Toxic oil syndrome: the perspective after 20 years.

Toxic oil syndrome burst upon the scene in Spain in May of 1981, draining the resources of a newly evolving political and social medicine system. The vehicle of the causative toxic agent was identified as an illicit oil that had been diverted from industrial use and refined in order to remove the aniline denaturant, and that was sold in unlabeled 5-liter containers by itinerant salesmen. Over 20,000 people were ultimately affected, and over 1,200 deaths from all causes have been recorded in the affected cohort. The epidemiologic investigation of toxic oil syndrome involved all facets of investigative and analytical work; from visits to factories and interviewing workers, to sophisticated chemical and statistical analytical techniques. This investigation serves as a further illustration that data and information of all types, and from a wide range of fields, need to be systematically collected and evaluated in order to best resolve an epidemiologic mystery. Astute clinical observation of the patients, however, led to the hypothesis that toxic oil syndrome was a result of a toxic exposure. In this and other epidemics of unknown etiology, clinical observation and the intense scrutiny of patients' histories, signs, and symptoms by treating clinicians have often led to hypotheses that could be tested epidemiologically. When there are medical unknowns, the role of the astute clinician continues to be crucial. The toxic oil syndrome epidemic is an example of how even a developed country can be affected by a massive epidemic of environmental origin if failures occur in the systems that control and regulate the food supply or other consumer products. However, such failures could occur anywhere that large commercial networks operate on the regulatory edge, and if these business lack an in depth knowledge of the consequences of alterations in manufacturing conditions. Such was the case with eosinophilia-myalgia syndrome as well, when apparently minor alterations in manufacturing conditions of L-tryptophan led to an increase in impurities in the product that were later associated with the illness. These risks are even greater in countries with few or inconsistent control systems, making the food and drug supply potential portals of entry for serious health hazards, as is further exemplified by the tragic episode of pediatric renal failure in Haiti associated with a legitimate consumer product, paracetamol elixir, that had been manufactured using a fraudulently supplied toxic ingredient, diethylene glycol (81). The potential toxicants in the adulterated rapeseed oil were present in extremely small amounts. If fatty acid anilides or related compounds are indeed the etiologic agents in toxic oil syndrome, then these compounds must be extremely toxic at the parts per million concentrations at which they were found. Further, the roles of causative agents in the development of disorders such as scleroderma, eosinophilic fasciitis, eosinophilic perimyositis, and other similar diseases are unknown, but scientists can speculate that some sort of low level environmental agent may play a role if such extremely small quantities of contaminants are indeed capable of causing disease. Although the exact identity of the etiologic agent in toxic oil syndrome remains unknown, work on toxic oil syndrome continues. Follow-up clinical studies and long-term mortality studies are under way. Investigation of the mechanisms involved in toxic oil syndrome continues. The identification of suspect chemical compounds, their characterization, and effects will hopefully one day contribute to the prevention of other similar diseases.

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 mortality: the first 13 years.

BACKGROUND: The toxic oil syndrome (TOS) epidemic that occurred in Spain in the spring of 1981 caused approximately 20000 cases of a new illness. Overall mortality and mortality by cause in this cohort through 1994 are described for the first time in this report. METHODS: We contacted, via mail or telephone, almost every living member of the cohort and family members of those who were known to have died in order to identify all deaths from 1 May 1981 through 31 December 1994. Cause of death data were collected from death certificates and underlying causes of death were coded using the International Classification of Diseases, 9th Revision. RESULTS: We identified 1663 deaths between 1 May 1981 and 31 December 1994 among 19 754 TOS cohort members, for a crude mortality rate of 8.4%. Mortality was highest during 1981, with a standardized mortality ratio (SMR) of 4.92 (95% confidence interval [CI]: 4.39-5.50) compared with the Spanish population as a whole. The highest SMR, (20.41, 95% CI: 15.97-25.71) was seen among women aged 20-39 years during the period from 1 May 1981 through 31 December 1982. Women <40 years old, who were affected by TOS , were at greater risk for death in most time periods than their unaffected peers, while older women and men were not. Over the follow-up period, mortality of the cohort was less than expected when compared with mortality of the general Spanish population, or with mortality of the population of the 14 provinces where the epidemic occurred. We also found that, except for deaths attributed to external causes including TOS and deaths due to pulmonary hypertension, all causes of death were decreased in TOS patients compared to the Spanish population. The most frequent underlying causes of death were TOS, 350 (21.1%); circulatory disorders, 536 (32.3%); and malignancies, 310 (18.7%). CONCLUSIONS: We conclude that while on average people affected by toxic oil syndrome are not at greater risk for death over the 13-year study period than any of the comparison groups, women <40 years old were at greater risk of death.

