Spanish Toxic Oil Syndrome Research Articles

The role of cross-species microphysiological systems in understanding target organ toxicity in Oncology drug projects

The eosinophilia-myalgia syndrome (EMS) outbreak that occurred in the USA and elsewhere in 1989 was caused by the ingestion of Showa Denko K.K. (SD) L-tryptophan (L-Trp). “Six compounds” detected in the L-Trp were reported as case-associated contaminants. Recently the final and most statistically significant contaminant, “Peak AAA” was structurally characterized. The “compound” was actually shown to be two structural isomers resulting from condensation reactions of L-Trp with fatty acids derived from the bacterial cell membrane. They were identified as the indole C-2 anteiso (AAA1-343) and linear (AAA2-343) aliphatic chain isomers. Based on those findings, we utilized a combination of on-line HPLC-electrospray ionization mass spectrometry (LC–MS), as well as both precursor and product ion tandem mass spectrometry (MS/MS) to facilitate identification of a homologous family of condensation products related to AAA1-343 and AAA2-343. We structurally characterized eight new AAA1-XXX/AAA2-XXX contaminants, where XXX represents the integer molecular ions of all the related homologs, differing by aliphatic chain length and isomer configuration. The contaminants were derived from the following fatty acids of the bacterial cell membrane, 5-methylheptanoic acid (anteiso-C8:0) for AAA1-315; n-octanoic acid (n-C8:0) for AAA2-315; 6-methyloctanoic acid (anteiso-C9:0) for AAA1-329; n-nonanoic acid (n-C9:0) for AAA2-329; 10-methyldodecanoic acid (anteiso-C13:0) for AAA1-385; n-tridecanoic acid (n-C13:0) for AAA2-385; 11-methyltridecanoic acid (anteiso-C14:0) for AAA1-399; and n-tetradecanoic acid (n-C14:0) for AAA2-399. The concentration levels for these contaminants were estimated to be 0.1–7.9 μg / 500 mg of an individual SD L-Trp tablet or capsule The structural similarity of these homologs to case-related contaminants of Spanish Toxic Oil Syndrome (TOS) is discussed.

Peak AAA fatty acid homolog contaminants present in the dietary supplement l-Tryptophan associated with the onset of eosinophilia-myalgia syndrome

The eosinophilia-myalgia syndrome (EMS) outbreak that occurred in the USA and elsewhere in 1989 was caused by the ingestion of Showa Denko K.K. (SD) L-tryptophan (L-Trp). “Six compounds” detected in the L-Trp were reported as case-associated contaminants. Recently the final and most statistically significant contaminant, “Peak AAA” was structurally characterized. The “compound” was actually shown to be two structural isomers resulting from condensation reactions of L-Trp with fatty acids derived from the bacterial cell membrane. They were identified as the indole C-2 anteiso (AAA1-343) and linear (AAA2-343) aliphatic chain isomers. Based on those findings, we utilized a combination of on-line HPLC-electrospray ionization mass spectrometry (LC–MS), as well as both precursor and product ion tandem mass spectrometry (MS/MS) to facilitate identification of a homologous family of condensation products related to AAA1-343 and AAA2-343. We structurally characterized eight new AAA1-XXX/AAA2-XXX contaminants, where XXX represents the integer molecular ions of all the related homologs, differing by aliphatic chain length and isomer configuration. The contaminants were derived from the following fatty acids of the bacterial cell membrane, 5-methylheptanoic acid (anteiso-C8:0) for AAA1-315; n-octanoic acid (n-C8:0) for AAA2-315; 6-methyloctanoic acid (anteiso-C9:0) for AAA1-329; n-nonanoic acid (n-C9:0) for AAA2-329; 10-methyldodecanoic acid (anteiso-C13:0) for AAA1-385; n-tridecanoic acid (n-C13:0) for AAA2-385; 11-methyltridecanoic acid (anteiso-C14:0) for AAA1-399; and n-tetradecanoic acid (n-C14:0) for AAA2-399. The concentration levels for these contaminants were estimated to be 0.1–7.9 μg / 500 mg of an individual SD L-Trp tablet or capsule The structural similarity of these homologs to case-related contaminants of Spanish Toxic Oil Syndrome (TOS) is discussed.

Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria.

In 1964, Miyoshi reported a series of patients with diverse symptoms after receiving treatment with silicone or paraffin fillers. Miyoshi named this condition 'human adjuvant disease'. Since then, the literature has been flooded with case reports and case series of granulomatous and systemic autoimmune disorders related to vaccines, infection or other adjuvants such as silicone and other biomaterials. A new term -autoimmune/inflammatory syndrome induced by adjuvants--has recently been coined for a process that includes several clinical features previously described by Miyoshi plus other clinical and laboratory parameters related to exposure to diverse external stimuli. Disorders such as siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, sick building syndrome and post-vaccination syndrome have been included in autoimmune/inflammatory syndrome induced by adjuvants. Disorders such as Spanish toxic oil syndrome and Ardystil syndrome could also be included. Furthermore, biomaterials other than silicone should also be considered as triggering factors for these adjuvant-related syndromes. New diagnostic criteria in this field have been proposed. Nevertheless, many of these criteria are too subjective, leading to some patients being diagnosed with chronic fatigue syndrome or other 'central sensitization syndromes'. Diagnostic criteria based only on objective clinical and laboratory data to be further discussed and validated are proposed herein.

Severe Eosinophilic Syndrome Associated with the Use of Probiotic Supplements: A New Entity?

Severe eosinophilic syndromes related to the administration or use of unsuspected immunogenic substances have been described previously. Many of these diseases presented initially as clusters or isolated cases. The spanish toxic oil syndrome, the eosinophilia myalgia syndrome, and nephrogenic systemic fibrosis are examples of such diseases. We describe 2 cases of a severe eosinophilic syndrome characterized by marked peripheral blood eosinophilia (>15,000 cells/ml), mononeuritis multiplex, and necrotizing vasculitis which developed in a close temporal association with the recent onset use of nonprescription probiotics. There was no history of a prior autoimmune disease. Although both cases had prompt response to immunosuppression with rapid resolution of peripheral blood eosinophilia and accompanying constitutional symptoms, they remained with permanent neurological deficits.

Participation of eosinophils in the toxic oil syndrome

The participation of eosinophils in the Spanish toxic oil syndrome (TOS) was investigated. Eosinophil infiltration and degranulation in tissues from 52 patients with the TOS were examined by immunofluorescence staining for the eosinophil granule major basic protein (MBP). Serum MBP levels were determined in sera from 323 patients. Eosinophil infiltration and degranulation were found in several tissues, especially during the acute phase of the TOS, and serum MBP was significantly elevated during all phases of the disease, suggesting that eosinophils play a role in the pathogenesis of the TOS.

Spanish Toxic Oil Syndrome

Spanish Toxic Oil Syndrome

A search for an animal model of the Spanish toxic oil syndrome

To date, pathology characteristics of toxic oil syndrome (TOS), a disease associated with consumption of a contaminated cooking oil in Spain in 1981, have not been reproduced in an animal model. As vasculitis, eosinophilia, and a rise in circulating IgE levels were features of the acute phase of TOS, leading to an autoimmune outcome, a review of predisposition to these aspects across species was conducted. The intent was to determine predisposed strains or species that potentially might be effective in testing the toxic oils and thus defining the precise identity of the toxic contaminant(s). A number of potential candidates emerge from this review. Among mice, these include the NZB mouse hybrids, the MRL/lpr and SJL/J strains, and a transgenic mouse model of eosinophilia. The Brown Norway may be the most appropriate rat strain, while beagle dogs inbred to be genetically predisposed to immune complex disease and vasculitis are also a candidate species. Of the more exotic species, the mink and ferret have characteristics that might make them suitable candidates for testing oil samples.

The Spanish toxic oil syndrome 20 years after its onset: a multidisciplinary review of scientific knowledge.

