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2212
b-Benzene Hexachloride in Breast Adipose Tissue
and Risk of Breast Carcinoma
Tongzhang Zheng, Sc.D.1
Theodore R. Holford, Ph.D.1
Susan T. Mayne, Ph.D.1
Patricia H. Owens, M.Sc.1
Barbara Ward, M.D.1
Darryl Carter, M.D.1
Robert Dubrow, M.D.1
Shelia H. Zahm, Sc.D.2
Peter Boyle, Ph.D.3
John Tessari, Ph.D.4
1
Yale University School of Medicine and Cancer
Center, New Haven, Connecticut.
2
National Cancer Institute, National Institutes of
Health, Bethesda, Maryland.
3
European Institute of Oncology, Milan, Italy.
4
Colorado State University, Fort Collins, Colorado.
BACKGROUND. Epidemiologic studies have recently related benzene hexachloride
(BHC) to breast carcinoma risk. Experimental studies have also shown that b-BHC
is weakly estrogenic, hence supporting the alleged association. By directly comparing b-BHC levels in breast adipose tissue from incident breast carcinoma cases
and controls, this study examined the hypothesis that exposure to b-BHC increases
the risk of breast carcinoma in females.
METHODS. A total of 490 Connecticut women (304 cases and 186 controls) were
enrolled in the study during the period 1994 –1997. Cases were patients ages 40 –79
years with histologically confirmed incident primary breast carcinoma. Controls
were patients with histologically confirmed incident benign breast disease. Breast
adipose tissue was collected and analyzed for BHC isomers. A linear logistic
regression model was used to adjust for potential confounders in estimating the
association of exposure with disease.
RESULTS. No significant differences in breast adipose tissue levels of b-BHC were
observed between the cases and their controls overall, nor by menopausal status or
estrogen and progesterone receptor status of the breast carcinoma cases. A nonsignificant reduced risk was observed among all subjects and among pre- and
postmenopausal women when the highest quartile was compared with the lowest.
Parous women with higher b-BHC levels, regardless of lactation status, had a
nonsignificantly reduced breast carcinoma risk, whereas a nonsignificantly increased risk was observed among nulliparous women with higher b-BHC levels,
based on very few study subjects.
CONCLUSIONS. The results of this study do not support the hypothesis that increasing adipose tissue levels of b-BHC are associated with an increased risk of breast
carcinoma in females. Cancer 1999;85:2212– 8. © 1999 American Cancer Society.
KEYWORDS: b-benzene hexachloride, breast carcinoma, case– control, environment, epidemiology.
E
The authors thank Dr. Leticia DeDios and Dr.
Christine Howe for their assistance in the collection of study materials. The authors also thank
Donna Carrano, Melita Bosnyak, Heather Hutson,
and Sylvia Ullman for their high quality interviewing, and the surgeons and nurses at the Yale–New
Haven Hospital and the Temple Medical Center for
their support of the study.
Address for reprints: Dr. Tongzhang Zheng, 129
Church Street, Suite 700, New Haven, CT 06510.
Received September 4, 1998; revision received
December 23, 1998; accepted January 15, 1999.
© 1999 American Cancer Society
nvironmental estrogens have recently been associated with the
risk of breast carcinoma. Most of the studies, however, have centered on polychlorinated biphenyls and 1,1-dichloro-2,29bis(p-chlorophenyl)ethylene as risk factors.1– 8 Benzene hexachloride (BHC),
also known as hexachlorocyclohexane (HCH), an organochlorine insecticide, has also recently been related to breast carcinoma risk.
Mussalo-Rauhamaa et al.9 reported that residues of b-BHC, one of the
isomers of BHC, were higher in breast fat tissue from breast carcinoma patients than that from controls. After adjustment for age and
parity, b-BHC remained significant as a risk factor for breast carcinoma. For residue levels of b-BHC in breast adipose tissue containing
more than 0.1 mg/kg fat, the odds ratio was 10.5 (95% CI, 2.0 –55.3)
compared with tissue containing 0.1 or less mg/kg fat.
