MD, MS Wolff, AI Neugut, SM Eng, SL Teitelbaum, JA Britton, MB Terry,
B Levin, SD Stellman, GC Kabat, M Hatch, R Senie, G Berkowitz, HL
Bradlow, G Garbowski, C Maffeo, P Montalvan, M Kemeny, M Citron,
F Schnabel, A Schuss, S Hajdu, V Vinceguerra, N Niguidula, K Ireland
and RM Santella. 2002. Environmental Toxins and Breast Cancer
on Long Island. II. Organochlorine Compound Levels in Blood.
Epidemiology Biomarkers & Prevention
2001 review of breast cancer epidemiology
coverage of this report
new study led by Marilie Gammon finds few associations between the
risk of breast cancer and serum levels environmental toxins measured
around the time of diagnosis. While that might seem to be good news,
the study has severe limitations which undermine the policy implications
of its conclusions.
in 1993 as a result of a law mandating the National Cancer Institute
to study links between environmental contaminants and breast cancer,
the study examined risk of breast cancer as a function of current
body burden levels of a series of compounds of traditional, historic
concern (DDT, DDE, PCBs, chlordane and dieldrin).
authors conclude that "it seems unlikely that breast
cancer risk is associated with organochlorines when measured close
to the time of breast cancer diagnosis." They imbed
this conclusion in a series of cautionary statements, the most important
of which is:
data do not rule out the possibility, however, that breast
cancer risk is elevated by high organochlorine exposures several
decades earlier that, through variations in individual metabolism,
now measure as low body burden levels. Also, very limited
data recently suggest that breast cancer mortality may be
associated with some organochlorine compounds. These possibilities
require additional research.
possibility... that breast cancer risk may be elevated by exposure
to organochlorine exposures several decades earlier... is the
heart of the endocrine disruption hypothesis: exposure
during crucial times in development causes developmental errors
which (in the case of breast
cancer) increase the likelihood of cancer later in life. Hence
the results presented by Gammon et al., while potentially
reassuring (but see below) about the impact of current exposures,
are very limited what they tell us about endocrine disruption's
contribution to breast cancer risk, even with respect to the chemicals
work by Warner et al. showing signficant links between
dioxin exposure and breast cancer in Seveso, Italy, residents reinforces
this point. Breast cancer cases decades later are more likely in
women with increased dioxin, measured in serum samples shortly after
et al. face another methodological limitation, however,
which is at least as important. Their study focuses principally
on a small number of traditional organochlorines (listed above).
Women on Long Island are exposed to a significantly larger list
of OCs, as well as non-organochlorine compounds that are active
endocrinologically, including as estrogens... compounds like bisphenol
A and nonylphenol. There are many more.
et al.'s work tells us nothing about the contribution to
breast cancer risk that these compounds make. That's no surprise.
But the presence of these compounds introduces another,
less obvious flaw into this study which directly undermines their
central conclusion, that there is no link between current
OC exposure and breast cancer risk.
is because of the ubiquity
of mixtures. Everyone is exposed to multiple estrogen-like contaminants
but the precise composition of the mixtures vary from person to
person depending upon their individual history of exposure.
the link between compounds and breast cancer risk is that they share
the ability to bind with the estrogen receptor (for example), then
what matters is likely to be the estrogenicity of the mixtures,
not the individual compounds that are present. If there are many
estrogen-like compounds in the mixture, and there is significant
variability in the precise composition of the mixtures from woman
to woman, then epidemiology will have a very difficult time discovering
a link between one compound and breast cancer risk if measurements
are only made of a small number of the estrogen-like contaminants.
the following hypothetical but very plausible situation: In one
woman, the mix of xenoestrogens that has led to breast cancer might
be composed of one suite of compounds; in another, the causal mix
could be different. If the epidemiological analysis focuses on individual
components of mixtures, it easily could miss finding a statistically
signficant link between any one compound and breast cancer, even
though their presence in some women was the causal agent while the
presence of other xenoestrogens in other women caused their cancers.
this reality of mixtures complicates epidemiological research to
the point that real impacts can be literally undetectable,
at least by epidemiology as it is currently practiced. More...
flaw is not Gammon et al's fault. It is a reality that
we face because of mixtures are the rule, not the exception, and
because these mixtures are made up of tens, if not hundreds, of
compounds. And recent
research has demonstrated unequivocally that the combined
impact of even a small number of estrogen-like compounds in a mixture
can be very significant. To complicate matters still further,
contaminants sometimes interact
with viruses in ways that can dramatically increase risk. No
published studies of breast cancer epidemiology have tested explicitly
for this possibility.
this means in the real world is that epidemiological studies like
this are virtually useless to disprove links between
hormonally-active compounds and disease. The converse, however,
is not true. A positive result of a carefully-conducted
case-control study with large sample sizes should be taken very
seriously. If a signal emerges out of the statistical noise that
characterize these systems, despite all the limitations of epidemiology,
then the links are likely to be very strong.
did they do? Gammon et al. conducted a case-control
study involving 1508 cases and 1556 controls from Nassau and Suffolk
Counties on Long Island, New York. Most participants (93%) were
white. Cases were recruited shortly after diagnosis of breast cancer.
Controls were chosen using a randomizing procedure designed to match
the age structure of the cases.
samples for chemical analysis were selected from blood samples gathered
on the basis of several criteria: (1) random selection of 415 cases
and 406 controls; (2) all African American samples; (3) an additional
184 cases diagnosed with in situ disease that made blood
chemical analysis determined serum concentrations of p,p'-DDE,
p,p'-DDT, oxychlordane, trans-nonachlor, dieldrin, and
24 PCB congeners.
the data analysis, factors known to affect breast cancer risk on
the basis of previous studies (e.g., history of breast feeding,
alcohol and tobacco use, family history of breast cancer, etc.)
were controlled statistically.
did they find? Gammon et al. analyzed their data
in several different ways. Simply comparing the concentrations of
the measured organochlorines in cases vs. controls, they found no
differences. Then using a multivariate model to control for the
multiple variables known to influence breast cancer rate (such as
those listed above), they found a suggested elevation of breast
cancer risk for women in the top quintile of exposure of DDE, DDT
and dieldrin, but not for PCBs or chlordane. There was not indication
of a dose response curve for any of the OCs.
were suggestions of higher risk for women that had not given birth
and had higher levels of chlordane (a greater than 2 fold elevation
in risk) but the sample size was small.
authors conclude: "In this population-based case-control study
conducted among women on Long Island, there was little evidence
of an increased risk of breast cancer in relation to DDE, DDT, PCBs,
chlordane, or dieldrin."
does it mean? As noted above, little can be concluded with
certainty from this study. Perhaps its greatest value will be to
push future research in two directions: first, to test explicitly
for links between breast cancer risk and exposure during crucial
windows of development, instead of contamination levels at the time
of diagnosis; and second, toward tackling the problem of mixtures.
Our understanding of the contribution of contaminants to
breast cancer risk await progress on these issues.