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Great Lakes
Article:
Environmental dioxins and endometriosis.
S. Rier and WG Foster
Toxicological Sciences 70:161-170.
12/30/2002
Rier
and Foster review evidence from animal and human studies
indicating that dioxin (and other dioxin-like
compounds) causes endometriosis via its ability to disrupt
immune and endocrine system function. They conclude
that existing data support this interpretation but that
the details of the mechanisms are not yet clear.
They also show that human
exposure to dioxin is significantly higher than that
associated with endometriosis in monkeys., and
cite published work which concludes that current public
health standards are not strong enough to provide guarantees
against the potential for dioxin causing endometriosis.
What
does this mean? Dioxins are highly likely to
be involved in the causation of endometriosis. Many people
carry dioxin body burdens that animal experiments predict
should cause endometriosis. The disease itself has likely
increased dramatically in prevalence over the past century,
the same period over which human dioxin body burdens grew.
In the US alone, endometriosis forces over 100,000 hysterectomies
each year, with health care costs for the disease exceeding
$1 billion annually. Strong measures to reduce dioxin
exposures are warranted.
Key
parts of their review:
A
summary of the action of dioxin and dioxin-like compounds:
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- This
group of chemicals, the polyhalogenated aromatic
hydrocarbons (PHAHs), includes not just dioxins
(PCDDs) but also furans (PDDFs) and biphenyls
(PCBs).
- PHAH
compounds bind with the aryl hydrocarbon receptor
(AhR), migrate to the nucleus and activate genes,
including several involved in controlling cell
growth, differentiation and inflammation.
- Evidence
demonstrates that different dioxins can act additively
via this mechanism. To assess the effects of dioxin
mixtures, scientists have developed a dioxin "toxic
equivalency factor" (TEF) based upon the
relative potency of different congeners compared
to TCDD(2,3,7,8-tetrachlorodibenzo-p-dioxin)
the most potent of the compounds, and then used
the summed TEFs to calculate the total TCDD equivalency
(TEQ).
- Most
human exposure to dioxin comes via food. "In
developed countries, blood levels typically run
1-5 parts per trillion TCDD and 25 ppt TEQ, at
least for people without industrial exposure.
- "Although
the toxic effects of TCDD in animals are unequivocal,
its effects in humans are less clear."
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A
review of data on dioxin-endometriosis links in monkeys:
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- The
first hard data linking endometriosis and dioxin
came from Rier
et al.'s 1993 work with rhesus monkeys.
They discovered, 10 years after TCDD exposure
was ended, that exposed monkeys had developed
endometriosis: the more dioxin, the greater the
incidence and severity of the disease. Exposures
were in the low parts per trillion.
- Subsequent
studies with monkeys have strengthened this conclusion.
For example, a study of cynomolgus monkeys found
that TCDD exposure increased the implantation
rate of endometrial tissue.
- And
in 2001, Rier
et al. published additional work
with rhesus monkeys showing that higher TEQ levels
were associated with a higher prevalence of endometriosis.
Disease severity was positively related to PCB
congeners, but not to TCDD itself. In
this study, the animals were exposed to PHAH compounds
through food, as are people.
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Comparison
of exposures of people to those of the monkeys in these
experiments:
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- Their
comparison reveals that the body burdens in people
living in the real world are 2 to 20-fold higher
than the monkeys in the experiments.
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- Rier
and Foster cite a
Japanese calculation that "protection
against development of endometriosis cannot be
guaranteed by current regulatory safeguards, since
exposure to dioxin and dioxin-like compounds in
certain at-risk populations, such as local residents
living near incinerators or who are heavy fish
consumers are greater than the levels for which
adverse effects have been documented in rhesus
monkeys."
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It
would thus seem that if human endometriosis has a comparable
dose response relationship to that revealed by the experiments
with monkeys, then it is not surprising that endometriosis
is as widespread in people as data currently indicate.
Evaluation
of the value of animal models for understanding human
endometriosis:
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- Only
menstruating species like people and monkeys develop
endometriosis. Rhesus endometriosis closely resembles
the human form.
- Surgical
transplantation of endometrial tissues in other
species, such as rodents, can be used to study
the factors that affect the chances that the tissue
will thrive in other locations, but not of the
the earliest stages of development of endometriosis.
- New
approaches are being developed that transplant
endometrial tissues into immune-deficient mice.
The implants resemble endometrial lesions in people.
This may allow more cost-effective and rapid research
than studies with monkeys.
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Human
studies on dioxin and endometriosis:
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- Four
hospital based case-control studies have been
published. Results are mixed. None of the studies
are ideal, all with small sample sizes. Two (both
negative) failed to confirm surgically that the
control population did not have endometriosis.
A third negative study used a chemical assay that
probably underestimated TEQ. The one
positive study found that infertile women
with endometriosis were more likely to have detectable
levels of TCDD than fertile women without endometriosis.
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Potential
mechanisms by which dioxin could cause endometriosis:
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- Rier
and Foster begin this section summarizing studies
showing that the dioxin stimulates gene activation
in endometrial tissue through binding with the
Ah receptor.
- They
then propose that this gene activation may promote
endometriosis through three pathways:
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First,
by inducing an enzyme that increases estrogen
levels and results in "chronic exposure
of the endometrium to growth-promoting estrogen."
Second,
by stimulating certain cytokines (immune system
proteins) involved in immune system responses
and in the regulation of cycles of cell division
and death, thereby inducing inflammation and
immune dysfunction.
Third,
by interfering with progesterone. This hormone
normally helps block formation of endometrial
lesions.
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They
conclude: "Although preliminary work suggests
a potential involvement of exposure to dioxins in
the pathogenesis of endometriosis, much work remains
to clearly define cause and effect and to understand
the potential mechanism of toxicity."
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