L-tryptophan Produced by Genetically Engineered Bacteria
Here is a selected sample of references on the disease Eosinophilia Myalgia that emerged in relation to the consumption of genetically engineered L-tryptophan apparently in 1989. 37 deaths and 1500 largely permanent cripplings were involved. The sample is given to illustrate that there is a large scientific literature on this and other biosafety issues and to incourage you to use Medline to follow developments that are being published in the scientific literature. The list has not been updated.
Medline is available through most biomedical libraries
and there may be a charge for non-students and faculty. But you may find
the charge justified.
Database: MEDLINE <1985 to present>
001 exp eosinophilia-myalgia syndrome/ci 96
002 exp eosinophilia-myalgia syndrome/ 251
003 new england journal of medicine.jn. 15631
004 2 and 3 1
005 from 2 keep 3,5-9 6
006 exp eosinophilia-myalgia syndrome/ 251
007 limit 6 to english language 220
008 from 7 keep 4,6,9-12,16-20,23,25-26,29,31-32,35-38,42,46,50- 54
009 8 54
[Use LINK to view the full text]
Intimidation of researchers by special-interest groups [letter; comment].
Comment on: N Engl J Med 1997 Apr 17;336(16):1176-80
New England Journal of Medicine. 337(18):1316; discussion 1316-7, 1997
Kaufman LD. Krupp LB.
Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis
with eosinophilia. [Review] [89 refs]
Current Opinion in Rheumatology. 7(6):560-7, 1995 Nov.
The similarity of eosinophilia-myalgia syndrome (EMS) and toxic-oil
syndrome (TOS) to systemic sclerosis and diffuse fasciitis with
eosinophilia (DFE) highlights the potential for environmental agents to
induce autoimmune disease. Further, a candidate etiologic agent for EMS,
3-(phenylamino)alanine, is chemically similar to the aniline derivative
identified in samples of oil implicated in TOS,
3-(N-phenylamino)-1,2-propanediol, suggesting pathogenic overlap. The
late-stage manifestations of EMS and TOS are muscle cramping, arthralgia,
severe fatigue, and cognitive impairment. This review focuses on the
divergent and parallel findings in EMS, TOS, and DFE. The formation of the
Environmentally Associated Connective Tissue Disease Study Group within
the American College of Rheumatology will provide a forum for the
development of registries to study suspected toxin-induced disorders.
Williamson BL. Tomlinson AJ. Naylor S. Gleich GJ.
Contaminants in commercial preparations of melatonin [letter].
Mayo Clinic Proceedings. 72(11):1094-5, 1997 Nov.
Williamson BL. Benson LM. Tomlinson AJ. Mayeno AN. Gleich GJ. Naylor
On-line HPLC-tandem mass spectrometry analysis of contaminants of
L-tryptophan associated with the onset of the eosinophilia-myalgia
Toxicology Letters. 92(2):139-48, 1997 Jul 21.
The structural characterization of a number of contaminants of
L-tryptophan (Trp) associated with eosinophilia myalgia syndrome has been
performed for the first time by the powerful structural elucidation
technique of tandem mass spectrometry coupled with on-line HPLC
(LC-ESI-MS/MS). The identity of the contaminants: peaks UV-5,
3-(phenylamino)alanine, (PAA); E 1,1'-ethylidenebis(tryptophan); 200,
2-(3-indolylmethyl)-L-tryptophan; (all identified as case related) and
peaks 1, 3-carboxy-1,2,3,4-tetrahydro-beta-carboline; 2,
3-carboxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline; 100, 2-(2,3
dihydroxy-1-[3-indolyl]propyl)-L-tryptophan; and 300 and 400,
been confirmed by this technique. By comparison of tandem MS (MS/MS) data
from these compounds with the MS/MS data of several other impurities, we
have structurally characterized peaks CC, KK and OO, as well as two
previously unreported components labeled as peak P18 and peak P31. Peak
P18 was unresolved from the large Trp peak and has been characterized as
indole-3-ethylamine. Peak P31 was previously unresolved from peak 200, a
case related compound and therefore its structure is of extreme
importance. This compound has been tentatively identified as
Blackburn WD Jr.
Eosinophilia myalgia syndrome [see comments]. [Review] [53 refs]
Comment in: Semin Arthritis Rheum 1997 Jun;26(6):781-4
Seminars in Arthritis & Rheumatism. 26(6):788-93, 1997 Jun.
The term eosinophilia myalgia syndrome (EMS) was coined in 1989 after a
cluster of cases with symptoms of incapacitating myalgias and eosinophilia
were reported. This syndrome has been only defined as varying degrees of
myalgias and peripheral eosinophilia. Case reports of EMS are protean and
do not show a consistent clinical picture, raising the question of whether
this reflects a single disorder or is a conflation of various disorders.
There have been only two studies evaluating the association of EMS with
1-tryptophan. These two included only 23 patients with EMS. Apart from the
obvious statistical fragility inherent in such small studies, each is
further weakened by differences in the mechanisms by which patients and
controls were selected. Furthermore, the continued reports of EMS after
1-tryptophan was removed from the market raise additional questions about
the association. Nonetheless, there has been an inordinate reliance on a
history of 1-tryptophan ingestion in making the diagnosis of EMS. When
presented case studies, clinicians were much more likely to make the
diagnosis of EMS when a history of 1-tryptophan ingestion was included.
These observations underscore the need for careful application of
well-considered diagnostic criteria to the study of new syndromes and
their potential associations. [References: 53]
The eosinophilia myalgia syndrome: to be or not to be [editorial;
comment]. [Review] [40 refs]
Comment on: Semin Arthritis Rheum 1997 Jun;26(6):788-93
Seminars in Arthritis & Rheumatism. 26(6):781-4, 1997 Jun.
Eosinophilia-myalgia syndrome: opportunities realized and missed [letter;
Comment on: J Rheumatol 1996 Oct;23(10):1679-81, Comment on: J Rheumatol
1996 Oct;23(10):1682-5, Comment on: J Rheumatol 1996 Oct;23(10):1784-7
Journal of Rheumatology. 24(6):1239-40, 1997 Jun.
Buss WC. Stepanek J. Bankhurst AD. Mayeno AN. Pastuszyn A. Peabody D.