Experimental studies show that b-BHC is weakly estrogenic, sup-
b-BHC and Breast Carcinoma Risk/Zheng et al.
porting a potential association with breast carcinoma
risk. In a breast carcinoma cell line, b-BHC was able to
increase progesterone receptor (PR) content10 and
stimulate proliferation in a dose-dependent manner
in the estrogen receptor positive (ER1) cell line
MLF-7, but not in an ER2 cell line.11 b-BHC was also
found to augment rat uterine weights in a dose-dependent fashion,12 and a daily b-BHC dose of 0.5
mg/kg body weight given orally has also produced
disturbances of the estrous cycle in female rats.13
It should be noted that DDT and PCBs also possess estrogenicity and have the ability to induce cytochrome p450 mixed-function oxidase enzymes, which
are intimately involved in steroid hormone metabolism. Although some epidemiologic studies have
found an association between DDT or PCBs and
breast carcinoma,1–5 recent epidemiologic studies
with large sample sizes have not shown an increased
risk of breast carcinoma.6 – 8 In fact, an inverse association was reported in one study.8 Results relating
more potent exogenous estrogens, such as postmenopausal hormone replacement therapy (HRT) and oral
contraceptive use, to the risk of breast carcinoma have
also been inconsistent.14 –16
Since 1978, technical grade BHC, which consists
of a mixture of five configurational isomers of a-, b-,
g-, d-, and e-BHC, has not been in use in the U.S.17
Therefore, in recent years, isomers of BHC other than
b-BHC have rarely been found in human serum or fat
tissue in the U.S. population because of their rapid
biotransformation and subsequent conjugation and
excretion. b-BHC, however, due to its resistance to
chemical and biologic breakdown, has contaminated
the environment and has been stored in fat tissue as a
result of its extensive use during the 1950s and
1960s.18 Because of the ubiquitous nature of exposure
to b-BHC through the food chain and the inconclusive
data regarding the health effects of b-BHC, we decided
to examine its correlation with the risk of breast carcinoma in females. This effort was part of a case–
control study of organochlorine compounds and
breast carcinoma risk in Connecticut.
This study compared b-BHC levels in breast adipose tissue from incident breast carcinoma cases and
noncancer controls. Breast adipose tissue was chosen
because organochlorine compounds are lipophilic
and highly persistent; thus, they tend to accumulate in
fat tissue. Adipose tissue levels of organochlorine
compounds, including BHC, are generally considered
the best indicators of human lifetime environmental
exposure. We measured three isomers of BHC (a-, b-,
and g-BHC), but only 2 of the 490 subjects had quantifiable a-BHC (quantitation limit, 5.0 pg/mg) and
none of the subjects had quantifiable g-BHC (quanti-
2213
tation limit, 10.0 pg/mg). In this article we report the
results relating b-BHC and breast carcinoma risk.
MATERIALS AND METHODS
Study subjects were women ages 40 –79 years who had
breast-related biopsy or surgery at Yale–New Haven
Hospital (YNHH) in New Haven, Connecticut, and
from whose breast pathology specimens we could collect at least 0.4 g of residual breast adipose tissue for
chemical analyses. Breast adipose tissue not needed
for diagnostic purposes was collected and placed into
a glass vial on ice by personnel from the Tissue Retrieval Facility at the Yale Cancer Center. The samples
were then coded and frozen within 30 minutes of
being excised and stored at 284°C. Study subjects
were enrolled consecutively between January 1, 1994,
and December 30, 1997.
Potential cases were patients with histologically
confirmed, incident primary breast carcinoma (International Classification of Diseases [ICD-O] 174.0–174.9).
The study pathologist (D.C.), who is responsible for almost all of the breast tissue diagnoses made at YNHH,
classified the potential participants as either potential
cases or controls and staged carcinomas according to
the TNM system.19 Potential controls were patients with
histologically confirmed incident benign breast disease
(excluding atypical hyperplasia). Cases of benign breast
disease were classified by the study pathologist and
grouped according to the 1985 Pathologists’ Consensus
Statement as proliferative benign breast disease without
atypia (n 5 91) or nonproliferative disease (n 5 95; 21
patients with normal breast tissue, 25 with fibroadenoma, and 49 with other nonproliferative disease).
