occupational asthma and extrinsic alveolitis to ...extrinsic alveolitis related to exposure to...

British J7ournal of Industrial Medicine 1993;50:213-228

Occupational asthma and extrinsic alveolitis due toisocyanates: current status and perspectives

Olivier Vandenplas, Jean-Luc Malo, Marina Saetta, Christina E Mapp, Leonardo M Fabbri

Isocyanates are used for the large scale productionof polyurethane polymers, which have an almostendless variety of applications in the manufactureof flexible and rigid foams, elastomers, adhesives,and surface coatings.' Acute or chronic exposure tohigh concentrations of isocyanates can result in res-piratory health hazards through a direct irritanteffect.23 Isocyanates are of special interest, how-ever, because, in some exposed workers, they cancause occupational asthma or extrinsic alveolitisthrough an apparently sensitising mechanism.23Because of their wide industrial use, isocyanates arethe principal cause of occupational asthma which isnow the most common respiratory disease linked tothe working environment.45 This review focuses onrecently studied aspects of occupational asthma andextrinsic alveolitis related to exposure to iso-cyanates.

IsocyanatesCHEMISTRYThe isocyanates are a class of low molecular weightchemicals that contain highly reactive isocyanate(NCO) groups. The NCO groups are attached toan organic radical that can be aromatic, aliphatic,or cycloaliphatic.' They have a high affinity forcompounds containing reactive hydrogen atomsbound to oxygen, nitrogen, or sulphur. They reactwith hydroxylic (OH) groups to form a urethane(fig 1) . This is the basic reaction in the productionof high molecular weight polymers referred to aspolyurethanes. Isocyanates also combine with pri-mary and secondary amines, water, ureas, and ure-thanes. On the other hand, the elementarymolecules of isocyanates, called monomers, arecapable of reacting with themselves to form dimers,trimers, and other oligomers. The self polymerisa-

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tion of isocyanates occurs spontaneously and canbe accelerated by heating.

INDUSTRIAL USESThe production of polyurethane polymers requiresat least two (diisocyanates) or more (polyiso-cyanates) NCO groups in the molecule. Figure 2shows the structure of the principal monomers ofdiisocyanates. Toluene diisocyanate (TDI) is anaromatic diisocyanate that is liquid and highlyvolatile at ambient temperature. It exists in two iso-meric forms, the 2,4- and the 2,6- isomers usuallymixed in a ratio of 80:20. The aromatic diphenyl-methane diisocyanate (MDI) was introduced in thelate 1960s because it has a lower vapour pressurethan TDI. The monomer of MDI is a crystallinesolid but MDI is usually available commercially inliquid mixtures containing the monomer and vari-ous oligomers of MDI. About 95% of allpolyurethanes are based on TDI and MDL. Theworld production of isocyanates was estimated in1986 to be 650 000 tonnes of TDI and 850 000tonnes of MDI.6 The third most commerciallyimportant diisocyanate is the aliphatic hexamethyl-ene diisocyanate (HDI) which, like TDI, is highlyvolatile at room temperature. There are other diiso-cyanates available including naphthylene diiso-cyanate (NDI), isophorone diisocyanate (IPDI)and dicylohexylmethane diisocyanate or hydro-genated MDI (HMDI) but their use is restricted toa few specialised applications.The molecular structures of polyurethanes vary

from rigid cross linked polymers to linear, highlyextensible elastomers. The properties of the finalproduct can be tailored by the proper selection ofthe isocyanates, polyols, and additives such as cata-lysts, blowing agents, foam stabilisers, cross linking

OCN-R-NCO+HO-R'-OH-- -C-N-R-N-C-O-R'--+11

O H H O nDepartnent of Chest Medicine, Sacre-CoeurHospital, Montreal, Canada0 Vandenplas, J-L MaloSezione di Fisiopatologia, RespiratoriaSperimentale, Instituto di Patologia Generale,Universita degli studi di Ferrara, Ferrara, ItalyM Saetta, C E Mapp, L M Fabbri

Diisocyanate Polyol (Poly)urethane

Figure I Addition reaction between an isocyanate (NCO)and a hydroxyl (OH) group to give a urethane linkage. Thisreaction is the basic mechanism for the production of highmolecular weight polymers called polyurethanes.

Vandenplas, Malo, Saetta, Mapp, Fabbri

Monomers of isocyanates

Aromatic radical

Toluene diisocyanate (TDI)

CH3 CH3

IN& NCO NC NCO

NCO

2,4-TDI 2,6-TDI

Diphenylmethane diisocyanate (MDI)

OCN ( CCH2 NCO

4, 4'-MDI

NCO

CH2 NCO

2,4'-MDI

1,5-naphthylene diisocyanate (NDI)

NCO

NCO

| Aliphatic radical

Hexamethylene diisocyanate (HDI)

OCN-(CH2)6-NCO

| Cycloaliphatic radical

Isophorone diisocyanate (IPDI) 4, 4'- dicyclohexylmethane diisocyanate(hydrogenated MDI, HMDI)

CH2- NCO

CH5& CH3 OCN e CH2 NCO

CH3 CH2-NCOFigure 2 Structures of the monomers of diisocyanates used in industry. They are classified according to the nature of theirorganic component (aromatic, aliphatic, or cycloaliphatic).

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Occupational asthma and extrinsic alveolitis due to isocyanates: current status and perspectives

Prepolymers of isocyanates

Derived from toluene diisocyanate (TDI)

0II

I CH2-0- C- HN JiCcH3

/ 0CH -CH2-C-CH2-0-C-HN CHH3 O3

\CH 2 - 0- C-HNgNCoH3

Derived from hexamethylene diisocyanate (HDI)

NCO

(OlH2 )6

N NONCON

C (C26-NCO

0I

IC-NH -(CH2)6-NCO)CN- (CH2)6.- N -NO

0Biuret structure of HDI

Trimer of HDI (isocyanurate ring)

Derved from diphenylmetane diisocyanate (MDI)

CH2

NCO

CH2 NCO

n

Polymethylene polyphenyl diisocyanate (PPI)

Figure 3 Structures ofsome of the principal prepolymers of diisocyanates used in industry. The prepolymers ofHDI include thebiuret and the trimer (isocyanurate ring) structures ofHDI. The most common prepolymer ofMDI is an oligomer often referred toas polymethylene polyphenyl diisocyanate. Note that the prepolymers of TDI and HDI have three functional NCO groups.

