Mr. Towns. Dr. Sternberg.

STATEMENT OF ESTHER M. STERNBERG, M.D., CHIEF, UNIT ON NEUROENDOCRINE IMMUNOLOGY AND BEHAVIOR, CLINICAL NEUROENDOCRINOLOGY BRANCH, NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH

Dr. STERNBERG. Thank you, Mr. Chairman, for giving me the opportunity to testify today.

I am Dr. Esther Sternberg, the chief of the Unit of Neuroendocrine Immunology and Behavior at the National Institute of Mental Health.

The last time I testified before this committee, 2 years ago, the hearings were directed at FDA's regulation of the dietary supplement L-tryptophan.

Since the outbreak of the L-tryptophan EMS epidemic, 2 years have elapsed. The late Congressman Ted Weiss' opening statement read: "Millions of Americans have used the supplement L-tryptophan to treat a variety of medical conditions. These consumers were led to believe that L-tryptophan was safe, and they were misled. This is a tragedy that should never have happened.'

Across the United States, in the summer of 1989, 1,500 to 5,000 people who ingested L-tryptophan became ill with a deadly crippling disease. Since I last testified, at least 6 more deaths have been attributed to this syndrome, with a total of 37 deaths. Because of widespread scarring throughout the body, 60 percent of surviving patients are left with chronic pain, crippled, with difficulties breathing, and life threatening heart arrhythmias.

At the 1991 hearing, I was asked, what do we do to prevent this from happening again? It is striking to me now that I am once again before this subcommittee, not to answer that question but to answer the opposite question. That is, should we make food supplements, of which L-tryptophan was classed as a member, more available, in order to provide the public with greater freedom of choice.

You have asked me to update the committee on the results of our research into the causes of EMS in order to determine the safety of such a move. Two things have now become apparent. Not only is impure L-tryptophan capable of causing the full-blown syndrome, but in rodents pure L-tryptophan alone can cause severe scarring in some organs.

It also has been long known that L-tryptophan in tablet form, but not as a component of foods, has significant dose-related effects on brain chemicals.

In this context, L-tryptophan associated with EMS represents a product which falls under three categories of risks, that is: production standards related risks associated with impurities; toxic effects, such as scarring of the pancreas; dose-related effects related to the natural biological effects of the chemical.

L-tryptophan also illustrates the fact that a single product can pose multiple risks. There is virtually no product to which we are exposed which is completely risk-free. In order to judge whether a product is worth taking and whether it is worth taking the risks, one must weigh the risks versus the benefits.

And to do that, one must have detailed chemical knowledge of the product. Knowledge like that is derived from a range of standards of testing which lie on a continuum, from testimonial reports to full-scale studies using multiple methodologies.

Since our goal should be to predict, to the best of our abilities, the product's risks and prevent them, the closer one approaches full testing, the closer one will be to achieving the desired goals of predicting efficacy and providing safety.

Where to draw the line on this continuum and whether or not to market a product before or after it has been fully tested is a difficult ethical dilemma. One must balance the cost and time involved in such testing against the cost in terms of human life, if inadequate product testing results in toxicity and death.

The L-tryptophan EMS epidemic can be viewed as a case study in the multidisciplinary analysis of causes of disease after an environmental exposure has occurred. It is an example that such associations can go unnoticed. And, therefore, history of safe use isalthough a possible first step, it is not sufficient proof of safety.

But in our increasingly technologically based society, people feel that the care of their own bodies is outside the realm of their control. They feel that the use of dietary supplements is one way to exercise control over their health.

It is tempting to assume, as did the L-tryptophan patients, that natural is safe and that use of natural products for treatment of medical conditions gives people greater control over their own health.

In fact, absence of knowledge of the chemical nature of a product, of its risks, and the quantities to which one is exposed, actually gives the consumer less control over their own health than if they were ingesting a well-defined product. Only knowledge can guarantee safety. Only knowledge can guarantee true control. And only knowledge can guarantee freedom of choice.

The occurrence of the L-tryptophan epidemic most vividly demonstrates the false sense of security provided by the assumption that natural is safe.

I hope that the next time that I testify before this committee it will not be to, once again, address another future epidemic. I hope that you will not again be asking how do we prevent such tragedies from happening, because uninformed choice is not freedom, particularly if that choice carries with it the risk of death.

Mr. Towns. Thank you very much.

[The prepared statement of Dr. Sternberg follows:]

THE L-TRYPTOPHAN EOSINOPHILIA MYALGIA SYNDROME (EMS): UPDATE ON CAUSES OF THE SYNDROME AND IMPLICATIONS FOR SAFETY OF FOOD SUPPLEMENTS.

L-tryptophan EMS epidemic: description and update of patients' condition:

L-tryptophan is a naturally occurring amino acid that can be manufactured synthetically, and was sold as an over-the-counter food supplement for conditions including insomnia, depression, and premenstrual syndrome, as well as to facilitate body building by increasing muscle mass. In its natural form in foods, L-tryptophan occurs as a part of protein, and not as the free form which was sold in tablets, capsules and powders as a food supplement. The L-tryptophan eosinophilia myalgia syndrome (L-tryptophan EMS) was a deadly, crippling inflammatory disease which occurred in epidemic proportions across the United States in 1989 in persons ingesting the amino acid L-tryptophan. The illness affected approximately 1500 to an estimated 5000 people across the United States. At least 37 deaths have been definitively attributed to L-tryptophan EMS to date, with a calculated mortality rate of approximately 2.5%. Cases occurred in every state in the United States, and showed a preponderance in Western states coinciding with the prevalence of Ltryptophan consumption.