Each participant, after approval by his or her physician, was approached by letter and then by phone.
Those who consented were interviewed in person,
generally in the woman’s home or in another convenient location. A standardized, structured questionnaire was used to obtain information about major
known or suspected risk factors for breast carcinoma,
including reproductive history, lactation history, past
medical history, occupation, and demographic factors. The dietary information was collected through a
scannable semiquantitative food frequency questionnaire, developed by the Fred Hutchinson Cancer Research Center, that was designed to optimize estimation of fat intake. Each subject was asked to
characterize her usual diet in the year before she had
the biopsy. Potential cases and controls were excluded
if they had had a previous diagnosis of cancer, with
the exception of nonmelanoma skin cancer. Interviews were completed for 79% of the potentially eligible cases and 74% of the controls.
Frozen breast adipose tissue samples were sent in
2214
CANCER May 15, 1999 / Volume 85 / Number 10
batches to the study laboratory at Colorado State University, where they remained frozen until analysis.
Tissue samples were analyzed in batches of 12, with
each batch containing approximately 6 cases, 4 controls, and 2 quality-control samples. Samples were
batched and coded at Yale; therefore, laboratory personnel in Colorado were blinded to the case– control
status of the samples being analyzed.
The laboratory method for analyzing BHC isomers
in breast adipose tissue has been described elsewhere.20 Briefly, the method involved extraction in
hexane, separation of the organochlorine pesticides
from the PCBs and purification of the sample using
Florisil (U.S. Silica Co., Berkeley Springs, WV) chromatography, and identification and quantification of the
compounds using gas chromatography. The quantitation limit of this method was 15 ppb for b-BHC. All
analyses were conducted under an established quality-control/quality-assessment program that included
method spikes, reagent blanks, and quality-control
windows. Quality-control spike mean recovery for
b-BHC was 95% during the sample analyses, with a
coefficient of variation of 15%. Adipose tissue levels of
b-BHC were reported as parts per billion (ppb), equivalent to pg/mg lipid. The amount of lipid in the sample was quantified gravimetrically. Lipid adjustment
was necessary because BHC isomers are lipid soluble
and tissue sample lipid contents vary between subjects. Therefore, lipid adjustment facilitates comparability of the results across studies.21
Breast adipose tissue levels of b-BHC were compared between cases and controls, among pre- and
postmenopausal women, and according to parity and
lactation history. Quartiles of adipose tissue levels of
b-BHC were formed based on the frequency distribution in the controls. Because earlier studies suggest
that environmental estrogens may only affect the incidence of hormone-responsive breast carcinoma,
b-BHC levels were also compared based on the cases’
ER and PR status. Both ER and PR levels were considered positive if the H-score was greater than 75, as
described by McCarty et al.23 b-BHC levels were also
compared based on breast carcinoma histology (lobular vs. ductal carcinoma), stage of diagnosis (Stage 0,
I, II vs. III and IV), and type of benign breast disease
(proliferative vs. nonproliferative disease). The statistical significance of the difference among multiple
means of adipose tissue levels of b-BHC was calculated using analysis of variance and rank sum tests,
and analysis of covariance was used to adjust for potential confounders. Because the distribution of
b-BHC was skewed, we present the median as a measure of location and the first and third quartile cutpoints (25% and 75%) as summaries of the degree of
variability. The log transformation was used to better
approximate the normality assumption, and thus the
antilog of the resulting adjusted mean values (i.e., the
adjusted geometric mean) was used as a summary
statistic.
A linear logistic regression model was used to
adjust for confounders when the association between
exposure and disease was estimated. The variables
included in the final model were age, body mass index
(kg/m2), lifetime months of lactation, age at menarche, age at first full-term pregnancy (nulliparous,
,25 or $25 years), race (white, black, and other),
family breast carcinoma history, fat intake, and lipidadjusted breast adipose tissue levels of total DDE and
PCBs (ppb). Odds ratios (OR) and 95% confidence
intervals were calculated using SAS statistical software.24
RESULTS
As shown in Table 1, the cases were older than the
controls. Because age was associated with body burden of b-BHC (r 5 0.30, P , 0.01), it was a potential
confounder and hence was controlled in all subsequent analyses. Also shown in Table 1 is that women
who experienced menarche at an early age had a nonsignificantly higher risk for breast carcinoma. Compared with those who had a first full-term pregnancy
before age 20 years, women who were older at the
time of their first full-term pregnancy showed a higher
risk. Those with a lifetime lactation of more than 12
months experienced a reduced risk (OR 5 0.7, 95% CI
0.4 –1.1) compared with those who had never lactated.