OCN

215

I I

L I


and chain extending compounds. The main appli-cation of TDI is in the manufacture of flexiblefoams for cushioning in the furniture and automo-bile industries. MDI has progressively replacedTDI and is widely used in the production of rigidfoams, thermal and sound insulation products,packaging materials, binding agents, elastomers,and coatings. HDI and IDPI are almost exclusivelyused in the formulation of coatings and paintsbecause the presence of the aliphatic radical pro-vides excellent light and weather resistance in thepolyurethane end product.New types of isocyanates, commonly referred to

as prepolymers, have been introduced to reducerespiratory hazards due to inhalation of monomervapours. These result either from the reaction of apolyhydroxyl compound with water, or an excess ofdiisocyanate molecules, or from the self combina-tion of diisocyanate monomers.' Figure 3 shows theideal structure of the principal prepolymers of iso-cyanates. Commercial prepolymers are most often acomplex mixture of various compounds with differ-ent molecular weights but, as a rule, the prepoly-mers are less volatile than their parent monomer.Over the past two decades, isocyanate prepolymershave gained increasing importance, particularly asmoulded foams and surface coatings, because theyoffer several processing advantages. Although prod-ucts based on prepolymers usually contain onlytrace amounts of the volatile monomer (less than1%), it is important to note that they still containconsiderable amounts of reactive isocyanate groupson the non-volatile prepolymer.7

SOURCES AND MODE OF EXPOSUREExposure to isocyanates may result from the inhala-tion of vapours generated by TDI and HDI atambient temperature and by MDI when heated.8 Aconsiderable source of exposure to non-volatile iso-cyanates (MDI and prepolymers) comes from theaerosols generated during spraying processes.89Less often, exposure results from the thermaldecomposition of polyurethanes-for example,during welding on surfaces coated with apolyurethane.8 10

Methods have been developed for analysis of iso-cyanates in working environments.7 High perfor-mance liquid chromatography (HPLC) is nowconsidered as the reference method but is discon-tinuous and time consuming. The paper tape moni-tors are based on a colorimetric method. They areless accurate than chromatography and have notbeen validated for the assessment of prepolymers.The tape monitors are, however, currently the onlyway to perform continuous monitoring of iso-cyanate concentrations.To prevent the irritant effects of isocyanates, the

threshold limit values (TLVs) have been estab-

lished at 5 ppb for a 10 hour workday time weight-ed average (TWA) and at 20 ppb as a ceilingvalue.71' 12 Some countries have also establishedsimilar permissible exposure limits for the prepoly-imers of isocyanates.79 At present it is not knownwhether the observance of these exposure limits iscapable of preventing or decreasing the occurrenceof respiratory hypersensitivity among exposedworkers. Furthermore, hypersensitive workers candevelop clinical manifestations at exposures wellbelow these recommended limits.

AsthmaOccupational asthma is variable airflow limitationcausally related to exposure to non-irritant levels ofisocyanates.'3 In 1951, Fuchs and Valade describedasthma like symptoms in seven workers exposed toTDI.'4 They suggested for the first time that con-tact with diisocyanates might lead to the develop-ment of hypersensitivity rather than direct toxicity.This initial observation as well as subsequentreports from Europe and North America showedthat the bronchial response in some workers ful-filled the clinical criteria for hypersensitivity;'5 onlya minority of workers equally exposed to iso-cyanates develop asthma after a variable symptom-free latency period, as opposed to what has beendescribed under the heading of reactive airwaysdysfunction syndrome (RADS).16 Furthermore, thesymptoms recur on each exposure even to concen-trations at which most subjects do not develop res-piratory symptoms.

NATURAL HISTORY AND EPIDEMIOLOGYLittle is known about the natural history and thefactors predisposing to occupational asthma. In arecent collaborative study comparing subjects withoccupational asthma due to low molecular weightchemicals (isocyanates, n = 107 and plicatic acidcontained in western red cedar, n = 433) and vari-ous high molecular weight agents (n = 121), wefound that the latency period was shorter for lowmolecular compared with high molecular weightagents.'7 Forty per cent of workers with occupa-tional asthma due to isocyanates and plicatic aciddeveloped symptoms within the first year of expo-sure compared with 20% of those with occupation-al asthma caused by high molecular weight agents.After five years of exposure, 60% of subjectsexposed to isocyanates and high molecular weightagents had symptoms compared with 80% of thoseexposed to western red cedar. The mean latencyperiod between the start of work exposure and theonset of symptoms was 7 03 years for isocyanates,3-63 years for plicatic acid, and 7-34 years for highmolecular weight agents. A continuous mode ofexposure increased the rate of developing symp-

216

Occupational asthmiia and extrinsic alveolitis due to isocyanates: current status and perspectives

Table I Prevalence of occupational asthma among various populations of workers exposed to isocyanates according to thecriteria used for establishing the diagnosis

Estimated prevalence PositiveNo of of occupational asthma Diagnostic inhalation

Isocivanate Population workers No (%) criteria* challengesl Reference No

TDI TDI production 166 29 (17) Questionnaire 9/13 32TDI Automotive industry 192 57 (30) Questionnaire 3/6 33TDI, MDI Various industries 195 55 (28) Questionnaire 12/17 34

or spirometryMDI Foundrv 78 12 (15) Questionnaire 7/11 21

and NSBHMDI, PPI Paint shops 51 7 (14) Questionnaire or 6/6 29

spirometry and NSBHMDI Foundry 26 7 (27) Questionnaire ND 35HDI Paint shops 150 1 (0-6) Questionnaire ND 36

*The criteria used for diagnosing occupational asthma included a questionnaire (history of work related symptoms) with or withoutspirometry (presence of airflow limitation) and/or assessment of non-specific bronchial hyperreactivity (NSBH); ¶number of positiveinhalation challenges/number of tested workers; PPI is polymethylene polyphenyl diisocyanate; ND: not done.

