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Vol. 7, 181-1 88, March 1998 Cancer Epidemiology, Biomarkers & Prevention 181
Environmental Organochiorine Exposure and Postmenopausal
Breast Cancer Risk’
Kirsten B. Moysich,2 Christine B. Ambrosone,John E. Vena, Peter G. Shields, Pauline Mendola,Paul Kostyniak, Hebe Greizerstein, Saxon Graham,James R. Marshall, Enrique F. Schisterman, andJo L. Freudenheim
Department of Social and Preventive Medicine, School of Medicine andBiomedical Sciences [K. B. M., J. E. V., P. M., S. G., E. F. S., J. L. F.] and
Toxicology Research Center [P. K., H. 0.], State University of New York atBuffalo, Buffalo, New York 14214; Arizona Cancer Center, Tucson, Arizona
85724 [J. R. M.]; National Cancer Institute, Bethesda, Maryland 20892[P. G. S.]; and National Center for Toxicological Research, Jefferson, Arizona72079 [C. B. A.]
Abstract
Environmental exposure to organochlorine compoundshas been associated with a potential role in breast canceretiology, but results from previous investigations yieldedinconsistent results.
In this case-control study, we examined the effect of1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE),hexachlorobenzene (HCB), mirex, and several measuresof polychlorinated biphenyls (PCBs) on postmenopausalbreast cancer risk.
The study sample included 154 primary, incident,histologically confirmed, postmenopausal breast cancer
cases and 192 postmenopausal community controls. Usualdiet, reproductive and medical histories, and otherlifestyle information was obtained by an extensive inperson interview. Serum levels (ng/g) of DDE, HCB,mirex, and 73 PCB congeners were determined by gaschromatography with electron capture. PCB exposurewas examined as total measured PCB levels, total number
of detected PCB peaks, and three PCB congener groups.In the total sample, there was no evidence of an
adverse effect of serum levels of DDE [odds ratio (OR),1.34; 95% confidence interval (CI) 0.71-2.55], HCB (OR,0.81; 95% CI, 0.43-1.53), or mirex (OR, 1.37; 95% CI,0.78-2.39). Further, higher serum levels of total PCBs
(OR, 1.14; 95% CI, 0.61-2.15), moderately chlorinatedPCBs (OR, 1.37; 95% CI, 0.73-2.59), more highlychlorinated PCBs (OR, 1.19; 95% CI, 0.60-2.36), orgreater number of detected peaks (OR, 1.34; 95% CI,0.72-2.47) were not associated with increased risk. There
Received 8/12/97; revised I l!24/97; accepted 12/1 1/97.
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.
I Supported in part by Grants DAMD1 7-94-J-4108, CAl 1535, and CA/ES 62995from the National Cancer Institute.
2 To whom requests for reprints should be addressed, at Department of Social andPreventive Medicine. State University of New York at Buffalo. 270 Farber Hall,
Buffalo, NY 14214. Phone: (716) 829-2975; Fax: (716) 829-2979; [email protected].
was some indication of a modest increase in risk forwomen with detectable levels of less chlorinated PCBs
(OR, 1.66; 95% CI, 1.07-2.88). Among parous womenwho had never lactated, there was some evidence forincreased risk, associated with having detectable levels ofmirex (OR, 2.42; 95% CI, 0.98-4.32), higher serumconcentrations of total PCBs (OR, 2.87; 95% CI, 1.01-7.29), moderately chlorinated PCBs (OR, 3.57; 95% CI,1.10-8.60), and greater numbers of detected PCBcongeners (OR, 3.31; 95% CI, 1.04-11.3).
These results suggest that an increase in risk ofpostmenopausal breast cancer associated withenvironmental exposure to PCBs and mirex, if at allpresent, is restricted to parous women who had neverbreast-fed an infant.
Future studies should consider lactation history ofparticipants, as well as use similar epidemiological andlaboratory methodologies, to ensure comparability ofresults across studies.
Introduction
Environmental factors have been implicated in breast cancer
etiology, due to the steady increase in incidence over the last
decades ( 1), regional and international differences in incidence,and observed changes in incidence rates in migrant populations
(2). One group of environmental exposures that has been ex-amined in relation to breast cancer are organochlorine corn-
pounds, such as DDE,3 the major metabolite of DDT, PCBs,
HCB, and mirex. From the early l940s to 1972, DDT was one
of the most widely used chemicals for controlling insect pests
on agricultural crops and for controlling insects that carry
diseases such as malaria and typhus. PCBs have been manu-
factured commercially since 1929 for a variety of applications,
including use as dielectrics in transformers and capacitors and
for cooling fluids in hydraulic systems. HCB is a widespreadchlorinated hydrocarbon originating from agricultural and in-
dustrial sources. It was originally used as a fungicide, but
currently, the major source of HCB is industrial emission as a
side product related to the manufacture of organochlorinated
products. Mirex was extensively used in the southeastern
United States for the control of the red fire ant and as a fire
retardant coating for various materials. Although commercialproduction of all of these compounds was banned in the early
19705, measurable levels of organochlorine residues are stillfound in human tissue and blood samples. This persistence hasbeen attributed to their slow metabolism and high lipid solu-
bility, leading to storage in adipose stores, including breast
3 The abbreviations used are: DDE. I.l-dichloro-2.2-bis(p-chlorophenyl)ethyl-
ene: DDT, 2.2-bis(p-chlorophenyl)- I , 1 . I -trichloroethane: PCB. polychlorinated
biphenyl; HCB, hexachlorobenzene: LOD. limit of detection: OR. odds ratio: CI.
confidence interval.
