- Email: [email protected]
Formaldehyde asthma—Rare or overlooked?
Henrik Nordman, Helsinki,
M.D., Helena Keskinen,
M.D., and Matii
Tuppurainen,
M.D.
Finland
A total of230 persons who had been exposed to formaldehyde and suffered from usthma-like respiratory symptoms were examined between January I, 1977, and May 31. 1983. All the subjects had a bronchial provocation test with formaldehyde. On the basis of the medical and occupationul history of the patients, the specihc bronchial provocation test, and other test results, 12 cases were considered to be caused by speci’c sensitization to formaldehyde. All subjects had been exposed occupationally. An exposure period of between I mo und 19 yr preceded the onset of symptoms. Three persons displayed no bronchial hyperreactivity us assessed with a histamine or metacholine provocation test. Eleven of the 12 reactions were triggered by about 2.5 mglm3 and one reaction by about I.2 mg/m3 of formaldehyde. The Itttc reaction in I patient was completely blocked by the inhalation of 100 pg of beclomethusone di-isoproprionate before the challenge with formaldehyde. Seventy-one of the 218 subjects bcho did not react when they were challenged with formaldehyde demonstrated bronchictl hyperreactivity. We conclude that formaldehyde asthma, although upparentiy u rure disease, is under reported. Removal from exposure has a favorable effect on the symptoms. Low’ domestic exposures, however, may maintain the symptoms in individuals already sensitized. (J lqLLk:RGY CLIN IMMVNOL 75:9I-9. 1985.)
During the early 1980s formaldehyde was brought to the attention of the general public, largely because of the heated debate about its carcinogenic properties.lms The irritant characteristics causing toxic contact dermatitis and irritation of the eye and upper respiratory tract have been well documented.‘-lo Discussion has been further stimulated by experimental evidence of irritation of the mucous membranes and conjunctiva of susceptible individuals at concentrations frequently encountered in residential indoor ak
Abbreviations used PEF: Peak expiratory
FEV: WV,: FVC:
flow
Forced expiratory vohne Forced expiratory volume in 1 set Forced vital capacity
FEW@: loo XJ= FVC
ppm:
parts per million (cmZ’/m3)
11-13
Sensitization of the skin by formaldehyde is wellknownr4; formaldehyde has been classified as a strong contact allergen on the basis of the guinea pig maximization test. I5 In dermatologic practice, however, formaldehyde rarely appears to live up to its bad reputation. 4* I* Similarly, all major reviews refer to formaldehyde as a cause of occupational asthma,1’--20 but surprisingly Iittle is known about specific sen-
From the Institute of Occupational Health, Helsinki, Finland. Received for publication Jan. 23, 1984. Accepted for publication July 18, 1984. Reprint requests: Hencik Nordman, M.D., Institute of Occupational Health, Haartmaninkatu 1, SF-00290 Helsinki 29, Finland.
de&de. sitization of the respiratory tract by Airway obstruction and acute effects airways have been reported in workers exposed to urea- or phenol-formaldehyde re~ins.*~-~” Owing to the design of these studies, the findings could not bes~?@ifically attributed to formaldehyde. Fo sidered the cause of asthma in case repo@s on a rubber tire worker,24 a laboratory technician,ag and a spray painter. 26 Hendrick and Ianez7* 2* reported on two nurses who responded to bronchial provocation with formaldehyde. Our report concerns 12 cases of fo~~hyde asthma diagnosed during the period January 1, 1977, to May 3 I , 1983. Five are described in more detail. 91
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Nordman
TABLE
I. Some
Case
Sex
1 2 3 4 5 6 7 8 9 10 11 12
F F M F F F F F F F M M
Lung
J ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al. characteristics
Exposure source
Furniture lacquer Ironing textiles Chipboard House paint Gluing plywood Gluing plywood Ironing textiles Laboratory chemicals Gluing plywood Footwear glue Heating polyethene House paint
of 12 subjects
with formaldehyde
Time of exposure before symptoms
Atow
2mo 1 mo 6yr 19 yr 4 mo 8 yr 6 mo 5yr 4 yr 5 Yr 4 yr 13 yr
+ + -
PEF diurnal variation (%I
8 15 14 5 9 6 14 5 14 18 7 25
asthma
FEV, (U
FVC (L)
2.84 2.06 4.41 2.70 2.22 2.60 2.50 2.81 2.93 2.0 3.78 2.80
3.47 2.90 4.92 3.17 2.80 3.43 2.99 3.25 3.67 2.7 4.65 4.48
FEV% deviation from predicted
-2 -8 + 10 +5 +2 -6 -3 +5 -4 -0.5 +8 -18
FEV, response bronchodilation (%I
0 +8 +3 0 +8 + 10 i-24 +6 +9 0 +6 0
function measured on admission to hospital and without medication.
