Skip to main content
Log in

Contaminants in L-Tryptophan associated with eosinophilia myalgia syndrome

  • Published:
Archives of Environmental Contamination and Toxicology Aims and scope Submit manuscript

Abstract

In late 1989, an epidemic of eosinophilia-myalgia syndrome (EMS) that resulted in several thousand cases of the syndrome and 36 deaths was recognized in the United States. Physicians in New Mexico linked the epidemic to the ingestion of L-tryptophan (LT). Results of studies indicated that one or more trace contaminants in LT were likely causes of the EMS epidemic. Investigators traced the LT that was taken by most patients with EMS to a single manufacturer, Showa Denko K.K. of Japan.

We now report results of high performance liquid chromatographic analysis of LT samples from this manufacturer. Three sets of blind-coded samples were analyzed: the priority case lot set, which included 54 case-associated LT lots and 50 noncase-associated LT lots that were taken by case and control subjects who used only one brand of LT; the single lot case set, which included 73 case-associated LT lots and 25 noncase associated LT lots taken by case and control subjects who used only a single lot of LT; and the South Carolina tablet set, which included LT tablets taken by case subjects (n=26) and by control subjects (n=52). We statistically compared the concentration of each contaminant in case-associated, noncase-associated, and control samples of each sample set. The analyses showed that there were more than 60 minor contaminants in the LT from Showa Denko K.K., and that six of these contaminants were associated with EMS. The structures of three contaminants are known, but the identities of the other three contaminants are currently unknown. In this paper, we discuss each sample set and results of the analysis of each, the combined results of all sets, the identity of the six contaminants, and implications for future research into the etiology of EMS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Barnhart ER, Maggio VL, Alexander LR, Turner WE, Patterson DG, Needham LL, Reilly MH, Gelbaum LT (1990) Bacitracin-associated peptides and contaminated L-tryptophan. Lancet ii:742.

    Google Scholar 

  • Belongia EA, Hedberg CW, Gleich GJ, White KE, Mayeno AN, Loegering DA, Dunnette SL, Pirie PL, MacDonald KL, Osterholm MT (1990) An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 323:357–365

    Google Scholar 

  • Caudill SP, Hill RH, Kamb ML, Philen R, Bailey SL, Gregg M, Needham LL (1992) Important issues affecting eosinophilia-myalgia syndrome investigations based on analyses of L-tryptophan samples. Int J Occup Med Toxicol (in press)

  • Centers for Disease Control (1989a) Eosinophilia-myalgia syndrome—New Mexico. Morb Mort Wkly Rep 38:765–767

  • --(1989b) Eosinophilia-myalgia syndrome and L-tryptophan-containing products—New Mexico, Minnesota, Oregon, and New York, 1989. Morb Mort Wkly Rep 38:785–788

  • --(1990a) Analysis of L-tryptophan for the etiology of eosinophilia-myalgia syndrome, Morb Mort Wkly Rep 39:589–591

  • --(1990b) Update: analysis of L-tryptophan for the etiology of eosinophilia-myalgia syndrome, Morb Mort Wkly Rep 39:789–790

  • Clauw DJ, Nashel DJ, Umhau A, and Katz P (1990) Tryptophan-associated eosinophilic connective-tissue disease. J Am Med Assoc 263:502–506

    Google Scholar 

  • Crofford LJ, Rader JI, Dalakas MC, Hill RH, Page SW, Needham LL, Brady LS, Heyes MP, Wilder RL, Gold PW, Illa I, Smith C, Sternberg EM (1990) L-Tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat. J Clin Invest 86:1757–1763

    Google Scholar 

  • Fisher RA (1958) Statistical methods for research workers. Hafner Publishing Co, Inc, NY, pp 100–101

    Google Scholar 

  • Goda Y, Suzuki J, Maitani T, Yoshihira K, Takeda M, Uchiyama M (1992) Anilino-L-alanine, structural determination of UV-5, a contaminant in EMS-associated L-tryptophan samples, Chem Pharmacol Bull (Japan) 40:2236–2238

    Google Scholar 

  • Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M, Gleich G (1990) Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 332:869–873

