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It has been over twenty years
since the official recognition of the L-Tryptophan
poisoning has occurred.
Since then, many of us who ingested
this supplement in 1989 or earlier, are still suffering
with
life changing pain and other
debilitating symptoms .
Below are 3 articles written for the
20 Year Edition of the NEMSN Newsletter by the
scientists
who were involved with investigating
the incident at the time and their thoughts now.
Could EMS have been Prevented?
Will Future Outbreaks be Prevented?
by Edward
Belongia, M.D.
EMS took everyone by surprise in 1989.
Now that 20 years have passed, it is useful to revisit
the question as to whether the EMS epidemic could have
been prevented, and what has been done since then to
protect consumers from unsafe dietary supplements? In
the 1980s there was no regulatory oversight of companies
that manufactured amino acids and other food
supplements, yet these products were widely sold and
consumed for their pharmacologic effects. L-tryptophan
in particular was widely promoted and used because
multiple studies had shown that it was beneficial for
insomnia, premenstrual syndrome, and other problems. It
was the pre-internet era, but books, magazines and news
articles amplified these findings and promoted them to
the general public. The product labels made no
therapeutic claims--they didn’t need to because all the
advertising was done through the media and word of
mouth.
In 1989 the FDA issued a recall of
L-tryptophan when the link to EMS was first demonstrated
by studies in Minnesota and New Mexico. It remained off
the market for several years, but the situation changed
in 1994 when Congress passed the Dietary Supplement
Health and Education Act (DSHEA). Under this law,
manufacturers of dietary supplements are responsible for
determining that their products are safe before they are
marketed, but there are no standards or requirements.
Premarketing approval by FDA is not required. In 2001
the FDA issued a position paper that specifically stated
that L-tryptophan could be marketed, and the
manufacturers are responsible for ensuring that the
products are safe. But how can that be done? The
specific contaminant that triggered EMS has never been
proven, and we know it was present in extremely low
concentrations. I don’t think a manufacturer can
determine that L-tryptophan is safe when there is no way
to test for the causative agent. We have some good
candidates, but it’s hard to prove that any of them
caused EMS because the syndrome cannot be reproduced in
animals. Although it was Showa Denko L-tryptophan that
caused the 1989 epidemic, we have no way of knowing
whether the same contaminant might occur in the
manufacturing process at another company. People who
take L-tryptophan now are choosing to participate in a
natural experiment on the safety of manufactured
L-tryptophan. No company or government agency can verify
the safety of these products.
DSHEA defined
‘dietary supplements’ so broadly that it included amino
acids, extracts, herbs, and other biologically active
products (think melatonin and DHEA) that are used almost
exclusively for therapeutic effect. Yet they are not
regulated as drugs even though they are clearly marketed
and purchased for their pharmacologic effects. In
addition, virtually nothing is known about the
interactions of these substances when people consume
many different types of supplements. Drug-drug
interactions are carefully evaluated in the world of
pharmaceuticals, but interactions among different
dietary supplements are largely unpredictable.
More than a decade after DSHEA, the FDA finally
implemented standards for good manufacturing practices
of dietary supplements. Since 2008, dietary supplement
manufacturers and distributors have been required to
monitor and document the production process for quality
assurance, and perform laboratory analysis of raw
materials and finished products to document product
purity and the absence of contaminants. This is a
meaningful step forward, but it does not guarantee
another EMS-like epidemic will not occur. The number and
variety of dietary supplements or ‘nutraceuticals’ is
enormous, and the burden of evaluating safety and
efficacy still falls on the consumer.
At least one private laboratory, ConsumerLab (www.consumerlab.com),
now offers independent test reports for dietary
supplements from different manufacturers. Their tests
can determine if the product label accurately reflects
the actual amount of active ingredient in the product,
and they evaluate product purity and the presence of
trace contaminants. The downside is that they charge a
subscription fee to view their reports and test results,
but I think it is a worthwhile service since the FDA is
not doing this testing. Unfortunately, this still does
not guarantee the safety of any particular product,
since we have learned from EMS that a dietary supplement
can be over 98% pure and still contain deadly
contaminants. In addition, a product may be pure and
still cause unanticipated health effects due to lack of
safety testing.
The bottom line is that we have made some progress but
we still have a long way to go. Hopefully the current
FDA leadership recognizes this and will make greater
efforts to protect consumers from unregulated products
that are widely purchased and used for therapeutic
purposes.
Eosinophilia Myalgia Syndrome
Revisited -- 1989-2009
by Luis R. Espinoza, M.D.
