— begin part 5 of 6, cut here —
reported only once, information regarding hospitalization of patients
requiring admission after their cases are reported is not available.
The surveillance definition for reporting EMS cases to CDC requires the
presence of severe, debilitating myalgias and eosinophilia greater than or
equal to 1000 eosinophils per mm3. Recent unpublished reports indicate that
this case definition may be overly restrictive for clinical purposes. Many
persons may have forms of EMS that are either less severe or in which the
constellation of clinical findings does not include the intense eosinophilia
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Volume 3, Number 31 September 17, 1990
or severe myalgias initially identified as the hallmarks of epidemic EMS. Thus
far, such cases have not been the object of national surveillance.
The failure of a case to meet criteria specified in the surveillance
definition does not preclude a clinical diagnosis of EMS in a person who
manifests other features of EMS or who has either a lower eosinophil count or
milder myalgias. As in other diseases with multiple connective tissue
manifestations, a set of clear-cut diagnostic criteria with both high
sensitivity and specificity may be difficult or impossible to establish. The
physician’s judgment and appropriate weighing of all available information are
important in the clinical diagnosis of EMS.
References
1. Eidson M, Philen RM, Sewell CM, Voorhees R, Kilbourne EM. L-tryptophan and
eosinophilia-myalgia syndrome in New Mexico. Lancet 1990;335:645-8.
2. CDC. Eosinophilia-myalgia syndrome–New Mexico. MMWR 1989;38:765-7.
3. CDC. Eosinophilia-myalgia syndrome and L-tryptophan-containing products–
New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989;38:785-8.
4. CDC. Update: eosinophilia-myalgia syndrome associated with ingestion of L-
tryptophan–United States. MMWR 1989;38:842-3.
5. CDC. Update: eosinophilia-myalgia syndrome associated with ingestion of L-
tryptophan–United States, as of January 9, 1990. MMWR 1990;39:14-5.
Health InfoCom Network News Page 37
Volume 3, Number 31 September 17, 1990
Analysis of L-Tryptophan for the Etiology of Eosinophilia-Myalgia
Syndrome
Eosinophilia-myalgia syndrome (EMS) has been associated with consumption
of L-tryptophan-containing products (LTCPs) (1,2) and most strongly associated
with consumption of LTCPs produced by one manufacturer (3-5). Epidemiologic
and laboratory investigations have suggested that the implicated LTCPs were
contaminated (3-5). To further examine this hypothesis, CDC and the Food and
Drug Administration (FDA) conducted additional laboratory studies. This report
summarizes preliminary data that indicate that implicated LTCPs were
contaminated with the di-tryptophan aminal of acetaldehyde (DTAA).
The laboratory investigation determined that case-associated L-tryptophan
(LT) cultures were negative for bacteria and viruses and that endotoxin levels
were not elevated in case-associated LT (6). Analysis of case-associated LT
for 37 elements identified none at toxicologically significant concentrations.
Fifty lots of LT produced between March 1985 and June 1989 by the
implicated manufacturer were analyzed by high-performance liquid
chromatography (HPLC). Thirteen lots were linked to EMS cases; other lots were
considered as controls because no link with cases could be identified. Several
HPLC peaks (called peaks 97, 100, and 200) were identified that were
predictive of case-associated LT lots. Amounts of peak 97 in LT lots from the
implicated manufacturer increased dramatically between March and June 1989.
Based on a Wilcoxon rank-sum test, peak 97 was the single most predictive peak
(p less than 0.0001) of case-associated LT lots. A bivariate plot of peaks 100
and 200 was as predictive as peak 97. HPLC analysis of samples exchanged
between CDC and the Mayo Clinic revealed that peak 97 is likely the same as
peak E (5).
HPLC was used to isolate peak 97 from case-associated LT lots. Proton
nuclear magnetic resonance indicated that peak 97 was a tryptophan derivative
with its characteristic aromatic indole protons and aliphatic protons but with
an unusual doublet at a chemical shift of 2.2 ppm. HPLC combined with
atmospheric pressure ionization/mass spectrometry/mass spectrometry determined
that peak 97 had a molecular weight of 434. High-resolution fast-atom
bombardment mass spectrometry determined the exact mass of peak 97 to be
434.2020 corresponding to a molecular formula of C 24H 26N 4O 4, indicating
that peak 97 contained two tryptophan molecules and an additional C 2H 2.
These data suggested that peak 97 was the DTAA (Figure 1A).