toms compared with intermittent exposure,'7 butthe prevalence of isocyanates does not seem to cor-relate closely with the cumulative level of exposureat work. Nevertheless, there is some evidence thatthe development of occupational asthma is asso-ciated with acute, often accidental, exposures tohigh concentrations of isocyanates (Spills). 16 18Atopy, smoking habits, and even pre-existing asth-ma or airway hyperresponsiveness have not beenshown to be significant risk factors for occupationalasthma.The most commonly used isocyanates, including

TDI,'9 MDI,20 21 HDI,2223 IPDI,24 and NDI,25cause asthma in various occupational and evennon-occupational26 settings. Occupational asthmahas generally been ascribed to the monomers ofthese diisocyanates. A role for the prepolymers inthe development of occupational asthma has beensuspected but not firmly shown.27-29 We recentlydescribed two subjects in whom specific inhalationchallenges elicited asthmatic reactions after expo-sure to a prepolymer of TDI present in a woodvarnish but who were not affected after exposure tothe monomer of TDI.30 We conducted a prospec-tive study among 20 workers referred for possibleoccupational asthma caused by spray paints con-taining both an HDI monomer and HDI prepoly-mers.3' The workers underwent inhalationchallenges with the monomer and prepolymers ofHDI separately. Among the 10 subjects who hadpositive inhalation challenges, four developed anasthmatic reaction only after exposure to the pre-polymer and not after exposure to the monomer.These observations suggest that prepolymers of iso-cyanates themselves can cause occupational asth-ma.

Isocyanates are the principal cause of occupa-tional asthma accounting for-about 25% of all casesidentified in industrialised countries.4 Informationon the prevalence of isocyanate induced occupa-tional asthma in exposed workers is scarce and

restricted to a few cross sectional studies (table1).21 29 32-36 Cross sectional surveys are likely tounderestimate the actual prevalence of occupation-al asthma as workers with work related respiratorysymptoms tend to leave their jobs. Furthermore,the prevalence of isocyanate asthma may be influ-enced by the type of industry and the criteria usedfor diagnosis (questionnaires, assessment of non-specific bronchial responsiveness, inhalation chal-lenges). According to the results of studies withobjective diagnostic tests, a prevalence of about10% seems to be a reasonable approximation.2' 29

PATHOGENESISA number of mechanisms have been proposed forisocyanate induced asthma. A classic IgE mediatedmechanism has been suggested,37 38 but the pres-ence of a diisocyanate specific IgE has been shownin only a few workers with symptoms.39 Morerecently, assessment of specific IgG antibodies hasbeen found to give better results than IgE.40 Reflexand pharmacological mechanisms have also beenproposed to explain isocyanate induced asthma andisocyanate induced airway hyperresponsiveness, butthese mechanisms cannot explain the developmentof sensitisation to isocyanates in only a certainnumber of exposed subjects.4' Isocyanates inhibitthe stimulation of cyclic adenosine monophosphate(cAMP) in human lymphocytes by isoproterenoland postaglandin El, whereas at some concentra-tions isocyanates act as cAMP stimulants. In sus-ceptible subjects, specific lymphocyte blastogenicactivity and lymphokine leucocyte inhibitory factorresponses to toluene diisocyanate (TDI) have beenfound.42 There are recent data to suggest animmune response after exposure to TDI. In fact anincreased number of circulating CD8+ lympho-cytes has been shown 48 hours after inhalationchallenge with TDI.43

Airway inflammation is a constant finding in iso-cyanate induced asthma primarily in dual and late

217


asthmatic reactions, which are more common thanearly reactions after inhalation challenges with iso-cyanates. The mechanisms of the late asthmaticresponse are still unknown. It has been proposedthat isocyanates cause late asthmatic reactions andincreases in non-specific airway responsiveness bycausing an acute inflammatory process in the air-ways. The airway response to isocyanates does notshow an asthmatic response after exposure toTDI.44 Airway responsiveness to methacholine,moreover, increases only in subjects who develop adual or late asthmatic reaction.45 Late asthmaticreactions are associated with an influx of neu-trophils followed by an influx of eosinophils in theairways, and with an increase in albumin in lavagesupematant liquid, suggesting the development ofan acute inflammatory reaction in the airways andthe development of microvascular leakage andoedema formation.4647 Inflammatory mediatorsmay be released by epithelial cells, alveolarmacrophages, or others. During late asthmaticreactions induced by TDI, an increase inleukotriene B4 has been found.48 As leukotriene B4is also released by neutrophils, it is not knownwhether LTB4 is the cause or the result of the influxof neutrophils in the airways. Whether otherchemotactic factors such as interleukin 8 and 5 (IL-8, IL-5) are involved in this model remains to beclarified.

Steroids block the late asthmatic reaction, theassociated increase in non-specific airway respon-siveness, the influx of neutrophils and eosinophils,and the extravasation of albumin, suggesting thatairway inflammation plays an important part in lateasthmatic reactions induced by exposure toTDI.47 49-51

Airway inflammation was seen at necropsy of acar painter with occupational asthma induced byTDI who died at work.52 The bronchi were con-stricted by the spasm of a thickened smooth mus-cle, and there was a massive infiltration of finflammatory cells, particularly eosinophils. Theoedematous airways were plugged with mucus, eexudate, and inflammatory cells. This is anextremely severe stage of the disease, however, andit is not clear to what extent these postmortem find-ings reflect the pathology of occupational asthma inreal life, particularly in the intervals betweenattacks.The nature and degree of mucosal inflammation

of the airways in TDI induced asthma in the inter-vals between attacks has recently been clarified byperforming bronchial biopsies in patients withoccupational asthma induced by TDI and in con-trol subjects.53 Subjects with TDI induced asthmaexhibit an increased number of inflammatory cellsin the airway mucosa compared with control sub-jects. Eosinophils were increased in the epithelium,

