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Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York 10029 [M. S. W.], and Departments of Obstetrics and Gynecology [P. T.] and Environmental Medicine [A. Z-J., N. D., P. T.] and Kaplan Comprehensive Cancer Center [A. Z-J., N. D., P. T.], New York University School of Medicine, New York, New York 10016
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Therefore, interest in human health effects of exposures to OCs continues, although the use of DDT and PCBs in developed countries has been banned for more than 20 years. Opportunities for exposures continue, inasmuch as DDT and other OCs are still widely used in developing countries. Another reason for continuing concern is that DDE and PCBs bioaccumulate in the environment and in the body. PCBs in North America still persist in significant amounts in freshwater fish and in estuarial sediments. However, during the past two decades, since the cessation of DDT and PCB use, levels in United States, Canadian, and European populations have declined (11) . Nevertheless, there are very few reports that have measured elimination rates in individuals, and indeed, some reports have suggested that PCB levels are constant or increasing (12) .
The fact that OC levels are variable over time is relevant to the issue of timing of hormonal and xenobiotic exposures. Timing of exposures has come to be recognized as an important aspect of their toxicological effects, including cancer risk (13) , yet a single measurement of OCs has been assumed to be a reliable estimate of historical exposure because of their persistence and their cumulative properties. Little information is available on individual changes in OC levels over time. Two small studies have suggested that OC levels in blood are steady over the course of a few months (14 , 15) . In our population, we have shown that the reliability is good between sequential measurements of estrogen taken over several years (16) .
We found an elevated risk for breast cancer and DDE levels in an earlier report on 58 women with breast cancer from New York City Women’s Health Study who were diagnosed within 6 months of entry into the cohort (prevalent cases) compared with their 171 individually matched controls (1) . In the current study, we have investigated levels of DDE and PCBs among incident breast cancer cases (diagnosed 6 months or more after enrollment in the study) and controls in this prospective cohort. Because some of these women had provided two or more sequential annual blood specimens, we were also able to evaluate persistence of these OCs in the body.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breast cancer cases were identified through active follow-up of the cohort by mailed questionnaires every 2 years and telephone interviews for nonrespondents, as well as record linkage with state cancer registries in New York, New Jersey, and Connecticut and with the National Death Index. A capture-recapture analysis estimated that the ascertainment rate for breast cancer in our cohort is 95% (18) . Medical and pathology reports were obtained to confirm diagnosis.
Incident case subjects were included in an ongoing case-control study of sex hormones and breast cancer nested within the cohort, as described previously (17) . For each case subject, controls were selected at random from the risk set of women who were alive and free of disease at the time of diagnosis of the case and who matched the case on menopausal status and age at enrollment (±6 months), number and dates of blood donations (±3 months), and day of the menstrual cycle for premenopausal women. Four controls were selected for each premenopausal case and two controls for each postmenopausal case.
Cases diagnosed up to October 1, 1994, and with a lag time of 6 months or more between blood donation and diagnosis were eligible for the present study on the association between serum levels of OCs and risk of breast cancer. Initially, participants were eligible irrespective of the number of blood donations, and either two or three yearly serum samples were assayed for OCs in cases and all of their individually matched controls. However, because we were also interested in assessing OC half-lives, after the first year of serum analyses, we decided that only cases with at least three yearly blood donations would be eligible for this study. In addition, we decided to reduce the number of controls to one per case. Therefore, one control was selected at random from the two (for postmenopausal case subjects) and from the four (for premenopausal case subjects) that were included in the study of sex hormones. As a result of these inclusion criteria, 148 cancer patients and 295 individually matched controls were selected for this study. Analyses involving lipid adjustment were conducted on the 110 cases and 213 controls for whom serum lipid measurements were available. OC half-lives were calculated for the 84 cases and 196 controls who had contributed more than one blood donation.
The method for determination of DDE and PCBs, including the quality control protocols, was the same as that described previously (19) . Limits of detection were less than 0.5 ng/ml for DDE and less than 1 ng/ml for PCBs based on three times the SD of the levels found in the lowest quality control serum pools (average of 0.3–0.7 ng/ml DDE, 1 ng/ml PCB) over the course of the analyses (n = 50). For the two higher level pools (DDE = 9 and 17 ng/ml, PCB = 5 and 9 ng/ml; n = 53 and 49, respectively) overall CVs were <10%. Serum lipids were determined by a commercial laboratory. The laboratory was blind with respect to any information concerning study subjects; all individually matched and multiple specimens from the same individual were analyzed in the same laboratory batch.
