Plasma Organochlorine Levels and the Risk of Breast Cancer
David J. Hunter, M.B., B.S., Susan E. Hankinson, Sc.D., Francine Laden, S.M., Graham A. Colditz, M.B., B.S., JoAnn E. Manson, M.D., Walter C. Willett, M.D., Frank E. Speizer, M.D., and Mary S. Wolff, Ph.D.
Background Exposure to "environmental estrogens" such as organochlorinesin pesticides and industrial chemicals has been proposed asa cause of increasing rates of breast cancer. Several studieshave reported higher blood levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene(DDE) and polychlorinated biphenyls (PCBs) in patients withbreast cancer than in controls.
Methods We measured plasma levels of DDE and PCBs prospectivelyamong 240 women who gave a blood sample in 1989 or 1990 andwho were subsequently given a diagnosis of breast cancer beforeJune 1, 1992. We compared these levels with those measured inmatched control women in whom breast cancer did not develop.Data on DDE were available for 236 pairs, and data on PCBs wereavailable for 230 pairs.
Results The median level of DDE was lower among case patientsthan among controls (4.71 vs. 5.35 parts per billion, P = 0.14),as was the median level of PCBs (4.49 vs. 4.68 parts per billion,P = 0.72). The multivariate relative risk of breast cancer forwomen in the highest quintile of exposure as compared with womenin the lowest quintile was 0.72 for DDE (95 percent confidenceinterval, 0.37 to 1.40) and 0.66 for PCBs (95 percent confidenceinterval, 0.32 to 1.37). Exposure to high levels of both DDEand PCBs was associated with a nonsignificantly lower risk ofbreast cancer (relative risk for women in the highest quintilesof both DDE and PCBs as compared with women in the lowest, 0.43;95 percent confidence interval, 0.13 to 1.44).
Conclusions Our data do not support the hypothesis that exposureto 2,2-bis (p-chlorophenyl)-1,1,1-trichloroethane (DDT) andPCBs increases the risk of breast cancer.
The fivefold variation in the rates of breast cancer aroundthe world,1 combined with the observation that the daughtersof women who migrate from a country with a low incidence ofbreast cancer to a country with a high incidence acquire thebreast-cancer risk prevailing in the high-incidence country,2strongly suggests that environmental and lifestyle factors arethe major causes of breast cancer. The incidence of breast cancerin the United States has risen by 1 percent per year since 1940,3and there is uncertainty about the extent to which establishedrisk factors can explain the increase. Environmental pollutantshave been suggested as potential causes.4,5
The hypothesis that among these pollutants, hormonally activeorganochlorine chemicals may be responsible has garnered wideattention. Many pesticides and industrial chemicals have thepotential to act as "environmental estrogens" and have beenshown to affect wildlife adversely. The most abundant organochlorinecontaminants are the pesticide 2,2-bis (p-chlorophenyl)-1,1,1-trichloroethane(DDT) and certain polychlorinated biphenyls (PCBs). DDT, whichwas introduced in the United States in 1945 and banned in 1972,6has been implicated as the cause of eggshell thinning in baldeagles,7 and certain PCBs used in a wide variety of industrialproducts and manufactured between 1929 and 19776 can alter sexdetermination in animals.8 In vitro assays demonstrate that1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the mainmetabolite of DDT, and certain PCB congeners have estrogen-likeactivity.9
Many of these compounds accumulate in the body because of theirlipid solubility and resistance to metabolism. They are alsopresent in human adipose tissue and breast milk.10 In a nationwidestudy of breast milk in the 1970s, 99 percent of samples haddetectable levels of DDT and PCBs.11 DDT promotes the growthof mammary tumors in some rodent models.12,13 Limited data areavailable to assess possible associations with breast cancerin humans. Two small case–control studies reported higherlevels of DDE among women with breast cancer than among controls.14,15In another study the association was limited to women with estrogen-receptor–positivebreast cancer.16 One of these studies15 also found higher levelsof PCBs among the women with breast cancer than among controls.In a recent case–control study from Europe, concentrationsof DDE in adipose tissue were lower in patients with breastcancer than in controls.17 A prospective study of 58 cases ofbreast cancer in New York18 found a significant increase inthe risk of breast cancer with higher serum levels of DDE anda nonsignificant positive association with PCBs. In a largerprospective study of 150 cases in the San Francisco Bay area,Krieger et al.19 observed no overall elevation in risk withhigher serum levels of either DDE or PCBs, but some have arguedthat the findings were not clearly null.20
To test the hypothesis that higher blood levels of DDE or PCBsare associated with an increased risk of breast cancer, we measuredlevels of these organochlorines in 240 women with breast cancerand 240 control women in the Nurses' Health Study, using bloodsamples prospectively collected from 1989 to 1990.