In 1981, in Spain, the ingestion of an oil fraudulently sold as olive oil caused an outbreak of a previously unrecorded condition, later known as toxic oil syndrome (TOS), clinically characterized by intense incapacitating myalgias, marked peripheral eosinophilia, and pulmonary infiltrates. Of the 20,000 persons affected, approximately 300 died shortly after the onset of the disease and a larger number developed chronic disease. For more than 15 years, a scientific committee supported by the World Health Organization's Regional Office for Europe and by the Institute of Health Carlos III in Madrid has guided investigation intended to identify the causal agent(s), to assess toxicity and mode of action, to establish the pathogenesis of the disease, and to detect late consequences. This report summarizes advances in research on this front. No late mortality excess has been detected. Among survivors, the prevalence of some chronic conditions (e.g., sclerodermia, neurologic changes) is high. Attempts to reproduce the condition in laboratory animals have been unsuccessful, and no condition similar to TOS has been reported in the scientific literature. Laboratory findings suggest an autoimmune mechanism for TOS, such as high levels of seric soluble interleukin-2 receptor. Epidemiologic studies integrated with chemical analyses of case-related oils have shown that the disease is strongly associated with the consumption of oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP). These chemicals have also been found in oils synthesized under conditions simulating those hypothesized to have occurred when the toxic oil was produced in 1981. Whether PAP esters are simply markers of toxicity of oils or have the capability to induce the disease remains to be elucidated.

The Spanish Toxic Oil Syndrome 20 Years after Its Onset: A Multidisciplinary Review of Scientific Knowledge

The Spanish Toxic Oil Syndrome 20 Years after Its Onset: A Multidisciplinary Review of Scientific Knowledge

Automated strong cation exchange extraction of fatty acid esters of 3-(N-phenylamino)-1,2-propanediol from oil samples for routine quantification by HPLC-APCI/MS/MS.

Fatty acid esters of 3-(N-phenylamino)-1,2-propanediol are currently considered the best chemical markers of toxic oils related to the Spanish toxic oil syndrome. Recent research in this area has undertaken the exhaustive and quantitative characterization of these compounds in oils collected during the epidemic outbreak. Current methods developed in this laboratory are based on solid phase extraction (SPE) using SCX cartridges followed by HPLC-APCI/MS/MS quantification. To circumvent the long and tedious extraction procedure, the SPE protocol was adapted for automatic extraction and the problems derived from the use of the immiscible solvents required for the SCX extraction were solved. Linearity of the analytical method was found in the same range as for the manual method. Extraction recoveries were 87 and 75% for 2-hydroxy-3-(N-phenylamino)propyl linoleate and 2-(linoleyloxy)-3-(N-phenylamino)propyl linoleate, respectively, and the corresponding coefficients of variation were approximately 1%, greatly improving reproducibility over manual procedures.

Determination of Aniline Derivatives in Oils Related to the Toxic Oil Syndrome by Atmospheric Pressure Ionization-Tandem Mass Spectrometry

In 1981, an unknown disease appeared in Spain, the Spanish Toxic Oil Syndrome. Nowadays and despite all efforts, the etiological agent is still unknown. Early studies showed a link between this illness and the consumption of denatured rapeseed oil fraudulently processed and marketed as edible oil. Two families of aniline derivatives present in these oils (fatty acid anilides and acylated phenyl amino propanediol derivatives or PAPs) were found to be good chemical markers of toxic oils. In this work, a new method has been developed to analyze these aniline derivatives in oil samples by HPLC-MS and HPLC-MS/MS with an API source. For their quantification, three different internal standards were used, one for anilides and two for PAPs. Quantification limits were 8 ppm for anilides and 0.2 ppm for PAPs. Anilides and PAPs were found in marker-positive samples at levels up to 50,000 and 330 ppm, respectively. The relative abundance of the different fatty acid anilides and PAPs correlates with the fatty acid composition of the oils. More than 2,600 different samples were analyzed by this method in the most exhaustive screening of suspected toxic oils carried out to date.

THE TOXIC OIL SYNDROME: 20 YEARS ON

SUMMARYWith hindsight, it is easy to criticise the standards of food regulation of two decades ago. Nevertheless, when the Spanish toxic oil syndrome (TOS) appeared in 1981, there were many who asked why aniline was permitted as an official adulterant for imported French rape seed oil, and why such adulterated oils were often illegally refined in Spain and marketed without difficulty. This review brings up to date a comprehensive survey of the ensuing research published in 1995 and concentrates on recent significant findings. These include the identification of the refinery that produced the toxic oil, and the detection of oil contaminants with possible aetiological significance. Possible chemical links have been found between oil contaminants and those detected in L‐tryptophan implicated in the eosinophilia‐myalgia syndrome (EMS). There is good evidence that the initial pathogenetic mechanism is immunological. On metabolic evidence, it is suggested that not one, but a group of, toxic agents was responsible for TOS.

