Spanish Toxic Oil Syndrome Research Articles

Spanish toxic oil syndrome (1981): Progress in the identification of suspected toxic components in simulated oils.

The Spanish toxic oil syndrome (TOS) caused a unique illness, including acute respiratory effects, eosinophilia, and muscle wasting, in 20 000 people in 1981; epidemiological evidence linked the disease with the consumption of rapeseed oils that had been denatured with aniline. In the study reported here, rapeseed oils were adulterated with aniline and processed to simulate the oils involved in TOS. The aniline-adulterated oils were investigated using radiotracer techniques, advanced sample preparation techniques, including preparative HPLC, and in uitro cell culture toxicity tests. HPLC and GC-MS analysis of the aniline-adulterated oils showed a profile similar to that of «case-related» oils (implicated in TOS), particularly with respect to the anilide contents

ChemInform Abstract: Synthesis of Aniline Derivatives with Potential Toxicological Implications to the Spanish Toxic Oil Syndrome.

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Synthesis of Aniline Derivatives with Potential Toxicological Implications to the Spanish Toxic Oil Syndrome

AbstractThe synthesis of anilides 2 from several saturated and unsaturated fatty acids 1 required for toxicological studies related to the Spanish Toxic Oil Syndrome is reported. In addition, a simple procedure for the microscale determination of the position of a carbon–carbon double bond of a fatty acid residue is described. This procedure involves epoxidation of the sample with 3,3‐dimethyldioxirane followed by oxidative cleavage with periodic acid to yield the corresponding carbonyl derivatives which are easily identifiable by GC‐MS analysis. Finally, the synthesis of anilino derivatives 5–8 formally derived from glycerol is also reported. For this purpose, a common precursor, i.e. 3‐(phenylamino)propane‐1,2‐diol (4) is prepared, and convenient procedures for its chemoselective acylation at either the hydroxy or the amino group have been developed.

Foodborne toxicants affecting the lung

Foods contain several toxicants that can exert adverse effects on the lung. Some of these toxicants are naturally occurring substances such as the pyrrolizidine alkaloids, histamine, the sweet potato toxins, perilla ketone, paralytic shellfish toxins, the red tide toxins, and botulinum toxins. Other foodborne toxicants affecting the lungs are additives (nitrite, BHT, carrageenan), processing-induced toxicants (the agent involved in Spanish toxic oil syndrome, the mutagens from cooked meats), or environmental contaminants (paraquat, PCBs, PCDFs). Some of these toxicants have primary effects on other organ systems. For example, paralytic shellfish toxins, the red tide toxin, and botulinum toxins are primarily neurotoxins whose effects on the lung are secondary. The pyrrolizidine alkaloids primarily affect the liver. However, some of the toxicants exert their primary effects on the lung (paraquat, the sweet potato toxins, perilla ketone). For some of the foodborne toxicants affecting the lungs, these effects are only noted in experimental animals fed high doses of the toxicant for prolonged periods of time. Examples would include BHT, nitrite, and carrageenan. These particular chemicals are likely to be safe to consume under more normal circumstances of exposure.

3-(Phenylamino)alanine, a Novel Aniline-Derived Amino Acid Associated With the Eosinophilia-Myalgia Syndrome: A Link to the Toxic Oil Syndrome?

The eosinophilia-myalgia syndrome (EMS) is an inflammatory disease that occurred in epidemic proportions in the United States during 1989. Cases of EMS were also reported in Europe and elsewhere. Clinically, EMS resembles the Spanish toxic oil syndrome. EMS has been associated with ingestion of manufactured L-tryptophan and, more specifically, with lots of tryptophan that contained the trace contaminant 1,1'-ethylidenebis(tryptophan) (EBT). Another trace contaminant ("peak UV-5") has been reported, but the strength of its association with EMS has not been demonstrated. Herein we report independently that peak UV-5 is 3-(phenylamino)alanine (PAA). Patients with EMS ingested significantly greater amounts of both PAA and EBT than did control tryptophan users. PAA is chemically similar to 3-phenylamino-1,2-propanediol, an aniline derivative isolated from samples of oil that were consumed by persons in whom the toxic oil syndrome developed. The discovery of an aniline-derived contaminant in tryptophan raises the possibility that EMS and toxic oil syndrome may have a common etiologic trigger.

