Pergamon
PII: S0003-4878(97)00047-l
Ann. occup. Hvg.. Vol. 42. No. I. pp. 33 36. 1998
c 1998 British Occupational Hygiene Society
Published by Elsevier Science Ltd. All rights reserved
Printed in Great Britain.
0003 4878 98SI9.O0 + 0.O0
Medhaumnsmms o f Occoiipattiioiniall Asttlhinnia lundlincei toy
FREDERIC OESCHAMPS,*f ALAIN PREVOST.J FRANCOIS
SERGE KOCHMANJ
and
* Department oj'Occupational Diseases, Hopital Maison Blanche, 45 Rue Cognacq—Jay 51092, Reims
Cedes, France; t/nstitut Jean-Goclinot, 1 Avenue clu General Koenig, 51056, Reims Cedex, France;
%Department of Respiratory and Allergic Diseases, Hopital Maison Blanche, 45 Rue Cognacq—Jay
51092, Reims Cedex, France
Isocyanates are some of the most important low molecular weight chemicals associated with
occupational asthma. These compounds are often volatile and they are highly reactive on mucous
membranes, especially the conjunctivae and respiratory tract. Despite numerous data derived
from experimental and clinical investigations, there is no agreement concerning the real
mechanisms involved in isocyanate-induced occupational asthma. In fact, the cause of occupational
asthma is multifactorial. The aim of this paper is to review the involved physiological causes of
isocyanate-induced asthma; the main mechanisms are immunological, pharmacological and/or
irritative. © 1998 British Occupational Hygiene Society. Published by Elsevier Science Ltd.
after only a few days or weeks. Late asthmatic reactions are more frequent than early ones for sick workers exposed to isocyanate (Mapp el al., 1988), and
are usually more severe and last longer. Patients with
these features of asthma are often symptomatic several
months or years after the end of exposure (Fabbri and
Mapp. 1992; O'Byrne et al., 1987). Finally, little is
known regarding the levels of exposure necessary to
produce asthma. In general, the pathological features
observed in isocyanate-induced asthma are not
different from those of status asthmaticus seen in nonoccupational asthma (Hogg, 1985). Lungs are overinflated, airways are plugged with mucus containing
abundant exudate, and the bronchial epithelium is
extensively desquamated. The mucosa is oedematous
and markedly infiltrated with eosinophils.
INTRODUCTION
Isocyanate-induced asthma is probably the most frequent type of occupational asthma in industrial countries (Diller, 1980), but the mechanisms of acute and
chronic toxicity of isocyanates are still largely
unknown.
The term 'isocyanate' should be understood as the
collective term characterizing substances with free
NCO-groups, therefore including mono-isocyanates,
di-isocyanates. poly-isocyanates and prepolymers
(Fig. I).
The aim of this paper is to update the different
mechanisms of isocyanate-induced asthma.
Although isocyanate-induced asthma has been
recognized for over 40 years (Fucks and Valade,
1951), the mechanisms of the reaction are still highly
controversial (Karol, 1988). Numerous recent data
derived from experimental and clinical investigations
suggest that the cause of isocyanate-induced occupational asthma is multifactorial. Consequently, we
are far from having an unitary model (Pauli and
Kopferschmitt-Kubler, 1991).
A feature of isocyanate-induced asthma is that
symptoms develop in only a small percentage of
exposed workers (5-10%) (Priam el al., 1988; McKay
and Brooks, 1984). A latent period after first exposure
of 3 or 4 years is more frequent than acute symptoms
In effect, three main physiological origins can be
identified. There are the pharmacological (Dewair et
al., 1983), the irritant (Bernstein, 1982; Davies and
Pepys. 1979), and the immunological mechanisms
(Karol, 1981, 1986). These may act separately or simultaneously, and their presence varies with individual
patients and occurences of exposure.