in the more superficial layer of the submucosa, andin the total submucosa, whereas CD45 positivecells were increased in the epithelium and in themore superficial layer of the submucosa, and mastcells were increased only in the epithelium (fig 4).Both eosinophils and mast cells seemed to bedegranulated. A thicker subepithelial reticular layerwas present in patients with TDI asthma, wheredeposition of collagen III has been shown byimmunohistochemistry. Seen through electronmicroscopy, the intercellular spaces between basalcells were wider in the asthmatic subjects, con-tributing to the development of epithelial fragility.The pathological features of TDI induced asthmaare similar to those described for non-occupationalasthma. We recently investigated whether cessationof exposure to the sensitising agent is able toreverse pathological findings in TDI induced asth-ma.54 In subjects sensitised to TDI, bronchial biop-sies were performed at diagnosis and six monthsafter cessation of exposure to TDI. The thicknessof the reticular basement membrane was signifi-cantly reduced compared with that at diagnosis,and it decreased to values similar to those of con-trol biopsies (fig 5). The inflammatory cell infiltratepersisted in most of the asthmatic subjects, and

Epithelium80 -

70- LII Controls

Asthmatic patients60 *

50

EE

40

30

20

10

CD45+ Eosinophils Mast cells

Figure 4 Numbers of imflammatory cells in the bronchialepithelium of controls and of subjects with TDI asthma. Fromreference 53 with permission.

218


degranulation of eosinophils and mast cells was stillpresent. At the end of the study, airway responsive-ness to methacholine, or sensitivity to TDI, or

both, also persisted in most of the asthmatic sub-jects, despite the cessation of exposure and the dis-appearance of asthmatic symptoms. These resultsin patients with occupational asthma induced byTDI suggest that non-exposure for six months isable to reverse the thickening of the reticular mem-brane in the bronchial mucosa, but the inflammato-ry cell infiltrate, the specific sensitivity to TDI, andthe non-specific airway hyperresponsiveness maypersist. Whether a longer period of cessation ofexposure is required to reverse these morphologicaland functional changes still remains to be investi-gated.More recently, an in vitro model to study the

mechanism of action of isocyanates has been estab-lished.5558 Exposure to TDI contracts the bronchialsmooth muscle in guinea pigs through the activa-tion, at least in part, of capsaicin sensitive primaryafferents. It is likely that the contraction is pro-

duced indirectly by the generation of a prostanoidthat activates capsaicin sensitive primary afferentsvia a ruthenium red sensitive mechanism.56The products of reaction between TDI and

water, such as toluenediamine (2, 4- TDA), alsocontract the bronchial smooth muscle through thesame mechanism. Whether this mechanism plays apart in the development of the adverse effects onthe respiratory tract seen after exposure to TDI,and whether it contributes to the development ofairway inflammation in subjects sensitised to iso-cyanates remains to be elucidated.

In conclusion, all of these studies suggest thatairway inflammation is significant in the late asth-matic reaction induced by exposure to TDI. Thepathology of TDI induced asthma is similar to thatof non-occupational asthma. The mechanism ofaccumulation of inflammatory cells in the airwaysand the role of an immunological mechanism in thepathogenesis of isocyanate induced asthma remainto be established.

DIAGNOSISSeveral procedures can help the physician to estab-lish the diagnosis of occupational asthma. It is

essential to take a careful clinical history bui thisproved to be an unsatisfactory diagnostic tool com-

pared with objective testing.59 A typical history ofoccupational asthma (occurrence or worsening ofchest symptoms at work or after work and improve-ment on days off work) had a low positive predic-tive value (46%) although the negative predictivevalue was better (83%). The low predictive value ofa suggestive history probably results from the factthat asthma can be exacerbated at work for severalreasons other than hypersensitivity to isocyanates-that is, cold weather, exercise, or exposure to non-specific irritant substances. Also subjects may tendto exaggerate their symptoms at the prospect ofcompensation.The many efforts made to show immunological

sensitisation to isocyanates have so far led to disap-pointing results.3540606" The presence of IgE anti-bodies to isocyanates has been documented in 20%to 39% of subjects with proved occupational asth-ma but has also been found in unaffected subjects(table 2).2137406163 An increased concentration ofspecific IgE antibodies was more often associatedwith asthmatic reactions of the immediate type insome studies6163 but not in others.40 6163 Morerecently, assessment of IgG antibodies to iso-cyanates has been found to be more sensitive thanassessment of IgE but also less specific.40 SpecificIgE and IgG antibodies are more often detected insubjects with occupational asthma due to HDI andMDI than in those with occupational asthma dueto TDI.40 61 63 Welinder et al suggested that the con-centrations of specific IgG to HDI could be more

closely related to the amount of exposure than tothe presence of respiratory symptoms.62 Theseresults probably reflect the difficulties in preparingsuitable isocyanate antigens for antibody assess-ment. Isocyanates act as haptens and need to beconjugated to an autologous carrier protein toinduce an immunological response.60 So far, mostimmunological studies have been performed usinghuman serum albumin (HSA) although the precisenature of the respiratory tract component to whichisocyanates bind in vivo remains unknown.Isocyanates are highly reactive chemicals that cancombine with OH, NH2, and SH groups on humanproteins leading to variable degrees of intra and

Table 2 Diagnostic value of specific IgE and IgG antibodies to isocyanates compared with the results of inhalation challenges

Presence of specific IgE antibodies Presence of specific IgG antibodies

Positive Negative Postive Negativeinhalation challenge inhalation challenge inhalation challenge inhalation challenge(sensitivity) (specificity) (sensitivity) (specificity)

Isocyanate No (%) No (%) No (%/o) No (%/.) Reference No

TDI 5/26 (19) 0/30 (100) - - - - 37MDI 1/7 (14) 1/4 (75) 2/7 (28) 8/32 (75) 21TDI, MDI 11/28 (39) 0/51 (100) - - - - 61TDI, HDI, MDI 7/35 (20) 0/46 (100) - - - - 63HDI, MDI 9/29 (31) 1/33 (97) 21/29 (72) 8/32 (75) 40