Spanish toxic oil syndrome: Ten years after the disaster

Toxic oil syndrome (TOS), a previously undescribed disease that occurred in Spain in epidemic form in 1981, has been associated with ingestion of a reprocessed denatured rapeseed oil illegally marketed. However, the association between the syndrome and the adulterated rapeseed oil rests exclusively on epidemiological data because of the absence of toxicologic confirmation and the inability to reproduce the disease in animals. An analysis of the epidemiological evidence available on TOS is carried out in this paper, in an attempt to elucidate the aetiological role of the purported toxic oil. The adulterated oil was found to be highly statistically associated with the syndrome, such an association being extremely unlikely to be due to the effects of bias and/or confounders. The association is very strong, as the estimated relative risk shows (odds ratio = 30), and a dose-response relationship was found. Likewise, the specificity of the association is very high. The temporal sequence of events, although not entirely clear, also helps to support the hypothesis of causality. No other criterion was met, but none of these unmet criteria stands against this hypothesis. From these findings, the adulterated rapeseed oil can be considered a necessary cause for the syndrome to have occurred. Further toxicologic investigations are required to elucidate the precise toxic agent.

Cardiac abnormalities in the toxic oil syndrome, with comparative observations on the eosinophilia-myalgia syndrome

Early in the course of studies of the Spanish toxic oil syndrome it was recognized that vascular lesions were a major problem, most logically attributable to endothelial damage by the toxic oil. However, most clinical attention has been directed to the pulmonary complications and the evolution into a scleroderma-like illness later. p]In this study of 11 victims of the toxic oil syndrome careful postmortem studies of the coronary arteries and conduction system and neural structures of the heart demonstrated major injury to all those components of the heart. Obliterative fibrosis of the sinus node in four cases resembled findings in fatal scleroderma heart disease, and in eight the cardiac lesions resembled those of lupus erythematosus.The more impressive pathologic features involved the coronary arteries and neural structures, which were abnormal in every heart. The arterial disease included widespread focal fibromuscular dysplasia, but there was also an unusual myointimal proliferative degeneration of both small and large coronary arteries in five patients, four of whom were young women. In two hearts, portions of the inner wall of the sinus node artery had actually detached and embolized downstream. Coronary arteritis was rarely found. Inflammatory and noninflammatory degeneration of cardiac nerves was widespread. Fatty infiltration, fibrosis and degeneration were present in the coronary chemoreceptor.In most respects these cardiac abnormalities resemble those described in the eosinophilia-myalgia syndrome caused by an altered form of l-tryptophan. In both diseases there is good reason to anticipate more clinical cardiac difficulties than have so far been reported, and even more basis for future concern, especially relative to coronary disease and cardiac electrical instability.

An improved synthesis of labelled fatty acid carboxamides. N ‐phenyl [9,10(n)‐3H] oleamide and N ‐[ring‐G‐13C6] phenyloleamide as standards for spanish toxic oil syndrome studies

AbstractA one‐pot procedure for the high yield preparation of title compounds is reported. The key features involve the conversion of the fatty acid into the corresponding mixed anhydride by reaction with ethyl chloroformate, followed by reaction with aniline, using acetonitrile as solvent to ensure homogeneous reaction mixtures and keeping reaction times short to avoid the formation of undesirable side products.

Lack of Correlation between in vitro Immunological Alterations and the Development of Scleroderma-Like Skin Lesions in Toxic Oil Syndrome Patients

We examined whether immunological disturbances could influence the development of scleroderma-like skin lesions in patients affected by the Spanish toxic oil syndrome (TOS). To this end, peripheral blood mononuclear cells (PBMC) were collected from 13 chronic patients and 8 control subjects. All patients had suffered a toxic-induced severe neuromyopathy, and 6, in addition, had developed sclerodermoid skin manifestations. The phenotypic profile and the concentrations of interleukin-2 (IL-2) and of molecules with B cell differentiation factor IgG activity (BCDF-IgG) in supernatants of phytohemagglutinin-stimulated lymphocytes were analyzed both in patients and in normal controls. Molecules with BCDF-IgG activity were found increased in supernatants of mitogen-stimulated lymphocytes from TOS patients. Concentrations of IgG secreted by staphylococcus aureus-SAC-B blasts in the presence of TOS PBMC supernatant was 88 +/- 32.62 ng/ml (mean +/- 1 SD) versus 53 +/- 5.34 ng/ml in the presence of control supernatant (p less than 0.01). Levels of BCDF-IgG activity in TOS PBMC supernatants positively correlated with IgG serum levels (r = 0.69, p less than 0.01). The phenotypic profile of lymphocyte populations and the production of IL-2 were not altered in TOS subjects. No statistically significant differences were observed in the lymphocyte distribution nor in the IL-2 and BCDF-IgG production when comparing patients with or without scleroderma-like skin lesions. The results indicate that there was a dysfunction of the immune response in TOS subjects, which, however, was not sufficient for the development of the sclerodermoid lesions.