PHARMACOLOGICAL THEORY
Isocyanates act as partial adrenergic receptor agonists (Butcher et al., 1980). The pharmacological theory
of increased beta-adrenergic blockade is a possibility
(Cartier et al., 1989). Davies el al. (1977) have suggested that isocyanates reduce the ability of beta-adre-
tAuthor to whom correspondence should be addressed.
Received I May 1997; in final form 8 September 1997.
33
F. Deschamps el al.
34
R-N=C=O
R-NH2
©
C0C12
PI ISOCYANATE
ISOCYANATE
PHOSGEN
R-N=C=O
R-NH-OO
1
l
O-R'-O-
OH
N
! 1
C
+
1 1
0
R'-OH
,
6H
-O-C
'l
NH
o"
DI ISOCYANATE
POLYHYDROXYL
POLYURETHANE
Fig. 1. Synthesis of isocyanates and polyurethane.
nergic receptors to produce cyclic adenosine
monophosphate in sufficient amounts to maintain
bronchial tone (Mapp el al., 1988).
Isocyanates may cause a pharmacological disturbance of the control of the bronchial smooth muscle; toluene di-isocyanate (TDI) is found to affect prostaglandin receptors in vitro (Wass and Belin, 1989).
However, it is unclear if these results reflect the in
vivo conditions. Furthermore, isocyanates have been
shown to be potent inhibitors of acetylcholinesterase
from human erythrocytes (Wass and Belin, 1989). Isocyanate-induced asthma could in fact result in a
chronic irreversible dysfunction of autonomic control
of bronchial tone, or a hyper-reactivity of bronchial
smooth muscle, or a chronic inflammatory reaction in
airways (Paggiaro el al., 1988).
Tachykinins may play a critical role in the increase
of in vivo responsiveness of bronchial smooth muscle
which follows exposure to isocyanate in guinea pigs.
This effect may be due both to release of tachykinins
and to inhibition of neutral endopeptidase or cell
membrane-bound enzyme which cleaves tachykinins
(Fabbriand Mapp, 1992).
IRRITATIVE THEORY
The disaster which occurred at Bhopal India, in
December 1984, tragically confirmed the acute toxicity of isocyanates (Bignon el al., 1988).
High concentrations (above 500 ppb) produce acute
inflammation of the conjunctivae and of the mucous
membranes of the upper and lower respiratory tract.
The mechanism is one of direct toxicity and the sever-
ity of the response depends on the level and duration
of exposure (Diem el al., 1982). There is a variable
inflammatory infiltrate of the bronchi. It is assessed by
broncho-alveolar lavage and mucosal biopsy. These
investigations show increased percentages of eosinophils (Saetta el al., 1992) or sometimes of neutrophils.
Chemotaxis and random migration of eosinophils and
neutrophils are increased compared with the normal
range. Electron microscopy shows that the basement
membrane thickness is similar in control subjects. In
vivo studies show after a single exposure to high isocyanate atmospheres (55mgm~ 3 ) rapid coagulation
and necrosis of the bronchial epithelium. Animals die
due to occlusion of bronchioles by necrotic tissue,
inflammation and edema (Duncan el al., 1962). No
significant correlation is found between histological
parameters and physiological data (Saetta el al.,
1992). In fact, this inflammatory cell reaction is nonspecific for isocyanate-induced asthma.
Reactive airway disease syndrome (RADS) is an
example of irritant-induced asthma. RADS can be
generated by other chemicals. It is defined as onset of
symptoms after a single overexposure to isocyanates
within 24 h after the first contact. There is a persistence
of symptoms for at least 3 months, of simulated
asthma with cough, wheeze and dyspnea (Brooks el
al., 1985).