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182 Organochlorines and Breast Cancer Risk
tissue. The primary route of excretion for these compounds for
women is lactation (3).Evidence from laboratory studies has demonstrated a com-
plex diversity of biological effects associated with these com-pounds. DDE, HCB, mirex, and some PCB congeners have
been associated with induction of cytochrome P450 enzymes(4-9), which may or may not be associated with estrogenic(10-14) and antiestrogenic effects (12) shown in some inves-tigations. Studies have also noted changes in immune responses(15-17) and tumor-promoting effects (4, 7, 18-20).
The body of evidence on the effect of organochlorines on
breast cancer risk is limited (21-30). Several studies comparedorganochlorine concentrations in neoplastic tissue with tissuelevels of women with benign breast disease or women who diedin accidents (21-25). Results from these mammary tissue stud-ies are inconsistent and were hampered by several methodolog-ical limitations, including small sample size and absent or
inadequate control for known breast cancer risk factors.Only recently, several epidemiological studies examined
this risk relationship with more precision (26-30). Wolff et a!.(26) examined DDE and total PCB concentrations in sera from
58 breast cancer cases and 1 7 1 controls. Although risk wasassociated with higher levels of serum DDE, there was no
evidence of a linear relationship with greater body burden ofPCBs. Increased risk, either statistically significant or of bor-
derline significance, was observed for all PCB exposure levelsabove the lowest. A nested case-control study was also con-
ducted by Krieger et a!. (27), consisting of 150 breast cancercases from three ethnic groups (Caucasian, African-American,
and Asian) and 150 matched controls, all of whom had bloodsamples stored in the late 1960s. No excess risks of breastcancer in association with serum levels of DDE and total PCBswere observed for the total sample, although there was some
evidence for nonsignificant increases in risk for Caucasian andAfrican-American women with higher DDE levels. More re-cently, a European study compared DDE adipose tissue levelsof 265 postmenopausal women with breast cancer to DDElevels of 341 controls (28). Participants were recruited in study
centers in Germany, the Netherlands, Northern Ireland, Swit-zerland, and Spain. Results indicated that mean adipose tissuelevels were lower among women with breast cancer than incontrols, and no increase in risk was observed in associationwith higher DDE body burden. Similarly, in a Mexican study
(29), no difference in mean serum concentrations of DDE andp’p’-DDT were found between 141 breast cancer patients and141 hospital controls, nor were higher serum levels of these
compounds related to increased risk. Finally, a case-controlstudy nested within the Nurses’ Health Study cohort was con-
ducted among 236 women with breast cancer and 236 controls(30). Blood samples were obtained before breast cancer wasdiagnosed in the case group. There was no evidence for greaterrisk of breast cancer among women with higher plasma levels
of DDE or PCBs.In this case-control study, we examined the overall asso-
ciation between serum levels of DDE, HCB, mirex, total PCBs,
and PCB congener groups and risk of postmenopausal breastcancer, and possible effect modification by history of lactation.This research adds to the existing body of evidence in severalways: first, the effect of organochlorines on breast cancer risk
was examined in a group homogenous with respect to meno-
pausal status, postmenopausal women; second, because of alarger sample size, we were able to determine the effects ofthese compounds in subgroups of women, defined by history of
lactation; third, because of the availability of the extensive
questionnaire data, we were able to adjust risk estimates for all
known and suspected confounders; fourth, all risk estimateswere adjusted for serum lipids; and fifth, we were able to
examine the effect of PCBs in much greater detail, due to the
availability of congener specific data.
Materials and Methods
The effect of environmental exposure to organochlonnes onbreast cancer risk was examined in a subset of participants from
a case-control study of postmenopausal breast cancer. A moredetailed description of this study population has been publishedelsewhere (31). Briefly, women in this study were enrolledfrom 1986 to 1991 in Erie and Niagara counties in western NewYork. Included were 439 postmenopausal breast cancer casesand 494 postmenopausal community controls between the agesof 41 and 85 years. All participants were Caucasian. Cases were
identified from most area hospitals and were interviewed within2 months of diagnosis. Of the eligible 777 women with breast
cancer, 439 (56.5%) were interviewed. The primary reason for
nonparticipation was physician refusal. Controls were 1076female residents of the two counties; names were obtained fromHealth Care Finance Administration and New York State De-partment of Motor Vehicles records. Of the eligible postmeno-pausal women, 494 (45.9%) agreed to participate. Cases andcontrols were interviewed in person by trained interviewers.
The interview took approximately 2 h to complete and includedassessment of medical history, reproductive history, occupa-tional history, exposure to exogenous hormones, family history
of cancer, and a food frequency questionnaire that assessedusual intake 2 years prior to the interview.
