Abstract
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 Organization's 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.
Full Text
The Full Text of this article is available as a PDF (727.3 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abaitua Borda I., Kilbourne E. M., Posada de la Paz M., Diez Ruiz-Navarro M., Gabriel Sanchez R., Falk H. Mortality among people affected by toxic oil syndrome. Int J Epidemiol. 1993 Dec;22(6):1077–1084. doi: 10.1093/ije/22.6.1077. [DOI] [PubMed] [Google Scholar]
- Abaitua Borda I., Philen R. M., Posada de la Paz M., Gómez de la Cámara A., Díez Ruiz-Navarro M., Giménez Ribota O., Alvargonzález Soldevilla J., Terracini B., Severiano Peña S., Fuentes Leal C. Toxic oil syndrome mortality: the first 13 years. Int J Epidemiol. 1998 Dec;27(6):1057–1063. doi: 10.1093/ije/27.6.1057. [DOI] [PubMed] [Google Scholar]
- Aldridge W. N. The toxic oil syndrome (TOS, 1981): from the disease towards a toxicological understanding of its chemical aetiology and mechanism. Toxicol Lett. 1992 Dec;64-65 Spec No:59–70. doi: 10.1016/0378-4274(92)90173-h. [DOI] [PubMed] [Google Scholar]
- Alonso J., Anto J. M., Moreno C. Spanish version of the Nottingham Health Profile: translation and preliminary validity. Am J Public Health. 1990 Jun;80(6):704–708. doi: 10.2105/ajph.80.6.704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arnaiz-Villena A., Martinez-Laso J., Corell A., Allende L., Rosal M., Gomez-Reino J. J., Vicario J. L. Frequencies of HLA-A24 and HLA-DR4-DQ8 are increased and that of HLA-B blank is decreased in chronic toxic oil syndrome. Eur J Immunogenet. 1996 Jun;23(3):211–219. doi: 10.1111/j.1744-313x.1996.tb00116.x. [DOI] [PubMed] [Google Scholar]
- Arnaiz-Villena A., Vicario J. L., Serrano-Rios M., Bellas C., Mampaso F. Glomerular basement-membrane antibodies and HLA-DR2 in Spanish rapeseed oil disease. N Engl J Med. 1982 Nov 25;307(22):1404–1405. [PubMed] [Google Scholar]
- Bioque G., Abián J., Bulbena O., Roselló-Catafau J., Gelpí E. Mass spectrometric identification of N-phenyllinoleamide metabolites in mouse peritoneal macrophages. Rapid Commun Mass Spectrom. 1995;9(9):753–760. doi: 10.1002/rcm.1290090907. [DOI] [PubMed] [Google Scholar]
- Bioque G., Abián J., Bulbena O., Roselló-Catafau J., Gelpí E. Metabolism of N-phenyllinoleamide by rat liver. J Chromatogr. 1993 Jun 2;615(2):191–196. doi: 10.1016/0378-4347(93)80332-x. [DOI] [PubMed] [Google Scholar]
- Bioque G., Abián J., Bulbena O., Roselló-Catafau J., Gelpí E. N-phenyllinoleamide metabolism by human polymorphonuclear leukocytes. Xenobiotica. 1994 Jul;24(7):613–621. doi: 10.3109/00498259409043264. [DOI] [PubMed] [Google Scholar]
- Bioque G., Vargas D., Bulbena O., Roselló-Catafau J., Gelpi E Cyclooxygenase and lipoxygenase arachidonate metabolites synthesized by mouse peritoneal macrophages: in vitro effect of N-phenyllinoleamide from toxic oil samples. Agents Actions. 1993 Jan;38(1-2):38–43. doi: 10.1007/BF02027211. [DOI] [PubMed] [Google Scholar]
- Bujons J., Ladona M. G., Messeguer A., Morató A., Ampurdanés C. Metabolism of (R)- and (S)-3-(phenylamino)propane-1,2-diol in C57BL/6- and A/J-strain mice. Identification of new metabolites with potential toxicological significance to the toxic oil syndrome. Chem Res Toxicol. 2001 Aug;14(8):1097–1106. doi: 10.1021/tx010001k. [DOI] [PubMed] [Google Scholar]
