HISTORY
In
the early 1980s, Spanish laws banned the importation
of
rapeseed oil for human consumption to protect the
Spanish
olive oil market. These laws required the
denaturation
of imported rapeseed oil with aniline,
methylene
blue, or castor oil as a means to make this
imported
oil unfi t for human consumption. During late
1980
and early 1981, a substantial amount of aniline -
denatured
rapeseed oil imported from France was
fraudulently
diverted for human consumption through
Catalonia.
These oils were diluted with other edible oils,
refi
ned, and resold through a network of distributors
and
itinerant salesmen. Although these oils contained
aniline,
the toxic oil syndrome was apparently not associated
with
the aniline.
During
the fi rst quarter of 1981, an oil distributor
based
in the center of Madrid named RAELCA entered
the
illicit oil sales market with mixed aniline - denatured
rapeseed
oil. In March 1981, RAELCA purchased fi ve
lots
of aniline - denatured rapeseed oil from two French
food
oil companies, and they shipped three lots to the
ITH
oil refi nery in Seville. The other two lots went to
the
Danesa Bau refi nery in Madrid. Although the denatured
oils
were intended for industrial use, roadside
vendors
sold the oils as “ olive oil ” to residents over a
2
- month period. Most of the cases of toxic oil syndrome
appeared
in the period from May to August 1981.
Figure displays the number of cases of toxic oil syndrome
diagnosed
in 1981. Epidemiological studies concluded
that
the ITH oil refi nery was the point source for
the
epidemic.
EXPOSURE
Source
The
exact causal agent in the contaminated oil involved
with
toxic oil syndrome remains unknown, in part,
because
of the many potential toxins in denatured
aniline
compounds associated with this illness. In a study
of
toxic oil syndrome - associated oils, fractionation of
the
oils by high performance liquid with ultraviolet
detection
(HPLC/UV) and analysis by high performance
liquid
chromatography/atmospheric pressure
chemical
ionization/ tandem mass spectrometry (HPLC/
APCI/MS/MS)
demonstrated 115 aniline derivatives
from
nine aniline - related families of chemicals. Toxic
oil
syndrome is a unique combination of vasculitis,
thrombosis,
and immunologic changes (e.g., T - lymphocyte
activation,
cytokine release) that differs from the
toxicity
previously associated with refi nery products,
additives,
or contaminants.The full spectrum of toxic
oil
syndrome has not been reproduced in experimental
animals. The two suspected groups of toxic compounds
are
fatty acid anilides and amino - propanediol derivatives
(fatty
acid mono - and di - esters). Analysis of contaminated
oil
samples indicates that pentachlorophenol
and
pentachloroanisole were not etiological agents of
toxic
oil syndrome.
Food
Processing
In
contrast to other illicit rapeseed oil distributors,
RAELCA
mixed the denatured rapeseed oil with other
oils
after the refi ning process. All other illicit refi ners of
denatured
rapeseed oil in Catalonia mixed the denatured
and
edible oils before refi ning the adulterated oils.
The
processing of the fraudulently diverted rapeseed oil
probably
contributed to the formation of toxic compounds
in
the oil. High temperatures during deodorization
catalyzed
the reaction of 2% aniline with triglycerides
in
the rapeseed oil associated with toxic oil syndrome.
In
experimental studies, the yield of 3 - ( N - phenylamino) -
1,2
- propanediol (PAP) esters in toxic oil syndrome is
highest
at 250 – 300 ° C ( ∼ 480–570 ° F), similar to those
temperatures
achieved during the deodorizing step of oil
refi
ning. These studies indicate that the heating of denatured
oil
samples stored for 3 weeks yields higher concentrations
of
potentially toxic PAP esters compared
with
samples stored for 1 week. Distillations times did
not
signifi cantly affect the formation of fatty acid anilide
compounds.
The development of toxic oil syndrome following
the
ingestion of denatured rapeseed oil stored for
about
1 year suggests that the toxic compounds in these
contaminated
cooking oils are stable for at least 1 year.
DOSE
RESPONSE
Dose
response in toxic oil syndrome was evaluated by
a
case control study known as the “ Toxi - Epi Study, ”
which
followed sales and distribution chains of the
fraudulently
distributed rapeseed oils using the chemical
markers,
oleyl - anilide and di - oleyl - 3 - phenylamino -
1,2
- propanediol (OOPAP). The content of these
compounds
varied several fold in different samples of
contaminated
cooking oil. Cooking oil containers with
a
characteristic shape purchased by residents were
traced
back to the ITH oil refi nery in Seville in southern
Spain.
Analytical studies showed a linear statistical correlation
between
the concentration of the chemical
markers
detected in the refi nery ’ s oil and the log of the
odds
ratio for dose - response. 50 Rapeseed oil concentrations
of
oleyl - anilide and OOPAP traced to this plant
were
1900 ppm and 150 ppm, respectively.
