JAI vu1 . 1 9 1 71 I ?I1 sept"et", 199101- 1

Toxic Oil Syndrome : A Current Clinical and Epidemiologic Summary, Including Comparisons With the -Myalgia Syndrome

EDWIN M . KILBOURNE, MD . MANUEL POSADA DE LA PAZ . M D .= IGNACIO ABAITUA BORDA. MD,* MERCEDES DIEZ RUIZ-NAVARRO,' ROSSANNE M. PHILEN, MD, MSc . HENRY F ALK. M D . MPH Atlanta, Georgia cord Madrid . Spain

In the spring and summer of 1981, an epidemic of a new illness f:pidemiologic and analytic chemical studies have dearly now referred to as the toxic oil syndrome occurrert in central and linked the toxic oil syndrome to the ingestion of oil mixtures northwestern Spain, resulting in some 20,000 cases, 12,000 hos- containing rapeseed oil drantured with aniline. However, the pital admissions and >300 deaths in the 1st year of the epidemic . precise identity of the etiologic agent within this oil has never been The initial onset of illness was usually acute, and patients pre- determined . Aniline itself did not cause the illness, but the causal sented primarily with a respiratory syndrome involving cough, agent may he a reaction product of aniline with some nil cnmpn- fever, dyspnea, hypoxemia, pulmonary infiltrates and pleural nent . Although many aspects of activity in the involved effusions. While approximately 50% of patients recovered from patients have lessened with time, the ultimate consequences of this acute phase of the illness without apparent sequelae. the their disease are not clear and are the subject of ongoing study . remaining patients developed an intermediate or chronic phase, or The recently described eosinophilia-myalgia syndrome in the both, of illness involving severe myalgia, eosinophilia, peripheral United States clinically resembles the toxic oil syndrome . nerve damage, sclerodermiform skin lesions, sicca syndrome, (J Am Coll Cordial 1991 ;18;711-) alopecia and joint contractures, among other findings .

The toxic oil syndrome epidemic occurred in Spain in the Clinical Aspects of the Toxic Oil Syndrome spring and summer of 1981 and was one of the largest ]lie At tire or Early Phase epidemics of an intoxication ever recorded, resulting in some The toxic oil syndrome epidemic is often reported to have 20,000 cases, 12,11011 hospital admissions and >300 deaths started on May 1 . 1981 . the day on which a boy from the during the 1st 12 months after the epidemic began 11-4). small town of Torrejon de Ardoz, Spain was admitted to a Information regarding the . clinical features hospital in Madrid with fulminant respiratory failure that led and etiology of the toxic oil syndrome is summarized and rapidly to death (1) . Over the next several weeks . this case reviewed here, both to provide an overall perspective of was followed by others in rapidly increasing numbers . So this unusual disease and to provide the background in- many acutely ill patients with the toxic oil syndrome pre- formation necessary for a comprehensive understanding sented for medical attention as to threaten to overwhelm the of the reports that will follow later in this Seminar on capacity for treatment in existing inpatient and outpatient cardiovascular manifestations of the toxic oil syndrome and facilities in affected areas . During the peak of case occur- related . In addition . information is presented re- rence in early June. the number of new cases reported each garding the eosinophi :ia-myalgia syndrome- an illness resem- week approached 2 .000 (1 .4,5) . bling the toxic oil syndrome that occurred in epidemic form Pulmonary involvement. Initially, clinical findings refer- in the United States in 1989 . The implications of this able to the respiratory system were particularly prominent . syndrome for research on the toxic oil syndrome are dis- Typically . disease manifestations included fever (usually low cussed. grade)- cough, hypoxemia. pulmonary infltrates and pleural effusions . The pulmonary infiltrates were generally bilateral and showed an interstitial radiographic pattern. Neverthe- less . many severely affected patients had alveolar and inter- stitiallalveolar infiltrates (2.3) . From the Cenmr, fur Daccic Comrul. Public HeAth Se-- U S. Other acute manifestations. Other disease manifestations Oepanmeto. of He,hh and Ho- Service, . Adanru. (ienrciu . :md' Pondo do during the acute phase seemed less important than the I ... evaciun Sanilaric. Sladrid . Spain . Address to, riot,: Edwin St . Kilhowne Nil). FACT' . Epidcminlagy dramatic picture of respiratory compromise affecting most Program O0cc IC-e81. ISO) Clifton Cued. Athmm . (vorpia 311333 . patients who were seen early in the course of their illness