219

Vandenplas, Malo, Saetta, Mapp, Fabbni

interprotein cross linking.6465 Thus the interactionof isocyanates with human proteins induces modifi-cations of their structure that can result in thedevelopment of new antigenic determinants. Somestudies on animal models and in humans indicatethat antibodies are directed to these new antigenicdeterminants rather than to the isocyanateitself.60 66 67 This could account for the observedimmunological cross reactivities between differenttypes of isocyanates.6568 This could also explainwhy the use of monofunctional isocyanates, such as

p-tolyl monoisocyanate,37 69 is not more valuablethan difunctional isocyanates in the preparation ofantigen substrates. Finally, assessing antibodiesdirected to the prepolymers of isocyanates ratherthan to the monomers should be furtherassessed.30 31 62 36 70

Non-specific bronchial hyperresponsiveness to

histamine or methacholine may be absent in seven

to 45% of subjects with occupational asthma at thetime of the diagnosis40 71 especially when the subjecthas not been exposed to isocyanates for a long peri-

od. Indeed, non-specific bronchial responsivenesscan increase or even develop progressively as thesubject is exposed to isocyanates72-74 and decreaseor disappear after the last exposure.72 There are

only two documented case reports in which thesubjects did not exhibit non-specific bronchialhyperresponsiveness either before or after asthmaticreactions to MDI.7576 The bronchial reactions to

isocyanates could, however, have been due to a

non-specific effect as the concentrations during thetests were in the irritant range (o 30 ppb in bothcases).A firm diagnosis of occupational asthma requires

objective demonstration that exposure to iso-cyanates results in an asthmatic reaction.77 Severalprocedures have been proposed to confirm thiscausal relation. Assessment of forced expiratoryvolume in one second (FEV,) before and after a

workshift is clearly an inadequate method.78Prolonged recording of peak expiratory flow rates

(PEFs) during periods at work and away from workhas been suggested as a valuable means of estab-lishing the diagnosis of occupational asthma.79Although simple and inexpensive, measurements ofPEF are effort dependent, require substantial moti-vation and honesty, and may not be feasible inworkers who have left their jobs.808' Recording ofPEFs does not make it possible to distinguishbetween bronchial response due to isocyanates andthat due to non-specific agents present in the work-place. The monitoring of PEFs is less sensitive andless specific than inhalation challenges even when itis combined with serial assessments of non-specificbronchial responsiveness.8' 82

Specific inhalation tests in the laboratory shouldstill be considered as the reference standard for

establishing the diagnosis of occupational asthma.6Inhalation challenges should be performed in spe-cialised centres by trained personnel and underclose medical supervision.77 The generation of iso-cyanates in test chambers can be achieved in severaldifferent ways. In the original procedure describedby Pepys and coworkers in the 1970s,'0 19 23 the sub-jects were challenged by brushing or spraying thecommercial isocyanate compound to which theywere exposed at work. More simply, vapours of thehighly volatile TDI and HDI can be generated byevaporation of the corresponding pure monomersat room temperature.6 83-86 Products containing pri-marily HDI prepolymers of HDI and only trace

amounts of the monomer can be used provided thatthey are nebulised.86 Exposure to MDI, which isnot volatile at room temperature, can be achievedby heating it to > 80C2'1 23 87 or spraying the prod-uct.29 Concentrations of isocyanate are influencedconsiderably by room temperature and humidity,absorption on surfaces other than stainless steel andteflon, opening of the door during the tests, and thesubject's own breathing88 and should therefore becontinuously assessed with a tape monitor.Although challenge rooms may be adapted,83 it isour experience that they do not allow for a fine reg-ulation of concentrations of isocyanate because oftheir large volume. The concentrations can there-fore exceed the recommended ceiling and result inunduly severe asthmatic reactions or in non-specificirritant responses. We have recently developed a

closed circuit system for the generation of iso-cyanates in gaseous form.89 Briefly, vapours of iso-cyanates are generated by passing a controlled flowof air on to the surface of pure monomers main-tained at constant temperature, mixed with a sec-

ond airstream that could be regulated for flow,humidity, and temperature, and then sent to a

0-25m3 cylindrical reservoir coated with teflon. Thesubject inhales gaseous isocyanates through an oro-facial mask supplied with a unidirectional valve andisocyanate vapours are removed to the outside ofthe laboratory. The pressure in the reservoir ismaintained at a constant concentration despite thesubject's breathing via a system of solenoid valvesconnected to an exhaust pump. The resultsobtained in 20 subjects showed that the concentra-tions of isocyanates were significantly more stablewith the closed circuit method than with the chal-lenge room method. The closed circuit method wasalso more effective for maintaining the concentra-tion of isocyanates below the recommended limit of20 ppb. Since we found selective asthmatic reac-tions to prepolymers of isocyanates303' the closedcircuit methodology is currently being developed toallow for the generation of stable and preselectedconcentrations of isocyanate prepolymers becausethey are not volatile and cannot be generated in a

220


0

S*SW F 8.

.f.S ..

,L , ,a*-'''

PA wb * dBS -b a *;F a E! i <.._<.t ~ ~ ~~~~~~~~A

Figure 5 Bronchial mucosal biopsy from a patient with TDIasthma. Upper panel, at diagnosis when a thickened reticularbasement membrane and an inflammatory cell infiltrate isapparent. Lower panel, six months later after cessation ofexposure to TDI when the basement membrane thickness isreduced, but the inflammatory cell infiltrate is still present.Magnification x 600; stain: haematoxylin-eosin; lightmicroscopy. From reference 54 with permission.

gaseous form.Baseline FEV, must be > 21 or 60% of the pre-

dicted value before the inhalation challenge is initi-ated. A control test should be carried out to ensure

that the patient's FEV, is stable-that is, fluctua-tions of FEV, are less than 10% over an eight hourperiod. During the control day, the subject shouldbe exposed to a control substance-namely, one

with an irritant but no known sensitising effect, to

distinguish between specific and non-specificbronchial responses. For isocyanate challenges, thecontrol substance could be the polyol components