Approximately 80% of patients report some improvement in symptoms since the worst part of their illness, but only 10% have completely recovered. Over 60% of patients have remained crippled with a painful, chronic disease that has left their skin, joints and internal organs scarred and has interfered with their ability to carry on productive lives. Scarring of the lungs has left many patients with difficulty breathing, some requiring oxygen. Scarring of the electrical system in the heart has been associated with palpitations (irregular heart beat) and death. Permanent nerve damage has been reported in 65% of patients, causing chronic pain, impaired walking, and compromised function of the hands. Patients also complain of memory loss. Scarring around the muscles, skin and joints has resulted in a crippling difficulty in moving fingers, shoulders, elbows and other joints, and severe muscle cramping and pain.

Political and social repercussions of the epidemic:

As the epidemic devastated the lives of thousands who had believed that the product they were taking was safe, public furor and demands for greater regulatory protection were raised (see July 18, 1991 Hearing before the Human Resources and Intergovernmental Relations Subcommittee). More recently, the pendulum has swung in the opposite direction, with demands from other sectors for greater freedom of choice, and less regulatory controls of such products. Thus, the epidemic, and L-tryptophan itself, can be viewed as pivotal fulcrums in an emotional public debate on the dilemma of balancing safety with freedom of choice in the arena of dietary supplements and selfmedication. The issues raised by the L-tryptophan EMS epidemic en body many of the issues and concerns relevant to science and health today, and in this sense, the L-tryptophan EMS epidemic can be viewed not only from the narrow and specific point of view of the epidemic itself, but as a symptom of the public perceptions and public health policies which may have facilitated its

occurrence.

Could the L-tryptophan EMS epidemic have been prevented, and what can we learn from the epidemic to prevent a similar tragedy from occurring again?

Defining the implications of the L-tryptophan EMS epidemic in an effort to prevent a similar occurrence in the future requires an understanding of our current knowledge of the causes of the epidemic, an understanding of scientific criteria and standards of proof of causation of disease, a knowledge of the categories of risks associated with food supplements, as well as an understanding of the reasons behind the increased public demands for these products. Summarized below are our most recent findings regarding the causes of the L-tryptophan epidemic, the effects of pure and impure L-tryptophan in animals, and the implications these studies have for the safety of this and related classes of products. Also addressed are scientific criteria for standards of proof, and some possible reasons for the public need for such products.

Results of scientific studies:

(1) Taken together, animal, in vitro, epidemiological and chemical studies strongly indicate that:

1. Specific lots of impure L-tryptophan, produced by a single company, Showa Denko K.K., appear to be an important factor in causing the L-tryptophan EMS epidemic;

2. Several changes were made simultaneously in the production of these lots: the genetically engineered strain of bacteria used in the production process and several steps in the purification process were modified.

3. These specific lots were found to contain over 60 different impurities.

4. One of these impurities, 1,1'-ethylidenebis [L-tryptophan], (EBT), is biologically active, and alone appears to have contributed to causing some but not all the features of the syndrome. 5. Pure L-tryptophan contributed to or amplified the scarring aspects, but alone did not cause the full blown syndrome.

6. Pure L-tryptophan alone, at doses comparable to intermediate doses taken by patients with L-tryptophan EMS, caused marked scarring of the pancreas in rats.

(2) Clinical studies:

Our clinical studies (N. Engl. J. Med. 322:874-881, 1990; Arth. Rheum. 35:1097-1105, 1992) indicated that while abnormalities of the tryptophan metabolic pathway (the body's chemical breakdown pathway) are found in patients with this syndrome, these are caused by exposure to inflammation or chemicals important in inflammation, called inflammatory mediators. Thus, the changes in the body's way of breaking down tryptophan are not something that the patients were born with, rather they result from inflammation. The contribution of variable individual susceptibility in relation to other metabolic pathways has not yet been fully elucidated.

(3) Animal studies:

Our most recent animal study, (Journal of Clin. Invest. 91:804-811, 1993) confirms and extends our initial animal study in rats (Journal of Clin. Invest. 86:1757-1763, 1990), and shows that:

1. Treatment with case-associated (impure) L-tryptophan was associated with development of one of the main pathologic characteristics of the syndrome, a more than two-fold increase in thickness (scarring) of the tissue surrounding muscle (the fascia).

2. Treatment with case-associated L-tryptophan was also associated with increased activity of the white blood cells important in immunity and inflammation.

3. Treatment with the synthetic contaminant 1,11-ethylidenebis [L-tryptophan], (EBT), alone was associated with an approximately two-fold increase in fascial thickening (scarring).

4. Treatment with non-case-associated L-tryptophan (pure L-tryptophan) alone was associated with a mild but significant increase in fascial thickness (scarring).

5. All groups of animals receiving case-associated L-tryptophan, non-case-associated Ltryptophan, EBT alone, or EBT plus non-case-associated L-tryptophan, developed significant and marked scarring of the pancreas.

6. Only animals receiving case-associated L-tryptophan showed both a more than two-fold increase in fascial thickness and increased activity of the white blood cells important in immunity and inflammation.

Other animal studies (R. Silver et al. Arth. Rheum. 1993; M. Jones et al. Arth. Rheum. 1992; A. Weller et al. J. Immunol. 150:172A;1993) have confirmed that impure L-tryptophan or one of the synthetic impurities alone (EBT) are associated with many of the features of the syndrome, and that pure L-tryptophan itself is also associated with some although milder features of the syndrome, as well as evidence of scarring in other tissues.