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Rier,
S and WG Foster. 2002. Environmental dioxins and endometriosis.
Toxicological
Sciences 70:161-170.
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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