SUBJECTS AND METHODS During 6% yr 230 patients were investigated because of suspected formaldehyde-induced bronchial asthma. The patients were referred to the Institute of Occupational Health from all over Finland. All subjects had been exposed to formaldehyde and were suffering from respiratory symptoms compatible with asthma attacks. The definition of asthma adopted here was that recommended by the joint committee of the American Thoracic Society and the American College of Chest Physicians.2s Clinical examinations included a detailed medical and occupational history, skin prick testing with common allergens, recording the spontaneous diurnal variations of the PEF, spirometry with a bronchodilation test, a histamine provocation test, an exercise test (when it was considered appropriate), and bronchial challenge with formaldehyde and a negative control. Serologic tests, including determination of eosinophil count and total serum IgE, were also performed. Skin sensitivity to about 20 common allergens including animal epithelia, pollens, house dust, and mite was tested with the skin prick technique according to the method of Aas and Belin.30 Atopy was defined as at least one reaction equal to or larger than the reaction to histamine. Routine epicutaneous testing with formaldehyde was performed by use of the occlusive Finn Chambers method,31 and a formaldehyde solution of 1 .O%. Dilution series (2% to 1% to 0.5%) were used when irritant reactions were suspected and in all patients with a positive test to exclude such reactions. The spirograms were recorded with a water-sealed spirometer (Kifa, Sweden). FVC and FEV, were expressed as a percentage of the predicted values,32j 33 and the FEV% (100 X FEV,,,/FVC) was calculated. Salbutamol (two puffs of 0.1 mg each) or rimiterol hydrobromide (three puffs of 0.2 mg each) was used in the bronchodilation test after spirometry. An increase of at least 15% and 1.50 ml in FEV, was regarded as significant. The PEF was measured with a
Wright peak flow meter. All PEF measurements were recorded by a nurse at the bed ward. In the determination of spontaneous diurnal variations, the PEF was recorded every 3 hr for at least 24 hr before the inhalation testing started. The best of three measurements was recorded. The degree of bronchial hyperreactivity was assessed with a histamine challenge test modified from the one described by Laitinen. 34 This involves inhaling a 1% solution of histamine diphosphate through a nebulizer in three stages involving one, four, and 16 inhalation(s), respectively. The nebulizer used was a De Vilbiss No. 40 (De Vilbiss Co., Somerset, Pa.) through which air flowed at a rate of 5 L per minute. Each stage was followed by a PEF measurement. A drop in PEF of 15% or more at any stage was considered significant, and the test was discontinued. A positive reaction after a single inhalation was classified as “strong” bronchial hyperreactivity, a reaction after four inhalations as “intermediate,” and a reaction after 16 inhalations as “slight. ” If a histamine or metacholine test had been performed during the previous 3 mo, the histamine test was not always considered necessary. The metacholine test was done according to Hargreave et al.35 The technical procedures of the bronchi provocation tests were close to those outlined by Pepys et a1.36 and Newman Taylor and Davies. 37 Exposure to formaldehyde was achieved by evaporating 35 or 70 ~1 of an aqueous solution (35%) of formaldehyde in an exposure chamber measuring 10 m3. Temperature and humidity could not be regulated. The standardized procedure was calibrated to generate concentrations as close to 1.2 mg/m3 (1 ppm) and 2.5 mg/m3 (2 ppm) as possible without exceeding these levels that correspond to the new and the old nationally recommended exposure limits. The formaldehyde concentrations were measured four times annually by use of the chromotropic assay.38 According to these measurements evaporation of 35 ~1 of formalin caused concentrations in
VOLUME 75 NUMBER 1. PART 1
TABLE
II. The results
Formaldehyde
of bronchial
provocation
tests in 12 subjects
with
asthma-Rare
formaldehyde ---
Bronchial
Case 1
2 3 4 5 6 7 8 9 10 11
12/l
Bronchial hyperreactivity
None Metacholine + None Slight Intermediate Slight Not done Slight None Metacholine + Slight Slight
Placebo provocation
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
Immediate PEF change (%I
-25 -24
provocation
with
Late PEF change (%I (latency)
-43 -31
(16 hr) (16 hr)
-22 -21
(14 hr) (14 hr)
-49 - 36t
- 19 -14$ -35 -213
-29 -47
(I6 hr) (1.5 hr)
or overlooked
asthma __.-. .-.-..--
formaldehyde -..-_-_.Response Wheeze on bronchod#lation* auscultation (%I
93
--
2.5 mg/m3
+ t+ t .-
to
t?ij t I4 t 58 . -.. -.+67 -+ 30
*Dash indicates that no bronchodilator was administered. fchallenged with 1.2 mg/m’. $A 30-minute bronchial challenge done with the patient’s own glue resulted in an immediate 20% decrease in PEF. Formaldehyde concentrations were not measured. #Welding polyethene boxes (about 450” C) resulted in ‘an immediate 17% decrease in PEF. J/Reported in 1977.” Reacted to the house paint with a drop of 42% at 3 hr and 59% at 12 hr.
