Edwin M. Kilbourne

Clinical epidemiology of toxic-oil syndrome. Manifestations of a New Illness.

An epidemic of a new illness involving multiple organ systems began in Spain in May 1981, with 19,828 cases and 315 deaths reported by June 1, 1982. An epidemiologic investigation has linked the occurrence of illness with ingestion of an unlabeled, illegally marketed cooking oil. To elucidate the natural history of this illness, we reviewed the medical records of 121 patients in one severely affected town 100 km northwest of Madrid. The findings during the first week after onset were those of a febrile, pneumonia-like illness. Gastrointestinal findings and striking eosinophilia became prominent later in the first month. Although the disease followed a self-limited course in many patients, severe neuromuscular manifestations (myalgia severe enough to restrict movement, motor deficits, atrophy of major muscle groups, and contractures of the jaw and extremities) occurred late in the course of the illness (an average of 96 days after onset) in 23 per cent of the patients. The onset of disease early in the epidemic and particularly severe initial systemic findings were associated with progression to neuromuscular illness.

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 Organizations 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.

Interim Guidance on the Eosinophilia-Myalgia Syndrome

Excerpt The Centers for Disease Control (CDC) has recently received a large volume of calls from physicians caring for patients with either clear-cut or suspected cases of the eosinophilia-myalgia ...

Toxic oil syndrome: A current clinical and epidemiologic summary, including comparisons with the eosinophilia-myalgia syndrome

In the spring and summer of 1981, an epidemic of a new illness now referred to as the toxic oil syndrome occurred in central and northwestern Spain, resulting in some 20,000 cases, 12,000 hospital admissions and greater than 300 deaths in the 1st year of the epidemic. The initial onset of illness was usually acute, and patients presented primarily with a respiratory syndrome involving cough, fever, dyspnea, hypoxemia, pulmonary infiltrates and pleural effusions. While approximately 50% of patients recovered from this acute phase of the illness without apparent sequelae, the remaining patients developed an intermediate or chronic phase, or both, of illness involving severe myalgia, eosinophilia, peripheral nerve damage, sclerodermiform skin lesions, sicca syndrome, alopecia and joint contractures, among other findings. Epidemiologic and analytic chemical studies have clearly linked the toxic oil syndrome to the ingestion of oil mixtures containing rapeseed oil denatured with aniline. However, the precise identity of the etiologic agent within this oil has never been determined. Aniline itself did not cause the illness, but the causal agent may be a reaction product of aniline with some oil component. Although many aspects of disease activity in the involved patients have lessened with time, the ultimate consequences of their disease are not clear and are the subject of ongoing study. The recently described eosinophilia-myalgia syndrome in the United States clinically resembles the toxic oil syndrome.

Possible etiologic agents for toxic oil syndrome: Fatty acid esters of 3-(N-phenylamino)-1,2-propanediol

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0–38) and 21.9 (95% 6.1–78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

Epidemiologic evidence for a new class of compounds associated with toxic oil syndrome.

Toxic oil syndrome appeared in epidemic form in Spain in 1981. Epidemiologic studies have demonstrated that illness was caused by consumption of rapeseed oil that had been denatured with aniline. Chemical analyses of oil specimens conducted in conjunction with epidemiologic studies have established that consumption of specific oils containing fatty acid anilide contaminants was associated with increased risk for disease. New chemical analytic methods identified a family of compounds, the di-fatty acid esters of phenylamino propane-diol, and one of these compounds, the 1,2-di-oleyl ester of 3-(N-phenylamino)-1,2-propanediol (DPAP), has been found to be more strongly associated with disease status than the fatty acid anilides. We found the odds ratio for exposure to DPAP (OR = 26.4, 95% CI = 6.4-76.3) is much higher than the odds ratio for exposure to oleyl anilide (OR = 4.1, 95% CI = 2.2-7.8), implying that exposure to DPAP was a more relevant risk factor for development of toxic oil syndrome than exposure to oleyl anilide. In this paper, we review and present analyses of data from multiple studies of the possible etiologic role of DPAP in toxic oil syndrome. The presence of DPAP in oil collected from affected and unaffected households was a more specific correlate of case relatedness than was the presence of fatty acid anilides, and it was equally sensitive. Moreover, DPAP was found in oil from the only refinery whose oil was clearly associated with illness.

Toxic-oil syndrome: case reports associated with the ITH oil refinery in Sevilla.

