Factors Associated with Pathogenicity of Oils Related to the Toxic Oil Syndrome Epidemic in Spain

Паз, Мануел Посада де ла; Philen, Rossanne M.; Borda, Ignacio Abaitua; Ruiz-Navarro, Mercedes Díez; Santos, Víctor Abraira; Rodríguez, Francisco Pozo; Mestre, Rosa Pla; Santamaría, Marina Pollán; Socias, J.M. Sicilia; Gamazo, Paloma Azpeitia; Dyer, Rebecca Woodruff; Kilbourne, Edwin M.

doi:10.1097/00001648-199407000-00005

Cited by 27 publications

(14 citation statements)

References 6 publications

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“…64,65 The early clinical manifestations included respiratory distress syndrome, myalgia, eosinophilia, and widespread vascular and neural lesions. PAH developed in 20% of the patients and, in many, it regressed spontaneously.…”

Section: Toxic Oil Syndromementioning

confidence: 99%

Primary Pulmonary Hypertension

Archer¹,

Rich²

2000

Circulation

307

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Primary pulmonary hypertension (PPH) is a syndrome of dyspnea, chest pain, and syncope defined by increased pulmonary vascular resistance and the absence of a known cause. It also occurs in a familial form, which is linked to unidentified genes on chromosome 2. This syndrome is characterized by abnormalities of pulmonary vascular biology in each compartment of the blood vessel. The lumen has a prothrombotic diathesis, the endothelium displays an excessive production of vasoconstrictors relative to vasodilators, and the smooth muscle cells are depolarized and calcium-overloaded, which is due in part to reduced expression of voltage-gated potassium channels (Kv). This causes vasoconstriction and may promote cell proliferation. The adventitia displays excessive remodeling, which is associated with exaggerated metalloproteinase and elastase activity. Conceptually, PPH seems to require a permissive genotype, a susceptible phenotype (eg, endothelial dysfunction) and, in many cases, an exogenous trigger (eg, an anorexigen). Although there is not a generally accepted, unifying hypothesis regarding its cause, impaired function and the expression of vascular and platelet Kv channels suggest PPH may be a disease of the ion channels. Abnormal matrix metalloproteinase and elastase activity could also explain the abnormal vascular tone, platelet activation, and remodeling in PPH. Although calcium-channel blockers and prostacyclin, particularly when coadministered with warfarin, improve survival, PPH has a 5-year mortality rate of approximately 50%. Pharmacological and gene therapies aimed at enhancing the activity of prostacyclin, nitric oxide synthases, and Kv channels or at inhibiting endothelin and matrix metalloproteinases are promising areas for future development.

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Section: Toxic Oil Syndromementioning

confidence: 99%

Primary Pulmonary Hypertension

Archer¹,

Rich²

2000

Circulation

307

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“…Although no explanation has been established for this, oil sold early in the epidemic may have contained more of the toxic agent than that sold later on, and we have found that concentrations of contaminants vary substantially from one bottle of oil to another (15). Evidence from toxicoepidemiologic studies (described below) has shown that the risk of developing toxic oil syndrome was related to the concentration of certain contaminants in the oil in a dose-response fashion (23,24). Toxic Oil Syndrome 235…”

Section: Risk Factorsmentioning

confidence: 84%

“…A subsequent study, called toxicoepidemiologic study II, used a similar design in the choice of case oils and noncase oils, but it covered all the geographic areas affected by the epidemic (24). The dose-response relation was similar to that found in toxicoepidemiologic study I (table 7).…”

Section: Toxicoepidemiologic Studiesmentioning

confidence: 93%

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Toxic Oil Syndrome: The Perspective after 20 Years

Паз

Philen

Borda

2001

Epidemiologic Reviews

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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 ...

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“…Researchers have determined that there exists a strong link between increased concentrations of fatty acid anilides in the oils and the risk of disease (Kilbourne et al, 1988;Posada de la Paz et al, 1994). Similarly, the formation of fatty acid esters of 3-(Nphenylamino)-1,2-propanediol (PAP esters) in general (Hill et al, 1995) and specifically the formation of the 1,2-di-oleyl ester of 3-(N-phenylamino)-1,2-propanediol (DPAP) has been strongly linked to the illness (Posada de la Paz et al, 1999).…”

Section: Original Researchmentioning

confidence: 99%

On‐Line HPLC‐UV‐mass spectrometry and tandem mass spectrometry for the rapid delineation and characterization of differences in complex mixtures: a case study using toxic oil variants

Crow

Cragun

Johnson

et al. 2002

Biomedical Chromatography

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An integrated differential approach to the characterization of complex mixtures is presented which includes the targeting of liquid chromatography (LC) peaks for identification using characteristic UV adsorption of the LC peak, subsequent molecular weight and formula determination using accurate mass LC mass spectrometry (MS), and structure characterization using accurate mass LC-tandem mass spectrometry. The use of differential UV adsorption aids in narrowing the scope of the study to only specific peaks of interest. Accurate mass measurement of the molecular ion species provides molecular weight information as well as atomic composition information. The tandem MS (MS/MS) spectra provide fragmentation information which allows for structural characterization of each component. Accurate mass assignment of each of the fragment ions in the MS/MS spectrum provides atomic composition for each of the fragment ions and thus further aids in the structural characterization. These experiments are facilitated through the use of on-line LC-MS and LC-MS/MS with in-line UV detection. A synthetic toxic oil (STO) related to Toxic Oil Syndrome is studied with a focus on possible contaminants resulting from the interaction of aniline, used as a denaturant, with the normal components of the oil. A differential analysis between the STO and a control oil is performed. LC peaks were targeted using UV absorbance to indicate the possible presence of the aniline moiety. Further differential analysis was performed through the determination of the MS signals associated with each component separated on the LC. Finally, the MS/MS data was also used to determine if the fragmentation of the targeted components indicated the presence of aniline. The MS/MS and accurate mass data were used to assign the structures for the targeted components.

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Factors Associated with Pathogenicity of Oils Related to the Toxic Oil Syndrome Epidemic in Spain

Cited by 27 publications

References 6 publications

Primary Pulmonary Hypertension

Primary Pulmonary Hypertension

Toxic Oil Syndrome: The Perspective after 20 Years

On‐Line HPLC‐UV‐mass spectrometry and tandem mass spectrometry for the rapid delineation and characterization of differences in complex mixtures: a case study using toxic oil variants

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