C. Lemière*, A. Desjardins*, Y. Cloutier**, D. Drolet**, G. Perrault**, A. Cartier*, J-L. Malo*

Eur Respir J, 1995, 8, 861 865 DOI: 1.1183/931936.95.85861 Printed in UK - all rigts reserved Copyrigt ERS Journals Ltd 1995 European Respiratory Journal ISSN 93-1936 CASE REPORT Occupational astma due to formaldeyde resin dust wit and witout reaction to formaldeyde gas C. Lemière*, A. Desjardins*, Y. Cloutier**, D. Drolet**, G. Perrault**, A. Cartier*, J-L. Malo* Occupational astma due to formaldeyde resin dust wit and witout reaction to formaldeyde gas. C. Lemière, A. Desjardins, Y. Cloutier, D. Drolet, G. Perrault, A. Cartier, J.L. Malo. ERS Journals Ltd 1995. ABSTRACT: We report te cases of tree subjects wo developed astma after being exposed to formaldeyde dust or gas. For two subjects, specific broncial provocation tests wit formaldeyde gas did not cause significant broncoconstriction, wereas exposure to formaldeyde resin dust did. One subject experienced astmatic reaction after being exposed to formaldeyde resin dust and gas. Tese findings suggest tat te pysical and cemical properties of formaldeyde are relevant to its likeliood of causing astma. Eur Respir J., 1995, 8, 861 865. *Dept of Cest Medicine, Hôpital du Sacré- Coeur and **Institut de recerce en santé et sécurité du Travail (IRSST), Montréal, Canada. Correspondence: J-L. Malo, Department of Cest Medicine, Sacré Coeur Hospital 54 West Gouin, Montreal, Canada H4J 1C5 Keywords: Broncial provocation tests occupational diseases Received: September 26 1994 Accepted after revision February 6 1995 Tis study was partly supported by te Centre québécois d'excellence en santé respiratoire. J.L.M. is a reaserc scolar wit te Fonds de la recerce en santé du Quebéc (FRSQ). C.L. is te recipient of a researc grant from L'Association recerce et partage (Paris. France). Formaldeyde is a low molecular weigt organic cemical. It can act as a sensitizer at low concentrations and cause occupational astma [1]. It can also ave irritant effects at ig concentrations (above 2. parts per million (ppm) or mg m -3 ) and cause immediate reactions tat are related to istae reactivity [2]. Formaldeyde is widely used in occupational settings (ospitals, furniture manufacturing, textiles, insulation). People can be exposed to formaldeyde as a gas [3, 4], or as resin dust [5, 6]. Previous reports ave documented cases of occupational astma due to gaseous formaldeyde [2, 7], or to urea formaldeyde dust [6]. We report two cases of occupational astma due to formaldeyde resin dust in subjects wo did not react to formaldeyde gas, and one case in a subject wo reacted bot to formaldeyde dust and gas. Tese observations suggest tat te pysical and cemical properties of a molecule are relevant to its likeliood of causing astma. Subject No. 1 Case reports A 24 year old female was ired as a cemist in te Researc and Development Department of a cemical factory in Marc 1993. Se ad no previous istory of astma or atopy and ad never smoked. Her work in te laboratory involved two sequential steps. Firstly, se syntesized a resin from formaldeyde, penol, caustic soda and water, eated at 8 C. Secondly, in a separate room, se prepared a polymer of penol formaldeyde resin powder by adding oleic acid and glycol etylene to te former resin, putting te resulting solution into a macine tat sprayed it onto eated partitions and transformed it into a fine powder ("spray-dry" process). Tere were no available data on concentrations of formaldeyde resin powder in te workplace. Two monts after beginning tis work, se developed eadaces, nasal congestion, rinorrea and sneezing, as well as episodic weezing, sortness of breat and cest tigtness. Her symptoms usually started 3 4 after exposure to penol formaldeyde resin powder and lasted for 24. Se was usually exposed 3 4 days a week for 2 at a time. Se ad been awakened at nigt a few times because of rinitis and eadace after aving been exposed to penol formaldeyde resin powder. Se usually improved witin 2 3 days after stopping exposure to "spray-dry" as well as during weekends. Se reported no symptoms wen andling formaldeyde in liquid form or wit te resin before it was processed in te "spraydry" department. Se was treated wit budesonide, 2 µg b.i.d., and salbutamol as needed, in October 1993. Se stopped working at te end of October 1993 and rapidly became asymptomatic. Se was able to stop