Dietary fat intake at the second tertile, but not the
third tertile, was associated with a 60% increased risk.
No other baseline factors showed a clear association
with breast carcinoma risk in this study.
The age-adjusted geometric means for adipose
tissue levels of b-BHC were similar for the 304 breast
carcinoma cases (27.1 ppb) and their 186 controls
(26.3 ppb), as shown in Table 2. There were also no
significant differences in age-adjusted geometric
mean adipose tissue levels of b-BHC between pre- or
postmenopausal cases and controls.
The age-adjusted geometric mean adipose tissue
levels of b-BHC for breast carcinoma cases and controls, based on the cases’ ER and PR status, are presented in Table 3. There were no significant differences in mean adipose tissue levels of b-BHC between
controls and various ER and PR status subgroups. The
cases’ mean adipose tissue levels of b-BHC also did
not differ by ER and PR status.
The age-adjusted geometric mean adipose tissue
level of b-BHC for 304 cases (27.1 ppb) was almost
identical to that of 91 controls with proliferative be-
b-BHC and Breast Carcinoma Risk/Zheng et al.
TABLE 1
Selected Characteristics of Breast Carcinoma Cases and Controls with
Benign Breast Disease
Characteristics
Age (yrs)
,50
$50
Age at menarche (yrs)
$15
13–14
,13
Unknown
Age at first full-term pregnancy (yrs)
,20
20–25
$26
Nulliparous
Lifetime lactation (mos)
0
1–6
6–12
$13
Family breast carcinoma history
Yes
No
BMI (kg/m2)
,21
21–24
$25
Fat intake (g/day)
,46
46–71
$72
Unknown
Race
White
Black
Other
Cases
Controls
OR
81
105
1.0
1.7
25
130
147
2
21
72
92
1
1.0
1.5
1.3
—
31
129
107
37
34
68
56
28
1.0
2.1
2.2
1.5
1.2–3.8
1.2–3.9
0.7–3.0
197
46
22
39
107
33
14
32
1.0
0.8
0.9
0.7
0.5–1.3
0.4–1.7
0.4–1.1
229
75
142
44
1.0
1.1
0.7–1.6
37
116
151
27
62
97
1.0
1.4
1.1
0.8–2.4
0.7–2.0
78
128
88
10
62
62
61
1
1.0
1.6
1.1
—
266
32
6
157
21
8
1.0
0.9
0.4
TABLE 2
Lipid-Adjusted Adipose Tissue Levels of b-BHC (ppb) among Breast
Carcinoma Cases and Benign Breast Disease Controls
95% CI
95
209
1.2–2.5
0.8–2.9
0.7–2.5
All subjects
Cases
Controls
Premenopausal
Cases
Controls
Postmenopausal
Cases
Controls
0.5–1.6
0.2–1.3
CI: confidence interval; BMI: body mass index.
nign breast disease (27.2 ppb) and similar to that of 95
controls with nonproliferative benign breast disease
(25.0 ppb). The two control groups were also not significantly different from each other (P 5 0.39). The
geometric mean adipose tissue levels of b-BHC were
also similar for 186 controls (26.3 ppb), for 262 women
with ductal carcinoma (27.1 ppb), and for 33 women
with lobular carcinoma (25.5 ppb). The geometric
mean tissue level of b-BHC for 273 women with Stage
0 –II disease was 27.2 ppb, which was similar to that
for 19 women with Stage III–IV disease (28.1 ppb) and
not significantly different from the controls (26.3 ppb).