Pharmacogenetic Profile of Xenobiotic Enzyme Metabolism in Survivors of the Spanish Toxic Oil Syndrome

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1), CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2), GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI), 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS.

Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome.

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1), CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2), GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI), 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS.

Meta-Analyses of TCE Carcinogenicity

LetterOpen AccessMeta-analyses of TCE carcinogenicity. J Borak, M Russi, and J P Puglisi J Borak Search for more papers by this author , M Russi Search for more papers by this author , and J P Puglisi Search for more papers by this author Published:1 December 2000https://doi.org/10.1289/ehp.108-a542Cited by:11AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit FiguresReferencesRelatedDetailsCited byChiu W, Caldwell J, Keshava N and Scott C (2006) Key Scientific Issues in the Health Risk Assessment of Trichloroethylene, Environmental Health Perspectives, 114:9, (1445-1449), Online publication date: 1-Sep-2006. Garabrant D and James R (2005) Trichloroethylene and cancer in humans: Recognizing the need for an evidence based analysis, Toxicology, 10.1016/j.tox.2005.04.001, 212:1, (80-84), Online publication date: 1-Aug-2005. Nerbert D (2018) Use of Reporter Genes and Vertebrate DNA Motifs in Transgenic Zebrafish as Sentinels for Assessing Aquatic Pollution, Environmental Health Perspectives, 110:1, (A15-A15), Online publication date: 1-Jan-2002.Frost F (2018) Detection of Excess Arsenic-Related Cancer Risks, Environmental Health Perspectives, 110:1, (A12-A13), Online publication date: 1-Jan-2002.Wartenberg D (2018) Carcinogenicity of Trichloroethylene, Environmental Health Perspectives, 110:1, (A13-A14), Online publication date: 1-Jan-2002.Ladero J (2018) N-Acetyltransferase 2 Polymorphism in Patients with Spanish Toxic Oil Syndrome, Environmental Health Perspectives, 110:1, (A14-A14), Online publication date: 1-Jan-2002.Lawrence D (2018) Psychologic stress and asthma: neuropeptide involvement., Environmental Health Perspectives, 110:5, (A230-A231), Online publication date: 1-May-2002.Wright R (2018) Psychologic Stress and Asthma: Wright's Response, Environmental Health Perspectives, 110:5, (A231-A231), Online publication date: 1-May-2002.Rhomberg L (2018) The a Posteriori Probability of a Kidney Cancer Cluster Attributed to Trichloroethylene Exposure, Environmental Health Perspectives, 110:5, (A232-A232), Online publication date: 1-May-2002.Arya S (2018) Canadian Hot Weather Health-Response Plan, Environmental Health Perspectives, 110:5, (A232-A233), Online publication date: 1-May-2002.Smoyer-Tomic K (2018) Hot Weather and Therapeutic Agents: Response to Arya, Environmental Health Perspectives, 110:5, (A233-A233), Online publication date: 1-May-2002. Vol. 108, No. 12 December 2000Metrics About Article Metrics Publication History Originally published1 December 2000Published in print1 December 2000 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Palmitic Acid Anilide-Induced Respiratory Burst In Human Polymorphonuclear Leukocytes is Inhibited by a Protein Kinase C Inhibitor, Ro 31-8220

Human polymorphonuclear leukocytes (PMNL) were exposed to palmitic acid anilide, an impurity in the case oils that caused the Spanish Toxic Oil Syndrome in 1981, and to the corresponding fatty acid, palmitic acid. The effects of these compounds were studied on the production of reactive oxygen metabolites (ROM) and changes in the levels of free intracellular calcium. Palmitic acid anilide induced the production of reactive oxygen metabolites in PMNL. Interestingly, the palmitic acid anilide-induced respiratory burst was completely blocked by a protein kinase C inhibitor, Ro 31-8220. Moreover, palmitic acid anilide additively amplified the production of ROM caused by a chemotactic peptide, formyl-Methionyl-Leucyl-Phenylalanine (FMLP). In contrast, palmitic acid anilide did not have any effect on the production of ROM induced by a tumor promoter, phorbol myristate acetate (PMA). Palmitic acid, in turn, did not markedly induce the production of ROM nor did it amplify the agonist-induced respiratory burst. Neither of the compounds, alone or in combination with FMLP, affected the levels of intracellular calcium in PMNL. These results indicate that the aniline moiety in palmitic acid modifies its effects on the activation of human PMNL, and the subsequent oxidative burst. The present results also suggest that palmitic acid anilide may activate PMNL through a protein kinase C-dependent mechanism. © 1997 Elsevier Science Inc.