Of women who provided usable interviews, approximately63% agreed to donate a blood sample. Blood was drawn for 262
postmenopausal breast cancer cases and 3 19 controls. Bloodsamples from most women with breast cancer were collected
within 3 months of surgery. Blood was processed immediately
in the laboratory staffed by a trained laboratory technician and
placed in a freezer. Since collection, the saved samples haveremained frozen at -70#{176}C.A subset of the stored blood spec-
imens was used for these toxicological analyses: 154 womenwith postmenopausal breast cancer and 192 controls. Caseswere only included in the final study sample if their blood was
drawn before chemotherapy or radiation, and within 3 monthsof surgery. Controls were frequency matched to cases by date
of blood draw (±3 months) and age (±3 years).
Laboratory Methods. The laboratory analyses were per-formed by the Toxicology Research Center Analytical Labora-tory at State University of New York at Buffalo. The concen-trations of DDE, HCB, mirex and 56 PCB peaks, representing
73 congeners, in the serum samples were determined by themethod of Greizerstein et a!. (32). The procedures includestandardized extraction, clean-up, and quantification by high-
resolution gas chromatography and comprehensive quality as-surance program to minimize systematic and random errors.Trained and blinded laboratory technicians used 2 g of serum
by weight to determine levels of DDE, HCB, mirex, and PCBcongeners, measured in ng/g of serum. The sample was mixedwith solutions containing International Union of Pure and Ap-plied Chemistry (IUPAC) isomers 46 and 142 (surrogate stand-
ards). Methanol was added to precipitate the proteins, and theresulting mixture was extracted with hexane. The extract was
concentrated and then cleaned by passing through a Florisil
column. The eluate was evaporated to a small volume, andisomers 30 and 204 were added as internal standards. An
aliquot of the mixture was injected into the gas chromatographequipped with an electron capture detector. Quantification was
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Cancer Epidemiology, Biomarkers & PreventIon /83
based on calibration standards and response factors calculatedusing purchased reference materials. The quality control activ-
ities consisted of analyses of samples in batches of 6-10
simultaneously with quality control samples. The quality as-
surance program checked that the procedures were under con-
trol by the use of control charts and set the criteria for data
acceptability. The LOD for each analyte was determined as themean of background noise plus 3 SDs in five reagent blank
samples. The LODs for the major analytes were 0.09 ng/g for
DDE, 0. 12 ng/g for HCB, 0.06 ng/g for mirex, and 0.09 nglg for
PCB congener 153, a congener that was detected in the sera ofall participants. The Toxicology Research Center participates inthe Great Lakes Research Program Quality Assurance/Quality
Control Program sponsored by the Agency for Toxic Sub-
stances and Disease Registry and in the Northeast/Mid-AtlanticBreast Cancer Quality Assurance/Quality Control Study.
Statistical Analyses. Risk of breast cancer was examined for
serum DDE, HCB, mirex, and PCBs. The effect of PCBs on
risk was examined using several measures of PCB exposure.
First, the detected levels of the 56 PCB peaks were added toobtain a measure of total PCBs. Second, the number of detected
PCB peaks was determined to obtain an alternative measure of
total PCB exposure. Third, three groups of PCB congeners were
determined by adding the detected levels of less chlorinated
PCB congeners (IUPAC numbers 6, 7 + 9, 18, 19, 22, 23, 33,15 + 17, 16 + 32, 25 + 50, 31 + 28, 40, 45, 49, 52, 55, 60,
64, 70, 42 + 59, 47 + 48, 66 + 95, and 77 + 1 10), moderatelychlorinated PCB congeners (IUPAC numbers 87, 97, 99, 101,118, 151 + 82, 129, 134, 135, 136, 138, 147, 149, 153, 141 +
179, 128 + 167, 171 + 156, 172, 176, 177, 180, 183, 185, 187,
188, 174 + 181), and more highly chlorinated PCB congeners
(IUPAC numbers 194, 195, 200, 203, 205, 206). Grouping wasbased on biological activity, as well as on data availability. In
our initial attempts to group these compounds (e.g. , by enzymeinduction or estrogenic activity), we discovered that mostwomen had no detectable levels for these highly reactive con-
geners. Thus, our decision to group by degree of chlorinationwas in part driven by the fact that we had available data for all
participants.
Descriptive analyses included Student’s t tests of means
for cases and controls for lifestyle, reproductive, and dietaryvariables, and �2 tests for categorical variables. Multivariate
ANOVA was used to obtain age and lipid adjusted means forthe organochlorine variables. ORs were calculated by uncon-ditional logistic regression with 95% CIs computed from the SE
of the regression coefficient. Most exposure categories were
examined in tertiles, based on the distribution of the individual
compounds in the controls. Serum mirex levels were dichoto-mized into detectable and nondetectable levels (referent) be-
cause of the small number of women with detectable levels(27.3%). For the less chlorinated congeners, women with levels
below the LOD (30.1%) served as the referent group and werecompared to women in the lower and upper halves of women
with detectable levels. ORs were adjusted for potential con-
founders, including age, education, family history of breast
cancer, parity, quetelet index, duration of lactation, age at first
birth, years since last pregnancy, fruit and vegetable intake, and
serum lipids. Covariates were only included in the final regres-sion model if they were established risk factors in these data or
changed the observed risk estimate by at least 15%. Lipidadjustment was modeled after the method described by Phillips
et a!. (33), in a study in which serum triglycerides and totalcholesterol levels were used to estimate total serum lipid con-
tent. To determine and describe effect modification by lacta-
lion, which was expected, due to differences in elimination of
organoch.lorines, women were also stratified by lactation his-
tory, excluding nulliparous women (n = 48). Subgroup analy-
ses were not performed for the less chlorinated PCB congeners
because lactation is not likely to be an important route of
excretion of these compounds in that they are metabolized
within weeks to months after exposure (34-36).