Methods
Study Population
In 1976, 121,700 married registered nurses from 11 states wereenrolled in the Nurses' Health Study and subsequently followedby questionnaire every two years. Self-reported diagnoses ofbreast cancer are confirmed by a review of medical records.21The completeness of follow-up as a proportion of potential person-yearsthrough 1992 is 95 percent.21 Information on risk factors forbreast cancer, such as family history (updated in 1982 and 1988)and reproductive history (updated until 1984), is obtained byquestionnaire. Menopausal status was defined on the basis ofa woman's response to the question whether her periods had ceasedpermanently. Women who had had a hysterectomy with one or bothovaries left intact were classified as premenopausal until theage at which 10 percent of the cohort had undergone naturalmenopause (46 years for smokers and 48 years for nonsmokers)and as postmenopausal at the age at which 90 percent of thecohort had undergone natural menopause (54 for smokers and 56for nonsmokers); in the intervening years these women were classifiedas being of uncertain menopausal status and excluded from menopause-specificanalyses.
From 1989 to 1990, 32,826 women sent us a blood sample, whichwas separated into aliquots of plasma, red cells, and buffycoat. Women who sent a blood sample were very similar to otherwomen in the cohort with respect to reproductive risk factorsfor breast cancer such as age at menarche, parity, and age atthe birth of their first child. Women who gave a blood specimenwere slightly more likely to have a history of benign breastdisease or a family history of breast cancer. These differencesshould not influence the internal validity of comparisons betweencase patients and controls in the subcohort of women who gavea blood specimen.
We defined case patients as women who did not have a diagnosisof cancer (other than nonmelanoma skin cancer) when they sentin the blood specimen and in whom breast cancer was subsequentlydiagnosed before June 1, 1992. There were 240 eligible casepatients: 200 women had invasive cancer, 39 had carcinoma insitu, and 1 had cancer with uncertain histologic features. Foreach case patient we matched a control subject who had not reporteda diagnosis of cancer according to the year of birth, menopausalstatus at the time of blood sampling, month in which the bloodsample was returned, time of day that the blood sample was obtained,fasting status at blood sampling, and for postmenopausal women,postmenopausal hormone use.
Laboratory Analyses
The laboratory methods have been described in detail elsewhere.18,22Briefly, a polar extract of plasma lipids was further treatedwith a step involving chromatographic cleanup and enrichmentof the column and then analyzed by gas chromatography with electron-capturedetection. All steps were scaled appropriately for 0.50-ml aliquotvolumes. We have previously demonstrated using Nurses' HealthStudy specimens that the precision with the use of this volumeand an optimized analytic procedure is similar to that withprevious procedures using 1-ml and 2-ml aliquots.23 The amountof methanol was optimized (0.3 ml) to create a good interfacebetween the aqueous layer and the ether–hexane extractant(1.25 ml). Results are reported as parts per billion (ppb) ofDDE (which is equivalent to nanograms of DDE per milliliter)and of the sum of the higher PCB congeners — compoundswith retention times longer than that of DDE (pentachlorobiphenyls,hexachlorobiphenyls, and heptachlorobiphenyls). The limits ofdetection were less than 1 ppb for both DDE and PCBs, on thebasis of a value that was three times the standard deviation24of 24 determinations over the course of sample analyses of aquality-control plasma pool with approximately 1 ppb of bothDDE and PCBs. Both DDE and PCBs are stable in frozen blood;organochlorine levels in serum frozen at -20°C were unchangedover a period of one year 22 (and unpublished data). Plasmacholesterol was determined with the procedure of Allain et al.25
Serum samples from pairs of case patients and controls (withthe order of samples randomized) were sent to the laboratoryin batches of 12 pairs; each batch included 2 unidentifiablesplit samples from pooled plasma from premenopausal or postmenopausalwomen. For each batch we calculated the coefficient of variation;the median coefficient of variation was 4.3 percent for DDEand 13.2 percent for PCBs. DDE values were missing for one memberof four case–control pairs, and PCB values were missingfor one member of an additional six pairs because the sampleswere lost or contaminated.
