4This section is based on the work of WHO (18), Abaitua Borda et al. (19) and Kilbourne et al. (20).
The first evidence of this incident (early May 1981) came from a number of children admitted to hospital with an unusual association of fever, pleuropneumonia, rash, myalgia and eosinophilia. Within a few weeks, some 20 000 people were affected in Madrid and in the north-western provinces of Spain; more than 300 died (18). This episode is unique for at least two reasons: the novelty and the etiology of the disease.
First, medical nosology had no previous record of toxic oil syndrome. Although currently interpreted as a non-necrotizing vasculitis affecting several organs, its pathogenesis, long-term sequelae and possible late complications are not yet understood.
Second, although a causal association has been established with a definite source of an exogenous agent, the agent itself (most likely a chemical) remains unknown. The source was allegedly edible olive oil contained in typically shaped, unlabelled, five-litre plastic bottles, sold by travelling salespeople in April and May of 1981. In fact, a sizeable proportion of this oil (hereafter called illegal oil) was rapeseed oil, imported for industrial use after denaturation with aniline (as required by Spanish law). It had later been illegally processed to look like olive oil, although substantial amounts of aniline derivatives were subsequently detected by chemical analysis. Assembling the evidence for a causal role of an agent so unusually defined took several years; dissent finally vanished as late as 1987.
Throughout May 1981, etiological clues were desperately needed to stop the spread of the disease. The distribution of hospital admissions was inconsistent with an infectious origin: no cases in children aged less than 6 months; no aggregation in hospitals, schools, barracks and underprivileged groups such as Gypsies; and resistance to treatment with antibiotics. Alert paediatricians first conceived the hypothesis of food poisoning. Over several weeks they had persisted in questioning the relatives of sick children about dietary habits: the use of illegal oil turned out to be common among children with the new syndrome and much less so in those hospitalized for other reasons. In the uncertainty prevailing at the time, these investigations - which some epidemiologists might consider crude - were carried out with a zeal and commitment reminiscent of John Snow’s search for clues to prevent the spread of cholera in London in the late summer of 1854.
An announcement by the Spanish Government on the role of the illegal oil on 10 June was followed by an official offer to exchange any suspect oil for guaranteed olive oil. This led to the creation of a bank of returned oils, sufficiently well organized to allow for the later identification of a number of containers of definitely case-related oils.
Case numbers started to subside in the second half of June, probably owing to both the Government’s announcement and a reduced availability of illegal oils in Spain.
Achieving more satisfactory proof of causality relied exclusively on observational epidemiological studies. No experimental model for toxic oil syndrome has been identified, and all attempts to reproduce it in animals treated with case-related oils have failed. Similarly, little information has yet been obtained from laboratory attempts to mimic the procedures that had plausibly been used for illegally refining denatured oils.
An ad hoc national plan for toxic oil syndrome was soon set up. Since 1986, research has been coordinated by the Spanish Social Security Health Research Fund (FIS), in collaboration with the Centers for Disease Control and Prevention in the United States and under the supervision of a joint Committee of FIS and the WHO Regional Office for Europe. Epidemiological investigations passed through a number of phases.
Within several weeks of the first suspicion, case-control studies independently carried out in different areas consistently confirmed the strong association between toxic oil syndrome and the consumption of illegal oil. Their design allowed for unquantifiable misclassification of exposure, recall bias and limited comparability between cases and controls. None provided evidence of a dose-response relationship. With a couple of exceptions, these early studies were not reported in peer-reviewed literature, which limited the interest of the international scientific community in the episode.
For some years, epidemiological findings were descriptive: reports of individual or small series of cases occurring after the spring of 1981 and/or in remote geographical areas. In the end, it was found that everyone whose symptoms corresponded to the clinical definition of toxic oil syndrome had consumed illegal oil produced or bought in the spring of 1981. In a couple of convents, it was found that only residents dressing their salads with the illegal oil were affected. At a time when the causes of the disease were chaotically debated in the mass media, identifying, evaluating and unravelling apparent clusters of cases was not easy. The exclusion of alternative hypotheses (such as non-correspondence to the clinical definition of toxic oil syndrome or non-consumption of illegal oil) required even more skill, scientific rigour and time than usually demanded by the demonstration of any negative. Eventually, more formal proof of causality came from comparisons - in a case-control model - of the concentration of aniline-derived impurities among case-related and non-case-related oils stored in the oil bank “toxico-epidemiologic studies” (20).