the range of 0.98 to 1.07 mg/m3; 70 11 of formalin caused 2.09 to 2.44 mg/n?. The higher concentration was routine up to May 1982. Since then the concentration in the first challenge has been 1.2 mg/m3. A negative response to 1.2 mgim” was followed by a provocation test with 2.5 mg/m”. A few patients who had suffered severe asthma attacks were challenged on the first occasion with a concentration of 0.3 to 0.5 mg/m3. Although in some instances the work place conditions were simulated in the exposure chamber, specific provocations with formaldehyde were always undertaken as well. Each provocation test began between 9:00 and 1l:OO A.M. and lasted for 30 min during which there was no tumover of air inside the chamber. The PEF was used as the indicator of ventilatory response. It was measured every 15 min during the first hour after the onset of exposure and longer if it was necessary. After the first hour the PEF was recorded hourly for 8 hr and thereafter at 3-hour intervals until the next morning. A 15% immediate and a 20% late drop in the PEF compared with the preexposure level was regarded as a positive reaction. The prerequisites for a provocation test were that the patient managed without drugs and had a spontaneous variation preferably not exceeding 1.5%#,i.e., the asthma was satisfactorily stable. Some exceptions from the latter criterion were made. Medication was discontinued not later than 3 days before the hospitalization. If it was needed, patients were sent home on sick leave for 2 to 3 wk with appropriate medication, including oral steroids when they were required. The next challenge was not performed until the preexposure PEF level had been achieved. A negative control test was always done with
Dome’s* base solution, following the same procedwes as with formaldehyde or with lactose pawdef .3’fSimulating the work tasks sometimes afforded s&q&z p&e&o tests, such as ironing fabrics treated or untreated with formaldehyde.
RESULTS Twelve patients were considered to have bronchial asthma speci6cally caused by ~o~~~~y~. Some characteristics of the ascertained cases are demon-
strated in Table I. All had been exposed occupationally . Some of the patients had been exposed while they wefe using formaldehyde en&&g glues or paints (eight), ironing textiles treated wit% resin containing formaldehyde (two), using f~~~~~ solut&ns in a laboratory (one), using fu~~~b~de ~~~ta~~g detergents (one), and welding ~l~~y~~~e boxes at a temperature of 450” (one). CMy two patients displayed atopy. The patients had beam exposed for a period of time between 1 mo and 19 yr before the onset of symptoms; six had been exposed for more than 5 yr, whereas four noted symIMms within 6 mo of exposure. The results of the bronchial provocation tests are illustrated immediate
. ts denzanstrated an in Table Il. Eight reaction, i.e., within 30 mirr of the begin-
*Division of Mites Laboratories Ltd., England.
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Nordman
J. ALLERGY CLIN. IMMUNOL JANUARY 1985
et al.
o----abase
PfZF L/min
+--+
line PEF
Case reports
lactose cant ro1 formaldehyde 2 5 mg/m’
Five casesrepresenting typical histories, different reaction patterns, and various responses to drugs are presented below. The number of the cases corresponds to the numbering in Tables I and II. Case 1
minutes
FIG.
1. Results
PEF L/mill I
hours time from beginning of Prov0catlonS
of bronchial
provocation
tests
e-----o
bss* line PEF
k----d
a----a
control ironing
l
*
FIG.
2. Results
of bronchial
provocation
in case
1.
ironi textile with “pormaldehyda formald.hydau~’ isofwnaline inhabtton 0.18mg ssltut~mol inhalation 02 mg
tests
in case
2.
A 31-yr-old woman was referred to us by an insurance company for further examination. She had started her employment in the furniture industry in 1980. Two of the varnishes that she used regularly for 1 yr contained ureaformaldehyde resin. There was no atopy in her personal or family history. She had been smoking for 8 yr. About 2 mo after she had started using the varnishes, she experienced rhinitis and a nonproductive cough at work, which improved over weekends. She was completely free from symptoms during vacations. On admission she had been unexposed for 2 mo and had no symptoms. There was no blood eosinophilia, and total IgE was 13 U/ml. Skin prick tests were negative. The results of spirometry demonstrated a slight obstruction (Table I). The histamine challenge did not indicate any bronchial hyperreactivity, and the spontaneous PEF diurnal variation was 8%. Lactose powder did not cause any bronchial reaction. The bronchial provocation test with 1.2 mg/m3 of formaldehyde did not cause a drop in PEF. When the patient was challenged with 2.5 mg/m3, she reacted with an immediate 25% decrease of PEF starting within 15 min of the beginning of the exposure (Fig. 1). Her symptoms were subjectively similar to those she had experienced at work.
Case 2 ning of exposure. Six late reactions, two of which were preceded by immediate drops in PEF, were recorded. The formaldehyde concentration used in 11 cases was 2.5 mg/m3 and in one case 1.2 mg/m3. Three patients did not react at all on provocation to histamine, indicating the absence of bronchial hyperreactivity. The bronchial provocation with formaldehyde was interpreted as negative in 218 patients; the diagnosis was bronchial asthma in 96 patients. The histamine provocation test was positive in 71 patients and negative in 127 of the 218 patients not reacting to formaldehyde. Ten workers had not been challenged with histamine or metacholine, and results wel;e not available for nine patients. Fifteen of the positive tests and seven of the negative tests had been done before admission to our institute. The histamine reactions of the 175 histamine tests performed at our institute on subjects not reacting when they were exposed to formaldehyde demonstrated seven patients reacting after one inhalation, 20 patients reacting after four inhalations, and 29 patients reacting after 16 inhalations, whereas 119 patients did not react.