- Calaf R. E., Peña J., Paytubi S., Blount B. C., Posada de la Paz M., Gelpi E., Abian J. Determination of aniline derivatives in oils related to the toxic oil syndrome by atmospheric pressure ionization-tandem mass spectrometry. Anal Chem. 2001 Aug 15;73(16):3828–3837. doi: 10.1021/ac0101712. [DOI] [PubMed] [Google Scholar]
- Carthew P., Edwards R. E., Dorman B. M., Verschoyle R. D. A comparison of the acute pathology induced by 3-phenylamino-1,2-propanediol (PAP) and its mono-oleoyl ester in rodents with the toxic oil syndrome in man. Hum Exp Toxicol. 1995 Feb;14(2):217–220. doi: 10.1177/096032719501400211. [DOI] [PubMed] [Google Scholar]
- Closa D., Folch E., Calaf R. E., Abián J., Roselló-Catafau J., Gelpí E. Absorption and effects of 3-(N-phenylamino)-1,2-propanediol esters in relation to toxic oil syndrome. Lipids. 2001 Oct;36(10):1125–1133. doi: 10.1007/s11745-001-0823-4. [DOI] [PubMed] [Google Scholar]
- Cárdaba B., Ezendam J., Gallardo S., del Pozo V., Izquierdo M., Martín C., Cortegano I., Aceituno E., Rojo M., Arrieta I. DR2 antigens are associated with severity of disease in toxic oil syndrome (TOS). Tissue Antigens. 2000 Feb;55(2):110–117. doi: 10.1034/j.1399-0039.2000.550202.x. [DOI] [PubMed] [Google Scholar]
- Fries J. F., Spitz P. W., Young D. Y. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol. 1982 Sep-Oct;9(5):789–793. [PubMed] [Google Scholar]
- Gallardo S., del Pozo V., Cárdaba B., de Andrés B., Martín-Orozco E., Fernandez J. C., Tramón P., Posada M., Abaitua I., Palomino P. Immunological basis of toxic oil syndrome (TOS). Toxicology. 1994 Nov 11;93(2-3):289–299. doi: 10.1016/0300-483x(94)90085-x. [DOI] [PubMed] [Google Scholar]
- Gómez de la Cámara A., Posada de la Paz M., Abaitua Borda I., Barainca Oyagüe M. T., Abraira Santos V., Ruiz-Navarro M. D., Terracini B. Health status measurement in Toxic Oil Syndrome. J Clin Epidemiol. 1998 Oct;51(10):867–873. doi: 10.1016/s0895-4356(98)00062-6. [DOI] [PubMed] [Google Scholar]
- Heiskanen K. M., Münzing S., Krombach F., Savolainen K. M. Effect of linoleic acid, linoleic acid anilide, and arachidonic acid on the expression of adhesion molecules on human neutrophils. Arch Toxicol. 1997;71(10):627–632. doi: 10.1007/s002040050436. [DOI] [PubMed] [Google Scholar]
- Heiskanen K. M., Savolainen K. M. Effects of 3-phenylamino-1,2-propanediol and its mono- and dioleylesters on the production of reactive oxygen metabolites in human polymorphonuclear leukocytes. Toxicol Lett. 1997 Mar 14;91(1):39–45. doi: 10.1016/s0378-4274(96)03862-3. [DOI] [PubMed] [Google Scholar]
- Heiskanen K., Ruotsalainen M., Savolainen K. Interactions of cis-fatty acids and their anilides with formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate and dioctanoyl-s,n-glycerol in human leukocytes. Toxicology. 1995 Dec 15;104(1-3):113–121. doi: 10.1016/0300-483x(95)03153-7. [DOI] [PubMed] [Google Scholar]
- Hill R. H., Jr, Schurz H. H., Posada de la Paz M., Abaitua Borda I., Philen R. M., Kilbourne E. M., Head S. L., Bailey S. L., Driskell W. J., Barr J. R. Possible etiologic agents for toxic oil syndrome: fatty acid esters of 3-(N-phenylamino)-1,2-propanediol. Arch Environ Contam Toxicol. 1995 Feb;28(2):259–264. doi: 10.1007/BF00217625. [DOI] [PubMed] [Google Scholar]
- Khan M. F., Kaphalia B. S., Ansari G. A. Heated linoleic acid anilide reduces serum enzyme activities in rats. Res Commun Chem Pathol Pharmacol. 1991 Jul;73(1):107–110. [PubMed] [Google Scholar]
- Khan M. F., Kaphalia B. S., Ansari G. A. Toxic response of linoleic acid anilide in female rats. Res Commun Chem Pathol Pharmacol. 1992 Aug;77(2):241–244. [PubMed] [Google Scholar]