(for example, paint diluents) that are mixed withthe isocyanates to produce the desired finalpolyurethane.294086 A standardised schedule ofexposure to isocyanates has not yet been adopted.In most centres, subjects are exposed to isocyanatesfor a fixed period (15-30 minuteS)6238590-92 andsometimes the concentration is increased from one

test to the next.67' It is our experience that some

subjects require more prolonged exposure to exhib-

it an asthmatic reaction so that we graduallyincrease the duration of exposure on separate daysaccording to the protocol presented in fig 6. Thereis only limited information on the factors that canaffect the bronchial response to isocyanates in sen-sitised subjects. Burge et al77 found that the con-centration of TDI required to induce a reaction insensitised subjects was inversely correlated to thebaseline of histamine reactivity, although histaminereactivity accounted for only 30% of the variationin threshold doses of TDI. With our closed circuitmethod,89 we recently assessed the dose responserelation in two subjects with asthma due to TDI bychallenging them with different concentrations ofTDI and different durations of exposure while thelevel of non-specific reactivity remained constantthroughout the tests. We found that the dose of iso-cyanate (concentration times duration of exposure)required to induce an asthmatic reaction, althoughvariable from one subject to the other, remainedconstant for each subject. These data suggest thatincreasing the duration of exposure for a given con-centration is equivalent to increasing the concentra-tion for a given duration of exposure, and isprobably less hazardous.

After challenge exposure to isocyanates, FEV,should be monitored at 10 to 15 minute intervalsfor the first hour, 30 minute intervals for the secondhour, then hourly for at least eight hours to detectlate reactions.77 A significant bronchial responseshould be considered as a sustained fall in FEV, ofmore than 20% from the prechallenge value in theabsence of such changes on a control day. Severalpatterns of bronchial response after specific inhala-tion challenges have been described, includingimmediate or early, early late, late, and dual reac-tions.10 Atypical patterns of reaction have also beennoted after exposure to isocyanates.21 29 In a recentstudy,86 we found that these atypical reactionsoccurred more often in subjects with isocyanateinduced occupational asthma (9/23) than in sub-jects with occupational asthma caused by high mol-ecular weight agents and plicatic acid (6/46). Thereactions were mainly of the progressive type, start-ing within minutes after the end of exposure andreaching a maximum five to six hours later. Lesscommon patterns were referred to as square waved(similar to dual reactions but without recoverybetween the two components of the response) andprolonged immediate (similar to immediate butwith functional recovery taking up to eight hours).In some subjects, inhalation challenges with iso-cyanates can induce recurrent nocturnal asthma forseveral days.90 91 Asthmatic cross reactivity betweendifferent isocyanates has been documented.232892Innocenti et a193 found that nearly 50% of subjectswith asthma induced by TDI also exhibited asth-matic reactions to MDI, which they were never

221


|Control day |

Exposure to a control substance for 30 min.Assessment of FEVI and methacholine PC20

Fluctuations of FEVI < 10%

K_Challenges with isocyanates

PC2o < 0.5 mg/mlor history of severeimmediate reaction

PC20 > 0.5 mg/mland no history of severe

immediate reaction

*Day2

Duration: 1 min (5, 15, 40 sec)Concentration: 5 ppb

Duration: 4 min (1, 3 min)Concentration: 10-15 ppb

Day4

Duration: 4 min (5, 15, 40 sec, 1, 2 min)Concentraion: 10-15 ppb

Day3

Duration: 30 min (5, 10, 15 min)Concentration: 10-15 ppb

Day4


Day 5



Re-assessment of methacholine PC20 |

2 3.2 -fold decrease in PC20

Duration: 240 min. Concentration: 10-15 ppbFigure 6 Schematic representation of the protocol usedfor inhalation challenges with isocyanates in our laboratory.

222

Occupational asthmiia anid extintsic alveolitis duie to isocyatnates: current status and perspectives

exposed to at work. The assessment of non-specificbronchial responsiveness before and after a specificinhalation test can provide further information as ithas been shown that late and dual but not immedi-ate reactions are associated with a significantincrease in non-specific bronchial responsiveness.44In a retrospective study that included a large num-ber of subjects, however,94 we found that 41 of 101(41 %) subjects with late reactions but also 1 1 of 63(17%) of subjects with immediate reactions had a

significant increase in non-specific bronchialresponsiveness.

Inhalation challenges may be falsely negativebecause the subject has been away from work for a

long period and lost his or her sensitivity to iso-cyanates.6 The subject may have been exposed tothe wrong agent. We have already mentioned thatsome subjects develop asthma only after exposure

to prepolymers of isocyanate and not after exposureto the parent monomers.30 31 False positive reac-tions could occur after exposure to irritant concen-

trations of isocyanates, particularly in subjects withpronounced non-specific bronchial responsiveness.Indeed, the temporal pattern of immediate reac-

tions due to hypersensitivity to isocyanates is simi-lar to what has been described for reactionsinduced by non-specific agents.95 For obvious ethi-cal reasons, the degree of exposure to isocyanatesthat could result in irritant reactions has never beenestablished for humans. Nevertheless, some studieshave shown that concentrations of TDI below20 ppb do not induce bronchial reactions in non-

exposed asthmatic and non-asthmatic subjects.4490The generation of low and stable concentrations ofisocyanates as provided by the closed circuitmethodology described should increase the diag-nostic reliability of inhalation challenges.Some physicians are reluctant to perform inhala-

tion tests because they can induce severe asthmaticreactions. Inhalation challenges with isocyanatescan be a safe method provided that the mentionedprecautions are taken. The data obtained using our

closed-circuit system indicate that it induces lesssevere reactions especially in the case of the imme-diate component.89 This suggests that improvingthe methodology of inhalation challenges to ensure

more accurate control of exposure to isocyanates

will further increase the safety of the tests. The use

of specific inhalation tests has also been restrictedbecause they are expensive and time consuming. Inthis respect, it should be kept in mind that a diag-nosis of occupational asthma implies considerablemedical, financial, and social consequences. Webelieve that the costs of inhalation tests are largelycounterbalanced by those related to the wrongdiagnoses that inevitably result when inhalationchallenges are not used.