    Google Scholar 

  • Kamb ML, Murphy JJ, Jones JL, Caston JC, Nederlof K, Horney LF, Sweygert LA, Falk H, Kilbourne EM (1992) Eosinophilia-myalgia syndrome in L-tryptophan exposed patients in a South Carolina psychiatric practice. J Am Med Assoc 267:77–82

    Google Scholar 

  • Kleinbaum DG, Kupper LL, Mortgenstern H (1982) Epidemiologic Research. Lifetime Learning Publications, Belmont, CA, pp 419–446

    Google Scholar 

  • Koziol JA (1989) A note on plots of p-values to evaluate many tests simultaneously. Biom J 31:969–972

    Google Scholar 

  • Love LA, Rader JI, Crofford LJ, Page SW, Hill RH, Raybourne RB, Sternberg EM (1991) L-Tryptophan (L-TRP) and 1,1′-ethylidenebis[tryptophan] (EBT), a contaminant in eosinophilia-myalgia syndrome (EMS) case-associated L-TRP, cause myofascial thickening and pancreatic fibrosis in Lewis rats. Arth Rheum (Supplement) 34:S131

    Google Scholar 

  • Mann HB, Whitney DR (1947) On a test of whether one of two random variables is statistically larger than the other. Ann Math Stat 18:50–60

    Google Scholar 

  • Mayeno AN, Lin F, Foote CS, Loegering DA, Ames MW, Hedberg CW, Gleich GJ (1990) Characterization of “peak E,” a novel amino acid associated with eosinophilia-myalgia syndrome. Science 250:1707–1708

    Google Scholar 

  • Miller RG (1981) Simultaneous statistical inference. Springer-Verlag, NY, pp 67–68

    Google Scholar 

  • Müller A, Busker E, Gunther K, Hoppe B (1991) Characterization of byproducts in L-tryptophan, Bioforum 14:350–354

    Google Scholar 

  • Philen RM, Hill RH, Flanders WD, Caudill SP, Needham LL, Sewell L, Sampson EJ, Falk H, Kilbourne EM, Oregon, New York, New Mexico EMS study groups. (1992) Tryptophan contaminants associated with eosinophilia-myalgia syndrome. Am J Epidemiol (submitted in September 1992)

  • Silver RM, Heyes MP, Maize JC, Quearry B, Vionnet-Fuasset M, Sternberg EM (1990) Scleroderma, fascitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 332:874–881

    Google Scholar 

  • Slutsker L, Hoesly FC, Miller L, Williams P, Watson JC, Fleming DW (1990) Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. J Am Med Assoc 264:213–217

    Google Scholar 

  • Smith MJ, Mazzola EP, Farrell TJ, Sphon JA, Page SW, Ashley D, Sirimanne SR, Hill RH, and Needham LL (1991) 1,1′-Ethylidenebis(L-tryptophan), structure determination of contaminant “97”—implicated in the eosinophilia-myalgia syndrome (EMS). Tetrahedron Lett 32:991–994

    Google Scholar 

  • Schweder T, Spjotvoll E (1982) Plots of p-values to evaluate many tests simultaneously. Biometrika 69:493–502

    Google Scholar 

  • Toyooka T, Yamazaki T, Tanimoto T, Sato M, Toyoda M, Ishibashi M, Yoshihira K, Uchiyama M (1991) Characterization of contaminants in EMS-associated L-tyrptophan samples by high-performance liquid chromatography. Chem Pharmacol Bull (Jpn) 39:820–822

    Google Scholar 

  • World Health Organization (1991) Toxic oil syndrome and eosinophilia-myalgia syndrome: pursuing parallels in pathogenesis, report on a WHO meeting, May 8–10, 1991, Washington, D.C. WHO Regional Office for Europe, Target 22, World Health Organization, Copenhagen, Denmark

  • — (1992) Toxic oil syndrome: current knowledge and future perspectives. WHO Regional Publications, European Series, No. 42, World Health Organization, Copenhagen, Denmark

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Use of trade names is for identification only and does not contitute endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hill, R.H., Caudill, S.P., Philen, R.M. et al. Contaminants in L-Tryptophan associated with eosinophilia myalgia syndrome. Arch. Environ. Contam. Toxicol. 25, 134–142 (1993). https://doi.org/10.1007/BF00230724

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00230724

Keywords

Navigation