With LT as a standard, the concentration of peak 97 was estimated at 0.01%
in a typical case-associated LT lot. Scientists at the implicated manufacturer
independently arrived at the same proposed structure (R. Hinds, personal
communication). Confirmation of this structure by synthesizing DTAA is in
progress. In addition to peaks 97, 100, and 200, ongoing investigation is
directed at 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid
(MTCA) (Figure 1B) and bacitracin, detected in LT lots from the implicated
manufacturer (6). MTCA could be produced from the breakdown of DTAA or
Health InfoCom Network News Page 38
Volume 3, Number 31 September 17, 1990
independently formed.
Reported by: Sciex, Div of MDS Health Group, Ontario, Canada. National
Institute of Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health. National Institute of Mental Health, Alcohol, Drug Abuse
and Mental Health Administration. Center for Food Safety and Applied
Nutrition, Food and Drug Administration. Center for Infectious Diseases;
Center for Environmental Health and Injury Control, CDC.
Editorial Note: The epidemiologic association of peak 97 and any other
particular compound with EMS indicates that these compounds may either be the
causative agent(s) or marker(s) for a different, as yet unidentified,
causative agent in case-associated LT lots. Based on an average daily dose of
2 g of LT for a 70-kg person and a 30-day delay before onset of EMS, the total
dose of peak 97 is approximately 90 ug/kg. The toxic properties of the aminals
are not well defined; however, the suspected decomposition products, the beta-
carbolines, exhibit a variety of biologic properties (7).
The full definition of biologic and toxic effects of the contaminants can
be determined only in an animal model for EMS. A joint National Institute of
Mental Health/National Institutes of Health/FDA/CDC study has recently
reproduced EMS-like changes in rats (E.M. Sternberg, personal communication).
Synthesizing these contaminants and testing them in the new rat model may help
to clarify their relationship to the etiology and pathogenesis of EMS.
Continuing studies include analyzing additional LT lots, identifying and
synthesizing contaminants, and attempting to associate changes in the
manufacturing process with these contaminants.
References
1. CDC. Eosinophilia-myalgia syndrome–New Mexico. MMWR 1989;38:765-7.
2. CDC. Eosinophilia-myalgia syndrome and L-tryptophan-containing products–
New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989;38:785-8.
3. Slutsker L, Hoesly FC, Miller L, Williams P, Watson JC, Fleming DW.
Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a
single manufacturer. JAMA 1990;264:213-7.
4. Belongia EA, Hedberg CW, White KE, MacDonald KL, Osterholm MT.
Epidemiology of eosinophilia-myalgia syndrome in Minnesota. Presented at the
39th Annual Epidemic Intelligence Service Conference, CDC, Atlanta, April 25,
1990.
5. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of
the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med
Health InfoCom Network News Page 39
Volume 3, Number 31 September 17, 1990
1990;323:357-65.
6. Needham L, Page S. Chemical analysis of LTCPS and related samples.
Conference on Eosinophilia-Myalgia Syndrome, Los Alamos National Laboratory,
Los Alamos, New Mexico, June 12, 1990.
7. Buckholtz NS. Neurobiology of tetrahydro-beta-carbolines. Life Sci
1980;27:893-903.
Health InfoCom Network News Page 40
Volume 3, Number 31 September 17, 1990
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Food & Drug Administration News
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Health Claims
P90-43 Food and Drug Administration
FOR IMMEDIATE RELEASE Jeff Nesbit – (301) 443-4177
Sept. 6, 1990 (Home) — (703) 273-1043
In its first set of health claims enforcement actions since announcing its
new policy earlier this year, the Food and Drug Administration has warned six
U.S. food companies to remove health claims from cereals, baked goods and
other food products because their claims are not backed by scientific evidence
In regulatory letters to the six companies, the agency said that the
labels on the companies’ products contained health messages that were in
violation of the federal Food, Drug and Cosmetic Act.
Although the health claims policy announced earlier this year is still a
proposed rule, FDA included an interim enforcement policy in the Federal
Register notice that explains when FDA will act against egregious health
claims until the regulation becomes final. FDA’s health claims proposal and
interim enforcement policy were announced last February by HHS Secretary Louis
W. Sullivan, M.D.
"The actions taken against these six companies fall within the scope of
FDA’s interim enforcement policy," said Acting FDA Commissioner James Benson.
"All of these products make health claims that are not adequately supported by
science."
In the regulatory letters, FDA also reserved the right to take action
against the companies for making illegal drug claims with their products.
One of the food products FDA moved against was "Oat Chex," a cereal made
by the Ralston Purina Co. of St. Louis, Mo. In its health claim, the company
said that eating the oat bran cereal "may help reduce cholesterol levels."
In its letter, FDA said that the label claims "suggest that a serving of
the product provides a nutritionally significant amount of fiber, and
particularly soluble fiber, which is contrary to fact." The agency concluded
that — even if scientific evidence eventually supports a link between eating
oat bran fiber and a reduction of coronary heart disease risk — there is not
enough fiber in "Oat Chex" to justify its health claim.