The etiological and clinical uncertainties surrounding toxic oil syndrome induced alertness for the occurrence of clusters of clinically comparable conditions. “Eosinophilia-myalgia syndrome” appeared several years later, associated with the consumption of one particular brand of tryptophan marketed in the United States. This syndrome does not show all the features of toxic oil syndrome, although its causes are as complex to understand. The point to emphasize, however, is that recent programmes developed jointly by the teams investigating both syndromes proved to be fruitful (21).
The clinical course of toxic oil syndrome deserved as much attention as its etiology. Exhaustive rosters of affected people were needed in order both to launch adequate prospective clinical studies and to ensure that attention was provided to everyone who needed it. In 1981/1982, the national plan for toxic oil syndrome compiled an official census of affected people to be used in programmes of financial compensation, social services and special medical care. At the time, diagnostic criteria for the syndrome may have not been consistently applied, so that the specificity of this census may have been lower than 100%. When FIS scientists started to design studies using this database, they were able to correct a sizeable number of errors and omissions by reviewing other medical files. The current (from 1985 onwards) version of the census includes over 20 000 people for whom a reasonably specific case definition of toxic oil syndrome has been verified. The sensitivity of the census is deemed satisfactory, on the basis of comparisons with lists of people requesting financial compensation and special medical care.
Since 1981, clinicians have consistently reported severe chronic changes in toxic oil syndrome patients, such as peripheral neuropathy, hepatopathy, scleroderma and pulmonary hypertension. In spite of the availability of an adequate database of affected people, clinical and epidemiological investigations have been hampered by drop-outs, inconsistencies in physicians’ attitudes towards reporting, recall bias and the inadequacy of control groups used as standards in the estimates of prevalent conditions. Currently the tendency is towards a retrospective estimate of the bias introduced by these limitations and towards a retrospective standardization in the collection of clinical data. It is assumed that follow-up will allow the identification of excess cases of cancer, if any.
Confidence in the completeness of the census allowed an assessment of late mortality. In Spain, mortality databases do not identify people by name. Thus, the deaths of people included in the census were retrospectively identified through direct contact with the families concerned and subsequently verified by other procedures. As yet, there is no evidence of any excess of late deaths, and findings (19) suggest decreased mortality among survivors of toxic oil syndrome as late as 1988; if confirmed, its interpretation will be complex but interesting. Analysing mortality by causes requires ad hoc studies on possible bias in death certificates.
This episode illustrates at least four issues in epidemiological studies following a chemical incident.
First, the biological plausibility of the only sustainable causal hypothesis was limited, but ad hoc studies centred on it turned out to be productive. The perception of the importance of apparently marginal, anecdotal episodes (such as the distribution of cases in convents) was crucial to the confirmation of causality. Equally crucial was, later, epidemiologists’ ability to design the “toxico-epidemiologic studies” (20) that formally provided proof of causality.
Second, in spite of the failure of experimental animal studies, the cooperation and exchange of ideas between toxicologists, chemists and epidemiologists has had a major role in the development of etiological knowledge. Over the years, the refinement of chemical analyses in the course of the “toxico-epidemiologic studies” has led to the retrospective identification of new substances in case-related oils, some of which may be candidate causes of toxic oil syndrome and worth being tested for toxicity in proper experimental systems.
Third, toxic oil syndrome, like other disasters, has probably modified individual lifestyles and interrelationships within the community, as suggested by the persisting decreased mortality, if confirmed. These aspects are as important and as difficult to investigate as more conventional etiological or clinical parameters.
Fourth, although the original goal of the victims’ associations was more related to civil rights than to epidemiology, the associations are taking part in a new dialogue in epidemiological research. This is most valuable for both the technical and the ethical aspects of investigations.