Systemic reactions associated with polyisocyanate exposure

LSEN J, SANao WINROTH G, HALLBERG T, SKERFVINa S. Systemic reactions associated with polyisocyanate exposure. Scand J Work Environ Health 11 (1985) 51-54. A spray-painter suf fered attacks of chills, fever, general malaise, dyspnea and wheezing, headache, art hralgia, and leuco cytosis a few hours after exposure to aerosols of varnishes containing two different polyisocyanates based upon monomers of hexamethylene or toluene diisocyana te. Immunologic studies revealed an increase in the serum immunoglobulin a level, but no specific antibodies against isocyanates conjugated to human . serum albumin. The polyisocyanate level in the workroom air was high [a time-weighted average of 4.2 mg/rn" , corresponding to 17 pmol NCO (isocyanate groups)/ m' ), the toluene diisocyanate monomer level being much lower (a time-weighted average of 0.03 rng/m', corresponding to 0.3 flmol NCO/ m').

Isocyanates are used in, eg, foams, synt hetic rubbers, adhe sives, and paint s. They are kno wn to produce irritation of mucou s membranes at high levels in the air. A second type of react ion is airway obstru ction in sensitive subjects at lower intensities of exposure. Type I allergy caused by specific immunoglobulin (Ig) E ant ibodies has been suggested as the pathomechanism of the latter reaction (1), even if the evidence is not fully consistent. Howe ver, there is a third , much less frequentl y not iced reaction pattern, reported in a handful of cases onl y (2,4,5,7,8,12,15), " flu-like" late reactions with general malai se, myalgia, fever , neut rophilic leucocytosis, diffuse infiltrate in the chest radiograph, reduced pulmonary volumes, low compliance, and impaired gas diffusion capacity in the lungs being the ma in clinical featu res, suggesting a type III response with hypersensitivity pneumonitis, which is also indica ted by histopathology (4). Specific IgG antibodies of a precipitating type have been demonstrated in one case (15). The three differ ent reaction patterns thus are similar to tho se reported in association with trimellitic anhydride (16).
The ad verse reactions to isocyanates were first observed in connection with exposure to tolu ene diisocyan ate (TDI) and hexamethylene diisocyanate (HOI) , both of which have high vapor pressures. Diphenylmethane diisocyanate (MOl) was initially considered less toxic because of its low vapor pres-Repr int s requests to : Dr J Nielsen , Departm ent o f Occupational Med icine. University Hospital. S-221 85 Lund , Sweden.
sure. However, even MDI (or probably rather volatile isocyanate impu rities) turned out to cause disease. Thus for medical and, probably more important , technical reason s, a new type of compound, polyisocyanates, based upon HDI or TDI, was introduced (3). These co mpounds are now widely used, mainl y in paints and varnishes. While much is stilI unknown regarding the toxicit y of the classical isocyanates, even less is known about the pol yisocyanates (3). Onl y limited data on animal toxicity (13,14) and a single case of ad verse reaction in man , an immediate asthmatic reaction (1), have been reported.
In the present communicat ion we report a case of hypersensitivity pneumonitis-like reaction to two different types of pol yisocyanates. The exposure levels were measured .