CLINICAL
RESPONSE
The
fi rst cases of toxic oil syndrome were reported on
May
1, 1981 in central and northwestern Spain. Initial
epidemiological
studies demonstrated clustering in incidence
and
mortality for toxic oil syndrome in households
distributed
along transportation routes throughout
the
affected regions. In July 1981, Spanish health offi -
cials
announced that a fraudulently distributed, industrial
oil
sold as edible cooking oil was the etiology of
this
illness, initially termed pneumonic paralytic eosinophilic
syndrome.The Spanish government subsequently
initiated
a consumer exchange program for
olive
oil, and they stockpiled the contaminated oil for
further
study.In 1983, the World Health Organization
named
the illness toxic oil syndrome. The offi cial
census
originally consisted of records of patients with
clinically
suspected toxic oil syndrome that did not necessarily
fulfi
ll the case defi nition of the 1981 Spanish
Clinical
Commission. A 1987 review of these records by
the
World Health Organization Regional Offi ce for
Europe
Scientifi c Committee for the Investigation of
the
Toxic Oil Syndrome indicated that about 20,000
people
were affected with over 10,000 hospitalizations.
Although
during the fi rst few years about 300 patients
died
of toxic oil syndrome, the overall mortality of the
cohort
with toxic oil syndrome was not elevated after
the
fi rst year of the epidemic when compared with the
general
Spanish population.
Toxic
oil syndrome is a progressive multisystemic
disease
with three distinct clinical phases (acute, intermediate,
chronic).
The average latency period was about
4
to 7 days after the ingestion of the contaminated oil
with
a maximum of about 10 days. 56 The basic underlying
pathological
lesion is a nonnecrotizing vasculitis with
associated
thrombotic events. Common initial symptoms
of
toxic oil syndrome included fever, cough, dyspnea, and
chest
pain. Other acute symptoms included urticarial
rash,
pruritus, abdominal cramping, and headache. The
differential
diagnosis for toxic oil syndrome includes
other
autoimmune disorders such as eosinophilia -
myalgia
syndrome, eosinophilic fasciitis, systemic sclerosis,
scleroderma,
and systemic lupus erythematosus.
Porphyria
cutanea tarda did not occur in these patients.
Acute
(Pulmonary)
The
characteristic manifestation of the acute phase is the
development
of noncardiogenic pulmonary edema with
dyspnea,
alveolar - interstitial infi ltrates with or without
pleural
effusions, peripheral eosinophilia, fever, and rash.
Most
patients recovered from this early pneumonic
phase
of the illness. Deaths during this phase occurred
from
respiratory insuffi ciency initially from degeneration
of
type I and type II pneumocytes and later from
thromboembolic
complications. During the acute phase
(i.e.,
fi rst 2 months), the primary lesion occurs in the
endothelium
of multiple organs with the exception of the
central
nervous system. Severe myalgias and muscle
cramps
occur at the end of the acute phase.
Intermediate
(Thrombotic)
About
60% of the patients with the acute phase progress
to
the intermediate phase that involved the development
of
sensory peripheral neuropathy along with
intense
myalgias, dermal induration, and weight loss.
More
serious complications during this phase began
about
2 months after the onset of illness, including pulmonary
hypertension
and thromboembolism of large
vessels.
In severe cases, histological examination demonstrated
proliferation
of the intimal lining of the vessels
along
with fi brosis and thrombosis.
Chronic
(Neuromuscular)
Approximately
2 months after the onset of the intermediate
phase,
the chronic phase of toxic oil syndrome
began,
characterized by sclerodermiform changes, motor
neuropathy,
musculoskeletal contractures, muscle
wasting,
myalgias, muscle cramps, weight loss, limited
joint
mobility, peripheral eosinophilia, hepatomegaly,
pulmonary
hypertension, and Sj ö gren syndrome. 60 Some
patients
developed this chronic phase without experiencing
the
acute pneumonic phase. The most common
persistent
symptoms were cough and dyspnea with
about
20% of affected patients developing reduction in
the
carbon monoxide diffusing capacity.Mortality in
the
chronic phase was primarily due to infectious complications
of
respiratory insuffi ciency secondary to neuromuscular
weakness,
thromboembolism, or pulmonary
hypertension
with cor pulmonale. A minority of toxic
oil
syndrome patients developed severe pulmonary
arterial
hypertension during exercise over 20 years after
exposure.Long - term follow - up studies of survivors
suggest
reduction in the quality of life of these patients
with
elevated rates of depression (odds ratio [OR] =
9.66),
functional disabilities (OR = 4.74), and psychosocial
disabilities
(OR = 2.82).