The agency also noted that consumption of foods containing bran fiber must
be considered within the context of a total diet.
Other food products making illegal health claims, according to the FDA,
include:
Health InfoCom Network News Page 41
Volume 3, Number 31 September 17, 1990
* "Toasted Oat Bran Shake," which is made by J&J Snack Foods Corp. of
Vernon, Calif.
* "Rice Bran Oil," which is made by Select Origins, Inc., of Yaphank, N.Y.
* "Oatmeal Goodness Bread Wheat Oatmeal," which is made by Continental
Baking Co., of St. Louis, Mo.
* "Vita Fiber Rice Bran," which is made by Pacific Rice Products, Inc., of
Woodland, Calif.
* "Oat Bran Fruit Jumbo Cookies," which is made by Health Valley Foods,
Inc., of Irwindale, Calif.
The proposal would allow companies to present specific health messages on
their products if they fall within a narrow range of messages regarding the
relationships between diet and health benefits outlined in recent studies by
the U.S. Surgeon General and the National Academy of Sciences.
The proposal also described the circumstances — in the period in which
the proposal is pending — in which FDA is likely to find that enforcement
action against a particular label is necessary.
Traditionally, FDA has not allowed companies to make particular claims on
their products’ labels linking a food to prevention or treatment of a
particular disease.
When the agency issued an earlier proposal in 1987 to allow health claims
— and said that the proposal would have the force of law for the purpose of
enforcement – many commenters said the proposal was too broad and allowed
label claims that may not be justified by scientific research.
After receiving hundreds of comments, FDA began to develop a more cautious
approach based upon the current state of scientific knowledge, which in turn
led to the health claims proposal outlined earlier this year.
"In hindsight, the l987 proposal has proved to be too permissive," Dr.
Sullivan said in February. "We need an interim policy to serve as a mid-course
correction and provide guidance to industry on what health messages will and
will not be allowed. Only with such a consistent set of standards can
Americans be sure of the meaning of health information on food labels."
In recent years, scientific evidence has accumulated that some specific
dietary components may have value in reducing the risk of certain diseases.
Reports by the National Academy and the Surgeon General summarized much of
that evidence.
FDA proposed to consider initially six areas discussed in those two
reports — calcium and osteoporosis; sodium and hypertension; lipids and
cardiovascular disease; lipids and cancer; dietary fiber and cancer; and fiber
and cardiovascular disease.
As science finds additional links between diet and health, the FDA could
also include additional areas in its health messages policy.
Health InfoCom Network News Page 42
Volume 3, Number 31 September 17, 1990
BST
P90-42 Food and Drug Administration
EMBARGOED FOR RELEASE Bonnie Aikman – (301) 443-3285
Aug. 24, 1990 (Home) — (301) 986-0697
In a report today in the journal Science, Food and Drug Administration
scientists summarize more than 120 studies they say document the safety of
milk and meat from dairy cows treated with genetically engineered duplications
of the cows’ own growth hormone, used to increase milk production.
The author-scientists say the studies have led FDA to conclude that the use
of recombinant bovine growth hormone — called bovine somatotropin or BST –
presents "no increased health risk to consumers."
In their summary report, the authors discuss previously unpublished data
from 16 studies supported by manufacturers, who are seeking approval to market
the substance, along with publicly available studies. These data demonstrate
that:
– BST is harmless when consumed orally, as in milk or meat, because it is
broken down into inactive fragments in the gastrointestinal tract while being
digested.
– Even if BST were injected in humans, as it is in treating cows, it would
remain inactive because bovine somatotropin is "species specific."
–Ninety percent of BST in milk is destroyed upon pasteurization.
–A protein controlled by BST is increased in the milk of BST-treated cows,
but data show that concentrations are within the normal physiological range
found in human breast milk." Moreover, this protein — Insulin-like Growth
Factor I or IGF-I — is denatured under the conditions used to process milk
for infant formulas. Other data demonstrate that oral toxicity studies have
shown that IGF-1 lacks oral activity in rats at even exaggerated doses.
In addition, the authors concluded, milk from cows treated with BST would
have BST residues within the normal range of the naturally occurring substance
Today’s report was prepared by toxicologist and pharmacologist Judith C.
Juskevich, formerly with FDA’s Center for Veterinary Medicine and now an FDA
consultant, and C. Greg Guyer, a chemist in the office of new animal drug
evaluation at FDA’s Center for Veterinary Medicine.
The report underwent extensive and lengthy peer review by a panel of expert
scientists selected by the editors of Science before it was published.
BST, produced in quantity by recombinant DNA technology, is identical in
biological activity to the growth hormone made by the cow’s pituitary gland.