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712 KII.9OURNh ET AL ., )ACC Vol. IN . No . 3 uvnswot .onv Or TOXIC OIL SYNDROME s,o,rolu 1 .1 :111-7

(within a week or so of onset) . A common accompanying many findings of the chronic phase (see later) began to make clinical finding was skin ra. .h-frequently a maculopapular their appearance at this point . There was frequently nonpit- erythema . However, other dermatologic presentations in- ting edema of the skin of the limbs and other pans of the cluded molar erythema or . less frequently, a frank petechial body. Although infrequent, there were numerous serious rash . Some patients had gastrointestinal symptoms . includ- thromboembolic complications among patients during the ing nausea. vomiting or diarrhea . But while such symptoms intermediate phase of the syndrome . For example, there were moderately frequent, they were not a particularly were reports of strokes, mesenteric thromboses and even a prominent part of the illness . Some patients also had hepa- report of hepatic vein thrombosis among patients during this tomegaly splenomegaly or lymphadenopathy alone or in phase of the illness (2,10) . In many patients, liver function combination . Serum immunoglobulin E was often elevated. tests remained abnormal during the intermediate phase (3 .7) . Biochemical evidence of liver involvement was frequent . and mild to moderate elevations of aspsrtate aminotrans- ferase (AST) . alaninc aminotransterase (ALT), alkaline Chronic or Late Phase phosphatase and gamma-glutamyl transpeptidase were com . Neuromuscular complications . The clinical manifesta- mon . Increases in serum bilirubin were seen somewhat less tions of chronic toxic oil syndrome were numerous and frequently (1-3,6,7) . varied . However, neuromuscular complications received Eosinophilia . One of the most striking findings in all particular attention because of the frequent development of phases of the toxic oil syndrome was intense peripheral severe weakness or paralysis . Many patients developed the eosinuphilia. Virtually all patients had absolute eosinophil findings of mononeuritis multiplex, with patchy sensory loss counts >500 cells/mm', but counts of >2,0001mm' were and associated muscular weakness. Nerve conduction and common . Eusinuphilia was so frequent as to he considered a electromyographtc studies typically showed peripheral hallmark of the disease . However, it was occasionally absent nerve axonopathy along with some degree of primary muscle very early in a patient's clinical course, even in the presence involvement . The extent of weakness associated with the of substantial pulmonary abnormalities (1 .3). Very often the neuromuscular lesion differed among patients, but in the cosinophilia was accompanied by a more general leukocyto- most severe cases there was progression to essentially sis with a left shift, but the increase in eosinophils was complete quadriplegia. In some patients ventilatory function disproportionate to the increase in absolute numbers of was compromised and mechanically assisted ventilation was leukocytes (1,3,5,8) . required . A number of patients eventually died of infectious The respiratory manifestations of acute toxic oil syn- complications of long-term mechanically assisted ventilation drome were generally more intense than those of the eosin- (1-3) . ophilia-myalgia syndrome (see later) and were frequently Other manifestations of chronic toxic oil syndrome. These life-threatening . Approximately 1%eof patients with the toxic included severe weight loss, muscle atrophy, chronic myal- oil syndrome died in the acute phase of illness, principally gia, muscle cramps, involuntary movements of the limbs, from respiratory failure (I) . scleroderma-like hardening and thickening of the skin, joint contractures (independent of the limitation in movement caused by sclerosis of overlying skin), sicca syndrome, Intermediate Phase alopecia, pruritus, chronic hepatitis (both hepatic inflamma- Many patients with the toxic oil syndrome recovered tion and fibrosis) and progressive pulmonary hypertension . from the early phase of illness, apparently without further Often, these components of the chronic illness worsened clinical sequelae . However, a substantial proportion (per- over a period of months to years (2,3.6,9) . Nevertheless, haps 50%, the precise percentage varying with the case recent informal reports of Spanish clinicians (9) suggest that series cited) experienced an intermediate and subsequently a many aspects of disease activity eventually seemed to lessen chronic or late phase of illness (3,9) . and, finally, to cease. Severe myalgia, eosinophitia and thromboembolic cee ;pll- After the dsemre stops progressing . some degree of cations . There is disagreement among investigators regard- remission of chronic manifestations of the syndrome occurs . ing both the precise period of illness and the exact clinical Peripheral nerve function improves, but often the clinical manifestations that should be regarded as constituting the gains are modest and come slowly . Hardened and thickened intermediate phase of the toxic oil syndrome (1 .3) . Never- skin regains some of its lost elasticity, and other disease theless, there is consensus regarding the existence of a more manifestations gradually become less evident . or less definable period of illness occurring perhaps I to 3 months after the initial onset of symptoms, involving incom- plete recovery from the acute phase of illness and heralding Pathology the onset of later disease . Extremely severe myalgia (includ- Vascular endothelial swelling and proliferation . The ing significant muscle tenderness to palpation) and particu- pathologic lesion common to many tissues in the acute phase larly high eosinophil counts (higher even than in the acute of this multisystemic disorder was swelling of the vascular phase) were characteristic of the intermediate phase, and endothelium . As the disease progressed through its early .