OUTCOME AND MANAGEMENTThere is now accumulating evidence that removalof the workers with occupational. asthma fromexposure to isocyanates does not lead to a completerecovery even though their condition oftenimproves. Several follow up studies have shownthat more than 50% of affected workers still havesymptoms of asthma and non-specific bronchialhyperresponsiveness after cessation of exposureeven after several years (table 3).9699 Specificbronchial reactivity to isocyanates may also persistfor a long time after exposure.'899 100 Little is knownabout the factors that can predict the remission or

persistence of asthma after exposure to isocyanatesends. Studies on occupational asthma due to vari-ous agents have shown that the persistence of asth-ma after cessation of work was associated with a

longer duration of symptoms before diagnosis andwith a more severe asthma as defined by the degreeof airway obstruction and non-specific bronchialhyperresponsiveness at the time of diagnosis.'0' 102These findings outline the importance of early diag-nosis. The mechanisms by which specific and non-

specific airway reactivity persist in most affectedsubjects after removal from exposure to the offend-ing agent are still unknown. Studies with bron-choalveolar lavage and bronchial biopsies showedthat airway inflammation persisted while the thick-ening of basement membrane reversed in subjectswith persistent bronchial hyperresponsiveness afterremoval from exposure.54 103

Affected subjects who remain exposed to even

very low concentrations of isocyanates at workdevelop chronic asthma and progressive worseningof lung function and non-specific bronchial respon-

siveness.97 104 This is consistent with our finding

Table 3 Outcome of isocyanate induced asthma: persistence ofsymptoms and non-specific bronchial hyper-responsiveness afterremovalfrom work exposure

Duration of Persistence of Persistence ofNo of follow up* asthma symptoms non-specific bronchialsubjects (y) (%) hyper-responsiveness(%/6)t Reference No

12 1-3 66 7/12 (58) 9650 > 4 82 12/19 (63) 9720 05-4 50 9/12 (75) 9822 1 77 17/22 (77) 99

*Mean or extreme values depending upon available data; tnumber of subjects with persistent bronchial hyper-responsiveness / number ofsubjects where bronchial responsiveness was reassessed during follow up.

223


that low concentrations of isocyanates can stillinduce asthmatic reactions provided that the dura-tion of exposure is long enough (unpublished data).There is so far no evidence that respiratory protec-tive devices are efficient in preventing chronic asth-ma and impairment of lung function. Furthermore,exposure to isocyanates at the workplace in sensi-tised subjects may lead to life threatening asthmaattacks.52 Subjects with occupational asthma shouldtherefore be definitively removed from exposure toisocyanates and benefit from adapted compensationand rehabilitation programmes.105 The guidelinesused to determine permanent disability shouldaccurately reflect the severity of asthma and includethe degree of airway obstruction, the level of non-specific bronchial hyperresponsiveness, and theneed for anti-asthma medication.The effectiveness of preventive measures on the

frequency of occupational asthma has so far beenassessed only rarely.'06 Pre-employment screeningprogrammes aimed at identifying susceptible work-ers-for example, those with atopy, non-specificbronchial hyperresponsiveness, or smoking habits-are inappropriately discriminatory as none of thesefeatures has been shown to be a significant risk fac-tor. Thus preventive measures should be primarilyaimed at reducing the level of exposure to iso-cyanates. Changes in production processes shouldbe considered whenever possible. The replacementof the highly volatile TDI and HDI by MDI andprepolymers that are less volatile has not been suc-

cessful, as the last can also cause asthma.

Extrinsic alveolitisIsocyanates have been found to cause a pattern ofreaction characterised by features of parenchymallung involvement (restrictive breathing defect,impairment of diffusion capacity for carbon mon-

oxide, and parenchymal infiltrates on chest radio-

graph) associated with systemic symptoms (generalmalaise, chills, fever and increased blood leucocytecount)28 107-119 These features are similar to thosedescribed in extrinsic alveolitis due to variousorganic substances.'20

NATURAL HISTORY AND EPIDEMIOLOGYBy contrast with asthma, extrinsic alveolitis hasonly been described in isolated case reports (table4).28 107-119 Using specific inhalation challenges, we

demonstrated extrinsic alveolitis in 8/167 (4-7%)workers exposed to a resin containing MDI in awood chipboard manufacturing plant.'2' The sub-jects we investigated were all those who filled aclaim at the local Workers' Compensation Boardafter the introduction of MDI to the plant as athorough medical survey of the whole workforcecould not be conducted. The 4-7% figure is there-fore probably an underestimate of the actual preva-lence of extrinsic alveolitis in the plant. Althoughwe have no definite explanation for this high preva-

lence, the possibility that extrinsic alveolitis mighthave been overlooked in previous cross sectionalsurveys should be considered. Indeed, in our study,systemic symptoms were so severe that affectedsubjects had to leave the plant shortly after theonset of symptoms. No single predisposing factorcould be identified but exposure to high concentra-tions ofMDI due to inadequate safety controls dur-ing the first weeks after the use of the MDI resinbegan at the plant should be suspected as theessential factor. Furthermore, it is interesting tonote that only one of our eight subjects was work-ing permanently near the source of the MDI, sug-

gesting that even intermittent exposure can lead toextrinsic alveolitis. Our study indicates that undersome undefined circumstances, extrinsic alveolitisdue to isocyanates could be a more common occur-

rence than is generally thought.

Table 4 Hypersensitivity pneumonitis caused by isocyanates: main features of the subjects reported in the literature

Inhalation Specific Specific Precipitating Bronchoalveolar ReferenceIsocyanate No challenge IgE IgG antibodies lavage No

TDI 3 ND + ND ND ND 107HDI 1 ND ND ND ND ND 107TDI 1 + ND - - ND 108MDI 1 ND + + + ND 109MDI 1 + ND + ND ND 110HDI 1 + - + ND ND 111MDI 1 + - + ND ND 112HDI 1 + - ND - ND 113MDI(?) 1 + ND ND ND 40%Ly, TH/TS < 1 114MDI 1 + ND + ND 67%Ly, anti-MDI IgG 115MDI 1 ND + + ND 116HDI 1 ND + ND ND 117TDI 1 ND ND + ND 74%Ly, TH/TS < 1 118

anti-TDI IgG and IgAHDI, TDI 1 NR + + ND ND 119MDI 8 + (8/8) 8/8 8/8 ND 24%Ly, 17%Ne, TH/TS < 1 121

37%Ly, 32%Neanti-MDI IgG and IgE

ND = Not done; Ly = lymphocytes; Ne = neutrophils; TH = T Helper lymphocytes (CD4); Ts = T suppressor lymphocytes (CD8).