EBT, a tryptophan contaminant associated with eosinophilia myalgia
syndrome, is incorporated into proteins during translation as an amino
Autoimmunity. 25(1):33-45, 1996.
The tryptophan dimer 1,1'-ethylidenebis[L-tryptophan] was identified as a
contaminant of tryptophan preparations associated with
Eosinophilia-Myalgia Syndrome. In this paper, we describe experiments
examining the hypothesis that 1,1'-ethylidenebis[L-tryptophan] acts as an
amino acid analog replacing L-tryptophan during the synthesis of proteins.
We propose further that proteins containing
1,1'-ethylidenebis[L-tryptophan] are rejected in an autoimmune process
identified clinically as Eosinophilia-Myalgia Syndrome. Rabbit
reticulocyte lysates containing an estimated 1 microM L-tryptophan were
used to assay the ability of 1,1'-ethylidenebis[L-tryptophan] to compete
with 3H-L-tryptophan for incorporation into proteins translated from BMV
RNA. 1,1'-Ethylidenebis[L-tryptophan] in concentrations of 40, 80 and 110
microM reduced lysate 3H-L-tryptophan incorporation to 81%, 76% and 75% of
control incorporation obtained in the absence of
1,1'-ethylidenebis[L-tryptophan]. In the presence of 20 microM
L-tryptophan, 110 microM 1,1'-ethylidenebis[L-tryptophan] reduced
3H-L-tryptophan incorporation to 56% of control incorporation. In
contrast, ethyl-L-tryptophan did not significantly reduce 3H-L-tryptophan
incorporation. In the presence of 110 microM
1,1'-ethylidenebis[L-tryptophan] and 20 microM L-tryptophan, 3H-L-leucine
incorporation was not significantly reduced compared to incorporation in
the absence of 1,1'-ethylidenebis[L-tryptophan], demonstrating that
proteins were translated to full length during elongation. These findings
suggest that 1,1'-ethylidenebis[L-tryptophan], but not ethyl-L-tryptophan,
reduced 3H-L-tryptophan incorporation into proteins by substituting for
L-tryptophan rather than by causing premature termination or significant
slowing of nascent protein chains.
Wagner KR. Elmore JG. Horwitz RI.
Diagnostic bias in clinical decision making: an example of L-tryptophan
and the diagnosis of eosinophilia-myalgia syndrome.
Journal of Rheumatology. 23(12):2079-85, 1996 Dec.
OBJECTIVE: Eosinophilia-myalgia syndrome (EMS) has been defined as the
clinical presentation of eosinophilia, severe myalgia, and the exclusion
of other infectious/malignant illnesses. Since the case definition does
not require exposure to L-tryptophan (LT), diagnostic bias would occur if
a physician's decision to diagnose EMS were influenced by knowledge of LT
use. METHODS: A random sample of 813 physicians practising in the United
States and Canada was obtained. Physicians were asked to provide diagnoses
for 6 case vignettes having diverse resemblances to EMS. Six weeks later,
participants were asked to provide diagnoses for a complementary series of
cases described in identical text except for different data regarding LT
use. RESULTS: Physicians who responded (N = 227, 28%) were more likely to
diagnose EMS when LT exposure was present compared to the same case
without LT use. In the most striking difference, EMS was diagnosed by 48%
of physicians when the case was described in a man using LT, but by only
8% of physicians for the same case without LT use. The McNemar bias
ratios, which compare responses provided by physicians completing both
series, ranged from 0.65 to 1.0. CONCLUSION: These data indicate that the
diagnosis of EMS may be biased by knowledge of LT. By showing the presence
of diagnostic bias in clinical decision making, we suggest an important
methodological problem that may arise in both clinical and research
Simat T. van Wickern B. Eulitz K. Steinhart EH.
Contaminants in biotechnologically manufactured L-tryptophan.
Journal of Chromatography B: Biomedical Applications. 685(1):41-51, 1996
The epidemic outbreak of a new disease, the eosinophilia-myalgia syndrome
(EMS), was traced back to the intake of L-tryptophan (Trp) of certain lots
from a single manufacturer. Since some trace contaminants were related to
EMS, it appeared to be necessary to identify and find the origin of most
trace contaminants in the EMS related Trp in order to apply this knowledge
to a prospective manufacturing practice. Seventeen contaminants were
determined in an implicated Trp lot by a single reversed-phase
high-performance liquid chromatography run using UV and fluorescence
detection. Most of these contaminants were classified as Trp metabolites,
non-physiological oxidation or carbonyl condensation compounds of Trp. The
amount and the pattern of contaminants were compared with recently
manufactured Trp and Trp-containing preparations.
Steinhart H. van Wickern B. Meyer K. Simat T.
Synthesis and analysis of contaminants in ems-related tryptophan.
Advances in Experimental Medicine & Biology. 398:667-75, 1996.
Nicolodi M. Sicuteri F.
Eosinophilia myalgia syndrome. The role of contaminants, the role of
serotonergic metabolism set up.
Advances in Experimental Medicine & Biology. 398:351-7, 1996.
The eosinophilia-myalgia syndrome and the toxic oil syndrome. Pursuing
parallels. [Review] [8 refs]
Advances in Experimental Medicine & Biology. 398:339-42, 1996.
Pathogenesis of L-tryptophan eosinophilia myalgia syndrome. [Review] [25
Advances in Experimental Medicine & Biology. 398:325-30, 1996.
Taken together, these studies suggest that many different etiologic agents
alone or together may initiate the common final pathways of tissue
pathologic response resulting in the clinical syndrome of eosinophilia,
myalgias and fasciitis. Tryptophan itself may contribute to some of the
scarring features of the illness, while impure L-tryptophan, and one or
more of the impurities cause the characteristic features of the illness.
The altered tryptophan metabolism in EMS is secondary to inflammation.
Kilbourne EM. Philen RM. Kamb ML. Falk H.
Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia
syndrome [comment]. [Review] [22 refs]
Comment on: J Rheumatol Suppl 1996 Oct;46 :44-58; discussion 58-9, Comment
on: J Rheumatol Suppl 1996 Oct;46 :60-72
Journal of Rheumatology - Supplement. 46:81-8; discussion 89-91, 1996
Evidence from an array of scientific studies strongly supports the
conclusion that ingestion of products containing L-tryptophan (LT)
produced by Showa Denko KK caused the 1989 epidemic of
eosinophilia-myalgia syndrome (EMS) in the United State. In case-control
studies of EMS, LT exposure was essentially universal among cases but rare
among controls. Of 6 manufacturers of LT, only LT manufactured by Showa
Denko KK was clearly associated with illness. The data meet other Hill
criteria for inferring a causal relationship. Consistent findings were
found in multiple independently conducted studies. There was a
dose-response effect, with risk of illness increasing as a function of the
amount of tryptophan consumed. The extremely small p values observed in
the multiple independently conducted studies effectively rule out the
possibility that the tryptophan-EMS association was the result of chance.
Moreover, no potential confounding factor or bias explains the
association. The incidence of EMS in the United States diminished abruptly
once LT containing products were recalled. [References: 22]
Horwitz RI. Daniels SR.
Bias or biology: evaluating the epidemiologic studies of L-tryptophan and
the eosinophilia-myalgia syndrome [see comments].
Comment in: J Rheumatol Suppl 1996 Oct;46 :81-8; discussion 89-91
Journal of Rheumatology - Supplement. 46:60-72, 1996 Oct.
When investigating the cause of a chronic disease, epidemiologists are
forced to substitute observational, nonexperimental methods such as cohort
or case-control studies for the scientifically preferred "gold standard,"
the randomized controlled trial. Because neither cohort nor case-control
studies are done under experimental conditions, the results may not
accurately reflect those that would be found in a randomized experiment.
Before the results of epidemiologic research can be used for inference
regarding a cause of disease, it is necessary to examine the design and
conduct of such studies to ensure their results could not have been
distorted by potential sources of bias. We evaluate the epidemiologic
studies of the relationship between intake of L-tryptophan (LT) and the
occurrence of eosinophilia-myalgia syndrome (EMS) from information
provided in the published reports and underlying data and documentation of
the studies obtained from the US Centers for Disease Control and state
health departments. We reviewed separately the initial 2 studies that
examined the link between LT and the risk for EMS and the subsequent
studies that focused on the specific manufacturing process or chemical
constitutents of LT that might have been responsible for EMS. The 2
initial studies compared cases of EMS with controls who were asymptomatic.
The investigators concluded that ingestion of LT was associated with the
occurrence of EMS. However, these studies contained methodologic problems,
including diagnostic bias, publicity, recall and reporting bias, bias in
the inclusion and exclusion of cases and controls, inequalities between
cases and controls in the indications for the use of LT, and failure to
ensure that the exposure to LT preceded the onset of symptoms of EMS.
These potential biases make it difficult to use the data derived from
these investigations to justify a causal inference. Subsequent studies
were conducted under the assumption that there was a valid association
between ingestion of LT and the occurrence of EMS. These studies focused
on tracing back LT to the manufacturer. These studies also had a variety
of methodologic shortcomings, including problems in the assembly of study
subjects leading to the selected samples of cases and controls, the lack
of information on the brand and lot of LT for many subjects, multiple
brand use, differences in the timing of exposure between cases and
controls, the difficulty of the process of tracing LT products to the
appropriate manufacturer, inconsistent classification of symptoms
depending on brand of LT used, and inconsistencies in the traceback
procedures between cases and controls. In light of these analyses, it
appears that the cause of EMS has not been definitively identified. The
search for the cause of EMS should continue without the underlying
assumption that LT or some contaminant is responsible.
Epidemiologic studies of the association of L-tryptophan with the
eosinophilia-myalgia syndrome: a critique [see comments].
Comment in: J Rheumatol Suppl 1996 Oct;46 :81-8; discussion 89-91
Journal of Rheumatology - Supplement. 46:44-58; discussion 58-9, 1996
In 1989 and 1990, 2 reports of a new disease labeled the
eosinophilia-myalgia syndrome (EMS) and attributed to L-tryptophan (LT)
were published. In subsequent studies a putative contaminant was
implicated. In this review the following studies are considered: the
initial 2 reports of the overall association, one report of an association
between LT and eosinophilic fasciitis, and one report describing the scale
of the apparent epidemic of LT induced EMS. Of the 2 initial studies, one
included previously reported exposed cases, failed to rule out the
possibility that early symptoms of EMS could have caused LT use rather
than the reverse, and failed to adhere to the methods, as published. The
2nd study has not been published in a peer reviewed journal. The study of
eosinophilic fasciitis was subject to information bias and
misclassification of the timing of LT use. The apparent epidemic could
have been an artefact of waxing and waning enthusiasm for reporting
exposed cases to an EMS registry, corresponding with the timing and the
amount of publicity given to the topic. The questionable validity of these
studies considerably weakens the claim that LT or a contaminant caused
Clauw DJ. Pincus T.
The eosinophilia-myalgia syndrome: what we know, what we think we know,
and what we need to know. [Review] [26 refs]
Journal of Rheumatology - Supplement. 46:2-6, 1996 Oct.
Sullivan EA. Staehling N. Philen RM.
Eosinophilia-myalgia syndrome among the non-L-tryptophan users and
pre-epidemic cases [see comments].
Comment in: J Rheumatol 1996 Oct;23(10):1679-81
Journal of Rheumatology. 23(10):1784-7, 1996 Oct.
OBJECTIVE: Eosinophilia-myalgia syndrome (EMS) has been associated with
L-tryptophan (LT) use since 1989, but as yet no etiologic agent has been
identified. We describe the non-L-tryptophan associated cases of EMS, and
those patients with illness onset preceding the 1989 epidemic. METHODS:
Review of all patients in the EMS national state based surveillance system
administered by the Centers for Disease Control and Prevention (CDC) who
satisfied the EMS surveillance case definition. RESULTS: Of 1345 persons
with EMS that satisfied the CDC surveillance case definition for EMS, 26
(2%) persons reported not having used LT (non-LT). Persons who did not use
LT were significantly younger (mean age 39 years; p = 0.02) and were more
likely than LT users to have onset of their illness before the EMS
epidemic (before July 1, 1989) (p < 0.001). Non-LT users reported fewer
pulmonary symptoms but had rates of neuropathy and scleroderma-like skin
changes similar to LT users. Non-LT users had lower mean eosinophil counts
(5.6 x 10(9) cells/I LT users 6.2 x 10(9) cells/I), reported no EMS
attributable deaths, but were hospitalized (48%) more often than LT users
(34%). Of the 1345 EMS cases, 191 (14%) reported a pre-epidemic illness
onset. Symptoms of peripheral edema, rash, scleroderma-like skin change,
alopecia, and neuropathy were more prevalent in pre-epidemic patients.
