Rossanne M. Philen

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.

Contaminants in L-Tryptophan associated with eosinophilia myalgia syndrome

In late 1989, an epidemic of eosinophilia-myalgia syndrome (EMS) that resulted in several thousand cases of the syndrome and 36 deaths was recognized in the United States. Physicians in New Mexico linked the epidemic to the ingestion of L-tryptophan (LT). Results of studies indicated that one or more trace contaminants in LT were likely causes of the EMS epidemic. Investigators traced the LT that was taken by most patients with EMS to a single manufacturer, Showa Denko K.K. of Japan.We now report results of high performance liquid chromatographic analysis of LT samples from this manufacturer. Three sets of blind-coded samples were analyzed: the priority case lot set, which included 54 case-associated LT lots and 50 noncase-associated LT lots that were taken by case and control subjects who used only one brand of LT; the single lot case set, which included 73 case-associated LT lots and 25 noncase associated LT lots taken by case and control subjects who used only a single lot of LT; and the South Carolina tablet set, which included LT tablets taken by case subjects (n=26) and by control subjects (n=52). We statistically compared the concentration of each contaminant in case-associated, noncase-associated, and control samples of each sample set. The analyses showed that there were more than 60 minor contaminants in the LT from Showa Denko K.K., and that six of these contaminants were associated with EMS. The structures of three contaminants are known, but the identities of the other three contaminants are currently unknown. In this paper, we discuss each sample set and results of the analysis of each, the combined results of all sets, the identity of the six contaminants, and implications for future research into the etiology of EMS.

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.

What's being used at home: a household pesticide survey

OBJECTIVE Since very little is known about the health effects that household pesticides have on children, we conducted this survey to identify what pesticides are being used in the home, where they are being used and stored, and what methods are used for their disposal. METHODS In the spring of 1999 we conducted a survey in a community in the state of Arizona, in the United States of America, on the border with Mexico. To be eligible to participate in the survey, households had to have used a pesticide in the 6 mo prior to the survey and to have at least one child under the age of 10 years. We gathered general information on pesticide usage, storage, and disposal, in addition to specific information about each of the pesticides currently being used and/or stored in the home. RESULTS In the 107 households surveyed, we found 148 pesticide products, for a mean of 1.4 per household. Half of the pesticides were stored less than 4 feet (1.22 m) from the ground, at a level a child could reach. Seventy percent of all the pesticides were stored inside the home, with the kitchen being the storage room most often mentioned. The kitchen was also the room where most of the pesticides were used, with 69% of the respondents saying they had used at least one pesticide there. CONCLUSIONS From our research we conclude that it will be important to continue to investigate all avenues of pesticide exposure in order to fully evaluate childhood exposures. Understanding household pesticide use and developing a model of exposure will help in this process. Profiles of the use, storage, and disposal of products will also guide the development of effective education and poison prevention programs in the community.

Storage time and deodorization temperature influence the formation of aniline-derived compounds in denatured rapeseed oils.

In 1981 an epidemic, named Toxic Oil Syndrome, occurred in Spain as a result of ingestion of rapeseed oil denatured with 2% aniline, which had been imported for industrial use but was fraudulently diverted and processed for human consumption. Two groups of chemical compounds have been identified in the ingested toxic oil: fatty acid anilides and amino-propanediol derivatives. The objective of this work was to assess the effect of several refining process variables on the formation of 3-(N-phenylamino)-1,2-propanediol (PAP) esters. The amount of PAP esters in aniline-denatured oil increased dramatically when oil was heated from 250 degrees C to 300 degrees C. However, the ones formed when 300 degrees C was reached were lost during processing at that temperature. The level maintained during the operation time at 300 degrees C was higher in denatured samples stored for 3 weeks before refining than in denatured samples stored only for 1 week. Anilides were also analyzed. We found that anilides decreased very little with distillation time. In this paper we discuss the influence of storage time prior to refining and of elevated refining temperature, such as temperatures that might occur in close proximity to a deodorizer coil.

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 μg 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.

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.

Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms.

OBJECTIVE To assess L-tryptophan (LT) dose, age, sex, and immunogenetic markers as possible risk or protective factors for the development of LT-associated eosinophilia-myalgia syndrome (EMS) and related clinical findings. METHODS HLA-DRB1 and DQA1 allele typing and Gm/Km phenotyping were performed on a cohort of 94 white subjects with documented LT ingestion and standardized evaluations. Multivariate analyses compared LT dose, age, sex, and alleles among groups of subjects who ingested LT and subsequently developed surveillance criteria for EMS, developed EMS or characteristic features of EMS (EMS spectrum disorder), or developed no features of EMS (unaffected). RESULTS Considering all sources of LT, higher LT dose (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8), age >45 years (OR 3.0, 95% CI 1.0-8.8), and HLA-DRB1*03 (OR 3.9, 95% CI 1.2-15.2), DRB1*04 (OR 3.9, 95% CI 1.1-16.4), and DQA1*0601 (OR 13.7, 95% CI 1.3-1.8) were risk factors for the development of EMS, whereas DRB1*07 (OR 0.12, 95% CI 0.02-0.48) and DQA1*0501 (OR 0.23, 95% CI 0.05-0.85) were protective. Similar risk and protective factors were seen for developing EMS following ingestion of implicated LT, except that DRB1*03 was not a risk factor and DQA1*0201 was an additional protective factor. EMS spectrum disorder also showed similar findings, but with DRB1*04 being a risk factor and DRB1*07 and DQA1*0201 being protective. There were no differences in sex distribution, Gm/Km allotypes, or Gm/Km phenotypes among any groups. CONCLUSION In addition to the xenobiotic dose and subject age, polymorphisms in immune response genes may underlie the development of certain xenobiotic-induced immune-mediated disorders, and these findings may have implications for future related epidemics.