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intermediate and chronic phases . intense endothelial prolif- almost 7i' . of the total number occurred . Flue incidence eration occurred . In many tissues the growth of endothelial rate . however . was not hiehest in Madrid . here- of it, tissue was exuberant, with occlusion or near occlusion of rclalivdy largo lotal population Other populous cities in vessel lumens (11 .12) . Spain (Barcelona. for example) were essentially unaffected Vasculitis. There were primarily mononuclear inflamma- 111 . tory infiltrates associated with blood vessels . In some tissue Gender distribution, Many more women than men were sections only perivascular collections of inflammatory cells affected . At the national level . >60%% of persons with the were seen ; in others, there was evidence of a nonnecrotizing toxic oil syndrome were female . Moreover . the disease vascutitis (I 1) . seemed it) he more severe for women . There were approx Perineural inflammatory infiltrates and fibrosis . Inflam- mately twice as many deaths due to the toxic oil syndrome matory infiltrates involved the perineurium of peripheral among women as among men ( 1) . nerves . In later stages of the diseases there was perineeral Socioeconomic status . The disease had a particularly high fibrosis . The muscular lesion involved inflammation primar- incidence among persons with a low to low-middle socioeco- ily of the perimysium and epimysium, with relative sparing nomic status . There was relative sparing of persons with of the endomysium. In the late stages of the toxic oil higher socioeconomic status. but the disease wns also infre- syndrome, however, there was endemysial fibrosis . A pecu- quent among the very poorest persons in affected areas ( 1) . liar finding was inflammation specifically involving muscle spindles and intramuscular nerves (12) . Etiolagie Epidrmiologv Examination of the bone morrow of patients Irish eosin- ophilia revealed a marked increase in numbers of eosinophil Suspect oil, As has frequently been the case in the precursors . solution of complex epidemiologic problems, the astute Observations of a clinician led to studies that eventually yielded data firmly implicating the vehicle of the etiologic Epidemiology agent . Dr . Juan Manuel Tahuenca-Oliver noticed that, al- There have been three major areas of epidemiologic though cases fended to cluster in families . children in af- research into the toxic oil syndrome : it development of fected families who were younger than approximately 6 descriptive data, including information about the demo- months remained well . Because the nutritional sources of graphics of affected persons, the extent to which different these infants (generally breast milk) differed substantially geographic areas were affected and the occurrence of cases from those of the rest of the family . Tabuenca wondered over time; 2) etiologic epidemiologic studies aimed at iden- whether the vehicle of the toxic oil syndrome agent might be tifying the etiologic agent and its mode of transmission : and an ingested item to which most family members (with the 31 studies of the specific clinical findings in affected persons . exception of breast-fed babies) were exposed. By question- their frequency and the extent to which they vary over time . ing his patients he found that . essentially without exception . all of those affected by the syndrome had consumed an unlabeled oil, marketed as pure and sold by Descriptive Epidemiology traveling nde,men either door to door or in the weekly open Although the epidemic has long been said to have begun air markets (rnerradillee) typical of Spain (5 .13) . Oil fining on May I . 1981, painstaking and detailed review of comput- this profile in most respects will be referred to as "suspect erized patient listings and clinical records has shown that oil" in the remainder of this review . cases occurred at least as early as April 23 . 1981 linternal The oil hypothesis . A number of studies comparing af- documents . Fondo de Investigation Sanitaria) . Increasing fected and unaffected persons or families (case-referent numbers of cases occurred throughout May and into early studies) and other epidemiologic work have now established June 1981 . In mid-June 1981 . the incidence began to de- the validity of the oil hypothesis . The food exposures of 62 crease . This decrease in the epidemic curve coincided ap- children with the toxic oil syndrome were compared with proximately with the public announcement of the association those of 62 children with other diseases at the Nino Jesus of the toxic oil syndrome with the consumption of a contam- Hospital in Madrid . All of the children with the syndrome inated oil being sold for food use (1 .4) . had consumed suspect oil compared with only 6% of the Location . The toxic oil syndrome epidemic affected pri- children being treated for other problems (13). In the town of marily central and northwestern Spain . Over 99% of the Las Navas del Marques (Avila Province). all of 27 case cases officially registered with the Spanish government oc- families had consumed suspect oil compared with only 13 curred in the following 14 provinces (listed in rank order (23ey) of 54 size-matched and 17 (3191 of 54 randomly according to the number of cases that occurred there) : chosen control families (4). In a door to door questionnaire Madrid, Valladolid . Leon . Palencia, Segovia, Avila. study conducted in 1981 in the working-class neighborhood Zamora . Burgos . Guadalajara . Salamanca. Soria, Toledo. of Orcasur in Madrid . participants were asked about the Santander and Orense . Cases were tremendously concen- types and sources of oils they consumed . Suspect oil had trated in Madrid Province, located in central .Spain, where been consumed in all five houses surveyed in which cases of

