Words from our Medical Advisory Panel
Twenty years after the
big EMS outbreak in 1989-90, we hear from our Medical Advisory Panel - Edward
Belongia, M.D., Luis R. Espinoza, M.D. and Gerald J. Gleich, M.D. - who
have just written these articles for NEMSN. These doctors write of EMS and
research, about concern over another possible outbreak, and about the question
of the safety of dietary supplements today, including L-tryptophan, which
since 2001 is legally sold again in the US after being temporary banned
by the FDA in 1989.
NEMSN is proud to have
this group of doctors on our Medical Advisory Panel. They have been involved
in EMS research and treatment of patients since the early days of the outbreak.
Unlike many in the medical community, they are still interested in understanding
the disease and treating it. They are still interested in us. Their articles
Could EMS have been Prevented?
Will Future Outbreaks be Prevented?
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.
Edward Belongia, M.D. is Senior Epidemiologist/Director of the Epidemiology
Research Center, Marshfield Clinic Research Foundation in Marshfield, Wisconsin.
As the center's website (www.marshfieldclinic.org) states, Epidemiology
research focuses on population health issues. The Marshfield Epidemiology
Research Center emphasizes consequential epidemiology - applied research
that has a positive effect on public health and disease prevention."
Dr. Belongia has published extensively on antibiotic resistance, vaccine-preventable
diseases and tick borne diseases as well as on other topics, including EMS.
Eosinophilia Myalgia Syndrome Revisited -- 1989-2009
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
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
Secondly, the precise
identification of the causative agent is difficult to be determined despite
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
Luis R. Espinoza,
M.D, is Chief, Section of Rheumatology, Department of Medicine, at Louisiana
State University in New Orleans. Over the years Dr. Espinoza has treated
many EMS patients. He has authored research articles on EMS and on many
other topics in rheumatology. His articles have been published in numerous
medical journals. Dr. Espinoza has recently been elected president of the
Pan-American League of Associations for Rheumatology.
Besides the above
article that Dr. Espinoza just wrote for us, NEMSN also recommends his excellent
article from 1999 which appears on our website: "Eosinophilia-Myalgia
Syndrome--Long Term Complications" (www.nemsn.org/Articles/Espinoza2.htm).
J. 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
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.
Gerald J. Gleich,
M.D. is recognized as one of the world's foremost experts on the eosinophil
and on eosinophilia of all sorts. From 1965 to 2001 he was a researcher
at the Mayo Clinic, Rochester, Minnesota. At present he is Research Professor
of Dermatology and Medicine at the University of Utah, Salt Lake City. He
lists his medical interests on the University of Utah website (http://uuhsc.utah.edu/derm/bios/facultybios/ggleich.htm)
as including "diseases associated with eosinophilia, such as the hypereosinophilic
syndrome, Churg-Strauss syndrome, the eosinophilia myalgia syndrome, the
Spanish toxic oil syndrome, and the syndrome of episodic angioedema and
eosinophilia . . . " Dr. Gleich's research papers and articles have
been published in many medical journals.