Twenty years have
elapsed since a newly recognized systemic inflammatory
disorder of epidemic proportions, eosinophilia myalgia
syndrome (EMS), began to unravel in the United States of
America and several other countries worldwide. The CDC
defined EMS on the basis of three laboratory and
clinical criteria: a) presence of peripheral blood
eosinophilia greater than 1000 cells/ul; b)
incapacitating myalgias (muscle pain); and c) absence of
infection or malignancy that could account for the
previous findings. By July 1991, 1543 cases had been
reported by the US Centers for Disease Control and
Prevention (CDC) in Atlanta. Epidemiological and
clinical observation made by several astute clinicians,
however, rapidly led to the conclusion that EMS was
secondary to the intake of L-tryptophan containing trace
amounts of several contaminants and, more specifically,
with particular lots of tryptophan that contained the
trace contaminant 1,1’-ethylidenebis (tryptophan) (EBT)
and another trace contaminant (“peak UV-5”)
3-(phenylamino) alanine (PAA). Patients with EMS
ingested significantly higher amounts of both EBT and
PAA than did control tryptophan users. Of great interest
and importance is the fact that PAA is chemically
similar to 3-phenylamino-1,2-propanediol, an aniline
derivative isolated from samples of oil that were
consumed by persons from Spain in whom the toxic oil
syndrome developed. [Editor's note: Toxic oil syndrome
broke out abruptly in Spain in 1981. The disease has
symptoms similar to EMS and was found to be caused by
contaminated cooking oil.]
From its initial
description in 1989 to subsequent follow-up it became
clearly established that EMS was associated with a
relatively high morbidity and mortality. The
overwhelming majority of patients (>97%) were white,
most (>80%) were female, and age of occurrence was
between 35 and 60 years. Early stages of the disease
(lasting 3 to 6 months) were characterized by the
presence of severe generalized myalgias, fatigue,
weakness, edema, and skin rash. During the acute
illness, over 30% of patients required hospitalization
for incapacitating myalgias, muscle cramps, or pulmonary
involvement. Late clinical stages were characterized by
the presence of a multitude of ill-defined complaints
including paresthesias [skin sensations such as
tingling, numbness, burning, etc.], muscle cramps, and
alopecia [hair loss]. Long-term follow-up exceeding a
year demonstrated that most EMS patients continued to be
symptomatic with fatigue, cognitive dysfunction,
arthralgias [joint pain], myalgias, alopecia, and skin
rash as main clinical manifestations. Follow-up over 5
years has shown that a significant proportion of EMS
patients have exhibited significant improvement of their
major complaints, although a large proportion remains
symptomatic but with a tendency for a gradual and slow
recovery. A significant high mortality was seen during
the early stages in some epidemiological studies, and by
July 1991, 31 deaths had been reported. Most deaths were
secondary to severe neurologic and cardiovascular
involvement, and also to superimposed infection.
Epidemiological
studies have conclusively demonstrated that the most
important and reproducible risk factor for EMS was the
dose of contaminated L-tryptophan consumed. In addition,
the severity of symptoms experienced by individual
patients and degree of disability were directly related
to the daily dose of L-tryptophan ingested (individuals
taking doses higher than 4000 mg/day were more
predisposed to develop definite EMS).
What have we learned
from this epidemic?
The similarity of
EMS and other contaminated foodstuff products-related
disorders such as the toxic oil syndrome (TOS)
highlights the potential for environmental agents to
induce autoimmune disorders, particularly systemic
sclerosis and related disorders.
Secondly, the
precise identification of the causative agent is
difficult to be determined despite intense
investigation.
Thirdly, the
development of EMS and TOS reminds us that even
developed countries are not exempt from being affected
by large epidemics of environmental origin.
Lastly, although
disease activity in a large proportion of affected
individuals continues to lessen, the ultimate
consequences of their disease are not well-defined and
need further study.
---------------------------------
NEMSN suggests you
read the above article by Dr. Espinoza along with his
article on our website (www.nemsn.org/Articles/Espinoza2.htm),
"Eosinophilia-Myalgia Syndrome -- Long
Term Complications".
In the website article Dr. Espinoza
compares major studies of long-term outcomes for EMS
patients, onc of which shows milder long term effects
and others of which demonstrate major long term
symptoms.
EMS Disappointments
by
Gerald Gleich, M.D.
It was
late in October 1989. Three women in New Mexico had
become ill with a devastating illness that was
associated with marked increases in blood eosinophils.
All of them had ingested a popular health food,
L-tryptophan. Shortly thereafter, other cases came to
light prompting the Centers for Disease Control to track
down the cause of epidemic. By early November the
Minnesota Department of Health had linked the illness
and the eosinophilia to L-tryptophan ingestion. By
mid-November the Food and Drug Administration banned the
sale of L-tryptophan, and existing supplies were removed
from the shelves of drug stores across the land country.
In our laboratory at the
Mayo Clinic in Rochester Minnesota, the activity level
was high. The disease, now termed the eosinophilia
myalgia syndrome (EMS), was a serious systemic illness
with marked increases in eosinophils in the blood and
with striking fibrosis in affected individuals. Because
the link to L-tryptophan was so strong, it seemed that
investigation of this link would be important in
understanding how EMS occurs. However, L-tryptophan
itself was an unlikely cause of the disease because
L-tryptophan is part of our diet and a normal body
constituent. Therefore, it seemed that an L-tryptophan
contaminant must be responsible for the disease. If so,
then the bottles of L-tryptophan being removed from the
shelves of drug stores should be useful as a tool for
EMS investigation.
