Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic—Background Information
by William E. Crist
Background Information: The EMS Epidemic, Initial Research Studies and News of Biotech Link
During the summer and autumn of 1989, an outbreak of a tragic and mysterious disease swept across the U.S. First scores, then hundreds of people fell seriously ill with a rare blood and muscle disorder. Doctors and hospital staffs were baffled by the unusual cluster of symptoms and were largely ineffective in treating the victims.
The disease was characterized by an overproduction of white blood cells called eosinophils (1000 or more cells per mm) and severe and often debilitating myalgia (muscle pain). Hence, it was called eosinophilia-myalgia syndrome or EMS. In addition to elevated eosinophils and severe muscle pain, EMS patients exhibited a variety of other symptoms including physical weakness, leg and arm swelling (edema), fever, breathing difficulties, skin rashes, arthralgia, and pneumonia. In some instances, patients displayed signs of congestive heart failure and complete paralysis. An initial report showed that as many as half of EMS patients were hospitalized.[1-3] (Refer also to comments by patients and physicians.)
By late October of 1989, three physicians in New Mexico discovered a connection between the disorder and patients who had been taking food supplements of L-tryptophan.
On November 11, the U.S. Food and Drug Administration (FDA) issued a nationwide warning that advised consumers to discontinue use of L-tryptophan after 30 potential cases of EMS had been identified in New Mexico. Within a few days of this first publicity alert, the Center for Disease Control (CDC) in Atlanta received reports of 154 potential cases of a similar illness from public health agencies, physicians and the general public in 17 states and the District of Columbia.1 The FDA quickly issued a recall of all dietary supplements of L-tryptophan sold in doses of 100 mg. or more.
By early December of that same year, reports of EMS cases had soared to 707 in 48 states. One death had been reported and several others were under investigation. Expanding its constraints, FDA imposed an automatic detention at U.S. ports on all L-tryptophan products coming into the country.
For the next few months researchers and epidemiologists traced the multiple retail brands of L-tryptophan involved with the disease back through hundreds of wholesalers, distributors, tablet makers, encapsulators and importers.
On March 22, 1990, the FDA expanded its recall of L-tryptophan to include any dosages of the dietary supplement after it was discovered that one person with EMS had taken less than 100 milligrams a day. Meanwhile, the number of EMS cases linked to use of L-tryptophan had risen to 1,411, including 19 deaths.
In late April, the first preliminary scientific data on the outbreak was reported in meetings at the CDC that linked victims of EMS to L-tryptophan produced by a single Japanese company, Showa Denko K.K. In two separate studies virtually all EMS-case patients whose L-tryptophan consumption could be reliably traced had taken product that came wholly or in part from this one manufacturer.L-Tryptophan: A Key Amino Acid
L-tryptophan is known to play a key role in the functioning of the human body as a constituent of protein. It is important for the production of serotonin, a neurotransmitter in the brain that helps regulate sleep, mood, and perception of pain. For years, it was used by many Americans to treat insomnia, depression, premenstrual syndrome and other disorders. The FDA classified it as a food nutrient rather than a drug. Most people obtain sufficient amounts of natural tryptophan in dietary sources contained in high protein foods such as mother's milk, cow's milk, cheese, soybeans, fish, poultry and meat.[1,2,6,7]
All L-tryptophan marketed in the U.S. was manufactured by six companies in Japan. It was available by mail order and through a wide variety of retail outlets including pharmacies, grocery stores and health food stores. It was sold in tablet, capsule, powder and liquid form as a dietary supplement.[8-10]Showa Denko Altered Manufacturing Process
On July 11, 1990, the Journal of the American Medical Association (JAMA)7 published a study showing that 98 percent, and possibly 100 percent, of the EMS cases in Oregon had taken L-tryptophan product made by one manufacturer, Showa Denko, and that there was a significant correlation between these case patients and product manufactured by the company between January and June 1989. The JAMA study also noted that Showa Denko produced L-tryptophan by bacterial fermentation using a genetically engineered Bacillus species that had been introduced in its manufacturing process in December 1988.