Mean eosinophil count was significantly higher for epidemic patients than
for pre-epidemic patients (p = 0.004). CONCLUSION: Non-LT EMS cases were
more likely to be younger and to have a pre-epidemic illness onset of EMS,
but otherwise were similar to LT associated EMS cases. Pre-epidemic EMS
cases were more likely to report the presence of neuropathy and
scleroderma-like skin change, but not pulmonary symptoms, hospitalization,
Belongia EA. Gleich GJ.
The eosinophilia-myalgia syndrome revisited [editorial].
Journal of Rheumatology. 23(10):1682-5, 1996 Oct.
The eosinophilia-myalgia syndrome: opportunities realized and missed
Comment on: J Rheumatol 1996 Oct;23(10):1784-7
Journal of Rheumatology. 23(10):1679-81, 1996 Oct.
Sullivan EA. Kamb ML. Jones JL. Meyer P. Philen RM. Falk H. Sinks T.
The natural history of eosinophilia-myalgia syndrome in a
tryptophan-exposed cohort in South Carolina.
Archives of Internal Medicine. 156(9):973-9, 1996 May 13.
BACKGROUND: In a previous study, we did follow-up on 418 patients who were
exposed to tryptophan in 1989, of whom 47 (11%) had definite and 63 (9%)
possible eosinophilia-myalgia syndrome (EMS). METHODS: We assessed
mortality and clinical spectrum of illness since 1989 for 242 (58%) of the
418 tryptophan-exposed patients from the original study. To assess
outcomes, we used hospital and death records, interviewer-administered
questionnaires, physical examinations, and laboratory tests. RESULTS:
During the follow-up interval, mortality from all causes was 19% in those
with definite EMS, 7% in possible EMS, and 3% in those who were not ill.
The age- and sex-adjusted mortality in those with definite EMS was more
than 3 times that of the general population or of tryptophan users in the
practice who were not ill. Six deaths (66%) among the definite EMS case
patients occurred during the 18 months immediately after symptom onset.
Compared with the tryptophan users who were not ill, survivors with
definite EMS continued to report excess morbidity for 6 major EMS symptoms
(myalgia, arthralgia, weakness, rash, alopecia, and sclerodermiform skin
changes), but they also reported that the symptom number and severity
diminished with time. None of the tryptophan users who were not ill in
1989 developed a symptom complex suggesting new EMS during the follow-up
interval. CONCLUSIONS: This study assessing a tryptophan-exposed
population found those persons who developed EMS during the 1989 epidemic
were at increased risk for death, particularly early after disease onset.
Survivors reported improvement or resolution of major symptoms, suggesting
that the severity of EMS diminishes with time. We found no evidence of
delayed onset of EMS in tryptophan users who were not ill in 1989,
regardless of the brand used.
Eosinophilia-Myalgia Syndrome: Review and Reappraisal of Clinical,
Epidemiologic and Animal Studies Symposium. Washington, D.C., USA,
December 7-8, 1994. Proceedings.
Journal of Rheumatology - Supplement. 46:1-110, 1996 Oct.
1995 Bailey K. Ashford lecture. Public health lessons from two
catastrophic epidemics: the toxic oil syndrome and the
Puerto Rico Health Sciences Journal. 15(1):45-8, 1996 Mar.
Zangrilli JG. Mayeno AN. Vining V. Varga J.
1,1'-Ethylidenebis[L-tryptophan], an impurity in L-tryptophan associated
with eosinophilia-myalgia syndrome, stimulates type I collagen gene
expression in human fibroblasts in vitro.
Biochemistry & Molecular Biology International. 37(5):925-33, 1995 Nov.
Eosinophilia-myalgia syndrome (EMS), a recently described inflammatory
disorder characterized by myalgia, peripheral eosinophilia, and
multisystem inflammation is associated with L-tryptophan consumption.
Fibrosis of various tissues due to excessive accumulation of type I
collagen is a prominent late manifestation of the syndrome.
1,1'-Ethylidenebis[L-tryptophan] (EBT), an impurity distinct from
L-tryptophan found in case-associated lots, has been implicated in
function in vitro. Incubation of confluent fibroblasts with EBT, but not
its hydrolysis product 1-methyl-tetrahydro-beta-carboline-3-carboxylic
acid, caused a dose-dependent increase in collagen synthesis and in type I
collagen mRNA levels independent of its effect on proliferation. In
contrast, expression mRNA for fibronectin was not affected. These findings
indicate that EBT stimulates type I collagen production by human
fibroblast, and suggest that EBT may be involved in the development of
fibrosis in EMS.
Daniels SR. Hudson JI. Horwitz RI.
Epidemiology of potential association between L-tryptophan ingestion and
eosinophilia-myalgia syndrome. [Review] [64 refs]
Journal of Clinical Epidemiology. 48(12):1413-27; discussion 1429-40,
This article examines the methodology of the epidemiological studies of
the association between L-tryptophan and eosinophilia-myalgia syndrome
(EMS) and evaluates the validity of the conclusions from these studies. In
the initial case-control studies of L-tryptophantryptophan and EMS there
were a variety of methodological problems, including different sources and
different exclusion criteria for cases and controls, which could have
resulted in selection bias, as well as problems with information bias and
confounding. The studies of manufacturer and brand also had similar
potential for bias. The L-tryptophan-EMS association is based on two small
studies that had important methodological inadequacies. Subsequent studies
of brand of L-tryptophan also contained errors in design, which may have
produced biased results and call the conclusions into question. The cause
of eosinophilia-myalgia syndrome remains unknown. [References: 64]
Sato F. Hagiwara Y. Kawase Y.
Subchronic toxicity of 3-phenylamino alanine, an impurity in L-tryptophan
reported to be associated with eosinophilia-myalgia syndrome.
Archives of Toxicology. 69(7):444-9, 1995.