Case history
The patient (a male 56 years of age) was first seen in June 1978. He had no histor y of atopy. From the age of 20 he had smoked, maximum consumption being 20 cigarettes per day , but in the last year only four cigarett es per day. He had a budge rigar at home. After school he worked as a carpenter. In 1977 he, in add ition, started to spray-paint furniture in a spraying chamber. Two different two-component varnishes were used (A and B).
In 1977, when he was stilI only a carpenter, he had su ffered several att acks of laryngitis and one episode of obstru ctive bronchiti s. A few months after he had begun spray-painting, symptoms occurred in association with varnish A. Each time, after about an hour, he suffered dyspnea with cough and wheezing. After a bout a year each attack also included chills, general malaise, headache, and arthralgia . His body temperature rose to a maximum of 39 .5°C in about 12 h, TIME Figure 1. Blood white-cell count and body temperature of a sensitive subject in connection with spray-painting with a varnish containing a polyisocyanate based upon toluene diisocyanate. no eosinophilia. The total serum IgE was normal, but IgG was raised to 30 gil (upper reference limit 15 gil). A skin prick-test with a standard panel of 14 different common antigens was negative. He had no precipitating serum antibodies to farmer's lung antigens or paraquete antigens (including budgerigar). Epicutaneous tests with the two polyisocyanates revealed a slight reaction after 2 h but thereafter soon faded.
When, in 1979, he was repeatedly studied at the worksite while spraying TDI-based polyisocyanate (varnish A), he suffered the typical attacks already described. There was a marked increase both in the white blood cell count (86 070 neutrophils) and in temperature (figure 1). The lung function parameters deteriorated simultaneously (figure 2). Physical examination revealed rhonchi and rales. Chest radiographs showed no changes. Provocation with varnish B caused no symptoms, fever, leucocytosis, or lung function impairment.
At two of the provocations with the TDI-based polyisocyanate already mentioned, the exposure was measured by a liquid chromatographic method (10). The method involves absorption of the isocyanates in the breathing zone in a midget impinger filled with 10 ml of the reagent [9-(N-methylaminomethyl)-anthracene I . 10--4 mol· 1-1 in toluene]. Sixteen samples were obtained during periods of 15-30 min. Polyisocyanate standards with known composition were obtained from Bayer AG.
Serum obtained in 1979 was studied further immunologically. A radioallergosorbent test (RAST) (1) revealed no specific serum IgE antibodies against HDI, TDI, MDI, and the two types of polyisocyanates conjugated with human serum albumin (HSA).
Prausnitz-Kiistner tests with some of these conjugates (HDI-HSA, TDI-HSA, and MDI-HSA), as well as with HSA conjugates with p-tolyl monoisocyanate and phenyl monoisocyanate, were negative. Serum samples from the patient did not agglutinate sheep red blood cells coated with the conjugates by a modified chromium chloride procedure (11), and the result remained negative in an indirect Coombs' test using three different antihuman Ig sera. The conjugates did not cause precipitation when tested in gel diffusion assay according to Ouchterlony.
Further examinations were performed in 1981 and 1982, when the patient had been out of exposure for two to three years. Serum IgG was still high, 22 gil. There was no reactivity in the skin prick-test or specific serum IgE or IgG antibodies [determined by enzyme-linked immunosorbent assay (ELISA)] to the aforementioned conjugates. HDI-HSA, TDI-HSA, and MDI-HSA did not release histamine from the patient's basophilic granulocytes in vitro. Varnish A contained initially a polyisocyanate of the biuret type, based upon HDI (Desmodur N@, Bayer AG). Later on, a polyisocyanate of polyurethane type, based upon TDI (Desmodur L®, Bayer AG), was used. The content of the monomer was I 0J0 or less for both polyisocyanates. The patient suffered identical attacks at exposure to both varnishes. Varnish B, which caused no symptoms, was a urea resin cured by p-toluenesulfonic acid.
Repeated physical examinations in 1978 at varying times after exposure (hours to days) revealed pulmonary rales on the left base. The chest radiograph was normal. In a spirometry test vital capacity (Ve) was 4.  .-. 150001~~.
!f "'. In a metacholine test in 1981 the patient displayed bronchial hyperreactivity (18 070 decrease in FEV 1.0 after a metacholine dose of 0.02 mg). The lung mechanics were normal at that time .

Discussion
Exposure to polyisocyanate varnishes is not harmless, at least not in spray-painting operations, as was clearly shown by our case, as well as by a single earlier-described one (1).
The polyisocyanate levels measured were considerable . The concentration ranged between 1.5 and 704 mg/ru', which corresponds to 504-30 /lmol NCO (isocyanate groupsj/m'. Corresponding levels of a biuret-type of polyisocyanate induced toxic pulmonary effects in mice after 2 h of exposure (14). The concentrations are far above the tentative Swedish standard for polyisocyanate vapor (0.005 ppm, corresponding to 0.2 mg/rrr' = 0.6 /lmol NCO/m'; ceiling concentration 0.01 ppm, corresponding to 0.3 mg/m' = 1.2 /lmol NCO /m 3 ) . For aerosols (as in the present case) there is no hygienic standard.
The hygienic conditions in our case were not exceptionally bad. Similar or even higher levels should be present in many other workshops, as has been shown in one other study (9). As the vapor pressure of polyisocyanates is low, occupational risks should mainly be encountered in operations where aerosols are produced.
As it is well known that NCO groups present in compounds with different chemical structure may cause adverse reactions, we consider it possible that those present in the polyisocyanates may have caused the toxic reactions, although we cannot exclude the monomers as the cause . We find it reasonable to establish a definite hygienic standard for polyisocyanates, both as an aerosol and as a vapor. One suitable way would be to employ a standard value expressed as the sum NCO in micromoles per cubic meter, including borh monomer and polymers. The present standards for TOI and HDl may be used until more to xicologic information is available.
The general reaction pattern of our patient is interesting. As was already mentioned, only a few similar cases associated with isocyanate exposure have been reported. However , the phenomenon may not be very rare . The reaction is late and its association with isocyanate exposure is not well known. The cause may thus easily be overlooked.
Of particular interest is the fact that the reaction in our case was caused both by a biuret-type polyisocya-nate based upon HDI and a polyurethane type based upon TO!. A cross-reactivity thus must exist.
We do not know the pathomechanism behind the reaction. In other reported cases, radiographic changes, the presence of precipitating antibodies, and/or histopathological findings suggested a hypersensitivity pneumonitis. We do not have such evidence, even though the serum IgG level was high in our case. The fact that our examinations did not reveal specific antibodies does not of course exclude the possibility of an allergy. The antibody concentration may be below the detection limit, or the antibodies may be directed against antigenic determinants in the complex of isocyanates and body proteins other than those present in our HSA conjugates . On the other hand, the most impressive clinical finding was the neutrophilic leucocytosis, similar to the reaction caused by thermal degradation products of polyfluoroethylene (6). Such a reaction might be mediated through a direct toxic nonallergic action upon pulmonary macrophages.