862 C. LEMIERE ET AL. budesonide in December 1993. Skin tests performed by te prick metod wit 22 common inalants sowed immediate weal reactions to ouse dust mites (D. pteronyssinus, D. farinae), ouse dust, cat fur, dog fur and cockroac. Serial monitoring of peak expiratory flow rates for a period at work and away from work suggested work-related astma. Specific inalation callenges were performed in November 1993. Te forced expiratory volume in one second (FEV1) was L (1% pred) [8] wit a forced vital capacity (FVC) of 4.5 L (11% pred). Nonspecific broncial responsiveness to metacoline was assessed wit a Wrigt nebulizer (output =.14 L -1 ) at tidal volume breating for 2 using te procedure of COCKROFT and co-workers [9]. Te provocative concentration causing a fall of 2% in FEV1 (PC2) was 3.8 mg ml -1, reflecting mild broncial yperresponsiveness [1]. Graps of broncial provocation tests are illustrated in fig. 1a. A control day witout exposure did not sow any significant canges in FEV1. On te next day, te subject was exposed to penol formaldeyde resin powder by tipping te dust from one tray to te oter in a provocation camber [11] in a progressive fasion for a total of one our. One our after te end of exposure to resin dust, te FEV1 decreased from 3.6 to 2.9 L (21% fall). Te day afterwards, te PC2 was mg ml -1, sowing no significant canges [12]. On te tird day, te subject was exposed to gaseous formaldeyde for 2 in a provocation camber. Se breated normally 2 cm away from a small jar filled wit liquid formaldeyde [11]. No significant canges in FEV1 occurred in te utes and ours following exposure, te PC2 being uncanged (4.3 mg ml -1 ) at te end of te day (not illustrated). Tis unexpected result led us to carry out te following investigation, wic took place 6 monts after te subject ad stopped using inaled steroids. We exposed er to controlled concentrations of formaldeyde gas wit a recently developed closed circuit inalation callenge apparatus equipped wit regulating and monitoring systems. Se was progressively exposed for a cumulative time of 2, at concentrations of 1 mg m -3 for te first 15, 2 mg m -3 for te subsequent 3, and 3 mg m -3 for te last 75 (ceiling value: 3 mg m -3 or 2. ppm). Again, tere were no canges in FEV1 nor in PC2 following exposure. To furter demonstrate tat te reaction experienced by our subject was not due to a nonspecific irritant effect of formaldeyde, an astmatic subject wit a PC2 of.28 mg ml -1 was asked to tip formaldeyde dust in te same way. No astmatic reaction occurred. Tere was no increase in metacoline-induced responsiveness after te callenge (PC2 =.39 mg ml -1 ). Subject No. 2 A 28 year old male subject ad been working since 1992 in a factory tat processed wood cips into boards. He ad never smoked and ad a negative personal atopic istory. Aspen wood cips are stirred wit wax and a resin, including an ae (see below), penol and formaldeyde. Te subject first worked across several areas witin te factory, but after e ad been promoted to quality control e stayed mainly at te end of te wood a) b) c) 2. 1.5 4.5 2. Pre 2 4 6 9 2 4 6 8 1 Pre 2 4 6 9 2 4 6 8 Pre 2 4 6 9 2 4 6 8 Time Fig. 1. Results of specific inalation callenges to penol formaldeyde resin and formaldeyde gas in te tree subjects. a) Subject No. 1. : control day; : penol formaldeyde resin (6 ); :formaldeyde gas (12 ). b) Subject No. 2. : MEK tinner (3 ); : penol formaldeyde resin (3 ); : formaldeyde gas (75 ). c) Subject No. 3. : control wood-dust (3 ); : penol formaldeyde resin (2 ); : formaldeyde gas ( ). Te duration of exposure is sown in parentesis. to formaldeyde gas represents results obtained wit te special apparatus (second exposure to formaldeyde gas for Subjects Nos. 1 and 2, te first test aving been performed in a "realistic" way - more like te exposure at work). MEK: metyl etyl ketone; : broncodilation terapy wit inaled salbutamol (2 µg); FEV 1 : forced expiratory volume in one second. Note tat te vertical axes are cut off from zero.