714 Kit IiOURNE LT AL, JACC Vol . I 5. No, 3 urIDL.MIOW(iY (7L TOXIC 011. SYNDROME 5cplember 1991 :711-7

the toxic oil syndrome had occurred but in only 71 (347,) of Long-Term Evolution of the Toxic 207 unaffected families (14). Oil Syndrome The pattern of occurrence of cases of the toxic oil . Data developed to date regarding the long- syndrome among the residents of two convents of the same Mortality term evolution of the toxic oil syndrome are relatively few . order located side by side in the city of Madrid was of Recent unpublished information (Fondo de Investigacion particular interest . The residents of the convents included Sanitaria) strongly suggests that the current age-adjusted nuns, novices and laywomen . All residents at each convent death rate among affected persons does not differ substan- ate the same . with the exception that nuns and novices tially from that of the Spanish population as a whole . were permitted to use olive oil as a condiment. whereas Although there was a clear-cut and statistically significant laywomen were not. (The "olive oil" used in each convent increase in mortality during the Is[ year of the epidemic, at the time of the epidemic was bought from stores and came subsequent mortality in a sample of 5% of patients with the in 5-liter plastic contairo-v .) In one convent, 23 (66%) of the toxic oil syndrome has not differed significantly from that 35 nuns and novices but none of 56 laywomen had symptoms expected . However, there may have been a tendency for of the toxic oil syndrome. In the other convent, 42 (98%) of patients with the syndrome to die at a relatively young age, 43 nuns became ill while all of approximately 70 laywomen and this finding requires further investigation . In general, living there stayed well (15) . these epidemiologic data are consistent with the informal Sources of suspect oil . Work done toward tracing the clinical observation that disease activity diminishes and sources of suspect oil and chemical analyses of such oils had shown the oils to be complex mixtures of low quality olive disease manifestations tend to regress some months to years after the onset of illness . Spanish health authorities are oil, various seed oils and rapeseed oil . The rapeseed oil currently implementing further epidemiologic and clinico- component drew attention because it was not produced in Spain and could only be imported after being mixed with one epidemiologic studies that should address more fully the question of whether excess morbidity or mortality, or both, of several denaturants truest commonly aniline) designed to is already occurring or may be expected to occur among make it unfit for human consumption . The specific oil vehicle persons with the toxic oil syndrome . of the etiologic agent was thus thought to be aniline- Risk of cancer and cardiovascular disease. Patients with denatured rapeseed oil . but doubts arose regarding this conclusion when such oils failed to produce illness resem- the toxic oil syndrome are particularly concerned about the possibility that their long-term risk for cancer may have been bling the toxic oil syndrome in experimental toxicologic increased by their