Consumption of certain product lots of L-tryptophan (LT) has been reported
to be epidemiologically associated with an outbreak of
eosinophilia-myalgia syndrome (EMS) in the United States. Since the
production lots were found to contain 3-phenylamino alanine (PAA) as an
impurity, its effects were studied by administering the substance orally
by gavage to 5-week-old Sprague-Dawley rats. Groups of animals were given
PAA for 13 consecutive weeks at dose levels of 1, 10 and 100 mg/kg per
day. The animals were killed at 4 or 8 weeks. Hematological and blood
biochemical tests were performed and detailed histopathological
observations were made. No significant abnormalities were observed in the
test animals and in particular no EMS-like conditions. A brief summary of
other animal studies using several species of rats and mice performed in
our laboratory since 1989 on various LT related substances is also
presented. No EMS-like effects were observed in these studies.
Mayeno AN. Benson LM. Naylor S. Colberg-Beers M. Puchalski JT. Gleich
Biotransformation of 3-(phenylamino)-1,2-propanediol to
3-(phenylamino)alanine: a chemical link between toxic oil syndrome and
Chemical Research in Toxicology. 8(7):911-6, 1995 Oct-Nov.
During late 1989, the eosinophilia-myalgia syndrome (EMS) developed as an
epidemic in the United States, with numerous additional cases reported in
several other countries worldwide. Eight years earlier, a closely-related
disease, the toxic oil syndrome (TOS), occurred in Spain as a massive
food-borne epidemic. Although EMS was linked to the ingestion of tainted
L-tryptophan, and TOS to aniline-denatured rapeseed oil, the etiologic
agent(s) responsible for both diseases remains undetermined. Contaminants
in these foodstuffs are believed to have triggered the diseases. Aniline
contaminants, including 3-(phenylamino)-1,2-propanediol (PAP), have been
reported in oil used by patients who developed TOS. A related aniline
derivative, 3-(phenylamino)-L-alanine (PAA), was recently isolated from
L-tryptophan associated with the onset of EMS. Here, we demonstrate the
biotransformation of PAP into PAA by both rat hepatocytes and human liver
tissue. The structural characterization of PAA was unequivocally
determined using on-line HPLC coupled with atmospheric pressure chemical
ionization tandem mass spectrometry (LC-APCI-MS/MS). This finding is the
first reported chemical link between TOS and EMS and suggests that these
two related diseases share a common etiology, namely, PAA.
L-tryptophan: eosinophilia-myalgia syndrome. [Review] [45 refs]
Adverse Drug Reactions & Toxicological Reviews. 14(1):37-43, 1995 Spring.
Spitzer WO. Haggerty JL. Berkson L. Davis W. Palmer W. Tamblyn R.
Laprise R. Faith JM. Elmore JG. Horwitz RI.
Continuing occurrence of eosinophilia myalgia syndrome in Canada.
British Journal of Rheumatology. 34(3):246-51, 1995 Mar.
Eosinophilia myalgia syndrome (EMS), was defined by the Centers for
Disease Control (CDC) as eosinophilia > 1000 mm3 and incapacitating
myalgia without infection or neoplasm. Studies suggested that use of
L-tryptophan (L-T), was a risk factor. We conducted a
pharmacoepidemiological survey in Canada where access to L-T is limited.
Using the active surveillance method, a 100% sample of potentially
involved specialists and a 15% sample of family physicians from Ontario
and Quebec were surveyed regarding treatment of patients with severe
myalgia within the past year. Follow-up amplified clinical and laboratory
information. Overall response rates were 61.4%. Thirty-eight per cent of
respondents reported at least one patient. Of 6423 patients assessed, 19
'definite' and 25 'possible' EMS cases were identified. Information from
physicians did not suggest use of L-T in patients with definite or
possible EMS. It was considered that the cases found an underestimate of
the incidence of EMS. Its continuing occurrence in Canada brings causal
interpretations of earlier studies into question.
Eosinophilia-myalgia syndrome: a recent syndrome serving as an alert to
new diseases ahead. [Review] [44 refs]
Modern Pathology. 7(7):806-10, 1994 Sep.
A recently recognized disease, the eosinophilia-myalgia syndrome, is
described and presented as a new condition attributable to nutritional
toxicology. Its etiology is related to the ingestion of L-tryptophan,
manufactured by a single Japanese supplier who had modified its production
system, which, though of high purity, contained in minute concentrations a
number of contaminants or impurities. Patients with eosinophilia-myalgia
syndrome develop an eosinophilia with pathologic changes mainly involving
skin, muscle, and connective tissue. The findings suggest an autoimmune
response. Experimental studies with the implicated L-tryptophan as well as
with some contaminants have as yet failed to develop a suitable animal
model of eosinophilia-myalgia syndrome. Further studies are needed to
unravel the pathogenesis of this complex syndrome. At present, physicians
need to be cognizant of this recent syndrome and be aware that other new
diseases, induced by nutritional toxicological alterations and possibly
related to technicological developments, lie ahead. [References: 44]
[Use LINK to view the full text]
L-tryptophan and eosinophilia-myalgia syndrome [letter; comment].
Comment on: Lancet 1994 Apr 23;343(8904):1035-7
Lancet. 344(8925):817-9, 1994 Sep 17.
Mayeno AN. Gleich GJ.
Eosinophilia-myalgia syndrome and tryptophan production: a cautionary
Trends In Biotechnology. 12(9):346-52, 1994 Sep.
An epidemic of a new disease, termed eosinophilia-myalgia syndrome,
occurred in the USA in 1989. This syndrome was linked to the consumption
of L-tryptophan manufactured by a single company utilizing a fermentation
process. All the findings indicate that the illness was probably triggered
by an impurity formed when the manufacturing conditions were modified.
This outbreak highlights the need for close monitoring of the chemical
purity of biotechnology-derived products, and for rigorous testing of such
products following any significant changes to the manufacturing process.
Mayeno AN. Gleich GJ.
The eosinophilia-myalgia syndrome: lessons from Germany [editorial;
Comment on: Mayo Clin Proc 1994 Jul;69(7):620-34
Mayo Clinic Proceedings. 69(7):702-4, 1994 Jul.
Carr L. Ruther E. Berg PA. Lehnert H.
