Toxic Oil Syndrome: A new disease A perspective of interaction between host and environment - PowerPoint PPT Presentation

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Toxic Oil Syndrome: A new disease A perspective of interaction between host and environment

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... of the disease with scleroderma and neuropathy arouse my interest as we had been ... Neuropathy. Contractures. Hepatopathy. Pulmonary Hypertension. Sicca Syndrome ... – PowerPoint PPT presentation

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Title: Toxic Oil Syndrome: A new disease A perspective of interaction between host and environment


1
Toxic Oil SyndromeA new disease A perspective
of interaction between host and environment
  • Manuel Posada de la Paz, M.D.
  • Toxic Oil Research Centre
  • Centro de Investigación sobre el
  • Síndrome del Aceite Tóxico (CISAT)
  • Instituto de Salud Carlos III

2
In 1981 when the epidemic started, and in my
position as a specialist in internal medicine I
had to face a strange lung disease.
Inmediately, my colleagues and I were surprised
by an illness with the appearance of an
infectious disease but presenting a clinical
course that could not be improved by the use of
antibiotics. Most of our patients came from the
same family and same geographical areas. The
evolution of the disease with scleroderma and
neuropathy arouse my interest as we had been
working in scleroderma and this situation gave us
the opportunity to try to know what could be the
cause and pathogenesis of this type of illness
Later, I was involved in clinical investigation
and finally I was introduced in the epidemiology
field. Since then, I have been devoted to the
study of the etiology and pathogenesis of this
interesting disease.
3
Mystery What is this Disease? What is its
origin? How can we prevent it?
4
TOXIC OIL SYNDROME A Brief Summary
  • New Disease
  • Spain, 1981
  • Point Source Epidemic
  • Rapeseed Oil Denatured with 2 Aniline
  • Systemic Disease
  • Three Clinical Phases
  • Vasculopathy (Endothelium)
  • Evolution Unknown

Rate of Toxic Oil Syndrome Cases by Province
Number of cases per 100.000
gt290 211-290 141-210 140-71 1-71 no
5
Descriptive Epidemiology
  • First Case 1st May, 1981
  • 20,643 affected
  • 10,000 hospital admissions
  • 80 deaths in the first month
  • 303 deaths as to 31 Dec 1982
  • 2,500 deaths by all causes
  • Ratio M/F 1.5/1
  • Central and northwestern areas

Males
Females
0-9 40-49 gt80 20-29 60-69
Epidemic Curve for TOS
May 1 June 10 August 1 October 15
1981, weeks
6
Toxic Oil Syndrome Acute Phase
  • Rash
  • Interstitial pattern in X-ray
  • Pruritus
  • Eosinophilia
  • Fever
  • Cramps
  • Cephalea

7
Toxic Oil Syndrome Chronic Phase
  • Scleroderma
  • Neuropathy
  • Contractures
  • Hepatopathy
  • Pulmonary Hypertension
  • Sicca Syndrome

8
  • Frequency of Major Events in TOS
  • Acute Lung disease 70.0
  • Sclerodermiform changes 21.3
  • Neuropathy 32.0
  • Pulmonary Hypertension 8.2
  • Liver disease 7.2
  • Sicca Syndrome 35.0
  • Eosinophilia 78.0
  • Myalgias 80.0

9

First Case-Control study Hospital Niño
Jesús
Case Control



Consumed fraudulent oil Did not consume

62 4 0 58
Odds Ratio gt 1,000 CI 95 ( 145.6 - Inf)
10

Second Group of Studies Navas del Marqués study
Study number 1 Study
number 2
Case Control
Case Control

Consumed fraudulent oil Did not consume
Bought oil from good woman in April or
May,1981 Bought oil from other salesmen or
other time

24 5 12 18
27 0
30 108
Odds Ratio194 Odds Ratio7.2 CI 95 (19.2 -
Inf) CI 95 (2.2 - 23.2)
11
Case Control Studies Made at the Beginnig of the
TOS Outbreak after the Official Anouncement of
the Cause
  • Location Cases Controls OR (CI) or p value
  • Pozuelo 42/48 32/96 21 (7.7-64.8)
  • Chozas (León) 19/19 15/19 Inf. (p0.05)
  • Cerezo (Seg) 13/13 25/44 Inf (p0.002)
  • San Cristobal 10/10 8/19 Inf (p0.002)
  • Bocigas (Soria) 11/11 22/33 Inf (p0.03)
  • Arconada (Pal) 18/18 9/21 Inf (p0.001)
  • Colmenar (Mad)16/20 6/20 9.3 (1.8-52.7)
  • Madrid 52/58 615/1,725 15.6 (6.7-44.8)
  • Madrid (nuns) 23/35 0/56 Inf (p4x10-13)
  • Madrid (nuns) 42/43 0/70 Inf (p2.3x10-31)

12
Ethiologic ResearchToxi-Epi Study
  • Accuracy in the definition of the vehicle of
    exposure
  • Dose-Response relationship

0 200 400 600 800 1000 1200 1400
Oleyl Anilide (m g / g )
13
1 2 3 4
Typical Bottle (number 1) and Contents in
Oleyl-anilide
positive
negative
Potential Misclassification Bias in the First
Case-Control Studies
14

TOXI-EPI- I study TOXI-EPI- II study
(Oleyl-anilides)
(Oleyl-anilides)
Case Control
Case Control


18 11
16 48
30 10 29 60
-
Odds Ratio4.91
Odds Ratio6.21 CI 95 (1.74-14.01)
CI 95 (2.50-16.04)
15
(No Transcript)
16
Dose-Response OOPAP against Oleyl-anilide
OOPAP
Log Odds Ratio
Oleyl Anilide
Oleyl Anilide and OOPAP( g / g)
m
17
Rapeseed oil not denatured sold in France
Refineries
OA OOPAP Contents Contents

lt100 ppm Not detectable
Catalonian Circuit
Sabater
France
Danesa-Bau
450 ppm Not detectable
Central Circuit
Aniline added
ITH- Seville
1,900 ppm 150 ppm
18
EPIDEMIC CURVE FOR TOS
New cases
ITH
Weeks
May 1 June 10 August 1 October 15
Weeks
May 1
June 10
August 1
October 15
1981
19
  • IMMUNOLOGICAL MECHANISM(S)
  • LIKELY INVOLVED
  • Some humoral evidence
  • - Eosinophilia
  • - In acute phase of soluble IL-2 receptor
  • - Serum Major Basic Protein increased in all
    phases
  • - Major Basic Protein deposits in tissues from
    acute phase (eosinophile degranulation)
  • - GM-CSF in acute phase
  • T-Cell activation

20
  • IMMUNOLOGICAL MECHANISM(S)
  • LIKELY INVOLVED- II
  • Some histological evidence
  • IL-4 and IL-5 deposits in cases pulmonary tissues
    from the deceased in the acute phase
  • High proportion of HLA DR2 in death patients
  • Controversial findings with HLA DR3-DR4 and DQ3-8
  • CD4 lymphocytes surrounded the main lesions
  • NAT2 genotype is a risk factor of the disease

21
TOS COHORT Standart Mortality Ratio
22
Conclusions
  • Our data suggest that TOS is a Point Source
    Epidemic. This assertion is based on
  • Linkage between rapeseed oil denatured with 2
    aniline and the disease
  • Presence of a chemical marker (OOPAP) in the oil
    refined in ITH (Seville)
  • The OOPAPs are new chemical compounds very
    difficult to obtain in a regular refining process
  • Causal agent responsible for this disease is
    produced by only one or various compounds from
    OOPAPs derivatives
  • Further studies in toxicology are being performed
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