Mortality
was high during the fi rst year, with a signifi
cant
decline in mortality rates in subsequent years.
Most
of the decline in mortality was observed in elderly
populations;
however, the mortality rate in women < 40
years
of age increased as a result of complications from
pulmonary
hypertension.Concurrent clustering of
incidence
and mortality in toxic oil syndrome suggested
that
a genetic predisposition determines the severity of
toxic
oil syndrome. Linkage mapping of the human
genome
revealed increased mortality in patients with a
chromosome
6 - associated risk factor for the HLA - DR2
phenotype.Studies in enzyme mechanics implicate a
role
for impaired hepatic acetylation in mediating individual
susceptibilities
to toxic oil syndrome.
DIAGNOSTIC
TESTING
Analytical
Methods
Analytical
methods to identify and quantify OOPAP
and
other PAPs in contaminated cooking oil samples
include
high performance liquid chromatography/atmospheric
pressure
ionization/tandem mass spectrometry
(HPLC/API/MS/MS)
and HPLC/MS.
Biomarkers
The
analysis of contaminated oil was complicated by
poor
identifi cation markers on cooking oil bottles during
the
recall process. Two case control studies suggested a
dose
- related association between the presence of three
fatty
acid anilide compounds (oleyl, linoleyl, palmityl)
and
the risk of developing toxic oil syndrome. Of
these
fatty acid anilide compounds, oleyl anilide occurred
in
the highest concentration. Subsequent analyses
suggested
that 3 - ( N - phenylamino) - 1,2 - propanediol
(DEPAP),
a by - product of the same reaction of aniline
with
triglycerides, is an equally sensitive and a more
specifi
c biomarker of toxic oil syndrome than fatty
anilide
compounds. 71 Animal studies suggest that the
liver
converts fatty acid mono - and diesters of 3 - ( N -
phenylamino)propane
- 1,2 - diol to 3 - (4 ′ - hydroxyphenylamino)
-
propane - 1,2 - diol, which generates the
electrophilic
metabolite quinoneimine intermediate - 2
(QI
- 2). However, the specifi c chemical causing toxic
oil
syndrome has not been identifi ed.
Abnormalities
Laboratory
changes associated with toxic oil syndrome
include
peripheral eosinophilia, hypertriglyceridemia,
and
coagulation disorders in patients with liver involvement.
Analytical
studies of toxic oil syndrome patients
demonstrate
eosinophilia and a high concentration of
mRNA
for T - helper - 2 cytokines, IL - 4 and IL - 5, in the
lungs. Antemortem sera from fatal cases of toxic oil
syndrome
also contained elevated serum IL - 2R and
total
IgE concentrations along with a high frequency of
HLA
- DR2 on chromosome 6. The sinus and atrioventricular
nodes
may exhibit dense fi brosis, hemorrhages,
or
cystic degeneration similar to fi ndings in scleroderma
and
systemic lupus erythematosus. Coronary arteries
may
exhibit focal fi bromuscular dysplasia and cystic
myointimal
degeneration with embolization. Histopathological
analyses
show lymphocytic infl ammatory lesions
of
coronary arteries and the cardiac conduction system,
similar
to the fi ndings in eosinophilia - myalgia syndrome.
Cardiac
lesions associated with eosinophilia - myalgia
syndrome,
however, are distinguished by cytotoxic T -
cells
directed against cardiac neural structures and sinus
nodal
myocytes, whereas toxic oil syndrome cardiac
lesions
are characterized by a prominence of B cells and
T
- helper cells.
Chest
x - ray demonstrates an interstitial - alveolar
pattern
with progression to acute respiratory distress
syndrome
(adult respiratory distress syndrome or
ARDS)
in the acute phase of toxic oil syndrome. Eosinophilia
is
a universal fi nding in toxic oil syndrome
patients. Hypoxemia, respiratory alkalosis, and an
increased
alveolar - arterial oxygen gradient (A - a gradient)
as
determined by arterial blood gases are common
in
patients with severe toxic oil syndrome - induced noncardiogenic
pulmonary
edema during the acute phase.
TREATMENT
During
the acute phase, respiratory compromise from
ARDS
is the most serious complications of toxic oil
syndrome.
Patients with toxic oil syndrome are also at
increased
risk of cardiovascular disease that may manifest
several
years after exposure. Echocardiography,
cholesterol
screening, and weight management are effective
tools
for the screening and detection of cardiovascular
sequelae
in patients with toxic oil syndrome.
Long
- term neuromuscular and articular complaints are
prominent,
and abnormalities are treated symptomatically.
Patients should be monitored for the prominent
risk
factors most closely associated with early mortality:
female
< 40 years old, liver disease, pulmonary hypertension,
frequent
pulmonary infections, motor neuropathy,
and
eosinophilia.