Age and covariate-adjusted ORs for the association between b-BHC and breast carcinoma risk are
presented in Table 4. There was an inverse association
between b-BHC in breast adipose tissue and breast
carcinoma risk when the highest quartile was com-
No. of
subjects
Median
(25%, 75%)a
Age-adjusted
geometric
mean
304
186
27.1 (16.1, 41.6)
25.2 (16.3, 41.2)
27.1
26.3
0.61
87
75
17.3 (13.3, 28.3)
19.7 (14.4, 30.4)
18.8
19.7
0.62
217
111
30.1 (20.7, 46.0)
31.3 (19.3, 47.6)
31.3
31.9
0.82
P valueb
b-BHC: b-benzene hydrochloride; ppb: parts per billion, equivalent to pg/mg lipid.
a
The cutpoints at the first quartile (25%) and the third quartile (75%) for the lipid adjusted breast
adipose tissue levels of b-BHC.
b
P values for test of geometric means between cases and controls after adjustment for age using
analysis of covariance.
TABLE 3
Lipid-Adjusted Adipose Tissue of b-BHC (ppb) in Breast Carcinoma
Cases and Controls, by Estrogen and Progesterone Receptor Status
Hormone status
1.0–2.6
0.7–1.8
2215
Controls
Cases
ER1
ER2
Unknown
Cases
PR1
PR2
Unknown
No. of
subjects
Median
(25%, 75%)a
Age-adjusted
geometric
mean
186
25.2 (16.3, 41.2)
26.3
157
126
21
27.5 (16.4, 44.9)
26.3 (15.5, 40.3)
23.6 (14.4, 37.5)
28.1
26.5
23.4
0.34
0.90
0.46
116
128
60
26.7 (15.7, 42.5)
27.9 (16.8, 43.9)
26.4 (15.1, 38.1)
27.6
27.7
24.8
0.52
0.45
0.55
P valueb
b-BHC: b-benzene hexachloride; ER: estrogen receptor; PR: progesterone receptor; ppb: parts per
billion, equivalent to pg/mg lipid.
a
The cutpoints at the first quartile (25%) and the third quartile (75%) for the lipid-adjusted breast
adipose tissue levels of b-BHC.
b
P value for the geometric mean difference between controls and each type of case adjusted for age
using analysis of covariance.
pared with the lowest for the covariate-adjusted odds
ratio (OR) (OR 5 0.6, 95% CI 0.3–1.1). An inverse
association was also observed among pre- and postmenopausal women, but none of these achieved statistical significance at the nominal 5% level.
Further analysis by parity and history of lactation
showed an inverse association of breast carcinoma
risk with increasing tissue levels of b-BHC among
parous women (Table 5). For those who reported
breastfeeding, the covariate adjusted OR was 0.4 (95%
2216
CANCER May 15, 1999 / Volume 85 / Number 10
TABLE 4
Breast Carcinoma Risk Associated with Breast Adipose Tissue Levels of b-BHC (ppb), by Menopausal Status
b-BHC
All subjects
,16.5
16.5–25.2
25.3–41.4
41.5–
P value for trend
Premenopausal
,14.7
14.7–20.0
20.1–30.3
30.4–
P value for trend
Postmenopausal
,20.0
20.0–31.2
31.3–47.6
47.7–
P value for trend
Cases
Controls
OR1
95% CI
OR2
95% CI
81
59
87
77
48
46
46
46
1.0
0.7
0.8
0.5
0.30
0.4–1.1
0.4–1.3
0.3–1.0
1.0
0.7
0.8
0.6
0.26
0.4–1.2
0.5–1.5
0.3–1.1
33
16
21
17
19
19
18
19
1.0
0.5
0.6
0.4
0.98
0.2–1.1
0.3–1.5
0.2–1.1
1.0
0.5
0.6
0.4
0.90
0.2–1.2
0.2–1.6
0.1–1.1
54
56
62
45
28
27
29
27
1.0
0.9
0.7
0.5
0.27
0.5–1.8
0.4–1.5
0.2–1.1
1.0
1.0
0.8
0.6
0.27
0.5–1.9
0.4–1.6
0.3–1.3
b-BHC: b-benzene hexachloride; CI: confidence interval; ppb: parts per billion, equivalent to pg/mg lipid.
