# Toxic oil syndrome

Toxic oil syndrome (TOS) or simply toxic syndrome (Spanish: síndrome del aceite tóxico or síndrome tóxico) is a musculoskeletal disease. A 1981 outbreak in Spain which affected about 25,600 people, with over 4,000 dying within a few months and a few thousand remaining disabled, is thought to have been caused by contaminated colza (rapeseed) oil. It was unique because of its size, the novelty of the clinical condition, and the complexity of its aetiology. Its first appearance was as a lung disease, with unusual features, though the symptoms initially resembled a lung infection. The disease appeared to be restricted to certain geographical localities, and several members of a family could be affected, even while their neighbours had no symptoms. Following the acute phase, a range of other chronic symptoms was apparent.

## Investigation

In 1987, TOS was found by epidemology to have been linked to the ingestion of a "food-grade" rapeseed oil containing aniline derivatives. Two separate studies on levels of fatty acid anilides (which would arise from reaction between aniline and fats) confirmed that case-related oils have an elevated level of this substance. In 1991, Posada de la Paz et al. found that French rapeseed oil was imported to Spain after denaturation with 2% aniline, allegedly for industrial use. (Spanish regulations of the time allowed imports of rapeseed oil only for industrial use, and only if it has been denatured with aniline to prevent use as food.) They concluded that the toxic oil was produced from this industrial oil, illegally refined to remove aniline, and mixed with other edible oils. In 1992, the WHO published a review on the knowledge on the incident up to that point.
During the 1990s, improved chemical methods found a new class of chemicals in multiple samples of toxic oil: 3-(N-phenylamino)-1,2-propanediol (abbreviated as PAP) and its esters, which would also be produced as aniline reacts with triglycerides. The factory responsible for illegally refining the oil was identified as Industria Trianera de Hidrogenación (ITH) of Seville.
The WHO has since then tried to recreate the poisoning in laboratory animals with less-than-satisfactory results. Specifically, three possible causative agents of TOS are PAP (3-(N-phenylamino)-1,2-propanediol), the 1,2-dioleoyl ester of PAP (abbreviated OOPAP), and the 3-oleoyl ester of PAP (abbreviated OPAP). These three compounds are formed by means of similar chemical processes, and oil that contains one of the three substances is likely to contain the other two. Oil samples that are suspected to have been ingested by people who later developed TOS often contain all three of these contaminants (among other substances), but are most likely to contain OOPAP. However, when these three substances were given to laboratory animals, OOPAP was not acutely toxic, PAP was toxic only after injection, but not after oral administration, and OPAP was toxic only after injection of high doses. Therefore, none of these three substances is thought to cause TOS. Similar results were obtained after administration of fatty acid anilides.

## Alternative theory

The conclusion of the Joint WHO/CISAT Scientific Committee for the Toxic Oil Syndrome from 2002, that oil was the cause for TOS, is based only on epidemiological evidence, since up to now, experimental studies performed in a variety of laboratory animals have failed to reproduce the symptoms of human TOS. None of the in vivo or in vitro studies performed with toxic-oil-specific components, such as fatty acid anilides, and esters of PAP, have provided evidence that these markers are causally involved in the pathogenesis of TOS.
Data discrepancies combined with both a high level of secrecy surrounding the huge investigation and the fact that the first cases of the syndrome were located in Madrid (near the U.S. military base in Torrejón de Ardoz) spread the idea of a conspiracy. Several of those affected by TOS claim they never consumed any of the tainted oil products. Furthermore, the tainted oil was primarily sold in low-cost street markets; yet, a considerable percentage of the patients were wealthy. Another theory suggests the toxic reaction was triggered by organophosphate poisoning (e. g., from pesticide residues in tomatoes) and covered up by the Spanish government and the WHO.