OCCUPATIONAL ASTHMA DUE TO FORMALDEHYDE 863 cip production line. In te summer of 1993, e started aving episodes of sortness of breat, couging and weezing, usually in te afternoon during workdays. Tese symptoms improved in te evening and during weekends, and completely disappeared on olidays. Since is respiratory symptoms progressively worsened, e was transferred to te office witin te factory, were e was no longer exposed to wood cips. He stopped working in December 1993 on te advice of a local cest pysician, wo performed serial monitoring of peak expiratory flow rates at work and away from work. He became completely asymptomatic. Skin tests wit common inalants (see above) were entirely negative. In February 1994, is FEV1 was 3.8 L (86% pred) and is FVC was 5.5 L (18% pred), wereas is PC2 metacoline was 4.9 mg ml -1, reflecting mild broncial yperresponsiveness. Serial monitoring of peak expiratory flow rates for a period at work and away from work was igly suggestive of work-related astma. Specific inalation callenges were performed in February 1994 (fig. 1b). On te first day, used as control, te patient was exposed to a paint tinner (metyl etyl ketone), wic was nebulized for a 3 cumulative period. No significant cange in FEV1 occurred witin te next 8. Next, te patient was exposed to fumes from te eated resin containing penol, formaldeyde and exametylenetetrae, in a progressive fasion for 5, 3 and 12, respectively, on tree consecutive days, witout developing any symptoms or canges in FEV1 (not illustrated). Furter inquiry about te work process disclosed obvious dispersion of penol formaldeyde resin powder in te area, wen it was poured troug a large open funnel into te particle board oven, adjacent to te subject's work location. We terefore decided to pursue te callenge by aving te subject inale te penol formaldeyde resin dust wit our closedcircuit particle generator at concentrations lower tan 1 mg m -3 [13]. Tis resin contained.1 1% formaldeyde, 1 2% penol, 3 7% sodium ydroxide and 5 1% exametylenetetrae. Two ours after starting te test, te FEV1 decreased from 3.3 to 2 L (41% fall) and te subject began to complain of dyspnoea, cest tigtness, weezing and coug. Tese symptoms were partly relieved by salbutamol. Two monts later, e was callenged wit gaseous formaldeyde wit te novel apparatus (see above) for a total of 75 : e was exposed for 7.5 to 1 mg m -3 of formaldeyde, and ten for 67.5 to 3 mg m -3 of formaldeyde. No cange in FEV1 occurred. At te end of te day, te PC2 metacoline was 7 mg ml -1. Subsequently, astma due to exametylenetetrae dust was ruled out (since tis ae accompanied penol formaldeyde witin te resin used above), as te subject was exposed to te ae dust only for a 3 cumulative period witout significant cange in FEV1 following exposure (not illustrated). At te end of te day, PC2 metacoline was 13 mg ml -1. Subject No. 3 A 31 year old male subject ad been working as a carpenter since 1983. He ad ad astma in cildood. He ad never smoked. He made furniture, cutting different types of wood (oak, pine, maple). He also cut boards made of pine and penol formaldeyde (.1%). In 1986, e started noticing nasal congestion, rinorrea and sneezing, as well as episodic weezing, cest tigtness and sortness of breat. He reported nasal congestion a few utes after beginning work, but respiratory symptoms usually occurred in te evening or at nigt, often waking im up at nigt. Tese symptoms improved at weekends and on olidays. He was treated by salbutamol as needed. Skin tests wit common inalants were negative. In July 1994, after a day spent at work, is FEV1 was 4.33 L (93% pred) wit a FVC of 5.29 L (119% pred), wereas is PC2 metacoline was 2. mg ml -1, reflecting mild broncial yperresponsiveness. Serial monitoring of peak expiratory flow rates for a period including time at work and time away from work was igly suggestive of work-related astma. Specific