exposure to the toxic ail syndrome agent . animals (1) . Because the clinical findings of the toxic oil However, given the fact that endothelium and blood vessels syndrome are quite distinct from those of aniline toxicity . were prime target tissues for the initial insult, the possible the idea arose that perhaps another component of the oil development of cardiovascular disease, cerebrovascular dis- mixtures carried the etiologic agent . Some even speculated ease or other vascular diseases is also a concern that should that some food exposure other than suspect oil was the true be addressed in future studies . cause of the syndrome. Aniline-denatured rapeseed oil . A study of oils turned in to the government by affected and unaffected families and meeting the general description of suspect oils helped to Etiology and Pathogenesis resolve these questions . Measurements of specific chemical The precise identity of the etiologic agent of the toxic oil analytes in oils turned in by affected families (case oils) were syndrome has yet to be determined . Toxico-epidemiologic compared with similar measurements in oils turned in by data strongly implicate aniline-denatured rapeseed oil as the unaffected families (control oils) . The results showed a clear vehicle of the etiologic agent (16). However, the clinical association of illness in a family with the presence of aniline manifestations of the syndrome are not those of aniline and fatty acid anilides (reaction products of oil constituents toxicity . The estimated doses of aniline ingested by patients and the aniline denaturant) in that family's oil . Moreover, were not toxicologically significant and typical manifesta- there was a clear-cut dose-response effect : the greater the tions of aniline poisoning (methemoglobinemia, for example) extent of contamination, the more likely it was that an oil were absent (5,13). Thus, unmodified aniline could not have had come from an affected family . Consistent with these caused the disease, findings was the fact that fatty acids and sterols occurring in Fatty acid anilides. These reaction products, involving an particularly high concentrations in rapeseed oil were signif- amide linkage between aniline and fatty acids (the principal icantly higher in case than in control oils . Conversely, the chemical components of edible oils), have been proposed as specific fatty acid and sterol components in which rapeseed the etiologic agents of the syndrome . However, attempts to oil is relatively poor were found in reduced concentrations in reproduce toxic oil syndrome-like biologic phenomena in in case oils . These findings provided strong evidence to support vitro and in vivo systems to which fatty acid anilides have the hypothesis that aniline-denatured rapeseed oil land not been added have not, so far, met with unequivocally positive some other component of oil mixtures) was the vehicle of the results (17) . Of course, the absence of positive findings in toxic oil syndrome etiologic agent (16) . these experiments is difficult to interpret, because whole .

JACC Vot . 18, No . 3 Kit or t R,VF ET ii 71s Scn4•mbcr 17Y .OI l-7 IS'IOEp110LOGti 10,111 On 11 111.0111