OR1: odds ratio adjusted only for age; OR2: odds ratio adjusted for age, body mass index (kg/m2), lifetime mos of lactation, age at menarche, age at first full-term pregnancy (nulliparous, ,25, $25 yrs), race (white,
black, and other), family breast carcinoma history, fat intakes, and lipid-adjusted breast adipose tissue levels of total DDE: 1,1-dichloro-2,29bis(p-chlorophenyl)ethylene and PCB: polychlorinated biphenyls1 (ppb).
TABLE 5
Odds Ratios Associated with Adipose Tissue Levels of b-BHC among Parous and Nulliparous Women, by Lactation History
b-BHC
Parous women with history of lactation
,16.2
16.2–22.6
22.7–40.4
40.5–
P value for trend
Parous women with no history of lactationa
,16.9
16.9–27.7
27.8–42.9
43.0–
P value for trend
Nulliparous womenb
,18.6
18.6–31.8
31.9–
P value for trend
Cases
Controls
OR1
95% CI
OR2
95% CI
35
19
34
19
20
20
19
20
1.0
0.5
0.7
0.3
0.10
0.2–1.2
0.3–1.6
0.1–0.8
1.0
0.6
0.9
0.4
0.16
0.2–1.4
0.4–2.3
0.1–1.1
37
34
44
45
19
19
20
19
1.0
0.7
0.7
0.6
0.96
0.3–1.7
0.3–1.6
0.2–1.4
1.0
0.7
0.7
0.6
0.91
0.3–1.7
0.3–1.6
0.2–1.7
9
12
16
10
10
10
1.0
1.3
1.5
0.63
0.4–4.4
0.4–5.5
1.0
1.4
3.1
0.88
0.4–5.5
0.6–15.1
b-BHC: b-benzene hexachloride; CI: confidence interval; ppb: parts per billion, equivalent to pg/mg lipid; OR1: odds ratio adjusted only for age; OR2: odds ratio adjusted for age, body mass index (kg/m2), lifetime
mos of lactation, age at menarche, age at first full-term pregnancy (nulliparous, ,25, $25 yrs), race (white, black, and other), family breast carcinoma history, fat intakes, and lipid-adjusted breast adipose tissue
levels of total DDE and PCBs (ppb).
a
No adjustment for lactation status.
b
No adjustment for lactation and age at first full-term pregnancy.
b-BHC and Breast Carcinoma Risk/Zheng et al.
CI, 0.1–1.1) when the highest quartile was compared
with the lowest. Among nulliparous women, however,
an adjusted OR of 3.1 (95% CI 0.6 –15.1) was observed
when the third tertile was compared with the lowest
based on only a very few subjects in this group.
DISCUSSION
No significant difference in breast adipose tissue levels
of b-BHC was observed between breast carcinoma
patients and their controls in this study. The mean
adipose tissue levels of b-BHC also did not vary by
case– control status when the subjects were stratified
by menopausal status or by ER or PR status for the
breast carcinoma cases. A nonsignificant inverse association with breast carcinoma risk was observed
among all study subjects and among pre- and postmenopausal women when the highest quartile was
compared with the lowest. Parous women, regardless
of lactation history, experienced a nonsignificantly reduced risk of breast carcinoma. Therefore, our results
do not support the hypothesis that increasing adipose
tissue levels of b-BHC are associated with an increased
risk of breast carcinoma in females.
The lack of a positive association in this study
contradicts the results of a case– control study of Finnish women reported by Mussalo-Rauhamaa et al.9
They found significantly higher (P 5 0.026) breast
adipose tissue levels of b-BHC for breast carcinoma
cases (130 ppb) than for controls (80 ppb). The risk
was found to be almost 11-fold higher for women
whose breast adipose tissue contained more than 100
ppb b-BHC compared with women whose tissue contained less.
Chance offers one possible explanation for the
difference between the results of our study and those
of Mussalo-Rauhamaa et al.,9 especially because of the
relatively small sample size of the latter (44 breast
carcinoma cases and 33 controls). It could be hypothesized that the discrepancy between the study of Mussalo-Rauhamaa and this study is due to a threshold
effect of b-BHC on breast carcinoma risk; that is, the
risk may only exist at much higher exposure levels.