DDE and PCB values were adjusted for total serum lipids using the method of Akins et al. (20) Lipid adjustment was also performed using the linear regression method described by Hunter et al. (3) . Because the lipid-adjusted values calculated with the two different methods were very highly correlated for both DDE and PCB (Spearman correlation coefficients > 0.97), only results using the Akins method are presented.
Crude and lipid-adjusted DDE and PCB values were log transformed to
reduce departures from the normal distribution. Mixed effects
regression models were used to test for differences in continuous
variables between case and control subjects, taking into account the
matching design. The Kruskal-Wallis test was used to test for
differences in the distribution of continuous risk factors for breast
cancer within tertiles of DDE and PCB levels among the controls. For
categorical variables, the 
2 test or
2 test for trend was used.
DDE and PCB half-lives were calculated for women who contributed more than one blood donation, assuming that the rate of elimination from the body may be described by the one-compartment exponential decay model (21) . For each woman, the half-life was therefore calculated by dividing ln (2) by the slope of the least squares regression of the logarithm of the OC levels versus time. Not all persons showed a decline in DDE and PCBs, which produced indeterminate or very long half-lives. Following the recommendation of Phillips (22) , some analyses were conducted after recoding these values as infinite.
ORs were computed using conditional logistic regression analysis with DDE and PCB levels as both quartiles and continuous variables. Percentiles were based on the frequency distribution of controls. Some analyses were also conducted comparing women in the highest category of both DDE and PCB levels with those in the lower levels. To have sufficient numbers of participants in all exposure levels, these analyses were conducted using tertiles rather than quartiles. Adjustment was made for potential confounders (other than the matching criteria); those included age at menarche, number of full-term pregnancies, age at first full-term pregnancy, first-degree family history of breast cancer, months of lactation, height, BMI, and an interaction term for BMI and menopausal status (menopausal status was not included in the model because it was one of the matching criteria). Effect modification by menopausal status, lactation history, and lag time between exposure measurement and diagnosis was explored by including interaction terms between these variables and OC levels in the logistic model, as well as by conducting stratified analyses. Because of the relatively small sample size of our study, OC levels were included as continuous variables in these analyses. All reported Ps are two-sided.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Two traditional risk factors, nulliparity and family history of breast
cancer, were found to be significantly associated with breast cancer
risk. Case subjects tended to have an older age at first pregnancy than
controls, but this difference was not statistically significant. Age at
menarche and duration of lactation were similar in cases and controls.
Case subjects had lower BMI than controls in premenopausal women
(P < 0.05), consistent with other studies
(23)
, whereas the reverse was true among postmenopausal
women (>0.10). There were no major differences in known risk factors
between participants for whom half-life estimates were available and
others.
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. Cholesterol and triglyceride levels, used to compute serum lipids,
were also similar. We examined the relationship of several variables
with respect to tertiles of serum DDE and PCB levels among control
subjects (Table 3)
. Age increased significantly across both the DDE and PCB tertiles.
Family history of breast cancer was more prevalent in the lowest
exposure tertiles, which we attribute to the younger age of women in
this tertile. Younger women who had a family history of breast cancer
may have been more likely to seek screening for breast cancer in the
setting in which the cohort was enrolled. BMI was lower in the upper
PCB tertile.
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. For PCBs, ORs were elevated in the three upper quartiles relative to
the lowest one. However, none of the ORs was statistically significant,
and there was no evidence of a trend. In addition, there was no
association between PCB on the continuous scale with breast cancer
risk. Finally, women for whom both DDE and PCB levels were in the
highest tertiles did not have an elevated risk for breast cancer when
compared to women in the lowest tertiles for both OCs (crude OR =
1.14, 95% CI = 0.49–2.66; adjusted OR = 1.60, 95% CI = 0.61–4.18; data not shown). There was no evidence of effect
modification by menopausal status or lactation history (data not
shown).
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. Levels of DDE and PCBs were higher in ER-negative cases than in their
controls, but these differences were not statistically significant.
Levels of DDE and PCB were very similar in the ER-positive cases and
their controls. In addition, there were no statistically significant
differences in OC levels between ER+ and ER– cases.
