Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic—Conclusion: Who’s Responsible?
by William E. Crist
What created the biologically potent trace contaminants in Showa Denko L-tryptophan that inflicted a seriously debilitating disease at such low dosages of a food supplement?
Researchers still do not know. Some, like Gleich and Maryanski, have stated that genetic engineering can't be ruled out as a causal factor, though they favor other scenarios, usually the manufacturer's inadequate purification system.
Showa Denko clearly had a filtration problem, as scientists and government regulatory agencies concur. But this is only clear in hindsight. In 1984, when Showa Denko introduced its first genetically engineered bacterial strain to bolster yields, no one was able to anticipate that novel impurities would appear, which might require more filtration (than does standard bacterial fermentation) to obtain a safe product.
Showa Denko daily monitored the levels of impurities in their L-tryptophan product and kept their product above the USP standard of 98.5% purity. A company position paper stated, "The cause of EMS remains unknown. Showa Denko had every reason to believe its product was safe. L-tryptophan manufactured by Showa Denko met all the purity standards of the United States, and had been extensively tested in animals. An attorney representing the firm said that to his knowledge none of the tests showed any adverse effect on animals or humans, and that prior to the 1989 EMS outbreak, "no complaint of any adverse reaction had been received, and there thus was no reason to believe that the product was ever capable of causing any harm…."
How was Showa Denko to know that their product had been, in fact, contaminated to varying degrees, even before the epidemic, and was silently causing harm that eventually would lead to over 2000 US litigation cases, representing more than $2 billion in settlements? If they had detected a problem, they would have had more filtration in place. But they didn't know, at least for several years, until the EMS outbreak tragically revealed that something was amiss.
Hundreds of studies by researchers worldwide since 1989 have not been able to clearly identify the trace contaminant(s) in Showa Denko's L-tryptophan that caused EMS, and bioassay and animal feeding models have failed to reproduce the disease. How could the manufacturer have done differently in testing their product to prevent the early cases of EMS and the epidemic?
Outdated Regulatory Standards
Sam Page, PhD, Scientific Director at FDA's Center for Food Safety & Applied Nutrition, said that if he had been asked to verify the purity of the [Showa Denko] product, he would not have found anything wrong with it either. This suggests that no existing regulatory procedure could have caught this problem in advance.
According to CDC researchers, "Although the tryptophan associated with the epidemic of 1989 was US Pharmacopoeia grade [98.5% pure], the presence of 60 micro contaminants, at least one of which can apparently cause disease at very low concentrations, raises the issue of purity standards for dietary supplements and other bacterial fermentation products as well."
"Other bacterial fermentation products" includes products manufactured via genetically engineered bacteria, which are used to increase yields but simultaneously increase impurities during the fermentation process. Regulators have yet to address the issue of purity standards for GE-manufactured products.
FDA did not require Showa Denko or any other manufacturer to notify it of the use of genetically engineered bacteria to produce a product marketed as a dietary supplement, i.e., a "food." The agency has imposed no new regulatory requirements to deal with the use of genetic engineering in the production of food products. Even after the EMS epidemic, a revised policy statement did not specify any additional safety testing for foods, including dietary supplements, produced using genetic engineering.
Like any business enterprise, Showa Denko simply responded to its regulatory environment. Companies are always looking for new ways to increase yields and reduce costs, without violating regulatory standards. But government regulators did not (and do not) regard genetically engineered (GE) foods or GE-produced food supplements as potentially different from conventional ones—so why would the manufacturers?
Page said that everything that FDA requested from Showa Denko with regard to records and samples of product—even beyond what was requested—had been supplied, with one exception: the genetically engineered material.
Why did Showa Denko withhold from FDA the five genetically engineered cultures/strains, which it eventually destroyed in 1996? (See Discrepancy over Genetically Engineered Cultures.) Was the company trying to hide something that it knew would have negative repercussions on biotechnology or on itself as a manufacturer? These questions may never be answered. Key evidence, possibly the "weapon" itself in this tragic disease and epidemic, has been destroyed, making the case much more difficult to solve than it need be.
In mid-1988, a German company tested Showa Denko L-tryptophan and discovered an impurity, called Peak D, and notified the manufacturer's headquarters (in Tokyo). The headquarters in turn corresponded on the issue with its Oita plant, where L-tryptophan was manufactured, and with Showa Denko Europe (SDE). One communication from headquarters to SDE reportedly stated, "The issue of genetic engineering is not a kind of information to be disclosed outside the company. We will convince the German company by explaining that we simply changed the refining process. Changing the refining process implied changing the pattern of contaminants, which would include the Peak D impurity.
Showa Denko had in fact made several changes in their manufacturing process from October 1988 to January 1989, including the introduction of three new GE strains (IV-1, IV-2, and V); a 50% reduction in the amount of activated carbon powder used in filtration of most batches; and the fermentation broth of some batches partially bypassed the ROM filter. CDC researchers later found that the contaminant "peaks predictive of case status reflected principally the differences in trace components between the bacterial strain V (and IV-2) fermentation processes and bacterial strain III fermentation process." Showa Denko apparently resolved the Peak D issue, but subsequent events would indicate that they created a far more serious contamination problem.
In EMS litigations with Showa Denko in the US, some three hundred thousand pages of Showa Denko internal documents were turned over to a Steering Committee of leading attorneys representing the victims. Paul Rheingold, an attorney on the committee, whose New York firm handled about 270 cases, gave me a copy of his personal notes (70 pages) from the discovery process. He agreed that I could make general use of them so long as I explained "there is no proof it was more than suspicions at the time and subsequent events have undoubtedly proved many of the statements incomplete or inaccurate." Nevertheless, one note said that Showa Denko recalled all pamphlets mentioning gene technology on December 13, 1989, just a few weeks after FDA and CDC officials had visited the manufacturer's Oita plant. (The visit was in response to the discovery by physicians and regulators in the US that L-tryptophan consumption was linked to the EMS epidemic then in progress.)