The mean adipose tissue level of b-BHC in the cases of
Mussalo-Rauhamaa et al. was 3.6 times that of cases in
our study. Data published in 1985 from the U.S. National Human Adipose Tissue Survey show that the
median residue level of b-BHC was 140 ppb for the
entire nation for the years 1970 –1983. The mean adipose tissue levels of b-BHC decreased from approximately 370 ppb in 1970 to approximately 100 ppb in
1983.18 Because the tissue samples studied by Mussalo-Rauhamaa were actually collected between 1985
and 1986,9 the levels of b-BHC appear to be quite
comparable to those found in the U.S. population and
2217
the Finnish population in the 1980s. The levels found
in our study are consistent with a continuing decline
in the level of exposure to this chemical.
Inclusion of BBD controls may also be partially
responsible for the weakness of or lack of association
between breast carcinoma and some of the established risk factors shown in Table 1. The risk factors
for BBD are currently poorly understood as reviewed
by Ernster,25 and it is possible that some of the reproductive and demographic variables shown in Table 1
are risk factors for both benign breast disease and
breast carcinoma. The weakness of or lack of association could also be a function of sample size, however;
a similar lack of association for established risk factors
has been seen in three recent case– control studies of
similar size4,5,7 that investigated the association between DDE and breast carcinoma risk.
Similarly, it could be argued that the overall lack
of association between b-BHC and breast carcinoma
risk in this study is due to the participation of patients
with benign breast disease as controls. If there were an
association between b-BHC and benign breast disease
(excluding atypical hyperplasia), this could lead to an
underestimation of the true relative risk for breast
carcinoma. Although this possibility cannot be ruled
out entirely, it is unlikely that the lack of association of
b-BHC with breast carcinoma risk is only attributable
to the participation of benign breast disease patients
as controls. Two previously observed positive associations between organochlorine compounds and female breast carcinoma risk came from studies in
which patients with benign breast disease served as
controls.2,3 In addition, the age-adjusted geometric
mean of adipose tissue levels of b-BHC for 91 women
diagnosed with proliferative benign breast disease
(27.2 ppb) was not significantly (P 5 0.39) higher than
that for 95 women with nonproliferative disease or
normal tissue (25.0 ppb).
It is a concern that breast adipose tissue levels of
b-BHC may be affected by case status. In particular,
the tissue levels of b-BHC for patients with advanced
disease may be affected by mobilization of energy
from fat stores. In our study, only 20 breast carcinoma
patients were diagnosed with Stage III/IV disease, and
exclusion of these patients from the study did not
result in any material change to the conclusion. A
recent follow-up study7 also does not support that
disease stage at diagnosis significantly impacts serum
levels of DDE and PCBs.
Another concern is the possibility that some patients in this study may have had chemotherapy or
radiation therapy prior to surgery to reduce tumor
bulk, and that such treatment could affect lipids and
lipophilic substances in the breast. In the current
2218
CANCER May 15, 1999 / Volume 85 / Number 10
study, breast adipose tissue not needed for diagnostic
purposes was collected by personnel from the Tissue
Retrieval Facility at the Yale Cancer Center for chemical analyses. The majority of the breast adipose tissue
samples were collected at the time of biopsy, before
the final diagnosis was made. Although a small number of tissue samples may have been collected at the
time of surgical treatment, according to the information provided by YNHH surgeons, only in rare instances would a patient at YNHH receive chemotherapy or radiation therapy prior to surgical treatment.
The age difference between the cases and the
controls in this study also cannot be used to explain
the observed inverse association. Age was found to be
positively associated with the body burden of b-BHC
in our study (r 5 0.30, P , 0.01). Therefore, if the
residual confounding from the age difference has any
impact on the observed effect, it should cause a falsepositive association rather than a negative one.
In conclusion, our overall results do not support a
positive association between environmental exposure
to b-BHC and risk of breast carcinoma in females. We
did not find an increased risk among either pre- or
postmenopausal women, among different types of
breast carcinoma histologies, or among different types
of benign breast disease. The risk also did not vary
based on the ER or PR status of the cases.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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