Chaparral-associated hepatotoxicity.

BACKGROUND: Personal health care practices that may include the use of dietary supplements are common in the United States. Products marketed as dietary supplements are diverse and may include botanicals, vitamins, and/or minerals. Chaparral (Larrea tridentata) is a botanical dietary supplement made from a desert shrub and used for its antioxidant properties. Several reports of chaparral-associated hepatitis have been published since 1990, but a complete picture of the clinical presentation is still unclear. MATERIALS AND METHODS: We reviewed the 18 case reports of adverse events associated with the ingestion of chaparral reported to the Food and Drug Administration between 1992 and 1994. These reports were from health care professionals, state health departments, and individual consumers. RESULTS: Of 18 reports of illnesses associated with the ingestion of chaparral, there was evidence of hepatotoxicity in 13 cases. Clinical presentation, characterized as jaundice with a marked increase in serum liver chemistry values, occurred 3 to 52 weeks after the ingestion of chaparral, and it resolved 1 to 17 weeks after most individuals stopped their intake of chaparral. The predominant pattern of liver injury was characterized as toxic or drug-induced cholestatic hepatitis; in 4 individuals, there was progression to cirrhosis; and in 2 individuals, there was acute fulminant liver failure that required liver transplants. CONCLUSIONS: These data indicate that the use of chaparral may be associated with acute to chronic irreversible liver damage with fulminant hepatic failure, and they underscore the potential for certain dietary supplement ingredients to cause toxic effects on the liver. Health professionals should be encouraged to inquire routinely about the use of dietary supplements and other products, to be alert to potential adverse effects that may be associated with these products, and, finally, to report any serious adverse events associated with these products through the MEDWatch Program of the Food and Drug Administration.

Products of aniline and triglycerides in oil samples associated with the toxic oil syndrome.

The toxic oil syndrome (TOS) was a devastating disease that occurred in Spain in 1981. The disease was associated with the consumption of aniline-denatured and refined rapeseed oil that had been illegally sold as olive oil. Many aniline-derived oil components have been identified in the oils; however, no etiological agent has ever been identified for this disease. We have continued the study of the TOS problem by applying new technology in the form of liquid chromatography interfaced via atmospheric pressure ionization with tandem mass spectrometry. Using liquid chromatography tandem mass spectrometry, we studied diluted TOS-associated oils by direct analysis without prior sample treatment. Using this technology, we found new classes of compounds that are associated with disease-related oils. The compounds that have been identified are esters and ester amides of 3-(N-phenylamino)-1,2-propanediol and are products of aniline and triglycerides. Because of the varied fatty acid (oleic acid, etc.) content of the oils, many variations of the above compounds are possible. We now report the identities of more than 20 compounds not previously identified. These compounds are strongly associated with oils that caused the toxic oil syndrome. We believe these compounds should be considered for future animal studies.

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 Government's 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.

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.

Factors associated with pathogenicity of oils related to the toxic oil syndrome epidemic in Spain.