The subject was a 51-yr-old woman who had been working in the textile industry for 11 yr. She had been ironing formaldehyde-treated textiles for about 1% yr before examination. There was no atopy in her personal or family history. During the 50s she had suffered from pulmonary tuberculosis. Within 1 mo of ironing textiles, she experienced urticaria and 1 mo later experienced spells of breathlessness and a productive cough. At a pulmonary disease unit her asthmatic symptoms had been associated with her work place, although formaldehyde had not been suspected as the cause. Before the specific provocation tests two attempts to return to work failed because the symptoms reappeared immediately: however, on admission she had no symptoms. The diurnal vatialion of PEF was 15%. There was a slight obstruction (Table I), no blood eosiriophilia, and the total serum IgE was 13 U/ml. Skin prick tests with common allergens were negative.The histamine provocation test was discontinued because of nausea. A metacholine provocation test caused a 15% drop in PEF. In the placebo test the patient ironed a textile without any formaldehyde content. This did not affect the PEF. Ironing a textile from her work place for 44 hr resulted in an immediate 17% decrease of PEF accompanied by a wheeze. A late reaction with a maximum of 38% decrease of FEF occurred 16 hr after the onset of provocation. A provocation
VOLUME 75 NUMBER 1, PART 1
FIG. 3. Results
Formaldehyde
of bronchial
provocation
tests
in case
3.
FIG. 4. Results
asthma-Rare
of bronchial
provocation
of overiooked
tests
in case
95
4.
test with 2.5 mg/m3 of formaldehyde produced an almost identical pattern of PEF reaction (Fig. 2). Isoprenaline had no effect on the attack, which may have been due to technical errors in the administration of the drug. However, isoprenaline has been reported to increase airway resistance in some individuals.3e Salbutanol reversed the reaction completely. Six hours after the formaldehyde provocations, the patient complained of headache. Six months later she was almost free from symptoms. Unspecific agents such as dust and certain odors occasionally caused asthmatic symptoms, but she did not have to use bronchodilators regularly. She still had not returned to work. The results of spirometry were within predicted limits, and there was no response on bronchodilation. The diurnal PEF variations did not exceed 15%.
beclomethasone di-isoproprionate was successful; the formaldehyde concentration of 2.5 mg/m” did not produce a decrease in PEF (Fig. 3). Both provocation testS with the higher concentration were followed by headache during the night. When he was reexamined 16 mo Later, he was virtually no longer being exposed to formaldehyde. He had stopped working as a carpenter, and the itadoor concentrations at home were 0.1 mg/m3. On rare occasions he had had symptoms from unspecific stimuli, such as the smell of paint. He needed bronchodilators once or twice a month. The results of spirometry with broncbodilation and the maximum midexpiratory flow were normal. The result of the histamine provocation test was negative. The bronchial provocation tests were repeated. Both the placebo test and a test with 2.5 mgim” of formaldehyde were negative.
Case 3
Case 4
The subject was a 32-yr-old male carpenter who had been panelling indoor walls with chipboard for 6 yr. Formaldehyde concentration of 0.4 mg/m3 had been measured in his own house where the walls were laid with chipboard; the exposure level at his work place was unknown. He was a smoker without any atopy in his personal or family history. On admission he had been suffering for 3 mo from hoarseness, cough, and breathlessness in relation to his work with chipboard. He had been free from symptoms at weekends. The results of spirometry and of the histamine provocation test were normal. The PEF demonstrated a diurnal variation of 14%. Skin prick tests indicated no atopy. The scratch test with formaldehyde was negative. A metacholine provocation and an exercise test performed 1 mo earlier at the local hospital for pulmonary diseases had failed to reveal any bronchial hyperreactivity. He was first challenged with a formaldehyde concentration of 0.4 mg/m3, which elicited a 17% decrease in PEF and a sensation of breathlessness about 17 hr after exposure. A challenge with a concentration of 2.5 mg/m3 caused a drop of 31% in PEF at the same time during the night, indicating an exposure-effect relationship. A wheeze was audible on auscultation. An attempt to block the late reaction by the administration of four puffs (25 pg each) of
A 45-yr-old nonsmoking woman who had been cleaning buildings before and after they were painted for 22 yrs was examined in 1978. Some of the detergents and polish that she regularly used contained formd&hy&. She had no previous history of atopy herself, but her sisters suffered from atopic dermatitis and asthma. She had been suffering from rhinitis at work since starting the job as a cleaner. Periods of breathlessness at work had started about I yr before our examinatians. The patient related her respiratory symptoms to the smell of a certain paint, which proved to have a formaldehyde content. On adm&ion she was symptomless. There was no blood eosinophilia, and the total serum IgE was 95 U/ml. The only positive skin reaction was to cat; the RAST test was also positive to cat. Skin tests with plaster and formaldehyde were negative. FEV, and FVC were within predicted values. The his&mine provocation test revealed slight bronchial hyperreactivity . The baseline PEF demonstrated a diurnal variation of 5%. A bronchial provocation test with lactose powder was negative. A concentration of 2.5 mg/n? of formaldehyde produced an immediate 49% drop in FEF acLmmpanied by a wheeze. The patient was then administered two isoprenaline inhalations (0.08 mg each), which reversed the reaction completely (Fig. 4).
96
Nordman
o------a .--~.-w....~.* *-
PEF Llmin I
t
J. ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al.
I
-
ba88 line PEF lactose control fcfmaldehyde 1.2mg/m3 formaldehyde 1.2mslm’ +chromoglycate (Lomudal’)
hours minutes from beginning of provocaticas
FIG.
5. Results
of bronchial
provocation
tests
in case
5.