224


PATHOGENESISThe mechanisms leading to the extrinsic alveolitistype of reaction caused by isocyanates remain large-ly unknown. Hypersensitivity to isocyanates ratherthan a direct toxic effect is strongly supported bythe fact that symptoms occur after a latency periodand colleagues working in the same environmentfail to show any adverse effect. As for hypersensitiv-ity due to organic agents,'2' there are severaI linesof evidence supporting involvement of both type IIIIgG-dependent and type IV cellular immunity.Specific IgG antibodies to isocyanates have beendetected in the serum of affected sub-jects,28 109 110 115-118 122 although they may also be pre-

sent in exposed workers with no symptoms.6'Specific antibodies have also been found inbronchoalveolar lavage fluid of two subjects"5118but the role of these antibodies in the developmentof extrinsic alveolitis has not so far been estab-lished. An excess of alveolar T lymphocytes, pre-

dominantly of T suppressor lymphocytes, has beenshown to occur in five subjects in which bron-choalveolar lavage was performed,1116 121 suggest-ing that cell mediated immunity may also play an

important part. Conjugates of TDI with humanserum albumin were found to be capable of induc-ing an in vitro proliferation of bronchoalveolarlavage lymphocytes from one affected subject."8 Asoccurs for extrinsic alveolitis due to organicagents,'23 an increase in alveolar neutrophils may

precede the lymphocytic alveolitis.

DIAGNOSISThe subjects with extrinsic alveolitis induced byisocyanates typically experience a general malaise-a "flu-like syndrome" including headaches, nausea,

muscle aches, chills, and fever-which occurs latein the workshift or even after it. Most subjects failto show interstitial infiltrates and a restrictivebreathing pattern. These features may also beabsent in bird fancier's or farmer's lung disease.'20The presence of IgG antibodies directed at theincriminated isocyanate should not be regarded as

being pathognomonic of isocyanate induced extrin-sic alveolitis. In our study, high concentrations ofspecific IgG to MDI were found in only three of theeight subjects. Thus the diagnosis of isocyanateinduced extrinsic alveolitis should not be basedsolely on the clinical history, chest radiograph, andbaseline function tests but on the objective demon-stration that exposure to non-irritant concentra-tions of isocyanates causes alveolar and systemicreactions. A rise in body temperature above37 2°C, an increase in circulating neutrophils of2500/mm3 or more, and a fall in FVC > 15% are

the most sensitive and specific indices of a positivealveolar reaction.'24 Some degree of airwaysobstruction can be seen in association with the

alveolar response.28122 The monitoring of bodytemperature and assessments of white blood cellcount should be included as a routine procedure forinhalation challenges with isocyanates.

OUTCOME AND MANAGEMENTLittle is known about the prognosis of subjects withisocyanate induced extrinsic alveolitis.There hasonly been one case of life threatening respiratoryfailure due to a haemorrhagic pneumonitis in a sub-ject exposed to MDI who had specific IgG antibod-ies. 122 Some affected subjects show a significantfunctional impairment at the time of diagnosis'07but there is no information on the long term prog-nosis for these subjects. Most subjects, however,have no permanent disability after ceasing work.There is one report of a subject with extrinsic alve-olitis who remained without symptoms despite con-tinuous exposure to TDI;"8 however, the lastassertion has been seriously questioned.'25Complete removal from exposure at work shouldtherefore be recommended for all subjects.

ConclusionBecause of their high chemical reactivity and wide-spread industrial use, isocyanates are now the prin-cipal cause of occupational asthma in industrialisedcountries. Every isocyanate, regardless of its molec-ular form or volatility, should be considered aspotentially hazardous. The mechanisms leading toisocyanate induced occupational asthma are still amatter of intense research. An IgE or IgG mediatedmechanism has so far not been convincingly shownbut should not be categorically excluded becauseimmunological studies are limited by difficulties inpreparing adequate antigen substrates. There is alsoevidence that inflammation and morphologicalchanges of the bronchial mucosa and direct neuro-genic mechanisms could have an important role.The frequency of occupational asthma amongworkers exposed to isocyanates is still uncertainbecause there have been few population based sur-veys and all of them were cross sectional. Carefullongitudinal studies of exposed populations arerequired to determine the actual frequency of thedisease as well as to investigate its natural historyand identify potential risk factors. It is important toconfirm the diagnosis through objective tests and torecommend complete removal from exposure toisocyanates. Methods that allow for a more accu-rate control of the level of exposure to isocyanatesduring inhalation challenges should be furtherdeveloped. Such methods will increase the safety ofthe tests and will contribute to a more satisfactorystandardisation of inhalation challenges performedfor diagnostic and research purposes. The study ofisocyanate induced asthma can further our under-

225


standing of non-occupational asthma from thepathophysiological and epidemiological points ofview. Isocyanate induced asthma is a good modelbecause subjects can be examined before exposure,

to the causative agent, when they develop asthma,and after they have been removed from exposure,

which is not feasible for non-occupational asthma.Isocyanates have also been reported to cause

alveolar and systemic reactions consistent withextrinsic alveolitis. The pathogenesis of these reac-

tions is far from being elucidated. Current datasuggest that both IgG mediated and cellularimmunological mechanisms are involved. Althoughextrinsic alveolitis has only been described in anec-

dotal case reports, the possibility that such reac-

tions have been overlooked in cross sectionalsurveys of exposed workers should be considered.

We thank Katherine Tallman for reviewing themanuscript.

Requests for reprints to: Jean-Luc Malo MD,Department of Chest Medicine, H6pital du Sacr&-Coeur, 5400 West Gouin, Montreal, Canada H4JIC5.

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Accepted 7 September 1992

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