The following month, a study published in The New England Journal of Medicine (NEJM), reported that shortly after Showa Denko introduced the newest strain of Bacillus (Strain V) in its manufacturing process, it reduced the amount of carbon powder used in the filtration of L-tryptophan from 20kg. to 10kg. in most batches.
The final product still exceeded the standards specified by the United States Pharmacopoeia, of 98.5 percent purity. The NEJM study's coauthors noted, "Although the powdered carbon may have contributed to the removal of the etiologic agent, it does not explain how the agent was introduced into the product." They said that the newly introduced Strain V bacterium "may have produced larger quantities of the etiologic agent than earlier strains."
High performance liquid chromatography (HPLC) analysis of Strain V samples revealed a number of peak trace contaminants, but only one, Peak E, was initially found to be significantly associated with the EMS epidemic. The researchers observed that because the change in carbon used during manufacturing happened at about the same time as the introduction of the new bacterial strain, it was difficult to assess the contribution of the bacterial strain to the onset of EMS.
Hence, the authors concluded, "The outbreak of eosinophilia-myalgia syndrome in 1989 resulted from the ingestion of a chemical constituent that was associated with specific tryptophan-manufacturing conditions at one company. The chemical constituent represented by Peak E may contribute to the pathogenesis of eosinophilia-myalgia syndrome or it may be a surrogate to another chemical that induces the syndrome."News of Biotech Link to Epidemic
A few days later, on August 14, 1990, Newsday ran a story that linked genetic engineering to the EMS epidemic. In the article, Dr. Michael Osterholm, coauthor of the NEJM study on EMS and epidemiologist at the Minnesota Health Department, said, "Strain V was cranked up to make more L-tryptophan and something went wrong. This obviously leads to that whole debate about genetic engineering."
A flurry of newspaper headlines ensued on genetic engineering gone awry.
In late August, Science magazine published an article in which Sam Page, chief of natural products and instrumentation branch at FDA, "blasted Osterholm for 'propagating hysteria.' The whole question: Is there any relation to genetic engineering? is premature-especially given the impact on the industry."
According to the article, Osterholm seemed somewhat bewildered by Page's response. "Anyone who looks at the data comes to the same conclusion," he said, namely, that genetic engineering could be involved. "I think FDA doesn't want it to be so because of the implications for the agency."
The article said that the FDA knew for months that the batches of L-tryptophan implicated in EMS were produced by a genetically engineered organism, but government officials had withheld the information from the public "apparently hoping to keep the recombinant link quiet until they could determine whether it in fact did play a role in the outbreak."
The article also reported that researchers had identified the chemical structure of the contaminant Peak E as a "dimer" — essentially, two tryptophan molecules linked together.FDA Knew of the Danger
The FDA knew that genetic engineering could potentially promote toxicity in a plant or organism. According to its 1992 Statement of Policy: Foods Derived From New Plant Varieties:
Plants are known to produce naturally a number of toxicants and anti-nutritional factors… which often serve the plant as natural defense compounds against pests and pathogens… Many of these toxicants are present in today's foods at levels that do not cause acute toxicity… Plants, like other organisms, have metabolic pathways that no longer function due to mutations that occurred during evolution. Products or intermediates of some such pathways may include toxicants. In rare cases, such silent pathways may be activated by mutations, chromosomal rearrangements, or new regulatory regions introduced during breeding, and toxicants hitherto not associated with a plant species may thereby be produced. Similarly, toxicants ordinarily produced at low levels in a plant may be produced at high levels in a new variety as a result of such occurrences (e.g., using recombinant DNA techniques, also known as genetic engineering).
Four years later in a telephone interview, James Maryanski, FDA biotech policy coordinator, had a different view. I asked him whether the genetically engineered bacteria used by Showa Denko during fermentation could have created toxic impurities in their L-tryptophan product.
"We have no evidence of that, none whatsoever that the technique causes those kind of effects, differently from other methods of modifying organisms," he said.
Apparently Maryanski was unaware that a year earlier, in 1995, a study by scientists at Japan's Research Institute for Food Science, reported that genetically engineered yeast produced an accumulation of a highly toxic compound in yeast cells, compared to non-transformed control cells. The authors concluded, "These results illustrate that careful thought should be given to the potential metabolic products and their safety when a genetically engineered yeast is applied to food-related fermentation processes.
