Possible etiologic agents for toxic oil syndrome: Fatty acid esters of 3-(N-phenylamino)-1,2-propanediol

Abstract

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0-38) and 21.9 (95% 6.1-78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

The Spanish Toxic Oil Syndrome 20 Years after Its Onset: A Multidisciplinary Review of Scientific Knowledge

“…Therefore, in statistical terms, the association was stronger for OO PAP than for OA (28). OO PAP was also found in a sample of oil retrieved from the ITH refinery, but not in an oil derived from aniline-denatured rapeseed oil illegally produced at other refineries nor in unrefined anilinedenatured samples of rapeseed oil sent to ITH (26). Something unique must have occurred to a subset of aniline-denatured oils at ITH that both rendered them toxic and led to the appearance of OO PAP; these two consequences are not necessarily interrelated.…”

“…In 1995, PAP esters were found in two samples of rapeseed oil after, but not before, bringing them to a temperature of 300°C for 4 hr (26). Subsequent experiments at the Instituto de la Grasa in Seville (29,30) expanded these findings: Heating at 300°C but not at 250°C led to the formation of PAP esters.…”

“…A new group of chemicals associated with the risk of disease were so identified (26): the fatty acid esters of 3-(Nphenylamino)-1,2-propanediol (PAP)-its 1-oleyl-ester (O PAP) and 1,2-di-oleyl ester (OO PAP) (Figure 1). Indeed, their presence in case-related oils was reported as early as 1984 (27).…”

“…Oils from the latter contained no PAP esters and less OA than did case-related oils (26). This finally led to firmer hypotheses on how the refining stages could have been implemented when the toxic oil was produced.…”

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

“…Analysis of TOS case-related oils has shown that a number of contaminants were formed through the reaction between components of the oil and the aniline denaturant (Hill et al, 1995;Bernert et al, 1987). The BIOMEDICAL CHROMATOGRAPHY Biomed.…”