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Evidence Links Japanese Firm to Epidemic in 1989 : Research: A potentially fatal blood and muscle ailment has been tied to impurities in the manufacturer’s supply of the dietary supplement L-tryptophan.

TIMES MEDICAL WRITER

Researchers Tuesday presented the strongest evidence to date linking the dietary supplement L-tryptophan made by a Japanese manufacturer to an epidemic of the eosinophilia-myalgia syndrome in the United States in the fall of 1989.

They also announced that specific impurities in the tryptophan produced in late 1988 and early 1989 by the chemical company, Showa Denko of Tokyo, is being investigated as a possible cause of the potentially fatal blood and muscle ailment.

Tryptophan from Showa Denko “is largely if not exclusively responsible for the problem in the United States,” said Dr. Michael Osterholm, the Minnesota state epidemiologist, citing Minnesota studies and data from state health officials in New Mexico, New York, Oregon and the U.S. Centers for Disease Control. “No one presented data to refute that.”

“The magnitude of some of the impurities correlates very highly with the case-associated materials” from Showa Denko, said Larry Needham of the Centers for Disease Control.

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But Osterholm, Needham and others cautioned that far more must be learned about the ailment and its cause before sales of products containing tryptophan are resumed. For example, Needham said, the specific impurities must be fully identified and then shown to cause a similar disease in laboratory animals.

The first comprehensive medical meeting on eosinophilia-myalgia syndrome was organized by Dr. Phillip Hertzman, a Los Alamos family practitioner who helped discover the illness last October.

So far, more than 1,500 eosinophilia-myalgia cases, including 27 deaths, have been reported to federal health officials, and many patients remain seriously ill. Patients have high concentrations of eosinophils, a type of white blood cell that is usually uncommon, severe muscle pains and, depending on severity, other problems, such as nerve damage, lung damage and significant skin thickening.

The number of new cases has dropped precipitously, but a handful of illnesses continue to develop. Despite warnings, some individuals continue to use hoarded tryptophan supplies. Others have become ill several months after they stopped using the supplement.

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Tryptophan was widely used--perhaps by as many as 2% of adults, primarily non-Latino white women--before the U.S. Food and Drug Administration ordered a total recall of the product last November. The most common reasons were sleeping difficulties, anxiety, depression and premenstrual syndrome.

Showa Denko was the largest supplier of the bulk amino acid supplement to the American firms that packaged and marketed the drug.

Dr. Arthur I. Holleb, an American physician who advises Showa Denko, said that the company acknowledges the “statistical association” between its tryptophan and the development of the illness, but believes that “there is still a long ways to go to firmly establish the causative factor.”

At the meeting, health officials from Minnesota, Oregon, New Mexico and New York presented data showing that about 95% of the eosinophilia-myalgia cases they had studied extensively could be traced to Showa Denko.

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In Minnesota, state health department and Mayo Clinic researchers have identified specific changes in Showa Denko’s manufacturing techniques that appear to be related to increased amounts of an impurity in the company’s tryptophan.

Showa Denko produces tryptophan from sugars and other nutrients through bacterial fermentation. After the fermentation is complete, the chemical is isolated and purified so that it is about 99% pure.

The specific manufacturing changes appear to involve a new strain of bacteria introduced into the fermentation and a decrease in the concentration of activated charcoal used in the purification process, said Dr. Edward Belongia of the Minnesota Health Department. Both of these changes occurred in late 1988 and early 1989.

Minnesota researchers call the “signature” impurity “peak E,” a reference to its appearance on the high-performance liquid chromatography laboratory tests that were used to identify the material. The researchers do not know exactly what the impurity is, but they said it may belong to a family of organic chemicals known as “indoles” that are structurally related to tryptophan. Before 1988, this impurity was also present, but in virtually undetectable amounts.

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