implicated oils have failed to produce toxic oil syndrome-like that they meliorated pulmonary aspects of the acute phase findings in experimental animals l I I . Thus, the question of of the Illness I2Ill . Cilucoeorticoids caerc vcry effective in whether the ingestion of fatty acid anilides caused the tonic suppressing cosinophilia- but there are no firm data docu- oil syndrome remains unanswered . menting an overall beneficial effect on the course of inter- Chemical contaminants . Other chemical substances de- mediate and chronic toxic oil syndrome . rived from the reaction of aniline with other constituents of rapeseed oil have been proposed as potential etiologic agents of the toxic oil syndrome 117,18) . However, no convincing Relation to Other Illness evidence has yet been developed that any particular one of Appurrrlt Uniqueness of the Taxi(' these compounds was the cause . Thus, all of these hypoth- Oil Strndrotse eses remain highly speculative . Individual clinical findings of the toxic oil syndrome are It is possible that the etiologic agent of the toxic oil seen in other diseases and syndromes . For example, inter- syndrome has nothing to do with aniline . An investigation stitial pulmonary infiltrates can be seen in the hypersensitiv- sponsored by the Fonda de Investigation Sanitaria (unpub- ity pncumonitides, a variety of infectious conditions pro- lished data) involved a visit to the two French oil companies duced by toxicants that affect the lung (paraquat . for from which rapeseed oil implicated in the toxic oil syndrome example) . and many other disease states . The rashes de- epidemic originated. Apparently, rapeseed oil sent to Spain scribed in patients with the toxic oil syndrome are by no was taken from undenatured stock !hat was refined and means specific. Eosinophilia is commonly associated with distributed as edible oil on the domestic French market many parasitic , the hypereosinophilic syndrome, without any known adverse health consequences. The com- eosinophilic fasciitis . po'yarteritis nodosa and hypersensitiv- panies added aniline to denature their product before send- ity reactions to drugs and chemicals, among other condi- ing it to Spain. However . because that denatured product tions . Axonal neurupathy resembling that seen with the toxic was theoretically to be employed in industrial processes and oil syndrome can he produced by conditions that affect the not for use as a food, the usual precautions involved in the vascular supply of peripheral nerves, such as diabetes mel- handling and transportation of a food product were not litus and polyarteritis nodosa . Some of the skin findings in necessarily taken. The French company exporting the larg- chronic toxic oil syndrome resemble those of progressive est quantity of denatured rapeseed oil to Spain hired trucks systemic sclerosis . that usually carried industrial chemicals . The mixing of These similarities notwithstanding, the toxic oil syn- denatured rapeseed oil with some still unknown chemical drome was considered a new and distinct clincal entity contaminant during the process of transport cannot be ruled because none of the conditions or toxicants just mentimred out . produce the sequential evolution of clinical findings seen Pathogenesis: role of eosinophilia. Data on the pathogen- among patients with the syndrome: initial respiratory diffi- esis of the toxic oil syndrome are almost as sketchy as culty that resolves over a period of days to weeks only to those on the identity of the etiologic agent . It seems, lead to severe myalgias. persistent eosinophilia. thromboem- however, that cosinophilia may play an important role in the holic phenomena and late progression to a chronic syndrome tissue damage caused by the illness . In many histologic involving neuromuscular compromise, sclerodermiform skin sections, whole eosinophils are rare among the inflammatory changes. joint contracmres, chronic hepatopathy and the cells . Nevertheless, eosinophils degranulate in target tissues other manifestations of chronic toxic oil syndrome . and therefore may not appear in histologic sections as intact cells . In fact, special tests foreosinophil-derived proteins are positive in tissue sections (12,19) . Thus, tissue damage The Eo.sittrtphilia-Mvalgia Srwrh-orrte caused by eosinophil-derived products may at least partly The uniqueness of the toxic oil syndrome has now been explain many of the pathogenetic features of the toxic oil challenged by the appearance of the cosinophilia-myalgia syndrome . syndrome, which occurred in the United States in epidemic form in 1989 and involved >1 .500 cases 121 .221 . The disease was apparently caused by contaminated preparations of Treatment t-tryptophan taken as a food supplement (23-25) . Eariy in the course of the toxic oil syndrome e pidemic . i t Clinical manifestations of the eosinophilia-myalgia syn- was widely believed that the illness was caused by one of the drome. These are strikingly similar to those of the interme- that commonly produce the syndrome of diate and chronic stages of the toxic oil syndrome . Patients atypical pneumonia (4) . Consequently . erythromycin and with the eosinophilia-myalgia syndrome typically come to tetracycline were widely prescribed . although they had no medical attention because of persistent and severe myalgia, apparent effect on the illness 1131 . As the hypothesis of an much like that associated with intermediate and chronic- infectious cause seemed less tenable, glucocorticoids began and to some extent in acute-toxic oil syndrome .'rhe eosino- to be employed in therapy . Data regarding their efficacy in phil count is dramatically increased, usually >2 .000cellsimm' . acute toxic oil syndrome are few . but there is a consensus There is concomitant leukocytosis, and the bone marrow