Case 5 For the last 2 yr the tasks of a 56-yr-old woman who had been working in the plywood industry for 27 yr had entailed regular use of glue containing formaldehyde. According to determinations on a single occasion, the formaldehyde concentration in the air at her work place was 1.2 mg/m3. After 6 mo of exposure, she noticed that she was coughing and occasionally wheezing at work, and she herself related the symptoms to the use of the glue. She had no symptoms during vacations. Her brother suffered from bronchial asthma, but there was no atopy in her own history. The exercise test and a histamine provocation test performed at the local hospital for pulmonary diseases 3 mo before our examinations indicated exercise-induced asthma and intermediate bronchial hyperreactivity, respectively. She was referred to us in January 1983, having been free from symptoms after 3 mo of sick leave during which she had received asthma therapy including a short oral steroid cure. She had no symptoms on admission. Her blood eosinophils were normal, and total serum IgE was 12 U/ml. Skin prick tests with common allergens were negative. The epicutaneous test with formaldehyde yielded a positive reaction; hoyvever, she had no history of dermatitis. The baseline PEF displayed slight diurnal variations (9%) and the WV, and FVC were within predicted values without any response on bronchodilation. A bronchial provocation test with lactose powder did not cause any drop in PEF. Challenged with 1.2 mg/m3 of formaldehyde, she reacted with an immediate 36% drop in PEF accompanied by a wheeze. The reaction was reversed by two puffs of rimiterol hydrobromide (0.2 mg each). An attempt to block the reaction by administering inhalations of sodium chromoglycate at 7:00, ll:OO, and 11:45 A.M. before renewed provocation with 1.2 mg/m3 (starting at 11:55 A.M.) failed; a.n identical bronchial reac-
tion was triggered with an immediate 29% decreasein PEF (Fig. 5).
DlSbJSSlON The diagnosis of formaldehyde asthma in the 12 cases was justified by the medical history and clinical examinations, including a positive inhalation test to
formaldehyde.
The diagnosis
hinges
heavily
on the
bronchial provocation test, which is still the only way of demonstrating the causal specificity of the disease.23, *K $s, 4o The possibility of false positive cases cannot entirely be ruled out. For instance, cases 10 and 12 demonstrated PEF variability strong enough to
obscure the interpretation of the provocation tests. The variability in these, as in the other cases, was due to a morning dip. Case 10 reacted immediately on formaldehyde. The reaction of Case 12 concurred with that of the morning dip but was 39% stronger. He also reacted when he was challenged with formaldehyde emitting house paint with a 42% drop in PEF at 3 hr that deepened to 59% at 12 hr after the provocation. Moreover, the symptoms as perceived by these patients were similar to those experienced at work. On such grounds we interpreted the provocation test as clearly positive. In cases 1 and 3 an exposure-effect relationship was suggested by increasing the challenge level of formaldehyde from 1.2 to 2.5 mg/m3 and 0.4 to 2.4 mg/m3, respectively. The concentrations of formaldehyde were, however, not measured in conjunction with each test. This may have affected the claimed dose-response relationships because variability in humidity as well as fluctuations in the temperature in the chamber may have caused greater variability in concentrations than the control measurements four times a year revealed. However, measurements performed over the last 7 yr and during all seasons suggest that the variability in fact was rather small. The controlled exposure tests demonstrated that concentrations of about 1.2 and 2.5 mg/m3 (1 and 2 ppm) of formaldehyde are enough to trigger the attacks in individuals already sensitized; in case 3 there was a clear indication that 0.4 mg/m3 (0.3 ppm) may be sufficient. These levels frequently occur in work places where formaldehyde is handled, whereas 0.4 mg/m3 is not uncommon in homes and offices.41 Simulating the patients’ work tasks (case 2) and a specific provocation test with 2.5 mg/m3 of formaldehyde produced identical PEF reactions. This demonstrated that the reaction was reproducible, which was corroborated in case 5, who reacted identically to formaldehyde despite preadministration of sodium chromoglycate. The difficulty of finding a suitable placebo for formaldehyde has been discussed by Hendrick et al.42 Ironing a formaldehyde-free textile constituted an acceptable placebo test in case 2. In contrast, patients could easily distinguish lactose powder and Dome’s base solution from formaldehyde. These substances therefore merely served to identify subjects reacting to totally unspecific stimuli. Evaluating the outcome
VOLUME 75 NUMBER 1, PART 1