Interestingly, US scientists and government regulators appear to have used the same tactic as the implicated manufacturer, namely, that the issue of genetic engineering is not something to be disclosed outside (to the public). Instead, they offer a vague explanation that the contaminants linked to the EMS tragedy were caused by changes in the manufacturing process. But, from 1984 to 1989, genetically engineered bacteria were a key part of Showa Denko's manufacturing process.
In the absence of clear evidence either way, however, government regulators have acted on the assumption that GE wasn't at fault and that Showa Denko's filtration and/or L-tryptophan itself are to blame (see FDA Policy Statement on L-tryptophan). Hence, Showa Denko has borne the responsibility for EMS, because they had inadequate filtration and marketed batches of a contaminated product that resulted in thousands of consumers being seriously injured—even though the product met the USP standard for purity. This last point—that the regulatory environment was inadequate to assure consumers sufficient purity of the final product—indicates that regulatory agencies should shoulder at least a share of the responsibility. They, along with the manufacturer and biotech scientists, all may have grossly underestimated the power of genetically engineered bacteria to create biologically potent micro contaminants linked to EMS—and still do to this day.
Did a Novel Gene Technology Create a Novel Epidemic?
Assigning blame to the manufacturer's filtration problem is, in my view, only partially correct, because it disregards two crucial elements: the powerful new GE technology that Showa Denko introduced, and the regulatory environment at the time. All three factors—filtration, GE bacteria, and purity standards/regulations—appear to have contributed to creating a contaminated L-tryptophan product.
In the baseball analogy mentioned in Section 4, Where Did the Contaminants Come From?, it's easy at first glance to fault the catcher (filtration) when a ball gets by him, but to completely disregard the pitcher (GE bacteria) who threw the ball, as well as the context or rules of baseball within which the ball was thrown (regulatory environment), is absurd—and unscientific. But, that's precisely what scientists and regulators appear to have done.
This demonstrates a breakdown in scientific and regulatory logic. Regulators continue to claim that biotechnologically-produced foods are substantially equivalent to their natural counterparts, even though they have no clear evidence exonerating Showa Denko's GE strains as a causal factor in creating EMS. To say that the cause of a major disease/epidemic linked to GE technology is "unclear," and that there is no evidence of health risk associated with that technology, flies in the face of scientific logic, common sense, and regulators' mandate to safeguard public health. And it places consumers at risk for another tragic, mysterious GE-related disaster in the future.
Is the EMS tragedy a mystery? Or are biotech scientists downplaying the consequences of their genetic manipulations?
The late George Wald (d. 1997), Nobel Laureate in Medicine or Physiology in 1967 and Higgins Professor of Biology at Harvard University, was one of the first scientists to speak out about the potential dangers of genetic engineering.
In his essay "The Case Against Genetic Engineering: The Recombinant DNA Debate," published in 1976, Professor Wald wrote (emphasis added):
"Recombinant DNA technology [genetic engineering] faces our society with problems unprecedented, not only in the history of science, but of life on the Earth.... Now whole new proteins will be transposed overnight into wholly new associations, with consequences no one can foretell, either for the host organism or their neighbors.... It is all too big and is happening too fast.... For going ahead in this direction may not only be unwise but dangerous. Potentially, it could breed new animal and plant diseases, new sources of cancer, novel epidemics."
"Novel epidemics" indeed. Wald sounded the alarm thirteen years before the EMS outbreak occurred. Today, after more than 100 studies, scientists know that only Showa Denko's L-tryptophan was clearly associated with EMS. They still do not know the specific contaminant(s) in the product that created the disease.
Something clearly went wrong that Showa Denko, government regulators and biotech scientists did not anticipate. Genetic engineering looms as one of the few possible remaining etiologies for creating the novel trace impurities that caused the disease.
- Gerald J. Gleich, M.D., Mayo Clinic researcher, position statement for National EMS Network, May 25, 2000
- Dateline, NBC News, "Bitter Pill," August 22, 1995.
- Don Morgan email correspondence, April 19, 2001.
- Philip Raphals, "EMS deaths: Is recombinant DNA technology involved?" The Medical Post, November 6, 1990.
- Lee D. Kaufman and Rossanne M. Philen, "Tryptophan: Current Status and Future Trends for Oral Administration," Drug Safety (1993), Vol. 8 (2), pp. 89-98.
- Samuel Page, PhD, Chief, Natural Products, Center for Food Safety and Applied Nutrition, Congressional Hearing Subcommittee, July 18, 1991.
- NHK Special, "Product Liability Litigation in America," August 5, 1995 (English transcript).
- Hill R, Caudill S, el al, "Contaminants in L-Tryptophan Assoicated with Eosinophilia Myalgia Syndrome,"Archives of Environmental Contamination and Toxicology (1993), Vol. 25, pp. 134-142.
- Belongia, EA, et al., "An Investigation of the Cause of the Eosinophilia-Myalgia Syndrome Associated with Tryptophan Use," New England Journal of Medicine (August 9, 1990), Vol. 323, No. 6, pp. 357-365.
- Paul D. Rheingold, personal notes, "Known, Unknown and Suspect Information about LT, SDKK and EMS," Revised August, 1993.
- George Wald, "The Case Against Genetic Engineering"(essay), The Recombinant DNA Debate, Jackson and Stich (editors), pp. 127-128. (Reprinted from The Sciences, Sept./Oct. 1976).
© Copyright 2005 William E. Crist. All Rights Reserved