- Khan M. F., Kaphalia B. S., Palafox A., Jerrells T. R., Ansari G. A. Heated linoleic acid anilide: toxicity and relevance to toxic oil syndrome. Toxicology. 1991;68(2):143–155. doi: 10.1016/0300-483x(91)90017-u. [DOI] [PubMed] [Google Scholar]
- Kilbourne E. M., Bernert J. T., Jr, Posada de la Paz M., Hill R. H., Jr, Abaitua Borda I., Kilbourne B. W., Zack M. M. Chemical correlates of pathogenicity of oils related to the toxic oil syndrome epidemic in Spain. Am J Epidemiol. 1988 Jun;127(6):1210–1227. doi: 10.1093/oxfordjournals.aje.a114914. [DOI] [PubMed] [Google Scholar]
- Kilbourne E. M. Eosinophilia-myalgia syndrome: coming to grips with a new illness. Epidemiol Rev. 1992;14:16–36. doi: 10.1093/oxfordjournals.epirev.a036085. [DOI] [PubMed] [Google Scholar]
- Ladona M. G., Izquierdo-Martinez M., Posada de la Paz M. P., de la Torre R., Ampurdanés C., Segura J., Sanz E. J. Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome. Environ Health Perspect. 2001 Apr;109(4):369–375. doi: 10.1289/ehp.01109369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lassalle P., Sergant M., Delneste Y., Gosset P., Wallaert B., Zandecki M., Capron A., Joseph M., Tonnel A. B. Levels of soluble IL-2 receptor in plasma from asthmatics. Correlations with blood eosinophilia, lung function, and corticosteroid therapy. Clin Exp Immunol. 1992 Feb;87(2):266–271. doi: 10.1111/j.1365-2249.1992.tb02986.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martín Alvarez H., Plaza Cano M., Estirado de Cabo E., García de Aguinaga M., Izquierdo Martínez M., Posada de la Paz M. Hallazgos clínicos y analíticos en pacientes afectados por el síndrome del aceite tóxico. Estudio de una cohorte de 758 pacientes. Rev Clin Esp. 2000 Jun;200(6):305–309. doi: 10.1016/s0014-2565(00)70642-4. [DOI] [PubMed] [Google Scholar]
- Mayeno A. N., Benson L. M., Naylor S., Colberg-Beers M., Puchalski J. T., Gleich G. J. Biotransformation of 3-(phenylamino)-1,2-propanediol to 3-(phenylamino)alanine: a chemical link between toxic oil syndrome and eosinophilia-myalgia syndrome. Chem Res Toxicol. 1995 Oct-Nov;8(7):911–916. doi: 10.1021/tx00049a003. [DOI] [PubMed] [Google Scholar]
- Philen R. M., Hill R. H., Jr 3-(Phenylamino)alanine--a link between eosinophilia-myalgia syndrome and toxic oil syndrome? Mayo Clin Proc. 1993 Feb;68(2):197–200. doi: 10.1016/s0025-6196(12)60172-4. [DOI] [PubMed] [Google Scholar]
- Philen R. M., Ortiz D. I., Auerbach S. B., Falk H. Survey of advertising for nutritional supplements in health and bodybuilding magazines. JAMA. 1992 Aug 26;268(8):1008–1011. [PubMed] [Google Scholar]
- Pich I., López S., Vila L., Lagunas C., de Castellarnau C. Influence of fatty acid anilides present in toxic oils on the metabolism of exogenous arachidonic acid in cultured human endothelial cells. Toxicology. 1993 Jan 29;77(1-2):51–63. doi: 10.1016/0300-483x(93)90137-h. [DOI] [PubMed] [Google Scholar]
- Posada de la Paz M., Abaitua I., Terracini B., Giménez O., Sánchez-Porro P., Gómez-Mera C. Late deaths among young women affected by the toxic oil syndrome in Spain. Epidemiology. 1999 May;10(3):345–345. doi: 10.1097/00001648-199905000-00026. [DOI] [PubMed] [Google Scholar]
- Posada de la Paz M., Philen R. M., Abaitua Borda I., Bernert J. T., Jr, Gancedo J. C., DuClos P. J., Kilbourne E. M. Manufacturing processes at two French rapeseed oil companies: possible relationships to toxic oil syndrome in Spain. Food Chem Toxicol. 1991 Dec;29(12):797–803. doi: 10.1016/0278-6915(91)90105-g. [DOI] [PubMed] [Google Scholar]