inalation callenges were performed in October 1994. Graps of specific inalation callenges are sown in fig. 1c. On te control day, te subject was exposed to control wood-dust wit a closed-circuit particle generator for a 3 interval. No astmatic reaction occurred. Te PC2 was 1. mg ml -1 at te end of te day. Because tis subject was exposed to oak wooddust at work, e was exposed to it first, wit te closedcircuit particle generator for increasing intervals up to 2. No significant canges in eiter FEV1 or in PC2 were documented after exposure. A few days later, we exposed im to penol formaldeyde resin dust wit te closed-circuit particle generator in a progressive fasion for a total of 2. He developed an isolated immediate reaction (fig. 1c). At te end of te day, te PC2 was significantly reduced (.17 mg ml -1 ). A week later, we exposed im to formaldeyde gas wit te closedcircuit inalation callenge apparatus for a cumulative interval of at a concentration of 1 mg m -3. Te subject developed an isolated immediate astmatic reaction (fig. 1c). Te PC2 was.1 mg ml -1 at te end of te day. Discussion Two subjects presented astmatic reactions wit formaldeyde resin dust but not wit gaseous formaldeyde, wereas one subject experienced an astmatic reaction wit bot formaldeyde resin dust and gas. We can reasonably exclude tat te astmatic reaction can be explained in an irritant, nonspecific way. A control astmatic subject exposed to formaldeyde resin dust in a similar way to Subject No. 1 did not experience an astmatic reaction. Te two oter subjects were exposed to formaldeyde dust using a particle generator, wic allows for te exposure of subjects to concentrations below te tresold limit value (TLV)- sort-term exposure limit (STEL) levels. WITEK et al. [14] failed to demonstrate irritant effects among 15 astmatic volunteers after exposure to 2. ppm formaldeyde for 4 in an environmental camber. It is unlikely tat te lack of reaction after exposure to formaldeyde gas in te case of our

864 C. LEMIERE ET AL. first subject could be attributed to an inibitory effect of inaled steroids. Indeed, oral and inaled steroids can block te late or even te immediate reaction to allergen callenge. However, tis as been sown by adistering tis treatment immediately before te callenge [15]. In Subject No. 1, te last dose of inaled steroids took place 1 before te callenge. Moreover, te callenge to formaldeyde gas was performed te day after te callenge to formaldeyde resin. It is igly unlikely tat inaled steroids could suppress an astmatic reaction, wen te same subject on te same treatment experienced an astmatic reaction te day before. Altoug astma-like symptoms are often reported after exposure to formaldeyde [16, 17], few cases of workers wit occupational astma due to eiter gaseous or particulate formaldeyde ave been documented troug objective means [2, 6, 7]. However, in tese reports, te relevance of te pysical and cemical state of formaldeyde in causing astma was not explored. Interestingly, FRIGAS et al. [5] reported a case of severe astma tat developed following insulation of a ouse wit urea formaldeyde foam. Broncial callenge wit te buoyant dust of te foam caused an astmatic attack but inalation of formaldeyde gas did not. Te autors speculated tat as urea formaldeyde foam was a complex mixture of compounds, some of wic are unknown, formaldeyde was not te cause of teir patient's astma. An alternative ypotesis would be tat te patient described by FRIGAS et al. [5] may still ave suffered from astma due to formaldeyde foam dust, even toug se did not react to formaldeyde gas. Te pysiopatology of occupational astma caused by low molecular compounds remains unclear. Some cemicals can induce respiratory symptoms similar to an allergic type I reaction by binding to a protein in vivo and acting as an apten, but tey can cause disturbances in te respiratory tract troug nonimmunological