I contacted the local
drug stores and soon had cartons of L-tryptophan bottles
littering my office. However, later information would
show that the contaminants most strongly implicated in
the causation of EMS were in relatively low
concentrations in those particular bottles. Furthermore,
as information from the CDC and the various state health
departments accumulated, it seemed likely that EMS had
peaked in October and was decreasing by mid-November.
By early 1990, after studies by state departments of
health, especially in Minnesota, New York and Oregon,
L-tryptophan produced by Showa Denko and not by any of
the other Japanese companies was clearly the culprit.
The way seemed clear to utilize the Showa Denko
L-tryptophan to identify the critical contaminants and
to determine their role in EMS.
Arthur Mayeno, a skilled
analytical chemist working in our laboratory, set about
testing L-tryptophan from the various companies and from
various lots produced by Showa Denko. Our laboratory had
forged a strong link to the Minnesota Department of
Health, and Arthur was in daily contact with Michael
Osterholm, Craig Hedberg and Ed Belongia,
epidemiologists investigating EMS. With their help,
Arthur had the critical samples needed to find the
contaminant, and he employed high performance liquid
chromatography to dissect the L-tryptophan and to
determine which of the many contaminants marked EMS. One
day, Arthur called a meeting in our laboratory
conference room and showed the data. One constituent,
which we called peak E, was particularly prominent in
Showa Denko L-tryptophan consumed by EMS patients. Ed
Belongia then summarized the epidemiological data from
the Minnesota Department of Health’s efforts, and his
paper in the New England Journal of Medicine showed the
link to Showa Denko and the existence of Peak E. But
what was peak E? Arthur Mayeno focused his chemical
skills and soon had a tentative structure. Although his
solution was challenged, Arthur proved that the
structure he had identified was the correct one. Peak E
consisted of two tryptophan molecules linked together.
So the stage appeared to be set for a series of critical
experiments linking peak E to EMS.
Our optimism was
limitless at this point. Because EMS resembled other
diseases associated with fibrosis, particularly
scleroderma, it seemed that we had a wonderful
opportunity to not only understand the mechanism of EMS
but also to begin to understand why scleroderma occurs.
We applied for a grant from the National Institutes of
Health, and the grant was awarded. Hirohito Kita was a
visiting scientist from Japan and a skilled bench
scientist. Hirohito began experiments testing whether
blood from normal individuals and individuals with EMS
could be stimulated by the various L-tryptophan and Peak
E preparations we had accumulated.
At first our results
indicated that certain batches of L-tryptophan were
particularly active, and we thought we had a bioassay to
detect the contaminants. However, as we proceeded, it
became clear that the reactive factor in L-tryptophan
was a well known contaminant, endotoxin, that is the
bane of research scientists utilizing biological
systems.
[Editor's note: Endotoxin is known as a
dead end to research experiments since it falsifies
results.]
By this
time, implicated L-tryptophan from Showa Denko had been
injected into animal species from rats to mice to guinea
pigs and to monkeys, and, although the animals may have
become fat, they did not become ill. Moreover, although
we persisted in our studies on the blood from patients
with EMS, the results were unproductive; none of the
methods we employed to stimulate blood was fruitful.
Arthur Mayeno continued
his chemical analyses and was able to link the
contaminants in L-tryptophan to contaminants in the
toxic oil responsible for a massive epidemic in Spain in
1981, referred to as the Spanish toxic oil syndrome (TOS).
Remarkably, investigations of TOS had failed to generate
an animal model or a bioassay, even though many animal
species were exposed to contaminated oil. Thus, the same
frustrations experienced by the TOS investigators were
shared by our group (and many others) probing EMS. Both
TOS and EMS scientists failed to identify any useful
tools (such as a bioassay or an animal model) to
determine which contaminants in the L-tryptophan and the
toxic oil were the critical ones.
In retrospect, the
epidemiologists obtained the most significant
information about EMS. They showed the critical
relationship to L-tryptophan ingestion and the link to
L-tryptophan produced by Showa Denko. We were able to
identify a series of contaminants in Showa Denko
L-tryptophan, but without a bioassay or animal model we
were not able to understand how the contaminants caused
the disease or which contaminant(s) were the critical
ones.
Sometime in the future,
another epidemic related to TOS and EMS will likely
occur. Hopefully, the experiences from these epidemics
will allow future investigators to start where we ended.
However, the failure to provoke either the Spanish toxic
oil syndrome or EMS in experimental animals or stimulate
reactions in patients' cells in test tubes may indicate
that these diseases are uniquely human and related to a
peculiar human biochemical or immunological
characteristic.
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