Results
Descriptive characteristics for cases and controls are shown inTable 1 for the total study population and stratified by history
of lactation. In the total study population in this nested study,cases and controls did not differ significantly with respect to
demographic, reproductive, and dietary variables. Cases weremore likely to have a positive family history of breast cancer
and less likely to reside in rural areas than controls. Amongwomen who had never lactated, cases and controls were very
similar for most of these descriptive variables, with the excep-
tion of significantly older age of menopause for cases. Simi-larly, among women who had lactated, we observed few dif-
ferences between the study groups. Cases were more likely to
have a family history of breast cancer, consumed fewer vege-
tables, and were less likely to reside in rural areas than controls.Serum concentrations, adjusted for age and serum lipids,
of DDE, HCB, mirex, and PCBs in the entire study populationand in the lactation groups are presented in Table 2. Again,nulliparous women were excluded from these subgroup analy-
ses. In the total sample, cases tended to have slightly higher
mean serum organochlorine concentrations than controls, with
the exception of HCB. Among women who had never lactated,
cases had higher serum levels of all compounds under investi-
gation. Although these differences in means were of greater
magnitude than in the total study sample, none were statisticallysignificant. In contrast, among women who had ever lactated,
cases had slightly lower levels than controls of most of thesecompounds, with the exception of total number of PCB con-
gener peaks detected and more highly chlorinated PCBs.Risk of postmenopausal breast cancer associated with en-
vironmental exposure to DDE, HCB, and mirex is shown inTable 3. In the total sample there was no evidence of greater
risk of breast cancer for women with the highest serum levels
of DDE (third tertile OR, 1.34; 95% CI, 0.71-2.55) and HCB(third tertile OR, 0.81; 95% CI, 0.43-1.53) or with detectablelevels ofmirex (OR, 1.37; 95% CI, 0.78-2.39). Among women
who had never lactated, there was a suggestion of excess risk
among women in the second and third tertile of the DDE
distribution (OR, 1.95; 95% CI, 0.58-6.67; and OR, 1.83; 95%CI, 0.63-5.33, respectively). However, further adjustment forserum PCB levels reduced the magnitude of these estimates[OR, 1.61; 95% CI, 0.61-6.01 and OR, 1.32; 95% CI, 0.59-4.08, respectively (data not shown)]. Similarly, in this group,there was some evidence for an increase in risk as a function of
increasing HCB levels (third tertile OR, I .79; 95% CI, 0.59-
5.40), but again, further adjustment for serum PCBs substan-
tially reduced this estimate (OR, I .2 1 ; 95% CI, 0.50-4. 1 1 ; data
not shown). Among women who had never lactated, those with
detectable levels of mirex had a marginally significant 2-foldincrease in risk compared to women with no detectable levels.
This effect persisted after serum PCBs and DDE levels were
entered into the model. Among women who ever lactated, therewas no association with risk and serum DDE and mirex. As for
HCB, inverse associations were observed among women with
higher HCB levels, which were most pronounced and statisti-
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184 Organochlorines and Breast Cancer Risk
Table 1 Characteristics of postmenopausal breast cancer cases and community controls, westem New York, 1986-1991
Total Never lactated” Ever lactated
Characteristic Cases Controls � Cases Controls � Cases Controls
(n - 154) (n = 192) (n 46) (n 61) (n 85) (n 106)
Age” 64.1 (7.7) 63.2 (7.6) NS’ 63.9 (5.9) 60.8 (7.6) NS 64.5 (8.1) 64.8 (7.2) NS
Education (yr)” 12.5 (2.8) 12.2 (2.6) NS 12.5 (1.8) 12.4 (2.6) NS 12.5 (3.0) 12.0 (2.6) NS
Quetelet index” 25.7 (4.9) 25.9 (5.3) NS 26.1 (6.3) 26.1 (6.0) NS 25.6 (4.2) 26.1 (4.7) NS
Age at menarche5 12.9(1.6) 12.9(1.6) NS 12.8(1.5) 12.9(1.7) NS 13.0(1.6) 12.8(1.5) NS