of the bronchial provocation tests, it may be advocated that a preexisting bronchial hyperreactivity is the reason for the obstruction after the inhalation of the irritant formaldehyde vapor. However, three of the I2 did not react at all when histamine was administered. The histamine test was “old-fashioned” in not demonstrating the actual dose of histamine administered and may not totally rule out some degree of reactivity. It should, however, well suffice for the purposes of this study as it is doubtful whether formaldehyde, when it is inhaled at the concentrations administered (0.4 to 2.5 mg/m3), would reach the bronchial tree in concentrations high enough to cause any irritation at all. It has been demonstrated experimentally in dogs receiving high doses (about 180 mg/m”) of formaldehyde that less than 5% reaches the lungs.4” This is supported by the fact that 71 subjects with bronchial hyperreactivity demonstrated in a histamine or metacholine test did not react at all when they were exposed to 2.5 mg/m3 of formaldehyde. Thus, a finding of hyperreactivity in patients suspected of having formaldehyde asthma does not preclude the diagnosis. It is plausible that the hyperreactivity is often secondary to sensitization to formaldehyde as it is in other forms of extrinsic asthma. From the above arguments we considered that the 12 cases were caused by specific sensitization to formaldehyde rather than by nonspecific irritation. The mechanism leading to formaldehyde asthma is, however, unknown. Some features of the disease suggest a background of allergy: very few individuals in an exposed population contract the disease, a variable period of exposure to formaldehyde preceded the symptoms in each case confirmed, and the attacks were provoked by low concentrations that, apart from slight irritation of the eye, nose and throat, should cause little irritation of the bronchial tree. A similar conclusion was reached by Hendrick and Lane.z8 Beclomethasone inhalations before the exposure in case 3 blocked the late reaction totally. This was consistent with one of the cases reported by Hendrick and Lanez8 who, however, reported another case whose reaction could not be blocked by inhalation of bethametsone 7-valerate. Whether the inconsistency indicated different underlying mechanisms remained a matter of speculation. An attempt to block the immediate reaction of case 5 with sodium chromoglycate failed completely in contrast to other immediate, especially IgE-mediated, asthma reactions.“4 All our subjects with formaldehyde asthma had been exposed occupationally. No cases caused by domestic exposure have been reported to date. However, domestic exposure to urea-formaldehyde foam
Formaldehyde
asthma-4are
or overlooked
97
has caused one case of asthma, although the causative agent was not formaldehyde.“” In the provocation tests four of the 12 patients reacting specifically to formaidehyde compJained of headache during the afternoon. This may be worth noting as headache is one of the symptoms frequently complained of in occupational or domestic exposure to formaldehyde.“‘, ‘S -17None of the four patients experienced headache in conjunction with the placebo tests. The conspicuous discrepancy between the paucity of well documented cases of formaldehyde asthma and the vast global use of formaldehyde, both industrially and domesticaliy,4s evoked the question in the title as to whether formaldehye asthma is a rare disease or merely overlooked. The figures presented above answer the latter part of the question: 12 positive cases implies that the disorder is at Xeast under reported. However, the 230 patients subjected to bronchial provocation tests represented a highly selected material. They were referred to the institute, being the only place conducting routine specific formaldehyde provocation tests in Finland, from all over the country. The reason for their referral was either the suspicion of formaldehyde-induced asthma or an unspecified occupational asthma with an exposure history that raised such a suspicion at the Institute. Still, only 12 of 230 suspected cases could be confirmed with specific bronchial provocation tests. Jr can be concluded that respiratory sensitization to formaldehyde, although it certainly occurs, is a rare disease. This agrees with the opinion expressed by Hendrick et a1.12and is very similar to the finding by Wallenstein et a1.40 who reported that only two persons reacted to formaldehyde out of 13 1 who were exposed and had symptoms from the respiratory tmCt The removal from exposure of case 2 and 3 led to almost total recovery; in case 3 the bronchial reaction to 2.5 me/m3 of formaldehyde could not be repeated after 16 mo. However, as demonstrated in asthma caused by red cedar4g and isocyanate,SOthe symptoms in occupational asthma may continue. although the exposure is discontinued. The reaction of case 3 to 0.4 mg/m3 of formaldehyde implies that domestic exposures may suffice to maintain symptoms in occupationally acquired formaldehyde asthma. Although asthma as a result of domestic exposure to formaldehyde has not been reported to date, we should be well advised to pay special attention to exposure in the homes of persons suffering from occupational formaldehyde asthma. We thank Ms. H. Hahlman who superwed most of the provocation tests and Ms. A. Tolkki who tirew the figures.
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J. ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al.