Eosinophilia-myalgia syndrome in Germany: an epidemiologic review [see
Comment in: Mayo Clin Proc 1994 Jul;69(7):702-3
Mayo Clinic Proceedings. 69(7):620-5, 1994 Jul.
OBJECTIVE: To review the epidemiologic features of eosinophilia-myalgia
syndrome (EMS) in Germany. DESIGN: We determined the incidence of EMS in
Germany through May 1992 and analyzed the dose of L-tryptophan used, the
duration of intake, and the concurrent medications. MATERIAL AND METHODS:
All patients receiving L-tryptophan preparations in Germany were already
under medical supervision before the onset of the disease; thus,
information on patient history and other potential risk factors was
readily available. Because of the drug status of L-tryptophan
preparations, brands could be accurately traced back to suppliers of raw
materials. Statistical differences in age and gender of patients, dose of
L-tryptophan, eosinophil count, and skin involvement were sought between
patients with and those without concurrent medications. RESULTS: On the
basis of guidelines established by the Centers for Disease Control and
Prevention, 105 patients fulfilled the criteria for EMS. No apparent
correlation was found between the incidence of EMS and the dose of
L-tryptophan or the duration of intake before onset of EMS. Assessment of
the study group showed that 45% were taking various other medications,
whereas 55% were taking L-tryptophan only. Analysis by type of
pharmaceutical agent showed no preponderance of a specific concurrent drug
(in particular, psychotropic drugs). Thus, concurrently used medications
did not seem to be an important variable. All cases of EMS were associated
with L-tryptophan from formulators that had used raw materials from the
previously implicated source. CONCLUSION: This study supports the
pathophysiologic role of a contaminant in L-tryptophan in the occurrence
of cases of EMS in Germany.
Brady LS. Page SW. Thomas FS. Rader JL. Lynn AB. Misiewicz-Poltorak
B. Zelazowski E. Crofford LJ. Zelazowski P. Smith C. et al.
1,1'-Ethylidenebis[L-tryptophan], a contaminant implicated in L-tryptophan
eosinophilia myalgia syndrome, suppresses mRNA expression of hypothalamic
corticotropin-releasing hormone in Lewis (LEW/N) rat brain.
Neuroimmunomodulation. 1(1):59-65, 1994 Jan.
The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to
ingestion of impure L-Trp, occurred in epidemic proportions in the United
States in 1989. Epidemiologic studies implicated
1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly
associated with development of human L-Trp-EMS. We have previously shown
that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic
(case-associated L-Trp) develop fasciitis and perimyositis which is
associated with a reduction in corticotropin-releasing hormone (CRH) mRNA
expression in the hypothalamic paraventricular nucleus (PVN). In this
study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA
expression in the hypothalamic PVN and secretion of adrenocorticotropic
hormone (ACTH) and corticosterone (CORT) into the plasma over a time
course of 1-6 weeks in the same rats in which we have found fascial
thickening and immune cell activation induced by these compounds. Both
control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2
weeks, whereas case-associated L-Trp did not. EBT and case-associated
L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks, while control
L-Trp had no effect. The striking contrast in the effects of
case-associated L-Trp and EBT on the HPA axis suggests that the reduction
in CRH mRNA levels in the PVN seen in each case may be related to
different mechanisms. It is possible that EBT suppresses CRH mRNA
expression directly, in the absence of inflammation, while case-associated
L-Trp may act through multiple mechanisms, including that associated with
inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Clauw DJ. Flockhart DA. Mullins W. Katz P. Medsger TA Jr.
Eosinophilia-myalgia syndrome not associated with the ingestion of
nutritional supplements. [Review] [12 refs]
Journal of Rheumatology. 21(12):2385-7, 1994 Dec.
The eosinophilia-myalgia syndrome (EMS) is a recently recognized illness
characterized by peripheral eosinophilia, myalgias, and a variety of
neurologic, cutaneous, and pulmonary features. Most of those afflicted
with this disorder consumed L-tryptophan, but some cases have occurred in
association with the ingestion of other nutritional supplements. We
describe someone who developed EMS in 1986 without the ingestion of any
nutritional supplements. He was also found to have slowed P450 metabolism,
in a pattern seen in other patients with EMS. We postulate that EMS can
occur in association with the ingestion of multiple substances that share
minute quantities of a common, as yet unidentified, toxin(s), and that
metabolic host factors may contribute to disease susceptibility.
Michelson D. Page SW. Casey R. Trucksess MW. Love LA. Milstien S.
Wilson C. Massaquoi SG. Crofford LJ. Hallett M. et al.
An eosinophilia-myalgia syndrome related disorder associated with exposure
Journal of Rheumatology. 21(12):2261-5, 1994 Dec.
OBJECTIVE. To determine whether L-5-hydroxytryptophan (L-5-HTP) associated
with eosinophiliamyalgia syndrome (EMS) like illness contains impurities
in a fashion similar to that described in L-tryptophan associated with
EMS. METHODS. Members of a family who became ill after exposure to L-5-HTP
were evaluated at the National Institutes of Health. Data from patients
with extended exposure to L-5-HTP were also examined. Samples of L-5-HTP
were examined using high performance liquid chromatography. RESULTS. One
member of the family had EMS, and 2 others had eosinophilia. No patient in
the other group reviewed developed the syndrome, although 2 patients
developed eosinophilia. The L-5-HTP used by the family contained an
impurity not present in samples from the other patient group. After
replacement with L-5-HTP not containing this impurity, eosinophilia in 2
family members resolved. CONCLUSION. Some L-5-HTP contains impurities that
may be related to L-5-HTP associated EMS.
Kaufman LD. Izquierdo Martinez M. Gomez-Reino JJ.
Toxic oil syndrome and eosinophilia myalgia syndrome: similar, different
or the same disorder? [editorial].
Journal of Rheumatology. 21(12):2177-8, 1994 Dec.
The evolving spectrum of eosinophilia myalgia syndrome. [Review] [192
Rheumatic Diseases Clinics of North America. 20(4):973-94, 1994 Nov.
Eosinophilia myalgia syndrome (EMS) is a toxin-induced illness that
provides a model for the understanding of idiopathic immune-mediated
diseases that have overlapping features. The clinical development and
chronic sequelae of EMS, its relationship to related disorders, and the
accumulating data suggesting an important role for immune mechanisms in
the pathogenesis of this disease are reviewed in this article.