Age at menopause5 47.5 (5.7) 47.0 (5.9) NS 47.8 (5.9) 45.5 (5.4) 0.� 47.9 (5.6) 47.5 (5.7) NS
Age at first pregnancy” 24. 1 (4.8) 23.4 (4.3) NS 24.4 (4.6) 24.3 (4.5) NS 23.7 (4.7) 22.8 (4.2) NS
Number of live births(�.b 3.2 ( 1 .9) 3.4 ( 1 .9) NS 3.4 ( 1 .7) 3.0 ( I .5) NS 3.3 (2.0) 3.7 (2.0) NS
Years since last lactation5t 33.8 (9.9) 33.9 (8.6) NS NA NA NA 33.8 (9.9) 33.9 (8.6) NS
Months of lactationbf 8.6(13.1) 10.20(12.4) NS NA NA NA 8.6(13.1) 10.2 (12.4) NS
Benign breast diseases 23% 20% NS 26% 15% NS 21% 20% NS
Family history of breast cancers 18% 9% 0.02 13% 10% NS 20% 9% 0.04
Fruit (g/month)��h 8420 (5250) 8720 (5000) NS 7010 (4460) 7290 (4130) NS 8830 (5210) 9630 (5400) NS
Vegetables (g/month)i�h 12680 (5230) 13980 (7340) NS 12160 (5300) 12200 (4960) NS 12790 (5230) 14890 (8400) 0.05
Dairy (g/month)’� 8480 (6320) 7840 (6180) NS 6970 (5140) 7720 (7440) NS 9360 (6580) 7890 (5750) NS
Fish (g/month)’� 787 (586) 833 (621) NS 766 (597) 877 (529) NS 773 (582) 791 (666) NS
Meats (g/month)55 1640 (940) 1720 (1000) NS 1540 (840) 1800 (930) NS 1710 (1040) 1680 (1040) NS
Residence”’
Urban 36% 31% 33% 39% 38% 26%
Suburban 60% 53% 56% 44% NS 61% 57%
Rural 4% 16% 0.01 1 1% 17% 1% 17% 0.001
Occupation”�
Professional 18% 17% 11% 20% 18% 11%
Sales/administration 44% 43% 41% 44% 44% 43%
Service 17% 15% 22% 7% 19% 21%
Labor 21% 25% NS 26% 29% NS 20% 25% NS
‘, Women with at least one live birth, excluding 48 nulliparous women.S Mean (SD) differences in means were examined with Student’s : test.
(, NS, not significant (P > 0.05); NA, not applicable.d Weight/height2.
, Among women with at least one pregnancy.
I Among women who had ever breastfed an infant.
g Differences between groups were examined with the s� test.h Reflects intake 2 years before the interview.
‘ Place of residence at time of interview.J Occupation 2 years before the interview.
Table 2 Serum concentrations of organochlorines in postmenopausal breast cancer cases and community controls, western New York, 1986-1991”
Total Never lactated’ Ever lactatedMeasure in ng/g of serums’
Cases (n = 154) Controls (n = 192) Cases (n = 46) Controls (n = 61) Cases (n = 85) Controls (n = 106)
DDE 1 1.47 (10.49) 10.77 (10.64) 13.16 (1 1.65) 10.82 (10.91) 10.36 (8.97) 10.44 (10.43)
HCB 0.41 (0.19) 0.42 (0.19) 0.45 (0.24) 0.39 (0.18) 0.39 (0.16) 0.44(0.19)
Mirex 0.043 (0.09) 0.037 (0.09) 0.083 (0.12) 0.046 (0.14) 0.029 (0.06) 0.036(0.08)
Total PCBs 4.29 (2.40) 4.12 (2.24) 4.63 (2.88) 4.00 (1.96) 4.27 (2.50) 4.30(2.42)
Number of peaks detected 18.38 (5.40) 17.93 (4.99) 18.68 (4.63) 17.93 (5.34) 18.49 (5.98) 18.35 (4.66)
Less chlorinated PCBs 0.31 (0.34) 0.29 (0.35) NA” NA NA NA
Moderately chlorinated PCBs 3.1 1 (1.71) 3.06 (1.73) 3.43 (1.77) 2.90 (1.48) 3.10 (1.67) 3.20(1.91)
More highly chlorinated PCBs 0.43 (0.29) 0.40 (0.25) 0.50 (0.31) 0.40 (0.24) 0.41 (0.27) 0.40(0.26)
a Mean (SD).b Adjusted for age and serum lipids.
‘ Women with at least one live birth, excluding 48 nulliparous women.d NA. not applicable.
cally significant for women in the second tertile of the distri-bution (OR, 0.32; 95% CI, 0.14-0.71).
The effect of PCB body burden on breast cancer risk ispresented in Table 4. In the entire study population, womenwith the highest serum PCB levels or the greatest number of
detected PCB congeners were not at greater risk of breastcancer compared to women with the lowest levels or fewer
detected peaks (OR, 1.14; 95% CI, 0.61-2.15; and OR, 1.34;95% CI, 0.72-2.47, respectively). However, among women
who had never lactated, there was some indication of increasing
risk with increasing serum PCBs (third tertile OR, 2.87; 95%
CI, 1.01-7.29) and increasing number of detected peaks (thirdtertile OR, 3.31; 95% CI, 1.04-1 1.3). These effects were stillobserved after adjustment for serum DDE and HCB (data not
shown). For women who had ever lactated, there was no evi-dence for an adverse effect of these exposures on risk.