REFERENCES 1. Swenberg JA, Kerns WD, Mitchell RI, Gralla EJ, Pavkov KL: Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor. Cancer Res 40:3398, 1980 2. The health hazards of formaldehyde. Lancet 1:926, 1981 (editorial) 3. Bryson DD: Health hazards of formaldehyde. Lancet 1:1263, 1981 4. Berger JM, Lamm SH: Health hazards of formaldehyde. Lancet 1:1264, 1981 5. Morgan WKC: Health hazards of formaldehyde. Lancet 2:981, 1981 6. lnfante PF, Ulsamer AG, Groth D, Chu KC, Ward J: Health hazards of formaldehyde. Lancet 2:980, 1981 7. Pirill V, Kilpiii 0: On dermatitis caused by formaldehyde and its compounds. Ann Med lnt Fennial 38:38, 1949 8. Roths WC? Palmar and plantar eczema caused by steam ironing clothes containing formaldehyde. Berufs-Dermatosen 17: 263, 1969 9. Kerfoot EJ, Mooney TF: Formaldehyde and paraformaldehyde study in funeral homes. Am lnd Hyg Assoc J 36:533, 1975 10. Blejer HP, Banotes JT: Occupational health report of formaldehyde concentrations and effects on workers at the Bayly Manufacturing Company, Visalia, Calif., 1966. Study report number S-1806. Los Angeles, State of California Health and Welfare Agency, Dept. of Public Health, Bureau of Occupational Health. 11 Radar J: Reizwirkungen von Formaldehyde in Priipariersalen: analytische und experimentelle Untersuchungen. Inaugural Dissertation. W&burg University, 1974 1-J 1L. Andersen I, Molhave L: Controlled human studies with formaldehyde. In Gibson JE, editor: Formaldehyde toxicity. New York, 1983, Hemisphere Publishing Corp, pp 154-65 13. Andersen I: Formaldehyde in the indoor environment-health implications and the setting of standards. In Proceedings of International Climate Symposium SBl , Copenhagen, 1979 14. Marzulli FN, Maibach HI: Contact allergy: predictive testing in humans. In Marzulli FN, Maibach HI, editors: Dermatotoxicology and pharmacology. Hemisphere Publishing Corp, Washington, D.C., 1977, pp 353-72 15. Magnusson B, Kligman AM: Allergic contact dermatitis in the guinea pig. Springfield, Bl., 1970, A Thomas 16. Cronin E: Formaldehyde. In Cronin E, editor: Contact dermatitis. London, 1982, Churchill Livingstone, pp 788-94 17. Parkes WR: Occupational lung disorders, ed 2. London, 1982, Butterworths, pp 415-53 18. Pepys J: Occupational asthma: an overview. J Occup Med 24534, 1982 19. Brooks SM: Bronchial asthma of occupational origin. A rcview. Stand J Work Environ Health 3:53, 1977 20. Gandevia B: Occupational asthma. Part I. Med J Aust 57(suppl 2):332, 1970 21. Harris DK: Health problems in the manufacture and use of plastics. Br J lnd Med 10~255, 1953 22. Schoenberg JB, Mitchell ChA: Airway disease caused by phenolic (phenol-formaldehyde) resin exposure. Arch Environ Health 30:574, 1975 23. Gamble JF, McMichael AJ, Williams T, Battigelli M: Respnatory function and symptoms: an envitonmental-epidemiological study of rubber workers exposed to a phenol-formaldehyde type resin. Am Ind Hyg Assoc J 37:499, 1976 24. Popa V, Teculescu D, Stanescu D, Gavrilescu N: Bronchial
25. 26. 27. 28. 29. 30. 31. 32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
asthma and asthmatic bronchitis, determined by simple chemicals. Dis Chest 56:395, 1965 Sakula A: Formalin asthma in hospital laboratory staff. Lancet 1:816, 1975 Alanko K, Keskinen H, Saarinen L: Ammattiastma. Duodecim 93:306, 1977 Hendrick DJ, Lane DJ: Formalin asthma in hospital staff. Br Med J 1:607, 1975 Hendrick DJ, Lane DJ: Occupational formalin asthma. Br J Ind Med 34:11, 1977 ACCP-ATS Joint Committee on Pulmonary Nomenclature: pulmonary terms and symbols. Chest 67:383, 1975 Aas K, Belin L: Standardization of diagnostic work in allergy. lnt Arch Allergy Appl lmmunol 45:57, 1973 Phil& V: Chamber test versus patch test for epicutaneous testing. Contact Dermatitis 1:48, 1975 Berglund E, Birath G, Bjure J, Grimby G, Kjellmer J, Sandqvist L, Soderholm B: Spirometric studies in normal subjects. I. Forced expirograms in subjects between 7 and 70 years of age. Acta Med Stand 173:186, 1963 Birath G, Kjellmer 1, Sandqvist L: Spirometric studies in normal subjects. II Ventilatory capacity tests in adults. Acta Med Stand 173:193, 1963 Laitinen L: Histamine and metacholine challenge in the testing of bronchial reactivity. Stand J Respir Dis [Supp1]86:1, 1974 Hargreave FE, Ryan G, Thomson NC, O’Byme PM, Latimer Chk, Juniper EF, Dolovich J: Bronchial responsiveness to histamine or metacholine in asthma: measurement and clinical significance. J ALLERGY CLIN IMMUNOL 68:347, 1981 Pepys J, Pickering CAC, Loudon HWG: Asthma due to inhaled chemical agents-piperazine dihydrochloride. Clin Allergy 2:189, 1972 Newman Taylor AJ, Davies RJ: Inhalation challenge testing. In Weill H, Turner-Warwick M, editors: Occupational lung diseases. New York, 1981, Marcel Dekker lnc, pp 143-67 NIOSH Manual of Analytical methods. US Dept of Health, Education, and Welfare. Cincinnati, 1974, HEW Publication No. (NIOSH) pp 75-121 Stanescu D, van de Woestijne KP: Decrease of maximum expiratory flow rates following isoprenaline inhalation in patients with chronic obstructive lung disease. In Communications and abstracts. Meeting on bronchodilatation, Societas Europaea Physiologiae Clinicae Respiratotiae. Dublin, Ireland, 1972, P 46 Wallenstein G, Rebohle E, Bergmann I, Voight U, Schneider WD: Berufliche Erkrankungen des Atmungsorgans durch chemische Stoffe mit potentieller Allergenwirkung. Dtsch Gesundh-Wesen 33(24):1119, 1978 Niemela R, Vainio H: Formaldehyde exposure in work and the general environment. Occurrence and possibilities for prevention. Stand J Work Environ Health 7:95, 1981 Hendrick DJ, Rando RJ, Lane DJ, Morris MJ: Formaldehyde asthma: challenge exposure levels and fate after five years. J Occup Med 24:893, 1982 Egle JL Jr: Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Arch Environ Health 25:119, 1972 Pepys J, Hutchcroft BJ: Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 112:829, 1975 Frigas E, Filley WV, Reed CE: Asthma induced by dust from urea-formaldehyde foam insulating material. Chest 79:706, 1981