Philen RM. Hill RH Jr. Flanders WD. Caudill SP. Needham L. Sewell L.
Sampson EJ. Falk H. Kilbourne EM.
Tryptophan contaminants associated with eosinophilia-myalgia syndrome. The
Eosinophilia-Myalgia Studies of Oregon, New York and New Mexico.
American Journal of Epidemiology. 138(3):154-9, 1993 Aug 1.
Eosinophilia-myalgia syndrome (EMS) has been linked to ingestion of
tryptophan contaminated with 1,1'-ethylidene-bis[L-tryptophan] (EBT), but
other contaminants have received little study. The authors identified 101
lots of L-tryptophan that had been consumed either by persons with EMS or
by asymptomatic tryptophan users and quantified the amounts of EBT and
five other contaminants in each lot. After stratification of case and
noncase lots by time of manufacture to adjust for the strong sequential
pattern over time among case and noncase lots, higher EBT levels were
still associated with a lot's case status, but the association lacked
statistical significance (p = 0.120, odds ratio = 1.56, 95% confidence
interval 0.758-3.23). While these findings do not rule out the possibility
that EBT is the etiologic agent in EMS, they raise the possibility that
other chemical contaminants in manufactured tryptophan modify the effects
of EBT or that the causal agent of EMS is an entirely distinct compound.
Back EE. Henning KJ. Kallenbach LR. Brix KA. Gunn RA. Melius JM.
Risk factors for developing eosinophilia myalgia syndrome among
L-tryptophan users in New York.
Journal of Rheumatology. 20(4):666-72, 1993 Apr.
Using a case-control study design, patients with eosinophilia myalgia
syndrome (EMS) who had used L-tryptophan (LT) were compared with LT users
who did not develop EMS. Of the 113 case patients and 95 controls who had
used a retail brand that could be traced to a bulk LT producer, all (100%)
case-patients and 69 (73%) controls used LT brands that were traced to
Showa Denko K.K. (lower 95% CL = 10.0). Among the users of LT produced by
Showa Denko K.K., the risk of EMS was greater for persons who used LT
produced after December 1, 1988 (OR = 25.8, [95% CL = 7.1, 101.4]). The
risk of developing EMS increased with increased dosage of LT, increased
age, and use of LT as a sleeping aid. These epidemiologic data support the
hypothesis that the etiologic agent in EMS is a contaminant introduced
into LT products during production.
L-tryptophan and eosinophilia-myalgia syndrome [letter; comment].
Comment on: Med J Aust 1993 Jan 4;158(1):51-5
Medical Journal of Australia. 158(5):363-4, 1993 Mar 1.
Henning KJ. Jean-Baptiste E. Singh T. Hill RH. Friedman SM.
Eosinophilia-myalgia syndrome in patients ingesting a single source of
Journal of Rheumatology. 20(2):273-8, 1993 Feb.
OBJECTIVE. To estimate the attack rate for eosinophilia-myalgia syndrome
and to identify potential risk factors for illness among patients
attending a New York City medical clinic, who purchased L-tryptophan
containing products produced exclusively by Showa Denko K.K. METHODS. A
case-control design was used. Cases and controls purchased L-tryptophan
containing products at the medical clinic from July 1, 1989--December 1,
1989. All case-patients identified with illness onset during the study
period were included. Controls were selected by a systematic sample of the
683 purchasers of L-tryptophan attending the same clinic. RESULTS. Twelve
(2.2%) of an estimated 553 L-tryptophan users were case-patients.
Multivariate analysis suggested that lot 2 use (adjusted odds ratio [OR] =
35.9), concomitant use of chromium (adjusted OR = 12.3), and concomitant
use of pyridoxine (adjusted OR = 5.8) were associated with the development
of illness. Chemical analysis of tablets corresponding to the 3 Showa
Denko K.K. lots ingested by study participants showed that lot 2 had the
highest concentration of ethylidenebis (L-tryptophan), a proposed
causative agent or marker for a causative agent in the
eosinophilia-myalgia syndrome. CONCLUSIONS. Information from our study of
persons exposed to implicated L-tryptophan supports the role for a
contaminant as the causative agent in the eosinophilia-myalgia syndrome
and identifies possible cofactors that deserve further study.
Kaufman LD. Philen RM.
Tryptophan. Current status and future trends for oral administration.
[Review] [65 refs]
Drug Safety. 8(2):89-98, 1993 Feb.
Varga J. Jimenez SA. Uitto J.
L-tryptophan and the eosinophilia-myalgia syndrome: current understanding
of the etiology and pathogenesis. [Review] [66 refs]
Journal of Investigative Dermatology. 100(1):97S-105S, 1993 Jan.
The eosinophilia-myalgia syndrome (EMS) is a newly recognized illness that
occurred in an epidemic form during the summer of 1989. The illness was
characterized in the acute phase by myalgia and eosinophilia, followed in
many patients by chronic cutaneous lesions, progressive neuropathy, and
myopathy. EMS was associated with ingestion of L-tryptophan, an essential
amino acid marketed as a nutritional supplement but widely used as a
therapeutic agent. Evidence of abnormal L-tryptophan metabolism has been
described in patients with EMS, and most likely reflects increased
activity of indoleamine 2,3-dioxygenase, the rate-limiting enzyme of
tryptophan metabolism. A contaminant identified in EMS-associated
L-tryptophan preparations has been isolated and characterized, but its
biologic effects and role as the etiologic agent in EMS remain to be
established. Pathologic observations and experimental studies indicate
that eosinophils, mononuclear inflammatory cells, and fibroblasts are
potential effector cells, and interleukin-5 and transforming growth
factor-beta are important mediators in the pathogenesis of the syndrome.
Although few new cases of EMS occurred following the withdrawal of
L-tryptophan, affected patients continue to manifest late sequelae of the
disease, including dermal fibrotic conditions. This tragic outbreak of a
newly recognized illness has focused interest on the role of chemical and
environmental agents in the pathogenesis of various idiopathic illness
characterized by tissue inflammation and fibrosis. [References: 66]
Swygert LA. Back EE. Auerbach SB. Sewell LE. Falk H.