Toxic-oil syndrome (TOS), a new disease that occurred in epidemic form in Spain in 1981, has been associated with the ingestion of unlabelled oil bought principally from travelling salesmen. Chemical analysis of oils taken from ill families has shown them to consist of varying proportions of different vegetable oils and animal fats, often showing chemical evidence of prior treatment with aniline. We investigated the unusual circumstances surrounding the reported occurrence of three TOS cases in two families in Sevilla, a city located far away (approximately 300 km) from the group of 14 provinces in central and northwestern Spain where 99% of the TOS cases occurred. Each case we investigated fitted the clinical picture of TOS and was not consistent with any other diagnosis. Illness apparently occurred as a result of ingestion of oil taken from the ITH oil refinery in Sevilla, a plant in which rapeseed and grapeseed oils were refined for the distributing firm through which oil bearing the causative agent of TOS is thought to have entered the market. These data provide further strong support for the hypothesis that food oil was the vehicle by which the aetiological agent of TOS was transmitted. Because ingestion of refined denatured rapeseed oil was most closely associated with the illness in time, the TOS agent was probably contained initially in this type of oil. The agent very probably entered later oil mixtures through such contaminated rapeseed oil.

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.

Toxic oil syndrome: Traceback of the toxic, oil and evidence for a point source epidemic

Rapeseed oil denatured with aniline was the vehicle of the causal agent of the toxic oil syndrome (TOS) epidemic that occurred in Spain in 1981. Although the precise aetiologic agent remains unknown, researchers established that increasing concentrations of oleyl anilide and other fatty acid anilides were associated with an increased risk for disease. To examine the hypothesis that 5-litre plastic containers of rapeseed oil associated with TOS, and which contained oleyl anilide had a characteristic shape, we measured fatty acid, sterol and fatty acid anilide levels in oil from containers of different shapes. We identified 1673 bottles of oil that had been collected during the Spanish Governments oil exchange programme and linked these bottles to people with TOS as reported in the official government census of patients with TOS. Although rapeseed oil (identified by the presence of brassicasterol) was found in 798 (47.7%) of the 1673 bottles examined, contamination with fatty acid anilide occurred in only 329 (19.6%) of the 1673 bottles and 319 (97%) of the 329 were oil containers of the shape sold by RAELCA, an oil company in Madrid. The first aniline-denatured oil that RAELCA had purchased to be refined specifically for distribution was refined at the ITH refinery of Seville, and this oil has been most directly associated with the epidemic. Previous work has shown that the only toxic oil linked to a specific refinery was that associated with rapeseed oil from the ITH refinery in Seville, and the epidemic began shortly after this oil was delivered to RAELCA for retail sale. On the basis of these findings, we conclude that oil refined by ITH and distributed by RAELCA was the principal, and probably the only, oil responsible for the TOS epidemic. Information about the history and treatment of this oil may yield important clues towards identifying the aetiologic agent of TOS.

Postmortem Studies of the Heart in Three Fatal Cases of the Eosinophilia-Myalgia Syndrome

OBJECTIVE To examine the hearts of individuals who died from the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan, with particular attention paid to the coronary arteries, the neural structures, and the conduction system of the heart because of reported terminal disturbances of cardiac rhythm and conduction. STUDY MATERIAL Three hearts fixed in neutral formalin and well preserved with all the relevant areas of conduction system intact. METHODS Light microscopic examination of subserial sections of the sinus node, atrioventricular node and His bundle, coronary chemoreceptor and regional nerves, ganglia, and small coronary arteries. Routine stains used were Goldner trichrome and Verhoeff-van Gieson. RESULTS Arterial abnormalities were numerous and primarily of two types: focal fibromuscular dysplasia causing moderate to severe narrowing, as well as endarteritis and panarteritis. Extensive examples of neuritis and ganglionitis were present throughout the heart, including the conduction system, where arterial abnormalities were also abundant. In the coronary chemoreceptor there were both old and new lesions comprising focal inflammation with degeneration as well as older areas of fibrotic destruction. Within the sinus node, areas of dense fibrosis replaced all nodal tissue. These abnormalities were similar in nature and extent in all three hearts. CONCLUSIONS The pathologic lesions present in the coronary arteries, neural structures, and conduction system of the heart in patients who died from the eosinophilia-myalgia syndrome provide a suitable anatomic substrate for substantial cardiac electrical instability, including the occurrence of sudden death. In cases of unexplained cardiac electrical instability or sudden unexpected death an inquiry should be made about previous use of L-tryptophan. In patients with the eosinophilia-myalgia syndrome, the possibility of cardiac electrical instability should be considered as part of long-range clinical management.