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We computed the half-life of DDE and PCBs for all women who contributed repeated samples. Indeterminate (i.e., mathematically negative) half-lives were observed among participants whose later measurements were greater than or equal to their first measurement. For DDE, the half-life was indeterminate among 21 of 84 cases (25%) and in 40 of 140 controls (29%). The PCB half-life was indeterminate for 35 of 84 cases (42%) and 68 of 140 controls (49%). The half-lives of DDE and PCBs were almost identical among cases and controls who had positive values. The median half-life of DDE in the control subjects was 8.6 years, and that of PCB was 11.2 years. If indeterminate half-lives were assumed to be infinite (22) , the median half-life of DDE was 13.0 years among cases and 15.0 years among controls (not significant); median half-life of PCB was 37 years among cases and indeterminate among controls. Risk for breast cancer was not associated with DDE or PCB half-life (data not shown).
We examined exposure-related information with respect to
half-life among control patients with measurable OC elimination
half-lives using age-adjusted Spearman correlations (Table 6)
. Half-lives of DDE and PCB were strongly correlated
(r;s> = 0.71; n = 72). DDE and PCB
levels were moderately correlated (r;s> = 0.43;
n = 72). DDE levels in serum were weakly correlated
with the DDE serum half-lives (r;s> = 0.20;
n = 100). DDE half-life (but not DDE level) was
positively correlated with BMI. Also, the median BMI was higher in the
group with indeterminate DDE half-life than in the group with positive
half-life (26.0 versus 23.3 kg/m2;
P < 0.01, Wilcoxon test). PCB level (but not PCB
half-life) was inversely correlated with BMI. We did not find any
significant associations between duration of lactation and OC levels or
OC half-lives. However, only 35.2% of our participants had a history
of breastfeeding, and for 88% of those, breastfeeding was limited to 6
months or less.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results add to a growing body of evidence suggesting that current, low levels of DDE and PCBs are weakly, if at all, associated with risk for breast cancer. There have been eight studies that included more than 100 cases of breast cancer during the past 5 years (3 , 5 , 6 , 24, 25, 26, 27, 28) . None found significant elevated risk associated with OC exposures alone. Of six cohort studies with blood collected before breast cancer diagnosis (1 , 3, 4, 5 , 24 , 25) , five found relative risks below 1 for DDE (one was statistically significant), and four had relative risks less than 1 for PCBs.
One recent report found a modest increase in risk with dieldrin but not with DDT or PCB levels among women whose blood had been obtained in 1976, as long as 17 years prior to diagnosis (24) . In another study, increased risk was found among women with higher levels of PCBs if they had never lactated (6) or if they possessed the variant CYP1A1 allele (29) . However, these findings have not yet been widely duplicated. Clearly, large sample sizes will be needed to detect with confidence interactions between OC exposures and modifying factors.
Our data on relationships among serum OC levels, their half-lives, BMI,
and age offer insight into the source and disposition of OCs in humans
(Tables 3
4
5
6)
. The correlations of PCB and DDE with each other and
with age (as seen in many previous studies) suggest that their
absorption derives from common dietary sources over a long period of
time. This evidence has led to the view that, because OCs are
persistent and cumulative, a single measure is a biomarker that
represents lifetime accumulation. However, other recent findings
indicate that changes in OC levels over time may complicate
interpretation of persistent body burden measures in epidemiological
studies (4
, 30)
Our observation that levels of PCBs were higher among leaner women is consistent with a simple pharmacokinetic model of uptake, implying concurrent exposure to PCBs that may be incremental to cumulative past exposures (31 , 32) . A simple model predicts just such a negative correlation between OC levels and BMI during a period when exposures are ongoing, as long as absorption (a) exceeds elimination rate and (b) is comparable across the population. [The rationale is mathematical: the body burden (e.g., 20 mg DDT) is divided by the reservoir of adipose tissue (e.g., 10 kg, giving 2 mg/kg or 2 parts per million). A larger adipose tissue reservoir would yield a lower concentration, e.g., 20 mg/20 kg = 1 ppm.] Dorgan et al. (25) also found a negative association between PCBs and BMI, whereas Hunter et al. (3) found no relationship.
Also consistent with the idea of concurrent PCB exposures, we found that PCB half-life was indeterminate in approximately one-half of our women (103 of 224) and that PCB half-life did not vary by BMI. Thus, if absorption of PCB-contaminated foods continues today (albeit lower than in earlier years), a falsely long or indeterminate (mathematically negative) half-life will be seen. An alternative explanation for our findings is that the half-life of PCBs be very long (>25 years). In that case, our interval of measurement (average, 2.5 years) is too short to obtain an accurate estimate of half-life; as demonstrated by Phillips et al. (25) , to obtain a good estimate of half-life, the interval (in years) between two measurements must be similar to the half-life (in years). A very long half-life seems unlikely, because other studies, particularly of highly exposed occupational groups, have found a PCB half-life in the range 5–25 years, depending on specific congener make-up of the PCB mixtures (33) . Longer half-lives may be expected for PCB levels that do not include the lower-chlorinated, more readily metabolized congeners. Moreover, whereas PCB half-life in our study was not associated with BMI, and the half-life for DDE was inversely correlated with BMI, PCB-DDE half-lives were strongly correlated. Taken together with data on the DDE half-life described below, this evidence suggests that individual metabolism rates of persistent chlorinated aromatic compounds are the same.