Statistical Analysis
Since both DDE and PCBs are correlated with blood lipid content,26linear regression analysis of log-transformed DDE and PCB valueswas performed to adjust for plasma cholesterol concentration.We used these adjusted values in our principal analyses; wealso used the unadjusted values in supplementary analyses.
We assessed the relations of plasma DDE and PCBs using Spearmancorrelation coefficients for continuous variables and by examiningthe distribution of risk factors for breast cancer within thirdsof plasma organochlorine levels among the controls, testingfor statistical significance with the Kruskal–Wallis test.27We used the Wilcoxon signed-rank test for paired data and theWilcoxon rank-sum test for unpaired data to compare plasma DDEand PCB levels between case patients and controls.27 We dividedthe control distribution into quintiles and calculated the relativerisk and 95 percent confidence interval for each quintile relativeto the lowest quintile using conditional logistic regression,28controlling for established risk factors for breast cancer inaddition to the matched factors. To assess the potential synergismbetween organochlorine compounds, we compared women in the highestquintile of both DDE and PCBs with women in the lowest quintileof both. To examine whether the associations between organochlorineswere modified by conventional risk factors for breast cancer,we conducted unconditional analyses within strata of the otherrisk factors for breast cancer, controlling for the matchedvariables. All P values are two-sided.
Results
The median age of the subjects was 59 years (range, 43 to 69),68 percent of both case patients and controls were postmenopausal,and the median age at menopause was 49 years for the case patientsand 50 years for the controls. Differences in other risk factorsfor breast cancer between case patients and controls were notstatistically significant, with the exception of maternal historyof breast cancer (reported by 11 percent of case patients and5 percent of controls, P = 0.01), history of breast cancer ina sister (8 percent of case patients and 3 percent of controls,P = 0.03), and history of benign breast disease (56 percentof case patients and 41 percent of controls, P = 0.001).
Plasma levels of both DDE (r = 0.31, P<0.001 by Spearmanrank correlation) and PCBs (r = 0.25, P<0.001) increasedwith age (Table 1). The only statistically significant associationof either DDE or PCBs with established or suspected risk factorsfor breast cancer (Table 1) was a positive association betweenbody-mass index and plasma DDE levels. Among parous women, morewomen in the lowest thirds than in the highest thirds of DDEand PCB levels had breast-fed their children for more than sixmonths; however, these associations were not significant. Resultswere similar in analyses that were not adjusted for plasma cholesterolconcentration.
Table 1. Relation between Established or Suspected Risk Factors for Breast Cancer and Plasma Levels of DDE and PCBs among 236 Nurses' Health Study Participants without Diagnosed Breast Cancer.
Women who were given a diagnosis of breast cancer after providinga blood sample in 1989 or 1990 had lower levels of plasma DDEthan controls (Table 2); the median level was 4.71 ppb in casepatients and 5.35 ppb in controls (P = 0.14). Plasma PCB levelswere essentially the same in case patients and controls. Resultswere similar in analyses that were not adjusted for plasma cholesterolconcentration: the unadjusted median for DDE was 5.07 ppb incase patients and 5.59 ppb in controls (P = 0.14); the unadjustedmedian for PCBs was 4.58 ppb in case patients and 4.73 ppb incontrols (P = 0.60). Levels of DDE and PCBs were similar amongwomen with and those without axillary-lymph-node involvementat diagnosis. The exclusion of 101 pairs in which the case patientwas given a diagnosis of breast cancer within one year afterblood sampling had little effect on these findings. After restrictionof the analyses to 197 patients with invasive cancer and theircontrols for whom data were available, the median value forDDE among case patients was 5.02 ppb, as compared with 5.60ppb among controls (P = 0.20). For PCBs the median value amongboth patients with invasive cancer and controls was 4.69 ppb(P = 0.87). In analyses restricted to 139 case patients withestrogen-receptor–positive disease and their controls,the results were similar.