Michael Antoniou, PhD., Reader in Molecular Genetics in the U.K., commented, "[This example] illustrates that a product derived from a GE organism can be devoid of genetic material, but can still unexpectedly contain potentially harmful alterations to a GE product, a novel toxin or elevated levels of a known hazardous substance.
Later in my interview with Maryanski, he said that while theoretically genetic engineering could have played a role in causing EMS, it was not likely the cause:
We can not rule it (genetic engineering) out. However, close to two dozen cases of L-tryptophan linked EMS (cases) occurred before Showa Denko began using their engineered strain. So, there would have to be a cause other than just the mere engineering of the strains. I can't say that definitively because we don't have a lot of information on these earlier cases.
We can not say definitely that the engineering strains were not a contributing factor. However, we do have enough information that suggests that there are probably other factors involved, that either L-tryptophan itself, or L-tryptophan in combination with something that was the result of the purification process, was the more likely cause. Until the science advances far enough, we really can't say.[14,17]
That was before new information surfaced regarding the pre-epidemic cases (next section) >>
See also:The Severity of the Disease—Comments by Victims and Physicians
- Centers for Disease Control, "Eosinophilia-Myalgia Syndrome-New Mexico," Morbidity and Mortality Weekly Report (MMWR) (November 17, 1989), Vol. 38, No. 45, pp. 765-767.
- Food & Drug Administration, "Update on L-Tryptophan"(December 5, 1989),http://www.fda.gov/bbs/topics/ANSWERS/ANS00114.html.
- Food & Drug Administration, "Recall of L- 6 Tryptophan," P90-21, (March 22, 1990),http://www.fda.gov/bbs/topics/NEWS/NEW0004.html.
- Food & Drug Administration, "L-Tryptophan Update: Company Link Suggested" (April 26, 1990), http://www.fda.gov/bbs/topics/ANSWERS/ANS00089.html.
- Daily Appellate Report (April 22, 1996), "L-tryptophan Manufacturer is Per Se Negligent Under Food, Drug And Cosmetic Act in Products Liability Action," pp. 3534.
- David Swinbanks & Christopher Anderson "Search for contaminant in EMS outbreak goes slowly," Nature (July 9, 1992), Vol. 358, pp. 96.
- L Slutsker, et al., Journal of the American Medical Association (July 11, 1990), Vol. 264, No. 2, pp. 213-217.
- Food & Drug Administration, "L-Tryptophan Recall," P89-49 (November 17, 1989), http://www.fda.gov/bbs/topics/NEWS/NEW00091.html.
- Food & Drug Administration, "FDA's Regulatory Response to L-Tryptophan Situation," (July 18, 1991).
- Belongia, EA, et al., New England Journal of Medicine (August 9, 1990), Vol. 323, No. 6, pp. 357-365.
- Laurie Garrett, Newsday, "Genetic engineering flaw blamed for toxic deaths," The Ann Arbor News (August 14, 1990), pp C-1.
- Leslie Roberts, "L-tryptophan puzzle takes new twist," Science (August 31, 1990).
- Federal Register, Notices (May 29, 1992), Vol. 57, No. 104, pp. 22987.
- Jim Maryanski, biotech coordinator at FDA, personal interview July 5, 1996
- Tomoko Inose & Kousaku Murata, Department of Applied Microbiology, Research Institute for Food Sciences, Kyoto University, Japan, "Enhanced accumulation of toxic compound in yeast cells having high glycolytic activity: a case study on the safety of genetically engineered yeast," International Journal of Food Sciences and Technology (1995), Vol. 30, pp. 141-146.
- Michael Antoniou, PhD, Reader in Molecular Genetics, London, UK, "Is GM Food Devoid of DNA Safe?" Nutritional Therapy Today (1996).
- See also James Maryanski's comments in "Cornucopia of Biotech Food Awaits Labeling," by Paul Jacobs, The Los Angeles Times, January 31, 2000.
© Copyright 2005 William E. Crist. All Rights Reserved