Manufacturers are seeking FDA approval to market their copies of BST to
increase milk production and thereby reduce farming costs. Besides reviewing
the safety to humans consuming products from treated animals, FDA must
determine BST’s safety and effectiveness for the cows and its safety to the
environment before approving its sale.
Health InfoCom Network News Page 43
Volume 3, Number 31 September 17, 1990
However, limited amounts of milk from test cows — less than one percent of
the nation’s milk supply — have been released for sale for several years. In
the mid-1980s, under federal regulations and following FDA’s review of the
data for BST, the agency authorized this sale of food products and told
Congress of this action.
####
NOTE: Reprints of the Science article on BST are available to the press at the
FDA press offices, Room 3807, 200 C Street, S.W., Washington, D.C. 20204, and
Room 1505, 5600 Fishers Lane, Rockville, Md., 20857.
Health InfoCom Network News Page 44
Volume 3, Number 31 September 17, 1990
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Columns
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
DIABETES HIGHLIGHTS #11
J. Martin Wehlou MD
CompuServe: 72047,2444
Bitnet: WEHLOU@BGERUG51
FidoNet: 2:295/51
BBS: 32-91-30.46.25
(300/1200/2400 8N1 MNP5)
Voice: 32-91-31.67.40
Fax: 32-91-31.33.12
THROMBOXANE PRODUCTION IN TYPE II DIABETES
Thromboxane, produced by platelets, increases the tendency to aggregation of
platelets. Diabetics seem to produce an excessive amount of thromboxane,
partly explaining the vascular problems they may encounter. Strict control by
intensive insulin therapy can reduce the thromboxane levels, as can low dose
aspirin therapy. N.Engl.J.Med. 322:1769-74, 21 June 1990.
COUGH TEST FOR AUTONOMIC NEUROPATHY
A standardized test whereby an electrocardiogram is recorded during a series
of coughs can show diabetic neuropathy of the cardiovascular autonomic nerves
in a reliable way. Diabetes Care 13:719-24, July 1990.
FISH OIL: GOOD FOR YOU… AND BAD FOR YOU?
Max EPA (a commercially available fish oil preparation) raised both the LDL
and the HDL fractions significantly in diabetic test subjects. The question
is if the beneficial HDL increase is sufficient to offset the higher risk of
cardiovascular complications resulting from the concomitant increase in LDL.
Diabetes Care 13:725-32, July 1990.
HSH VERSUS GLUCOSE AS SWEETENER
Hydrogenated Starch Hydrolysates (HSH), used as sweetener in hard candies, was
Health InfoCom Network News Page 45
Volume 3, Number 31 September 17, 1990
compared to glucose. The HSH products resulted in decreased postmeal glycemia
through altered small intestinal carbohydrate absorption. HSH as a single
ingredient seems to be suitable for diabetics. Diabetes Care 13:733-40, July
1990.
LOW HbA1 IS GOOD FOR YOU IN THE LONG TERM
175 subjects with childhood-onset diabetes and a duration of diabetes of more
than 25 years were studied. 19% had no major complications. Those free of
advanced complications had better lipid profile and blood pressure. The most
significant factor was the considerably lower HbA1 levels (p<0.001). Diabetes
Care 13:741-47, July 1990.
AS LONG AS YOU EAT
Several different meal distribution schemes were tried in type II non-insulin
dependent diabetics. As long as the total calorie content and the food
composition are kept constant, blood glucose control is only modestly affected
by the pattern of food intake. The partition of food intake into meals and
snacks or a large dinner does not result in significantly different glucose
levels in the non-insulin dependent diabetic. Diabetes Care 13:748-55, July
1990.
PREDICTING TYPE I DIABETES
There are 3 tests that can be highly predictive of the development of type I
diabetes: 1. high-titer cytoplasmic islet cell antibodies, 2. insulin
autoantibodies detected with fluid-phase radiobinding assays, and 3. first-
phase insulin release after IV glucose being less that the 1st percentile.
Diabetes Care 13:762-75, July 1990.
KIDS WITH IDDM SHOULD BE TESTED
19% of children with IDDM have thyroid-specific antibodies. All children and
adolescents with IDDM should be screened for thyroid disease shortly after
diagnosis. Diabetes Care 13:801-03, July 1990.
LONG-TERM SUCCESSFUL ISLET TRANSPLANTS
5 out of 9 patients that received combined liver and islet transplants had
Health InfoCom Network News Page 46
Volume 3, Number 31 September 17, 1990
— end part 5 of 6, cut here —
————————————————————————-
St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
Bitnet: ATW1H @ ASUACAD Internet: ddod…@stjhmc.fidonet.org
FidoNet=> 1:114/15 FAX: +1 (602) 451-1165