Table 2. Plasma Levels of DDE and PCBs among Case Patients with Breast Cancer and Controls in the Nurses' Health Study.
We found no evidence of a positive association between highlevels of plasma DDE or PCBs and a risk of breast cancer (Table 3).The multivariate relative risk for the highest decile ofplasma DDE levels as compared with the lowest decile was 0.38(95 percent confidence interval, 0.13 to 1.09); for PCBs therisk was 0.44 (95 percent confidence interval, 0.15 to 1.29).Even among women with high levels of both DDE and PCBs, therewas still no evidence of a positive association. As comparedwith women who were in the lowest quintiles of both DDE andPCBs, women in the highest quintiles were at nonsignificantlylower risk of breast cancer (multivariate relative risk = 0.43;95 percent confidence interval, 0.13 to 1.44).
Table 3. Relative Risk of Breast Cancer According to Quintile of Plasma DDE and PCB Levels at Base Line in the Nurses' Health Study, 1989 to 1992.
Among 48 premenopausal case patients and 53 controls with valuesfor DDE, the median level was 3.72 ppb among case patients and3.30 ppb among controls (P = 0.95). For PCBs the median was3.91 ppb among 47 premenopausal case patients and 4.11 ppb among51 premenopausal controls (P = 0.54). The results for postmenopausalwomen were similar to the overall results. The absence of anassociation between DDE, PCBs, and breast cancer was similarwithin strata of age, age at menarche, age at birth of firstchild, number of children, and history of lactation.
Discussion
In this prospective study, we did not observe any evidence ofan increased risk of breast cancer among women with relativelyhigh levels of plasma DDE or PCBs. Most of the relative riskswe observed for higher levels of exposure were less than 1,and the upper bounds of the 95 percent confidence intervalsgenerally excluded all but small increases in risk. Moreover,women with high levels of both DDE and PCBs were not at higherrisk than women with the lowest levels of these compounds.
The hypothesis that environmental organochlorine contaminantscause breast cancer is based largely on indirect evidence. Somebut not all studies have shown that DDE and PCBs act as estrogensin vitro and in animals. Indeed, some PCB congeners and organochlorines,such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, have antiestrogenicactivity. In general, these compounds are very weak estrogensin in vitro assays, requiring concentrations of up to 100,000times more than the natural estrogen 17-estradiol to achieveequivalent estrogenic activity.9 On the basis of these in vitroassays, it has been estimated that humans are exposed to naturallyoccurring estrogenic compounds in our diet in amounts that aremany orders of magnitude higher than those of environmentalorganochlorine estrogens.29 Nevertheless, given that organochlorinesare fat soluble, persist in adipose tissue, and are excretedin breast milk,30 it may be that ductal and other cells in thebreast are exposed to these compounds over a period of manydecades. Such prolonged exposure may counterbalance the lowestrogenic potency of organochlorines.
Because they are highly lipophilic and metabolically resistant,DDE and PCBs undergo lifelong sequestration in human adiposetissue. Blood levels of these compounds are among the most stablebiologic markers of exposure known. In blood samples collectedbefore and after treatment for breast cancer (an average of56 days apart), the r values for the lipid-adjusted correlationsbetween the first and second samples were 0.99 for DDE and 0.96for PCBs.31 Among 31 healthy women who provided two blood samplestwo months apart, the r values were 0.96 for DDE and 0.89 forPCBs.32 The half-life of plasma DDE is approximately 10 years(Wolff M, Toniolo P: unpublished data). Among workers with occupationalexposure to organochlorines, the length of time that highlychlorinated PCBs persist in the body varies widely; the mostlong-lived congeners have half-lives of 7 to 30 years.33 Thesedata, and the consistent correlation of DDE and PCBs with age,suggest that the blood levels of DDE and PCBs we measured reflectexposure that occurred over a period of many years.