As for PCB congener groups, we observed some evidenceof greater risk of breast cancer for women with detectable levels
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Cancer Epidemiology, Biomarkers & Prevention 185
Table 3 Risk of postm enopausal breast cancer associated w ith enviro nmental exposure to DDE, HCB, and mirex, wes tern New York, 1986-1991
Measurements in Total (n 346) Never lactated (n = l07)� Ever lactated (n = 191)
ng/g of serum Cases Controls OR” (95% CI) Cases Controls OR’ (95% CI) Cases Controls OR” (95% Cl)
DDE”
1 (low) 54 60 1.0 15 23 1.0 29 29 1.0
2 46 69 1.01 (0.56-1.86) 13 17 1.95 (0.58-6.67) 30 44 0.76 (0.35-l.63
3 (high) 54 63 1.34 (0.71-2.55)
P=0.25
18 21 1.83 (0.63-5.33)
P=0.24
26 33 1.28 (0.54-3.05)
P=0.44
HCBdJ
I (low) 62 61 1.0 16 27 1.0 37 26 .0
2 40 66 0.56 (0.30-1.04) 12 14 1.26 (0.40-3.97) 23 44 0.32(0.14-0.71)
3 (high) 52 65 0.81 (0.43-1.53)
P=0.80
18 20 1.79 (0.59-5.40)
P=0.22
25 36 0.46(0.20-11)8)
P=0.1I
Mirex”
LOD 42 44 1.37 (0.78-2.39) 18 17 2.42 (0.98-4.32) 20 23 1.08 (0.52-2.25)
a ORs adjusted for age, education, family history ofbreast cancer, parity, quetelet index, duration oflactation, age at first birth, years since last pregnancy, fruit and vegetable
intake, and serum lipids.b Women with at least one live birth. excluding 48 nulliparous women.
� ORs adjusted for age. education, family history of breast cancer, parity, quetelet index, age at first birth, years since last pregnancy. fruit and vegetable intake, and serum
lipids.
d Tertiles based on the distribution in all controls.
, DDE tertile cutpoints (ng/g of serum): first tertile. 0.02-5.07: second tertile, 5.10-10.98: third tertile. 11.0-76.2.
1HCB tertile cutpoints (ng/g of serum): first tertile, 0-0.34; second tertile, 0.35-0.44; third tertile, 0.45-1.35.g Mirex levels > LOD ranged from 0.06 to 0.99 ng/g of serum.
of less chlorinated PCBs compared to those without detectable
levels, although this effect was most pronounced for women inthe lower half of the distribution (OR, 2.04; 95% CI, 1.09-
3.83). When all women with detectable levels were compared
to women without detectable levels, the OR was 1.61 and the95% CI was 1.07-3.51. The ORs were similar after adjustment
for serum DDE and HCB levels. No such effect was observedfor the moderately chlorinated PCBs (third tertile OR, 1.37;
95% CI, 0.73-2.59) or the more highly chlorinated PCBs (thirdtertile OR, 1.19; 95% CI, 0.60-2.36). Among women who hadnever lactated, higher levels of moderately chlorinated PCBs(third tertile OR, 3.57; 95% CI, 1.10-8.60), but not morehighly chlorinated PCBs (third tertile OR, 1 .53; 95% CI, 0.47-4.98) were associated with increased risk of breast cancer.
Among women who had ever lactated, there was no evidencefor an increase in breast cancer risk in relation to higher serumconcentrations of moderately or more highly chlorinated PCBs.
Discussion
Results from this case-control study indicated that environmen-tal exposure to organochlorine compounds was not related tobreast cancer risk among postmenopausal women who hadlactated but that higher body burden of PCBs and mirex may be
risk factor for parous women who had never lactated. In theentire sample, we did not observe increases in risk associatedwith higher serum levels of DDE, HCB, mirex, and PCBs, with
the exception of a modest increase in risk associated withhaving detectable levels of less chlorinated PCB congeners.
Elevated serum levels of DDE were not associated with
breast cancer risk, although there was some evidence for greater
risk with higher levels among women who had never lactated.Attenuation of this effect when serum PCB levels were in-
cluded into the model suggests that the observed risk waslargely driven by the association of DDE with serum PCB
levels. These findings are in contrast to those reported by Wolffet a!. (26), who observed a nearly 4-fold increase in risk forwomen with the highest levels of DDE, which was unaffectedby inclusion of PCB levels into the regression model. Similarly,
Krieger et a!. (27) observed a nonsignificant 2-fold increase in
risk of breast cancer among white women with the highest DDE
body burden. Results of three investigations indicated that
greater body burden of DDE or DDT was not associated with
greater risk of breast cancer (28-30).
The effect of HCB on breast cancer risk has not been
previously reported in studies using an epidemiological studydesign. In three studies, mammary adipose tissue levels of
breast cancer patients were compared to those of controls with
benign breast disease (24, 25) or accident fatalities (23). Noneof these studies reported a significant difference in HCB con-
centrations between breast cancer cases and controls. The ab-
sence of an adverse effect of HCB exposure in our data is
consistent with these earlier studies.