mecanisms. Tey are able to interfere wit receptor proteins or enzymes. WASS and BELIN [18] postulated a correlation between te ability of a substance to react wit proteins and its potential to induce respiratory tract dysfunction. Tey developed an in vitro metod for predicting sensitizing properties of inaled cemicals. Based on tese assumptions, te pysical and cemical state of formaldeyde (gas or dust) could significantly affect te likeliood of astma occurring after exposure. Te reaction of formaldeyde wit urea or penol results in te formation of a complex mixture of a ig molecular weigt polymer wit small percentages of unreacted formaldeyde and oter additives (catalysts, plasticizers, etc.). Tus, occupational astma caused by ig molecular weigt polymers of formaldeyde existing as dust, but not by formaldeyde oligomers or monomers existing as gas, is analogous to our cases of occupational astma due to toluene diisocyanate (TDI) or exametylene diisocyanate (HDI) prepolymers, witout broncial reaction to HDI or TDI monomers [19, 2]. Te pysical state of HDI and TDI monomers greatly differs from tat of HDI and TDI prepolymers. HDI prepolymers are encountered as a gas, wit a molecular weigt in te few undred daltons; TDI prepolymers take te form of an aerosol, wit a molecular weigt in te few tousand daltons. AGIUS et al. [21] underlined te potential importance of bifunctional reactivity of low molecular weigt substances in teir propensity to cause astma. Many compounds wic cause occupational astma ave at least two reactive functions (e.g etylene diae, piperazine, penylene diae) as opposed to teir monofunctional counterparts (etylae, piperidine, aniline), wic do not cause occupational astma. It can be ypotesized tat te likeliood of causing astma is related to te bifunctional reactivity. Formaldeyde (HCHO) does not ave bifunctional reactivity. However, in aqueous solution it exists almost exclusively as a diol (metane diol), wit supposedly altered functional reactivity. Consequent to tis ypotesis, te fact tat urea or penol formaldeyde resins are ig molecular weigt polymers is probably relevant to te likeliood of causing astma. IMBUS [22] suggested tat formaldeyde dust tat is absorbed onto particles could cause pulmonary reactions and greater airway response tan te formaldeyde gas alone. Te mecanism is tat particulate formaldeyde could reac te lower respiratory tract more easily tan formaldeyde gas. Moreover, formaldeyde gas can be largely absorbed on te upper respiratory tract and little of it would reac te lower respiratory tract. Te novel closed-circuit apparatus used to expose our tree subjects to formaldeyde gas is a modification of a previously described metodology adapted for use wit eiter aledydes or aes existing in gaseous form [13, 23]. Wit tis apparatus, we can obtain safe and nonirritant concentrations of te occupational agent. Controlling te exposure wit precision also allows us to exae dose-response relationsip in subjects wit occupational astma. Tis procedure allows for exposure to stable concentrations of te occupational agent in a dose-response fasion. From te practical point of view, tese tree cases empasize te need to expose subjects to te occupational agent in te same pysical and cemical state usually encountered at work. Specific inalation callenges in te laboratory sould indeed mimic te work exposure as closely as possible, as originally proposed by PEPYS and HUTCHCROFT [12]. Acknowledgements Te autors wis to tank L. Scubert for reviewing te manuscript. References 1. Malo JL, Bernstein IL. Oter cemical substances causing occupational astma. In: Bernstein IL, Can-Yeung M, Malo JL, Bernstein DI, eds. Astma in te workplace. New York, Marcel Dekker., 1993; pp. 481 52. 2. Burge PS, Harries MG, Lam WK, O'Brien IM, Patcett PA. Occupational astma due to formaldeyde. Torax 1985; 4: 255 26. 3. 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