716 611.11arlN1'. I.1 Al . . 1A CC .V,1 18 . Nu . 3 EPIO 6xtlt :l(1y Of'lOSIt' Oil . SY'SOE(JMI : Septcmbm 1991 :711-7

short, Iiypcrplasia ofcosinophil precursors . As in the toxic oil WelhakDr.Lai,SsWevillaforhis sslduouswork inFacilitating manyafthe syndrome . there are mild to moderate elevations in liver studies ae which thi, review i, ba,ed . enzyme levels, and aldolose is frequently increased despite a normal or minimally elevated creatine kinase level . Muscle inflammation tends to spare the endomysium and, as in the References toxic oil syndrome, there is selective inflammation of intramus- culer nerves and muscle spindles (21 .22 .26.27). I, Tabuenca-tlliver JM. Discovery of toxic oil as the cause of the epidemic . Skin lesions and neuropathy . Many patients with the In : Grandjean P . Tarkowski S rd, . Toxic Oil Syndrome: Mass Food Poisoning in Spain . Report of a WHO Meeting : Madrid 21-25 March 1983 . ensinophilia-myalgia syndrome have skin lesions typical of World Health Organization Regional Office far Europe : Copenhagen . cosinophilic fasciitis, and these reports may reflect a lesion 1984. similar to the nonpitting edema described clinically in 2. Toxic Epidemic Syndrome Study Group . Toxic epidemic syndrome : Spain 1981 . Lancet 1982 :2 :697-7n2. patients with the toxic oil syndrome . Sclerodermiform hard- 3. KilhourneEM,RigauPerezJO,Heath CWJr .etal .Clinical epidemiology ening and thickening of the skin occur in the eosinophilia- of -c-oil syndrome . N EngI J Med 1983809 :1408-14 . myalgia syndrome . Alopecia. joint contractures and pulmo- 4. Rigau-Perez JG . Perez-Alvarez L. Duenas-Castro S . et al . Epidemiologic investigation of en oil-associated pneumonic pamtytic easinophilic syn- nary hypertension have also been reported . Axonal drome in Spain. Am J Epidemicl 1984 :119 :250-fin. neuropathy (mononcuritis multiplex) similar to that seen in 5. Tabuenca JM . Toxic allergic syndrome caused by ingestion of rapeseed patients wan chronic toxic oil syndrome occurs with the oil denatured with aniline . Lancet 19812 :567-8. ensinophilia-myalgia syndrome and is severe among some 6. VeliciaR .SureC.Martinet-BareedoF,Sanchez-TapiasJM,BmguerM, Rules J. Hepatic disease in the Spanish toxic oil syndrome : a thirty patients . with some becoming quadriplegic and ventilator month follow-up study . J Hepatol 1986:3:59-65 . dependent. As in the toxic oil syndrome, glucocorticoids are 7. Diaz de Rojas F . Ca.. Garcia M, Abaitua Batch, L Posada de Ia Paz M . effective in reducing the eosinophil count, but their overall Tabuenca .Oliver JM . Hepatic injury in the toxic oil syndrome (lever] . Hepatol 1985:5:166 . effect on disease progression, while probably positive, is less 8. Gilsanz V, Lupce Alvarez J, Serrano S, Simon J . Evolution of the clear-cut (26.27) . alimentary toxic nil syndrome due to denatured rapeseed oil . Arch Imam Respiratory syndrome . Many patients with the cosino- Med 1984 :144254-6 . 9. Alumso-Rui,A,Zea-MandozaAC,Seleoar-VaNnas3M .Raamora-Ripoll philia-myalgia syndrome have a respiratory syndrome, par- A . Beltran-Gutierrez J . Toxic oil syndrome: a syndrome with features ticularly early in their illness, typically involving cough and overlapping those of various forms or seleroderma . Semin Arthritis dyspnca . Interstitial pulmonary infiltrates and pleural effu- Rheum 1986:15:200-12 . 10 . Posada M . Diaz de Rojas F, Aborts Bond . 