The association between body burden of mirex and breast
cancer risk has not been explored previously. In these data, we
found no increase in risk associated with having detectablelevels of mirex in the entire study population or among parous
women who had lactated. However, we observed a borderline
significant increase in risk among parous women who hadnever lactated. The latter finding needs to be considered with
caution, for the observed increase in risk was based on very
small numbers of women with detectable levels of this corn-
pound (n = 35). Future investigations should examine theassociation of mirex with breast cancer risk in populations withgreater exposure levels (e.g. , fish consumers or women residing
in the southern United States).In these data, we observed a modest increase in risk for
women with detectable levels of less chlorinated PCBs. Among
the never lactating parous women with higher levels of total
PCBs, moderately chlorinated PCBs, or greater numbers of
detected congener peaks, there was some increase in risk. The
investigation of the less chlorinated congeners in relation to risk
was problematic, because these compounds are metabolized
rapidly, and measured levels reflect only recent exposure (3).However, these congeners have been associated with greatertoxicological activity, including estrogenic activity, than someof the more highly chlorinated congeners (3). The rationale for
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Table 4 Risk of postmenopausal breast cancer associated with environmental exposure to PCBs, western New York, 1986-1991
Measures in ng/g
of serum
Total (n = 346) Never lactated (n = 107)” Ever lactated (n 191)
Cases Controls OR” (95% CI) Cases Controls OR’ (95% CI) Cases Controls OR” (95% CI)
Total �Bs”
I (low) 53 2 1.0 1 1 22 1.0 32 29 1.0
2 45 68 0.70(0.37-1.29) 15 21 1.71 (0.55-5.35) 22 41 0.38 (0.17-1.03)
3 (high) 56 61 1.14(0.61-2.15)
P = 0.51
20 18 2.87(1.01-7.29)
P = 0.07
31 36 0.71(0.31-1.61)
P = 0.72
No. of peaks detected’��
I (low) 48 64 1.0 10 21 1.0 30 21 1.0
2 43 64 0.88 (0.45-1.59) 14 20 1.61 (0.41-3.56) 23 37 0.63 (0.29-1.40)
3 (high) 63 64 1.34 (0.72-2.47)
P = 0.52
22 20 3.31 (1.04-1 1.3)
P = 0.10
32 38 0.82 (0.37-1.83)
P = 0.85
Less chlorinated PCBs”5
median, 0.32-1.65.
‘ NA. not applicable.
J Moderately chlorinated PCBs tertile cutpoints (ng/g of serum): first tertile, 0.47-2.19; second tertile, 2.20-3.12; third tertile, 3.13-15.07.k More highly chlorinated PCBs tertile cutpoints (ng/g of serum): first tertile, 0.01-0.25; second tertile, 0.26-0.44; third tertile, 0.45-1.30.
186 Organochlorines and Breast Cancer Risk
years since last pregnancy. fruit and vegetable
examining these less chlorinated PCBs was based on this bio-
logical significance, as well as on the assumption that exposureto these compounds was likely to be chronic in nature, notchanging significantly over time. Therefore, serum levels at thetime of the interview were assumed to be representative of
lifetime exposure, including the time critical for tumorigenesis.In these data, a statistically significant increase in risk (OR,I .66) was observed for women with detectable levels of theseless chlorinated compounds in comparison to women with no
detectable levels. There was, however, no evidence of a dose-response relationship. These results need to be interpreted withgreat caution, because of the underlying assumption that currentserum levels of these compounds actually reflect levels at the
biologically relevant time period. Furthermore, measurement ofthese rapidly metabolized congeners was more likely to besubject to laboratory error than measurement of the more stable
and persistent congeners. On the other hand, there is no reasonto believe that measurement error was different for cases and
controls, because the laboratory technicians were blinded todisease status. Nondifferential misclassification may have at-tenuated the true risk estimate. Clearly, the effect of thesecongeners on breast cancer risk needs to be explored in aprospective study design, in which it may be possible to obtain
serum levels of these compounds from a time period that
precedes disease onset by an appropriate induction period.The observed effects of total PCBs, moderately chlori-
nated PCBs, and number of detected peaks warrants furthercomment. Number of detected peaks was examined in additionto the measure of total serum PCB levels to determine whether
prevalence of a greater variety of congeners affects risk differ-ently than total amount of these compounds. In our data, therewas no evidence of such a difference. Furthermore, the greatest
contributor to serum PCB levels were the moderately chlori-
nated PCBs; thus, all three PCB exposure measures (totalPCBs, moderately chlorinated PCBs, and number of PCBpeaks) were highly correlated, and observed risk elevations
among women who had never lactated were likely to reflect thesame effect. However, the observation that all three PCB cx-posures produced similar risk associations among parouswomen who had never lactated strengthens the notion that
environmental exposure to PCBs may be related to risk in thisgroup.
As indicated above, previous epidemiological studies did
not report an adverse effect of serum PCB levels (26, 27, 30).However, the designs of these studies differed from that of this
research in some important aspects. First, these studies corn-
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Cancer Epidemiology, Biomarkers & Prevention 187
bined pre- and postmenopausal breast cancer patients in theircase group. There is some evidence that risk factors differ bymenopausal status (37-39). Nevertheless, the biological mech-
anism of an organochlorine effect on breast cancer risk is notwell understood. It may be that there is a threshold effect, that
high body burden and chronic exposure to these compounds isnecessary to produce a biological effect. Older, postmenopausalwomen would be more likely to have been exposed chronically
and to have experienced higher levels of exposure. Second, riskestimates in two of the earlier studies were not adjusted for
serum lipids (26, 27); such adjustment had some impact on themagnitude of the ORs in this study. Third, statistical adjustment
for potential confounders, such as parity (26, 27) and duration
of lactation (27), was lacking in some of these investigations.