Eosinophilia-myalgia syndrome: mortality data from the US national
surveillance system [see comments].
Comment in: J Rheumatol 1993 Oct;20(10):1644-6
Journal of Rheumatology. 20(10):1711-7, 1993 Oct.
OBJECTIVE. To describe some of the most severe features of
eosinophilia-myalgia syndrome (EMS) and identify potential prognostic
indicators. METHODS. Systematic review of data from initial case reports
and from followup supplemental death report forms forwarded to the
national surveillance system administered by the US Centers for Disease
Control (CDC). RESULTS. As of August 10, 1991 36 deaths related to EMS had
been reported to CDC. Among all patients fitting the surveillance case
definition for EMS, we found that patients who died were older, had higher
absolute leukocyte and eosinophil counts, and reported a greater frequency
of cough or dyspnea, neuropathy, hepatomegaly, leukocytosis, and elevated
erythrocyte sedimentation rate. All patients who died had illnesses
affecting multiple organ systems. Of the 36 patients who died, 33 (92%)
had neuromuscular sequelae, 29 (81%) had pulmonary complications, and 23
(64%) had cardiac manifestations. The most commonly observed disease
process leading to death was progressive polyneuropathy and myopathy (24
of the 36 reported deaths) which produced complications of pneumonia and
sepsis or respiratory failure due to weakness; cardiomyopathy was the
underlying cause of death for 4 patients, primary pulmonary disease for 3,
sudden death attributed to arrhythmia for 2, stroke for 2, and septic
complications of therapy for one. CONCLUSION. Although neuromuscular
complications were the most prominent sequelae among patients reported to
have died, this is clearly a multisystemic disease. Older age and
involvement of more than one organ system suggest a particularly poor
prognosis, and the neuromuscular, pulmonary and cardiovascular sequelae
appear to be the most worrisome.
Eosinophilia-myalgia syndrome: coming to grips with a new illness.
Epidemiologic Reviews. 14:16-36, 1992.
In late October 1989, over 1,500 cases of an unusual illness involving
severe myalgia and striking peripheral eosinophilia were reported in the
United States and several other countries. Other clinical manifestations
included pulmonary involvement (interstitial infiltrates and pleural
effusions), skin rash and edema, axonal polyneuropathy, perimyositis, and
possible adverse neurocognitive effects. Because of the primary
manifestations of the illness, it was named "eosinophilia-myalgia
syndrome" (EMS) by the Centers for Disease Control. Epidemiologic studies
clearly linked illness to the ingestion of tryptophan produced by a single
manufacturer in Japan, and the time course of the epidemic was most
consistent with its being caused by a product contaminant. Epidemiologic
analysis of plant operating conditions and data obtained from chemical
analyses of case- and control-associated lots implicated
1,1'-ethylidene-bis(tryptophan) (EBT) as a candidate for the compound that
causes EMS. However, the etiologic significance of EBT is still uncertain.
Factors found to increase a person's risk for EMS included higher
tryptophan dose and older age. Although cases occurred predominantly in
women and patients had frequently been taking other medications
concurrently with tryptophan, sex and use of several categories of other
medications were not shown to influence the risk of illness. Few patients
recovered rapidly and fully from the disease. Many were treated with
glucocorticoid medications, and although they may have benefited from
therapy in the short term, the development of chronic sequelae of EMS
appears not to have been prevented. Public health practitioners currently
depend on the reports of alert clinicians to detect this type of outbreak.
In this case, state and federal government epidemiologists, once they were
notified, were able to develop substantial basic information about the
epidemic in a relatively short time. Control measures were introduced
rapidly, effectively stopping the epidemic.
From the Food and Drug Administration.
JAMA. 268(14):1828, 1992 Oct 14.
Keating JP. Wardill K. Viggiano J.
Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan.
New Zealand Medical Journal. 105(939):317, 1992 Aug 12.
Hibbs JR. Mittleman B. Hill P. Medsger TA Jr.
L-tryptophan-associated eosinophilic fasciitis prior to the 1989
eosinophilia-myalgia syndrome outbreak.
Arthritis & Rheumatism. 35(3):299-303, 1992 Mar.
OBJECTIVE. To investigate the relationship between L-tryptophan (LT)
ingestion and eosinophilic fasciitis (EF) occurring prior to the outbreak
of eosinophilia-myalgia syndrome in 1989. METHODS. Interviews and record
reviews of 45 EF case-patients and 126 polymyositis patients (controls)
diagnosed prior to 1988. RESULTS. Nine case-patients (20%) and no controls
recalled taking LT before onset of the disease (odds ratio = infinity, 95%
confidence interval = 8.3-infinity). Among EF case-patients, LT ingestion
was associated with dyspnea. CONCLUSION. LT ingestion was associated with
EF prior to the 1989 outbreak of eosinophilia-myalgia syndrome. Lung
abnormalities may be a distinguishing feature of LT-mediated illness.
Eosinophilia-myalgia syndrome not associated with L-tryptophan.
New Jersey Medicine. 89(4):285-6, 1992 Apr.
The author reports a case of eosinophilia-myalgia syndrome (EMS), not
associated with the use of tryptophan. Other nutritional supplements
should be considered as possible etiologic agents in EMS. Further research
in this area is needed.
Shishikura T. Tsuchiya T. Sato F. Oguro K. Ebisawa H.
Eosinophilia caused by administration of L-tryptophan to animals with
Toxicology Letters. 58(3):315-21, 1991 Nov.
We have investigated an animal model of eosinophilia-myalgia syndrome
(EMS), a disease that occurred in various parts of the United States in
1989, with a view to determining its cause. We speculated that adrenal
dysfunction might have potentially contributed to the occurrence of EMS
and studied the effects of adrenal dysfunction on the eosinophil count in
peripheral blood by using rats and mice whose adrenals had been excised or
that had been metyrapone-treated, and giving them L-tryptophan. As a
result, a significant increase in the eosinophil count was observed in
both animal species. The results suggest that EMS may have been caused,
not by L-tryptophan alone, but by the combined effects of adrenal
dysfunction and L-tryptophan ingestion.
Biotechnology. Yellow light on L-tryptophan [news].
Nature. 353(6344):490, 1991 Oct 10.
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