1, sions have been seen, but less frequently than in acute toxic . Castro Garcia M Tabuenca-OliverJM. Hyperemagalable states and the toxic nit syndrome oil syndrome . Overall, the respiratory manifestations of the Ilenerl. Ann Intent Med 1986:104:730 . eosinophilia-myalgia syndrome tend to be either nonexistent II . MarliecoTniloPt,NavasPalaciosJt,RicoyJR,elal,Pathology ofenew or substantially milder than the typical acute pulmonary toxic syndrome caused by ingestion ofadullerated ail in Spain. Vitchows Arch IPathol Anna) 1982 :397 :261-85. findings of the toxic oil syndrome . This difference in the 12 . RicoyJR.Coheir)A,RodeguezJ,Tellez1.Neuropathologicalstudio on degree of respiratory manifestations is perhaps the most the toxic syndrome related to adulterated oil in Spain . Brain 1983:106: 817-35 significant factor distinguishing the eosinophilia-myalgia . 13. Casado Flores J. Casquero J . Colomar P, et al . Sindrome levico par syndrome from the toxic oil syndrome (22,26.27) . mo de aevite adulterado . Cicto Enseyos Medicos 1982 :31 :9-12 . Implications . Continuing epidemiologic and laboratory 14. Canal R, Kilbourne EM . Oil ingestion and the tonic-oil syndrome : results work on the eosinophilia-myalgia syndrome appears likely to of a survey of residents of the Crcason neighbourhood in Madrid, Spain . In1 J Epidemiol 1987 :16:3-6 . lead soon to the discovery of the specific etiologic agent (28) . 15 . Diaz de Rojas F . CasieoGarcia M . Abaitua Borda I . el al. The association Such a discovery would have substantial implications for of oil ingestion with toxic-oil syndrome in Iwo convents . Am J Epidermal toxic oil syndrome research . Chemical analytic work di- 1987 :125:907-11 . rected toward examining the possibility that a compound 16 . Kilbourne EM. Bernert JT Jr. Posada de la Paz M. el a1. Chemical correlates of pathogenicity of oils related to the toxic-oil syndrome in similar or identical to the eosinophilia-myalgia syndrome Spain . Am J Epidemiol 1988 :127:1210-27 . agent existed in case-related toxic oil syndrome oil speci- 17 . .Aldridge WN . Toxic od syndrome ]editorial] . Hum Toxicot 1985:4 :231-5 . mens would become particularly important . 18. Vasquez Rencero A . Janet del Valle C . Maestro Duran R . Graciani Consume E. New aniline derivatives in cooking oils associated with the The recent report of a possible animal model of the toxic oil syndrome (letter) . Lancet 1983;2 :1124-5. eosinophilia-myalgia syndrome is also of interest (2g) . At- 19. Ten KM . Kephan GM . Posada M, et al . The participation oreosinophils tempts to develop a similar animal model of the toxic oil in the toxic oil syndrome . Clin Exp immune] 1990 :8'_ :313-7. syndrome should continue . Development of a toxic oil 200 de la Cruz RioxIL .OteoOchoaLA .SueiecScrditoA.ESUdtoevoluti,'o de la radiologia toracica en al sindrome mxico : anali,is de Ia respuesle al syndrome animal model, if applied in conjunction with nalamiento corticoids . Rev Clin Esp 1983 :169:37-41 . careful chemical work with oils selected by appropriate 2-1 . Hcrtzman PA. Blevtns W L. Mayer 1, Greenfield B . Ting M . Gleich GJ. epidemiologic techniques, could lead to more precise iden- Association of the eosinophilia-myalgia syndrome with the ingestion of tification of the toxic oil syndrome agent even if it hears little Iryptophan. N Englt Med 1991,3 2222 .869-73 . ', Swygen LA . Mats EE Sexell LE, Millne L . Folk H. Kilbourne EM . or no chemical similarity to the compound responsible for Eosinoplalia-myalgia syndrome : results of national surveillance . JAMA the eosinophilia-myalgia syndrome . 19911:264:1698-7113 .

ME MOWN, MM3 7

m- K My M AM mmw- R Kll III I- lphan,d 16.33;Z-7. 24 . Sluisker LD. Sl,d- RJ . G,O, BL, I- . sm~l-mdnm- JANIA 1990 .21~21~3-7. 25 . Belanp, EA. Hedb~ CW . (ile, -Nh-