Eosinophilia myalgia syndrome and tryptophan production a cautionary tale Mayeno AN Gleich GJ Allergic Diseases Research Laboratory Mayo Clinic Rochester MN 55905 An epidemic of a new disease termed eosinophilia myalgia syndrome occurred in the USA in 1989 This syndrome was linked to the consumption of L tryptophan manufactured by a single company utilizing a fermentation process All the findings indicate that the illness was probably triggered by an impurity formed when the manufacturing conditions were modified This outbreak highlights the need for close monitoring of the chemical purity of biotechnology derived products and for rigorous testing of such products following any significant changes to the manufacturing process 1 Trends Biotechnol 1994 Sep 12 9 346 52 Accumulation of 3 phenylamino alanine a constituent in L tryptophan products implicated in eosinophilia myalgia syndrome in blood and organs of the Lewis rats Adachi J Gomez M Smith CC Sternberg EM Department of Legal Medicine Kobe University School of Medicine Japan 3 Phenylamino alanine PAA a newly discovered impurity in case associated Ltryptophan tablets has been investigated as a possible contributing factor in the etiology of eosinophilia myalgia syndrome EMS We have studied distribution and elimination of PAA in rats which were administered a single 5 mg kg dose of PAA by gastric gavage PAA concentrations in blood brain kidney and liver were measured by high performance liquid chromatography HPLC with electrochemical detection The concentration of PAA in each tissue reached a maximum at 5 h and then gradually declined A high level of PAA still remained at 24 h indicating gradual elimination The concentration of PAA in brain at 5 h was 2139 ng g tissue demonstrating passage through the blood brain barrier Consecutive administration of PAA 5 mg kg for 4 days resulted in approximately double the concentration in all tissues Chronic treatment using PAA incorporated into food pellets for 6 weeks resulted in similar accumulations in each tissue and following 12 days on a PAA free diet levels of this drug were still detectable in all tissues Arch Toxicol 1995 69 4 266 70 Subchronic toxicity of 3 phenylamino alanine an impurity in L tryptophan reported to be associated with eosinophilia myalgia syndrome Sato F Hagiwara Y Kawase Y Safety Evaluation Center Central Research Laboratory Chiba Japan Consumption of certain product lots of L tryptophan LT has been reported to be epidemiologically associated with an outbreak of eosinophilia myalgia syndrome EMS in the United States Since the production lots were found to contain 3phenylamino alanine PAA as an impurity its effects were studied by administering the substance orally by gavage to 5 week old Sprague Dawley rats Groups of animals were given PAA for 13 consecutive weeks at dose levels of 1 10 and 100 mg kg per day The animals were killed at 4 or 8 weeks Hematological and blood biochemical tests were performed and detailed histopathological observations were made No significant abnormalities were observed in the test animals and in particular no EMS like conditions A brief summary of other animal studies using several species of rats and mice performed in our laboratory since 1989 on various LT related substances is also presented No EMS like effects were observed in these studies Arch Toxicol 1995 69 7 444 9 Biotransformation of 3 phenylamino 1 2 propanediol to 3 phenylamino alanine a chemical link between toxic oil syndrome and eosinophilia myalgia syndrome Mayeno AN Benson LM Naylor S Colberg Beers M Puchalski JT Gleich GJ Department of Immunology Mayo Clinic Rochester Minnesota 55905 USA During late 1989 the eosinophilia myalgia syndrome EMS developed as an epidemic in the United States with numerous additional cases reported in several other countries worldwide Eight years earlier a closely related disease the toxic oil syndrome TOS occurred in Spain as a massive food borne epidemic Although EMS was linked to the ingestion of tainted L tryptophan and TOS to anilinedenatured rapeseed oil the etiologic agent s responsible for both diseases remains undetermined Contaminants in these foodstuffs are believed to have triggered the diseases Aniline contaminants including 3 phenylamino 1 2 propanediol PAP have been reported in oil used by patients who developed TOS A related aniline derivative 3 phenylamino L alanine PAA was recently isolated from L tryptophan associated with the onset of EMS Here we demonstrate the biotransformation of PAP into PAA by both rat hepatocytes and human liver tissue The structural characterization of PAA was unequivocally determined using on line HPLC coupled with atmospheric pressure chemical ionization tandem mass spectrometry LC APCIMS MS This finding is the first reported chemical link between TOS and EMS and suggests that these two related diseases share a common etiology namely PAA Chem Res Toxicol 1995 Oct Nov 8 7 911 6 Dietary Supplement Health and Education Act 1994 www brooks af mil web af altmed kava htm http nccam nih gov http nccam nih gov health alerts kava