Epidemiologic data regarding possible relations of organochlorineswith breast cancer are limited. Several small case–controlstudies reported higher levels of DDE14 or PCBs15 among casepatients than controls. A recent European case–controlstudy (264 case patients) reported a significant inverse trendbetween levels of adipose DDE and the risk of breast cancer;data on PCBs were not available.17 In a prospective study of14,290 women in New York,18 levels in serum were compared in58 women given a diagnosis of breast cancer within one to sixmonths after blood collection in 1985 to 1991 and 171 controls.The adjusted relative risk for the highest quintile of DDE ascompared with the lowest was 3.68 (95 percent confidence interval,1.10 to 13.50); for PCBs the risk was 4.35 (95 percent confidenceinterval, 0.92 to 20.47). In the largest prospective study todate, Krieger et al.19 examined serum from 150 case patientsselected from a cohort of 57,040 San Francisco Bay area womenwho had provided blood between 1964 and 1971. Little associationwas seen between organochlorine levels and the risk of breastcancer.
A strength of the three available prospective studies (includingthis study) is that the analyses of DDE and PCBs were all performedin the same laboratory; neither laboratory technique nor a variationin accuracy is likely to account for differences in findings.The levels of DDE we observed in this study among women whoprovided blood samples in 1989 or 1990 were similar to thoseobserved in samples obtained in 1985 to 1991 from New York women,18but the median was six times lower than the medians for womenin the San Francisco Bay area in the late 1960s.19 This findingis compatible with the long-term decline in DDE levels sincethe compound was banned in 1972 and suggests that there is norelation with breast cancer at either the levels currently prevailingor the higher levels that were present when DDT was still beingused. The PCB levels we observed were similar to those observedin both of the previous prospective studies, underlining thepersistence of these compounds in our environment even afterproduction ceased in 1977.
Although we cannot exclude the possibility that exposure inutero or during childhood could increase the risk of breastcancer decades later, because DDT and PCBs were introduced intothe environment largely in the 1940s and 1950s, exposure veryearly in life could not have accounted for most of the increasein the incidence of breast cancer over the past several decades,which has been greatest in postmenopausal women who were alreadyadults when the compounds were being most widely used. The absenceof an association with DDE and PCBs does not rule out the possibilitythat other pesticides and environmental contaminants may beassociated with breast cancer. There are good ecologic reasonsto avoid the release of DDT and PCBs into our environment, buton the basis of our results the use of these compounds doesnot explain the high and increasing rates of breast cancer.
Supported by grants (U01 CA/ES62984, CA40356, and CA49449) fromthe National Institutes of Health, by an Institutional NationalService Award (5 T32 CA 09001, to Ms. Laden), and by an AmericanCancer Society Faculty Research Award (FRA-455, to Dr. Hunter).
We are indebted to the nurse participants in this study; toRachel Meyer, Michele Lachance, Sherry Yaun, Karen Ireland,and Nancy Niguidula for expert technical assistance; and toTracey Corrigan for manuscript preparation.
Source Information
From the Channing Laboratory, Department of Medicine (D.J.H., S.E.H., F.L., G.A.C., J.E.M., W.C.W., F.E.S.), and the Division of Preventive Medicine (J.E.M.), Harvard Medical School and Brigham and Women's Hospital, Boston; the Departments of Epidemiology (D.J.H., S.E.H., F.L., G.A.C., J.E.M., W.C.W.), Environmental Health (F.E.S.), and Nutrition (W.C.W.), Harvard School of Public Health, Boston; Harvard Center for Cancer Prevention, Boston (D.J.H., G.A.C., W.C.W.); and the Division of Environmental and Occupational Medicine, Mount Sinai Hospital, New York (M.S.W.).
Address reprint requests to Dr. Hunter at the Channing Laboratory, 181 Longwood Ave., Boston, MA 02115.
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-estradiol to achieve equivalent estrogenic activity.9 On the basis of these in vitro assays, it has been estimated that humans are exposed to naturally occurring estrogenic compounds in our diet in amounts that are many orders of magnitude higher than those of environmental organochlorine estrogens.29 Nevertheless, given that organochlorines are fat soluble, persist in adipose tissue, and are excreted in breast milk,30 it may be that ductal and other cells in the breast are exposed to these compounds over a period of many decades. Such prolonged exposure may counterbalance the low estrogenic potency of organochlorines. 