In general, our results suggest that an adverse effect oforganochlorine body burden on breast cancer risk, if present at
all, is restricted to parous women who had never lactated. Theobserved effect modification may be explained in three ways.First, organochlorine body burden may have been measuredmore accurately among women who had never breast-fed an
infant. Serum levels in this group may represent a more validmeasure of chronic exposure, uninterrupted by elimination ofthese compounds through lactation. Second, women who had
ever breast-fed an infant may not be at increased risk of breastcancer, if they eliminated a substantial amount of organochlo-
rime body burden at a biologically relevant period of time.Third, lactation in itself may contribute to the terminal differ-
entiation of the mammary epithelium, resulting in larger corn-partments of nonproliferating cells (40, 41). Women who lac-
tated may be less susceptible to the potentially adverse effect of
PCBs. In this study population, history of lactation was asso-ciated with a slight reduction of breast cancer risk (42). We
were unable to examine the effect of organochlorines on riskamong nulliparous women, due to the small number of womenin this group (n = 48). Nulliparous women were excluded from
the subgroup analyses because of the lack of information on theeffect of pregnancy on organochlorine body burden and the
possibility that pregnancy itself may affect accumulation ofthese compounds (43). Further, when nulliparous women wereincluded in the group of women who had never lactated, the
observed increases in risk were more pronounced. Thus, in this
study, we were concerned about the appropriateness of corn-bining parous and nulliparous women without having a clear
understanding of the patterns of accumulation and kinetics inrelation to pregnancy and lactation.
There are several limitations associated with this research
that need to be considered in interpreting these findings. Thelow participation rates in the case and control group may haveintroduced error due to selection bias. Among the breast cancer
case group, nonparticipation may have resulted in a case sample
that is not representative of all women with breast cancer.However, the majority of nonparticipation of cases was due to
their physicians’ refusal to allow the patients to be contacted bythe interviewers. Thus, nonparticipation of the cases may reflect
physician characteristics, rather than patient characteristics,which may minimize the potential influence of bias on theseresults. Nonparticipation of controls was of equal concern; itmay have resulted in a more motivated and possibly morehealth-conscious control group. Results from a brief telephone
interview comparing a sample of controls who refused to par-ticipate with a sample of those who agreed to participate mdi-cated that these groups did not differ with regard to dietaryintake of fruits, vegetables, and meats, nor did they differ withrespect to cigarette use (31). It is unknown whether nonpartici-
pation among cases and controls was related to exposure to
PCBs. Selection bias may have been additionally introduced
among the participants included in the toxicological analyses.
Participants who agreed to provide a blood sample were more
likely to have breast-fed an infant than those who refused, for
both the case and control groups. Among participants who were
selected for toxicological analyses, however, this difference
with respect to lactation history was more pronounced in the
case group than in the control group. Thus, in the sample
available for this study, breast cancer cases with a history of
lactation were likely to be overrepresented.
Another concern in interpreting these findings relates to
the small number of women in both lactation groups. When
these groups of women were divided into tertiles, the numbers
in the cells became small and the corresponding risk estimates
became unstable. Despite these sample size restrictions, a sta-
tistically significant increase in risk was observed for several
PCB exposures. Lack of statistical power may have prevented
the detection of more subtle risk elevations in association with
organochlorine exposure in the entire sample.
Two further limitations of this study relate to the use of
serum levels of these compounds as a method of exposure
assessment. With regard to studying breast cancer, the obvious
tissue of choice would be mammary adipose tissue. Serum
organochlorine levels can only function as a surrogate measure
of body burden in the target tissue. Variations in serum organo-
chlorines have been observed with respect to serum lipids (44).
There is, however, good evidence that lipid adjusted serum
measures estimate the tissue levels (44-46). A more serious
concern with respect to use of serum levels involves the fact
that the blood sample in the case group was obtained after
diagnosis of breast cancer. It could not, therefore, be deter-
mined whether PCB levels were associated with the disease
process or were the result of metabolic changes associated with
disease progression. Although cancer treatment may affect or-
ganochlorine levels (47), case selection for toxicological anal-
ysis excluded those who underwent chemotherapy or radiation
therapy before the blood sample was selected. However, there
may still be an effect of the disease process on measured levels
of these compounds.
In conclusion, results from this study indicate that envi-
ronmental organochlorine exposure is a risk factor for breast
cancer among parous postmenopausal women who had never
lactated but not among women who had ever lactated. The
observed effects in the latter group should be considered with
caution, because they are based on a small number of partici-
pants. Clearly, the role of organochlorine exposure in breast
cancer etiology needs to be explored further in future research
efforts. Ideally, a long-term prospective study design should be
used to examine serum levels of these compounds that reflect
body burden of a time period preceding the onset of this
disease, thus ruling out a potential effect of the disease process
itself on measured levels of these compounds. A prospective
study could also examine the effect of the less chlorinated
congeners with more precision, avoiding the assumption that
present levels of these PCBs reflect past exposure. Future
research, case-control studies as well as cohort studies, should
also aim at examining this association among premenopausal
women. Finally, future studies should use similar epidemiolog-
ical (e.g. , determination of PCB congener group and treatment
of samples with measures below the LOD) and laboratory (e.g.,
proficiency testing and sample acquisition and storage) meth-
odologies, to ensure comparability of results across studies.
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188 Organochlorines and Breast Cancer Risk
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1998;7:181-188. Cancer Epidemiol Biomarkers Prev K B Moysich, C B Ambrosone, J E Vena, et al. breast cancer risk.Environmental organochlorine exposure and postmenopausal
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