cases and 83 controls. Of the cases 45 were men and 37 women and of the controls 48 were men and 35 were women. The mean age for the cases was 62.5 years (range 29-90 years) and for the controls 62.3 years (range 30-81 years). The age for one case was high, 90 years old, the next highest age for a case was 83 years. Exclusion of the 90-year-old case from the analyses did not change the results. Furthermore, no titers to EBV antigens were available for that case.

The following results are based on all 82 cases and 83 controls. Analyses of chlordanes was missing for one case for technical reasons. For TBDE, results were obtained for 53 cases and 65 controls since these chemical analyses were not available at the start of this study, c.f. Hardell et al.(15,25) Regarding interaction between organohalogen compounds and titers to EBV antigens the results were based on 67 cases and 78 controls, however for TBDE on 44 cases and 59 controls.

Concentrations of organohalogens for cases and controls are shown in Table I.

Significantly higher concentrations of the sum of PCBs (36 congeners), immunotoxic PCBs (11 congeners), and TBDE were found among the cases. The sum of chlordanes did not differ significantly between cases and controls, whereas the concentrations of MC6 and cis-nonachlordane were significantly higher in the cases.

HCB and TBDE did not correlate with the other study compounds. Some correlation was found between PCB and pp-DDE (cases rr=0.58, controls rr=0.61), PCB and chlordane (cases rr=0.69, controls rr=0.49), and pp-DDE and chlordane (cases rr=0.74, controls rr=0.33).

Analysis was also performed using the median level of organohalogens among the controls as cut-off. Adjusted ORs and CIs are presented in Table II. Significantly increased OR was found for immunotoxic PCBs (OR=3.2, CI=1.4-7.4), HCB (OR=2.3, CI=1.1-4.7) and TBDE (OR=11, CI=3.9-35).. In a multivariate analysis only TBDE remained as a significant risk factor, Table III. Including immunotoxic PCBs instead of the sum of all PCBs in the multivariate analysis yielded similar results. However, higher OR was calculated for immunotoxic PCBs than for the sum of all PCBs (OR=2.1, CI=0.56-9.0).

Data for antibodies to EBV-antigen in the subset of 67 cases and 78 controls are presented in Table IV. The median titer to EA IgG was higher among cases than controls. This produced an OR=1.9 (CI=0.94-3.8), Table V.

Results of analysis of interaction between titer of EA IgG and organohalogens are presented in Table VI. For all studied compounds the highest risk was found in the high concentration group and titer to EA IgG >80. Regarding sum of PCBs highest risk was found for immunotoxic PCBs (OR=6.4, CI=1.9-24).. No clear pattern of interaction between EA IgG and p,p-DDE was found and the risk was not significantly increased in the high exposure group (OR=2.9, CI=0.93-9.7).  A high risk was found for TBDE in the high exposure group with EA IgG >80 (OR=21, CI=4.6-124).

Of the 82 NHL cases 78 patients had B-cell lymphoma, 3 had T-cell lymphoma and for one case the type of NHL could not be determined. B-cell lymphoma was further divided in low-grade, 36 cases, and high-grade, 40 cases. For 2 cases the type of B-cell lymphoma could not be determined. Tables VII and VIII show that the highest risks in this study were found for low-grade B-cell lymphoma.


The now studied organohalogens are fat-soluble chemicals that bioaccumulate in the human body. For p,p´-DDE the half-life in plasma is approximately 10 years(28) and for chlordanes 10-20 years.(29) For HCB no half-life time in humans is documented. Regarding PCBs serum concentrations were measured twice during a 46-month interval among capacitor manufacturing workers. The half-life of PCBs was estimated to be between 7-30 years.(30) Thus it is possible to estimate previous exposure by measurement of lipid based concentrations of certain organohalogens.

Collection of adipose tissue and blood was performed during the same time period for cases and controls. Hence, bias of the results due to changes of the concentrations of organohalogens in the population over time was avoided.(31) Individual changes over time have been little studied, but in an investigation of non-occupational exposures, chlorinated hydrocarbons were measured in healthy women at two times with an average of 2 months apart. It was concluded that measurements of organochlorines are stable over a short time period.(32)

Changes in body weight might influence concentrations of organohalogens. Furthermore, the concentrations increase with age. Thus adjustment was made for BMI and age at the time of sampling of adipose tissue or blood. BMI was calculated for cases and controls also one year before the date of specimen sampling. No significant difference of BMI between cases and controls was found during that time period and the results were similar as now presented..

Thus, these results were not influenced by changes in body weight in cases and controls. All specimens from NHL cases were taken before any treatment in order to avoid potential influence of chemotherapy or radiation on the results.

Our now presented results confirm our previous results of increased risk for NHL associated with PCBs, chlordanes and TBDE.(15,21,25) Furthermore an increased risk was found for HCB. We found the highest risk in the high exposure group with elevated titer of EA IgG. An interaction between elevated EA IgG and PCBs (with highest risk for immunotoxic PCBs), HCB, chlordanes, and TBDE was found. Interestingly, when analyzing the chemicals only without considering EBV infection lower risk estimates were obtained. This suggests an interaction between these chemicals and EBV. An excess risk of malignant lymphoma/leukemia has been shown in a large Finnish cohort of subjects with elevated EA and EBNA-antibody titers.(33) In another study a dose-response effect was seen with increasing risk with increasing concentration of PCBs and interaction with EBV was suggested.(16)

An increased risk for NHL has also been suggested for high consumers of fish from the Baltic sea known to be contaminated by PCBs and other organochlorines.(34) In one study of male capacitor-manufacturing workers with PCB exposure an increased risk for NHL was found(35) whereas no increased risk was seen in another study.(36) Our current findings were not explained by occupational exposure as assessed by questionnaires.

In a case-control study on NHL an increased risk was found for farmers exposed to chlordanes,(37) whereas no increased risk for lymphatic malignancies was found in a cohort of chlordane and heptachlor applicators.(38)

A pooled analysis of three case-control studies in USA concluded that exposure to DDT was no risk factor for NHL(23) and similar results were found in Swedish case-control studies on NHL.( 5,22) In this study we did not find any clear pattern of interaction between concentration of p,p-DDE, the main metabolite of DDT, and titers of EA IgG. .

Recently we have published an interaction between PCBs, HCB, pp-DDE, chlordanes, and elevated titer of EA IgG in the etiology of hairy cell leukemia,(39) a B-cell malignancy which is included among different subtypes of NHL.(40) Our current results on NHL are in agreement with these results.


  The authors thank Lotti Schloss for serological analyses, and Ms Iréne Larsson for secretarial assistance. Karin Hardell, MSc, assisted in the chemical analyses.


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