The toxic oil syndrome (TOS), which affected over 20,000 persons in Spain in 1981, has been linked to the consumption of aniline-denatured rapeseed oil, but the precise etiologic agent is still unknown. We attempted to validate the use of high concentrations of oleyl anilide as a marker for oils that contain (or contained) the causal agent. We compared the chemical compositions of oils obtained from ill (N = 59) and unaffected (N = 70) families in 1981. Case oils had higher concentrations of fatty acids and sterols in which rapeseed oil is particularly rich. In addition, case oils had more frequent and extensive contamination with oleyl anilide and other fatty acid anilides. We observed a dose-response effect; risk increased sharply with increasing concentrations of oleyl anilide, and no control oil had more than about 825 micrograms per liter of that compound. We conclude that high concentrations of oleyl anilide specifically mark oils that contain (or used to contain) the TOS etiologic agent.

Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8-10, 1991, World Health Organization meeting report.

In May 1991, researchers and clinicians from throughout the world met at a workshop sponsored by the Regional Office for Europe of the World Health Organization in collaboration with the Fondo de Investigación Sanitaria, Spain, and the U.S. Food and Drug Administration, National Institutes of Health, National Institutes of Mental Health, and Centers for Disease Control and Prevention to share information about two very similar diseases--toxic oil syndrome and eosinophilia-myalgia syndrome. In this paper the interpretation of conference proceedings is presented, current knowledge of the two disorders is summarized, and some possible areas for future research are mentioned. Toxic oil syndrome and eosinophilia-myalgia syndrome have many similarities. Both are related to consumer products that were presumed to be safe but have been found to have numerous trace contaminants, many of which remain to be identified, including the etiologic agents of both disorders. Both illnesses affect patients clinically by causing intense, incapacitating myalgias and a marked peripheral eosinophilia. Other rheumatologic manifestations are common in both, including arthralgias, sicca syndrome, scleroderma-like skin changes, carpal tunnel syndrome, and joint contractures. No clinical or laboratory feature has been found to be pathognomonic of either disease, and accurate diagnosis rests on the clinical judgment of the attending physician. Deaths have occurred in both diseases, and the cumulative mortality for each is approximately 2.5% for the first 2 years. Long-term complications include pulmonary hypertension, peripheral neuropathies, and joint contractures. Although treatment with corticosteroids has resulted in significant symptomatic relief in persons with either disorder, it does not alter the clinical course or long-term outcome. Research into the etiologic agents, preferred treatments, and ways to avoid similar problems in the future is needed.

Manufacturing processes at two French rapeseed oil companies: possible relationships to toxic oil syndrome in Spain.

The toxic oil syndrome (TOS) epidemic that occurred in Spain in spring 1981 has been associated with the consumption of rapeseed oil that was denatured with aniline for industrial use but diverted for human consumption. The precise aetiologic agent in the oil responsible for the outbreak has not been identified. To learn more about possible contaminants and how the contamination might have occurred, we visited two French companies that process rapeseed oil and that were identified in Spanish administrative and judicial records as the ones exporting aniline-denatured rapeseed oil to Spain in 1981. With the apparently full and voluntary co-operation of personnel at both companies, we reviewed the processes involved in manufacturing, treating and transporting rapeseed oil, and we have summarized the information provided to us. Of particular importance is the finding that oil exported to Spain was taken from stock, the rest of which was sold for human consumption in the French domestic market, apparently without any adverse health effects. The differences between the oil exported to Spain and the oil sold as food in France were that aniline equivalent to 2% of the weight of the oil was added to most of the Spanish oil but not to that sold in France, and that contamination of the Spanish oil may have occurred in the tank trucks used for transportation to Spain, which had previously carried industrial chemicals. There is no assurance that the trucks were cleaned appropriately for transporting a food product before the oil was loaded for the journey to Spain. Since the clinical manifestations of TOS are not those of aniline toxicity, we conclude that the aetiological agent of TOS is likely to be one of the following: (1) a contaminant in the aniline, (2) a contaminant introduced during transportation, (3) a reaction product of normal oil components or materials used in refining with either aniline or the potential contaminants mentioned under (1) or (2) above.

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.