Immunogenicity of synthetic oil anilides, the reputed etiologic agents of spanish toxic oil syndrome (TOS)

Immunogenicity of synthetic oil anilides, the reputed etiologic agents of spanish toxic oil syndrome (TOS)

Immunogenicity of synthetic oil anilides, the reputed etiologic agents of Spanish toxic oil syndrome (TOS)

Immunogenicity of synthetic oil anilides, the reputed etiologic agents of Spanish toxic oil syndrome (TOS)

Improved analysis of fatty acid anilides: application to toxic and to aniline and citric acid-containing oils.

The Spanish Toxic Oil Syndrome (TOS) was traced to the consumption of some cheap oils sold at retail by street salesmen (Tabuenca 1981; Kilbourne et al. 1992). These oils contained different proportions of a refined batch of rapeseed oil initially denatured with 2% of aniline and imported from France for industrial use (Tabuenca 1981). However, although most of the free aniline was effectively extracted during the refining processes, a significant part of it reacted with fatty acids yielding the corresponding fatty acid anilides (FAAs) (Guitart and Gelpi 1992). Although toxicological data on FAAs are very controversial, they had been proposed as the causative agents of the illness or, at least, are considered as the best markers of toxic oils (Bernert Jr. et al. 1987; Kilbourne et al. 1991). Four gas chromatographic methods have been published for the analysis of FAAs in oils (Diachenko et al. 1982; Vazquez Roncero et al. 1983; Artigas et al. 1983; Balley et al. 1983). The chemical similarity with the methyl esters of fatty acids makes gas-liquid chromatography (GLC) the method of choice for the analysis of FAAs, although their higher molecular weights limited up to now the use of the more resolutive polar stationary phases. Since the introduction of cross-bonded polar phases which can be run at higher temperatures than columns available in the last decade, the possibility to obtain a better separation of FAAs is raised. This paper reports the development of such a method and its application to 10 case oil samples and to the study of the generation rate of FAAs in aniline-denatured rapeseed oils containing citric acid. This additive was used in some refineries that handled the TOS-suspected oils in 1981 as a stabilizer, preservative and antioxidant, and was added normally before the deodorizing process at a l-2% concentration (Special Investigation Team 1981).

The effects of N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA) on the changes in free intracellular calcium and the production of reactive oxygen metabolites in human leukocytes

Human leukocytes were exposed to N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA), a postulated impurity in the case oils that caused the Spanish Toxic Oil Syndrome in 1981. Changes induced by 5-VTPA alone and together with a chemotactic peptide, formyl-methionyl-leucyl-phenylalanine (FMLP), a tumor promoter, phorbol myristate acetate (PMA), or a synthetic diacylglycerol, dioctanoyl- s, n-glycerol (DiC 8) in free intracellular calcium levels ([Ca 2+] i) and in the induction of oxidative burst were measured. 5-VTPA elevated dose-dependently [Ca 2+] i and induced the production of reactive oxygen metabolites in leukocytes. 5-VTPA also amplified FMLP-induced increase in [Ca 2+] i, but was without an effect on FMLP-induced oxidative burst. On the contrary, 5-VTPA amplified dose-dependently PMA- and DiC 8-induced respiratory burst. The present results indicate that 5-VTPA may interfere with transmembrane signalling in human leukocytes. 5-VTPA may elevate [Ca 2+] i by acting directly on the membrane, or by acting through Ca 2+-mobilizing receptors. Moreover, 5-VTPA also clearly amplified responses produced through protein kinase C stimulation. Thus, 5-VTPA may act on human leukocytes by affecting Ca 2+-metabolism and the activity of protein kinase C.