IMMUNOLOCICAL THEORY
Several immunological mechanisms may be
involved. Atopy does not seem to be a factor of individual predisposition to isocyanate-induced asthma
Isocyanate induced asthma
(Diller, 1988). Likewise, no geographical or ethnical
effect on prevalence is found. Isocyanate asthma is a
complex syndrome. Isocyanates combine covalently
with body proteins to form hapten-protein conjugates
(Kochman et al., 1990) (Fig. 2). Isocyanate-specific
IgE is present in a small number of individuals (Butcher el al., 1980; Prevost et al., 1994). An association
between the presence of isocyanate-specific IgE,
immediate symptoms and heavy exposure to isocyanate is found (Keskinen et al., 1988). In contrast,
most delayed reactions give negative results with
Radio-allergo-sorbent test (RAST). High total IgE
levels are frequently associated with RAST positivity.
However, all these features are not fully understood.
In the studies related to isocyanate-exposed workers,
an average of 15% of symptomatic subjects have these
specific antibodies. In fact positive RAST varies from
0% (Keskinen et al., 1988) to 75% (Danks et al.,
1981).
Intracutaneous skin testing with human serum
albumin (HSA) bound to isocyanate generally produces significant immediate-type wheal and flare reactions in a quarter of symptomatic and none in
asymptomatic patients (Karol et al., 1978; Baur et al.,
1984). This test has a good specificity but a poor
sensitivity. In fact, there is a good correlation between
RAST and the results of skin testing. These give evidence of the existence of an immunologically-
REACTION OF TDI ON PROTEIN
CH3
N=C=O
N=C=O
(+)NH2
TOLUENE PI ISOCYANATE
PROTEI1
CH3
35
mediated sensitization of type I to isocyanate components.
IgG antibodies may be produced in patients sensitized to isocyanates. Isocyanate specific IgG have
been found in some instances, but not in others. Qualitative and quantitative aspects of isocyanate specific
IgG antibodies are similar, even higher than IgE levels
(Karol and Kamat, 1988; Baur et al., 1994; Baur,
1986). Recent assessments of specific IgG antibodies
against isocyanate-induced asthma showed a close
association with positive bronchial inhalation (Cartier
et ai, 1989). Higher levels of isocyanate humanserum-albumin specific IgG can be observed in
asymptomatic persons exposed to isocyanate with
lower frequency, than in symptomatic patients (Baur
etal., 1994).
Levels of IgM specific antibodies to isocyanates
have also been found to be increased in humans in a
particular circumstance (Karol and Kamat, 1988).
This was the case of the population exposed to the
industrial gas leak in Bhopal on 2 December 1984.
The exposure to methyl-isocyanate was high and
acute. But most of these antibodies were not detected
one year after the acute exposure.
Regarding the T-cell mediated mechanism, it has
been suggested that allergen-induced delayed asthmatic reactions are analogous to allergen-induced
delayed cutaneous reactions (Erjefalt and Persson,
1992). This is characterized by an acute inflammatory
reaction with infiltration of the bronchial mucosa by
neutrophils, eosinophils and mononuclear cells. Broncho-constriction and airway inflammation are
involved and the presence of polymorphonuclear leucocytes is required for hyper-responsiveness to occur.
The structure and the source of the chemostatic factors which attract neutrophils and eosinophils into
airspaces, as well as the mediators released by these
cells, are unknown (Paggiaro et al., 1988).
The small number of proven examples of sensitization to isocyanates is not necessarily only
because of inadequate methods for reliably identifying
specific immunoglobulins of each class of isocyanates.
For example TDI bound to HSA containing more
than forty moles of isocyanates per mole of HSA is a
less potent antigen than TDI-HSA containing around
twenty moles of isocyanates per mole of HSA (Baur
et al., 1984). But this technical finding cannot explain
the presence of a majority of isocyanate-induced
asthma patients without immunoreactivity.
N=C=O
CONCLUSION
HAPTEN-PROTEIN CONJUGATE
Fig. 2. Reaction of TDI on protein.
The low prevalence of specific IgE and other antibodies suggests that an immunological mechanism is
not the major cause of isocyanate-induced asthma.
On the other hand, the pharmacological and irritative
hypotheses cannot explain the majority of other situations of isocyanate-induced asthma. Further studies
are needed to evaluate and to confirm these and possibly new hypotheses.
36
F. Deschamps el at.
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