Detection and isolation of pentachlorophenol in oil samples associated with the Spanish toxic oil syndrome

Detection and isolation of pentachlorophenol in oil samples associated with the Spanish toxic oil syndrome

Cyclooxygenase products of metabolism of arachidonic acid in mouse macrophages exposed to N-phenyllinoleamide from toxic oil samples

N-phenyllinoleamide (NPLA), one of the major extraneous constituents of Spanish toxic oil samples, appears to enhance the cyclooxygenase metabolic pathway of arachidonic acid by peritoneal mouse macrophages. Results reported herein show an increased biosynthesis of 6-oxo-PGF 1α and TXB 2 by macrophages exposed to NPLA. However, light and electron microscopy failed to show cellular alterations in macrophages incubated with NPLA for two hours at 27°C. These data suggest a possible involvement of cyclooxygenase arachidonic acid metabolism in the etiopathogenesis of the Spanish Toxic Oil Syndrome.

Spanish toxic oil syndrome neuropathy in three patients with hereditary motor and sensory neuropathy type I.

We describe three patients with hereditary motor and sensory neuropathy type I coming from a family who suffered from Spanish toxic oil syndrome with neuromuscular manifestations. Their clinical course neither differed from other kin only affected with the inherited neuropathy nor from other patients with Spanish toxic oil syndrome studied by us. These findings suggest that patients with hereditary motor and sensory neuropathy do not exhibit a special susceptibility to vasculitic neuropathy associated with Spanish toxic oil syndrome.

Structural identification of a heterocyclic compound implicated in the Spanish toxic oil syndrome

The compound 1-phenyl-5-vinylimidazolidine-2-thione was previously reported to be the causative agent in the outbreak referred to as Spanish toxic oil syndrome. X-ray crystallography, together with nuclear magnetic resonance and infra-red spectroscopy, now show the correct structure of this compound to be N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA). Data for the structural characterization of 5-VTPA and the closely related isomer N-(4-vinyl-1,3-thiazolidin-2-ylidene)phenylamine are reported.

Synthesis of N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine and analysis of oils implicated in the spanish toxic oil syndrome for its presence

Previous reports have implicated 1-phenyl-5-vinyl imidazolidine-2-thione (PVIZT), a cyclic reaction product of aniline and naturally occurring rapeseed oil isothiocyanates, as the potential causative agent of the Spanish toxic oil syndrome (TOS). This report describes the synthesis, preliminary characterization and analysis of that reaction product, which has been identified as N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA) rather than PVIZT. Oil samples ( n = 21) that contained fatty acid anilides and were epidemiologically linked to TOS were analysed for the presence of 5-VTPA by extraction of the oil with methanol and clean-up on an ion-exchange column, followed by capillary gas chromatography mass spectrometry using selected ion detection. A limit of detection of less than 500 ppb was established for these analyses. No 5-VTPA could be detected, however, in any of the TOS oils. As 5-VTPA was shown to be unstable in both heated and unheated food oils, it is possible that the compound had been lost from the oils since the time of the epidemic in 1981. However, no direct evidence for the involvement of 5-VTPA in TOS could be obtained in this study.

Chemical-induced autoimmune reactions and Spanish toxic oil syndrome. Focus on hydantoins and related compounds.

Autoimmune diseases comprise a wide spectrum of overlapping, systemic and organ-specific disorders. Although, etiology and pathogenesis of such disorders are largely unknown, endogenous host factors and exogenous agents, such as viruses, bacteria, and small molecular weight chemicals, drugs and food components, are believed to be involved. The toxicological significance of low molecular weight compounds on induction of autoimmune disorders is illustrated by the toxic oil syndrome (TOS), a chemically induced epidemic, observed in Spain since 1981. The causative chemical(s) of TOS is still elusive, but an association between ingestion of refined aniline-adulterated rapeseed oil and the syndrome is well-documented. Epidemiological, clinical and immunopathological symptoms of TOS are briefly reviewed. The striking resemblance with immunological disorders, observed in man upon medication with hydantoins and related compounds, is demonstrated. The likeliness of formation of a hydantoin-related compound in the aniline-adulterated oil is evidenced and its role as possible toxic agent in TOS is proposed. Further, the presence of hydantoins and related compounds in food is briefly reviewed and it is suggested that these chemicals may account for a portion of idiopathic autoimmune diseases observed in man. The need for development of animal models to assess this kind of immunotoxicological effects is stressed.