In contrast to PCBs, DDE levels were not associated with BMI in our study and DDE half-life was shorter among leaner women. Lopez-Carrillo et al. (26) also found no association between DDE and BMI, but other recent studies of OCs have found a positive correlation between BMI and DDE or dieldrin levels in serum or adipose tissue (3 , 25 , 27) . Schildkraut et al. (30) examined DDE levels in relation to extremes of BMI and found a significant positive association of DDE with BMI and with African-American ethnicity; they found negative associations with weight loss and weight gain. Overall, these results are consistent with a proposed model in which (a) at the time of blood donation, more than one elimination half-life of DDE had elapsed since any prior significant DDE uptake, (b) less than three elimination half-lives had elapsed (because three half-lives would eliminate approximately 90% of the body burden (1/2 x 1/2 x 1/2), and (c) the half-life among more obese women was longer than half-life among leaner women (31 , 32) .
Our data on half-life of OCs provide additional knowledge about
lifetime levels of OCs. This is to our knowledge the first report of
half-life data on more than two serial samples in a normal population
and is the first such report in a breast cancer study. Earlier studies
of half-life had two measures (31
, 32)
or were of too
short a duration to establish half-life (14
, 15)
. The
median half lives of DDE and PCBs in our study (7–11 years) are
similar to reported half-lives of 6–15 years in other studies of OCs
(dieldrin and 2,3,7,8-tetrachlorodibenzodioxin but not PCB) in North
America, showing a dramatic decline over the past 40 years
(11)
. Assembled data from several breast cancer studies
also reflect the declining trend in OC levels in the United States and
elsewhere (Table 7)
. Levels of DDE in blood of California women in the late 1960s were
more than 4 times higher than most recent reports and approximately
twice the levels obtained in a study of women in 1982 from Missouri
(Table 7)
. Recent studies from different laboratories and from
different countries show similar levels of DDE, within a factor of 2
(Table 7)
. Moreover, the half-life of DDE estimated from these
cross-sectional data is 11 years, a rate of decline similar to that
found in other reports and in the current study. However, average PCB
levels shown in these varied reports over the past 30 years are all
within 2–10 ppb and show no decline, consistent with other
investigations (12
, 34)
. Compared to these findings,
higher OC pesticide levels can be expected in countries where there is
continued agricultural use (35
, 36)
.
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In summary, our results do not support a relationship between DDE or PCB levels and breast cancer in a prospective cohort of New York City women. Also, changes in OC levels over several years were similar for cases and controls, suggesting that OC elimination rates may not influence breast cancer risk. Correlations among DDE, PCBs, and age imply similar long-term accumulation of these residues by most women, but differences in correlations among DDE, PCBs, and BMI and their half-lives denote different intervals of exposure and rates of elimination across the population, whereas the strong correlation of DDE half-life with PCB half-life indicates similar individual rates of metabolism. Thus, a single OC measurement may not accurately represent the past exposure of a population. BMI may be a significant factor, causing marked disparities in circulating OC levels between lean and obese women and leading to interindividual variations that are not proportional over time. Therefore, although a measurement of persistent OC levels in the body may reflect lifetime exposure, these measures may not portray OC levels at a time that is relevant to cancer. After further research into this question in other populations, it may be possible to examine the association between lipid-adjusted OC levels and BMI to obtain clues to the history of exposures in a sample observed at only one point in time.
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Acknowledgments |
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Footnotes |
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1 Financial support was provided by National
Institutes of Health Grants ES06489, CA34588, and CA16087. 
2 To whom correspondence should be addressed, at
Department of Community and Preventive Medicine, Mount Sinai School of
Medicine, New York, NY 10029. No reprints will be available.
4 The abbreviations used are: DDT,
1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane;
dichlorodiphenyltrichloroethane; BMI, body mass index; CI, confidence
interval; DDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethene;
ER, estrogen receptor; GM, geometric mean; NYU, New York
University; OC, organochlorine; OR, odds ratio; PCB, polychlorinated
biphenyl.
Received 9/30/99; revised 12/15/99; accepted 12/24/99.
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