are several reasons, beginning with the fact that few epidemiological
studies even try to examine the effects of mixtures, and
instead consider contaminants one at a time. Yet mixtures
are the rule. No one encounters one contaminant at a time.
is especially problematic for epidemiology as it is currently practiced.
Mixtures can make it difficult to detect impacts of contaminants
even when the individual components of the mixtures cause
strong effects individually.
a suite of contaminants share the ability to cause the same health
effect, for example breast cancer, then the fact that people have
mixtures that vary from person to person depending upon their personal
histories will impair epidemiology's ability to demonstrate cause
and effect. For epidemiological studies that focus on individual
components within mixtures, the fewer the number of similarly-acting
contaminants in mixtures and the stronger their individual impacts,
the more likely it is that a cause-effect relationship can be established.
Consider the following exaggerated analogy. Police investigate what
appears to be a serial murderer who has a signature way of killing
and has dispatched 50 people, all the same way. They identify a
series of 50 suspects by establishing that each of them were the
last person seen with one of the victims. But then each of them
has a strong alibi for the 49 other murders. Hence the police eliminate
each of them as a potential suspect. Yet it turns out they were
working together, each one committing only one of the murders.
the case of breast cancer, life-time exposure to estrogen (natural
estrogens exist in the body in several forms) has been established
as a risk factor. Xenoestrogens (contaminants that behave as
estrogens) become a logical suspect, and considerable attention
has been paid to testing the impact of individual xenoestrogens,
one at a time. The reality is, however, that there are many xenoestrogens,
they always occur in mixtures, but the precise composition of the
mixtures vary from person to person. And, recent
research has established that mixtures of xenoestrogens, each
at levels at which they cause no effect, can dramatically increase
the effect of natural estrogen.
becomes even more challenging because of the likelihood of long
delays between when breast cancer is initiated and when it is detected.
This delay may involve decades; indeed some research is even exploring
the possibility that events in the womb set breast cancer in motion.
This is clearly the case for testicular
studies of breast cancer that have attempted to look at links betwen
contaminants and risk measure contamination levels at the time of
diagnosis (or later). These all assume that this measurement of
contamination is an indicator of contamination levels at the time
the disease was initiated. For the more persistent compounds like
DDE and PCBs note
this is at least plausible, although to the degree that it is wrong
it will weaken the strength of the association.
many xenoestrogens are not persistent, like bisphenol
A. Their concentrations will rise and fall over the short term
in ways that cannot be indicated by samples taken long after-the-fact.
If the key attribute in determining whether a contaminant is a risk
for breast cancer is its estrogenicity, and if xenoestrogens act
in mixtures the way that current research indicates, this will
render epidemiological studies of individual contaminants virtually
useless for detecting risks.
DDE and several PCB congeners have become the much-studied standard
suspects in epidemiological studies purporting to test whether xenoestrogens
are breast-cancer risks. The problem is that DDE and the commonly-studied
most persistent PCBs act as an anti-androgen and anti-estrogens,
respectively, not estrogens. Findings that indicate these contaminants
are not associated with breast cancer risk are completely
irrelevant to the hypothesis that xenoestrogens may induce
the forms in which they are manufactured, DDT and PCB mixtures show
weak estrogenic activity. Over time, however, as the compounds are
metabolized and less persistent forms disappear, this weak estrogenicity
most active component of commercial DDT at the time of sale is p,p'-DDT.
This chemical does have estrogenic activity. Both it and the metabolite
to which it is converted in the human body, however, disappear years
after exposure. What doesn't disappear is p-p'-DDE. This is the
most persistent metabolite of commercial DDT. It is the form that
lingers the longest. And rather than being a weak estrogen, p-p'-DDE
is an anti-androgen.
changes occur with PCB mixtures. It turns out that many of the estrogenic
PCBs (and their more active metabolites) are not persistent. The
most persistent of the PCB metabolites that are found in human tissue
actually are anti-estrogens.
this means is that the studies
measuring DDE and PCBs at the time of diagnosis (or afterward)
are actually studying anti-androgens, when the original estrogenic
forms of the compounds from which they were converted metabolically
have long-since disappeared. To conclude that negative findings
using this approach establishes that xenoestrogens are not risk
factors for breast cancer defies scientific logic.