Determination of oxidation products of N-phenyllinoleamide: Spanish toxic oil syndrome studies

The early identification of fatty acid anilides in suspect oils directed attention to their possible role in the Spanish toxic oil syndrome. These anilides or their oxidized derivatives could have been spontaneously formed during the handling and/or storage of the oil. The exact cause of the intoxication is still unknown but free radical and peroxidative mechanisms have been implicated in its etiology. Epoxy-hydroxylated derivatives from linoleic acid anilide were obtained using a model of accelerated oxidation. Their mass spectral patterns agree with the trimethylsilyl ethers of N-phenyl-9,10-epoxy-11-hydroxy-12-octadecenamide and N-phenyl-12,13-epoxy-11-hydroxy-9-octadecenamide, respectively. These compounds were also identified is rapeseed oil samples supplemented with N-phenyllinoleamide and submitted to the reported accelerated oxidation method.

1-phenyl-5-vinyl-2-imidazolidinethione, a proposed causative agent of Spanish toxic oil syndrome: Synthesis, and identification in one of a group of case-associated oil samples

A method is described for the synthesis and characterization of N-(2-hydroxy-3-butenyl)- N′-phenylthiourea, and its cyclization product, 1-phenyl-5-vinyl-2-imidazolidinethione (PVIZT). Fourteen coded oil samples associated with toxic oil syndrome cases in Spain were examined by gas chromatography-electron impact mass spectrometry for the presence of PVIZT. Although these samples were obtained from households where cases of toxic oil syndrome had been recorded, they differed extremely with regard to their anilide and sulphur contents. In one sample PVIZT was detected at an estimated concentration of 1 mg/kg.

Compositional Analysis of Oil Samples Implicated in the Spanish Toxic Oil Syndrome

ABSTRACTA selected group of 195 oils from the Spanish “Toxic Oil” Syndrome (TOS) epidemic including 29 high‐probability “case” and 64 “control” oils were examined to investigate the relationship between oil composition and the risk of TOS. As indicated by fatty acid and sterol patterns, the presence of rapeseed oil was significantly more prevalent in the case than in the control oils, but fatty acid anilides were the most useful markers of case‐related samples. Anilides were detected in 62% of case oils and at lower concentrations in 23% of the control samples. The ratios of individual anilides were quite constant in these oils and most consistent with their formation in the original (undiluted) rapeseed oil.

Gas chromatographic/mass spectrometric determination of aniline in food oils associated with the Spanish toxic oil syndrome.

In 1981, a new disease, known today as the toxic oil syndrome (TOS), descended upon the people of Spin. A strong association between TOS and contaminated food oil was established early. Subsequent investigations implicated food oils containing rapeseed oil denatured with aniline. However, little aniline was found in the oils; some other etiologic agent in the oil had apparently produced the illness. Many researchers have investigated these oils, but the specific etiologic agent has not been identified. Significant progress in this research has been hampered by the difficulty in identifying the specific oil samples that produced illness in specific TOS cases. In 1984, the Spanish Government invited the Centers for Disease Control (CDC) to participate in its research efforts to study the TOS problem. One of the authors was detailed to Spain to assist in the study of the illness. Part of their work in this area has been an attempt in their laboratories to classify a group of blind-coded case and control oils according to selected chemical measurements. They report here a newly developed method for determining aniline in these oils and the results of these analyses.

Psychosocial rehabilitation in disasters: experience of the Spanish toxic oil syndrome.

In May 1981 a new disease caused by widespread food poisoning with adulterated rape-seed oil appeared in Spain. A total of 20,640 people were affected and 380 patients have died. The clinical syndrome consisted of pulmonary, neuromuscular, and systemic symptoms, which evolved to produce mild or severe physical disabilities. Although the disease is not primarily a psychiatric condition, almost 8000 TOS patients have been referred to a psychiatrist: these patients show a well-defined post-traumatic stress disorder, vulnerability being associated with female sex, low income, and class and a personal history of "nervous' disorders. Since January of 1983 the main goal of the health authorities has been social reintegration in the community of TOS patients, and teams of psychiatrists and psychologists have played an important role in this task, moving integrative rehabilitation activities from the hospital into the community.