- Posada de la Paz M., Philen R. M., Abaitua Borda I., Diez Ruiz-Navarro M., Abraira Santos V., Pozo Rodríguez F., Pla Mestre R., Pollán Santamaría M., Sicilia Socias J. M., Azpeitia Gamazo P. Factors associated with pathogenicity of oils related to the toxic oil syndrome epidemic in Spain. Epidemiology. 1994 Jul;5(4):404–409. doi: 10.1097/00001648-199407000-00005. [DOI] [PubMed] [Google Scholar]
- Posada de la Paz M., Philen R. M., Borda I. A., Sicilia Socias J. M., Gómez de la Cámara A., Kilbourne E. M. Toxic oil syndrome: traceback of the toxic oil and evidence for a point source epidemic. Food Chem Toxicol. 1996 Mar;34(3):251–257. doi: 10.1016/0278-6915(95)00111-5. [DOI] [PubMed] [Google Scholar]
- Posada de la Paz M., Philen R. M., Schurz H., Hill R. H., Jr, Giménez Ribota O., Gómez de la Camara A., Kilbourne E. M., Abaitua I. Epidemiologic evidence for a new class of compounds associated with toxic oil syndrome. Epidemiology. 1999 Mar;10(2):130–134. [PubMed] [Google Scholar]
- Rodríguez-Martín A., Remesar X., Alemany M. Distribution of oleyl-anilide hydrolysing activity in rat and human tissues. Toxicology. 1993 Jun 11;80(2-3):131–139. doi: 10.1016/0300-483x(93)90176-s. [DOI] [PubMed] [Google Scholar]
- Ruiz-Gutiérrez V., Maestro-Durán R. Lymphatic absorption of 3-phenylamino-1,2-propanediol and its esters. Exp Toxicol Pathol. 1992 Mar;44(1):29–33. doi: 10.1016/S0940-2993(11)80134-X. [DOI] [PubMed] [Google Scholar]
- Ruiz-Méndez M. V., Posada de la Paz M., Abian J., Calaf R. E., Blount B., Castro-Molero N., Philen R., Gelpí E. Storage time and deodorization temperature influence the formation of aniline-derived compounds in denatured rapeseed oils. Food Chem Toxicol. 2001 Jan;39(1):91–96. doi: 10.1016/s0278-6915(00)00111-3. [DOI] [PubMed] [Google Scholar]
- Sanderson C. J. Interleukin-5, eosinophils, and disease. Blood. 1992 Jun 15;79(12):3101–3109. [PubMed] [Google Scholar]
- Sáenz Calvo A., García del Valle M., Cordón Rodríguez E., Izquierdo Martínez M., Ausejo Segura M., Rojas Hidalgo E. Hiperglucemia en el síndrome del aceite tóxico. Aten Primaria. 1995 May 31;15(9):542–546. [PubMed] [Google Scholar]
- Sánchez-Martín M. M., Sánchez-Bernal C., Sánchez-Llorente A., Cabezas J. A., Pérez-González N. Lysosomal enzyme activities in liver and sera from guinea pigs fed oil related to the toxic oil syndrome. Biol Chem Hoppe Seyler. 1993 Aug;374(8):665–670. doi: 10.1515/bchm3.1993.374.7-12.665. [DOI] [PubMed] [Google Scholar]
- Ten R. M., Kephart G. M., Posada M., Abaitua I., Soldevilla L., Kilbourne E. M., Dunnette S. L., Gleich G. J. Participation of eosinophils in the toxic oil syndrome. Clin Exp Immunol. 1990 Nov;82(2):313–317. doi: 10.1111/j.1365-2249.1990.tb05445.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de la Casa E., Pérez-González N., Sánchez-Bernal C., Llanillo M. Effects of dietary oil related to the toxic oil syndrome on the lipids of guinea pig liver microsomes. Lipids. 1995 Jun;30(6):575–579. doi: 10.1007/BF02537033. [DOI] [PubMed] [Google Scholar]
- del Pozo V., de Andrés B., Gallardo S., Cárdaba B., de Arruda-Chaves E., Cortegano M. I., Jurado A., Palomino P., Oliva H., Aguilera B. Cytokine mRNA expression in lung tissue from toxic oil syndrome patients: a TH2 immunological mechanism. Toxicology. 1997 Mar 14;118(1):61–70. doi: 10.1016/s0300-483x(96)03584-6. [DOI] [PubMed] [Google Scholar]