VOL.UME 75 NUMBER 1, PART 1
Formaldehyde
-26. Olsen JH. Diissing M: Formaldehyde induced symptoms in day care centers. Am Ind Hyg Assoc J 43:366, 1982 47. Gamble J: Effects of formaldehyde on the respiratory system. In Gibson JE, editor: Formaldehyde toxicity. New York, 1983, Hemisphere Publishing Corp, pp 175.97 48. NIOSH/OSHA: Formaldehyde: evidence of carcinogenicity. Joint NIOSHiOSHA Current Intelligence Bulletin 34:1, 1980
asthma--Rare
or overlooked
49. Chan-Yeung M, Lam S, Koener S- Clinical features and natural history of occupational asthma due to western red cedar (7’hcju p/km) Am J Med 72:JI 1. 1982 50. Adams WGF: Long-term effects on the he&h of men engaged in the manufacture of toluene di-lsocyanaie. Br .I lnd Med 32:72,
L97S
Erratum The following correctionsapply to the article “EicosapentaenoicAcid: Its Effects on Aracbidonic Acid Metabolism by Cells in Culture,” by Levine and Worth, which appeared on page 430 of the September 1984issue, Part 2, of TknzJOURNALOFALLERGYANDCLINJCALIMMLJNOLOGY: 1. The correct spelling of the acronym TPA (abbreviationsbox, page 430) is 12-O-tetradecanoyIphorbol- 13-acetate. 2. The fourth line of the legend to Fig. 1 (page 431) should read: “. . . @g/2 X lo5 (01, or 5 p,g/2 x 105 cells (a), or were not preloaded (1p). EPA treatment is nontoxic as . . ..‘. 3. In Table I (page 432), the sixth and ninth entries under “Stimulus” were misaligned with their values to the right. They should read: Immunoreactive SthllUS
A23 187, 2fiM A23187, 2kM
EPA preloded
3.10 k 0.822 (4) 2.89 + 0.968 (4)
PGE,
99
(nglml) Control
Immu~ EPA
PGiL
Inghd CMltrai
7.63 2 0.65 (4) 0.28 2 0.060 (4) 0.90 + 0.063 (4) 12.69 2 0.925 (4) 0.34 +- 0.055 (4) 1.49 i 0.065 (4)
M.D., Helena Keskinen,
M.D., and Matii
Tuppurainen,
M.D.
Finland
A total of230 persons who had been exposed to formaldehyde and suffered from usthma-like respiratory symptoms were examined between January I, 1977, and May 31. 1983. All the subjects had a bronchial provocation test with formaldehyde. On the basis of the medical and occupationul history of the patients, the specihc bronchial provocation test, and other test results, 12 cases were considered to be caused by speci’c sensitization to formaldehyde. All subjects had been exposed occupationally. An exposure period of between I mo und 19 yr preceded the onset of symptoms. Three persons displayed no bronchial hyperreactivity us assessed with a histamine or metacholine provocation test. Eleven of the 12 reactions were triggered by about 2.5 mglm3 and one reaction by about I.2 mg/m3 of formaldehyde. The Itttc reaction in I patient was completely blocked by the inhalation of 100 pg of beclomethusone di-isoproprionate before the challenge with formaldehyde. Seventy-one of the 218 subjects bcho did not react when they were challenged with formaldehyde demonstrated bronchictl hyperreactivity. We conclude that formaldehyde asthma, although upparentiy u rure disease, is under reported. Removal from exposure has a favorable effect on the symptoms. Low’ domestic exposures, however, may maintain the symptoms in individuals already sensitized. (J lqLLk:RGY CLIN IMMVNOL 75:9I-9. 1985.)
During the early 1980s formaldehyde was brought to the attention of the general public, largely because of the heated debate about its carcinogenic properties.lms The irritant characteristics causing toxic contact dermatitis and irritation of the eye and upper respiratory tract have been well documented.‘-lo Discussion has been further stimulated by experimental evidence of irritation of the mucous membranes and conjunctiva of susceptible individuals at concentrations frequently encountered in residential indoor ak
Abbreviations used PEF: Peak expiratory
FEV: WV,: FVC:
flow
Forced expiratory vohne Forced expiratory volume in 1 set Forced vital capacity
FEW@: loo XJ= FVC
ppm:
parts per million (cmZ’/m3)
11-13
Sensitization of the skin by formaldehyde is wellknownr4; formaldehyde has been classified as a strong contact allergen on the basis of the guinea pig maximization test. I5 In dermatologic practice, however, formaldehyde rarely appears to live up to its bad reputation. 4* I* Similarly, all major reviews refer to formaldehyde as a cause of occupational asthma,1’--20 but surprisingly Iittle is known about specific sen-
From the Institute of Occupational Health, Helsinki, Finland. Received for publication Jan. 23, 1984. Accepted for publication July 18, 1984. Reprint requests: Hencik Nordman, M.D., Institute of Occupational Health, Haartmaninkatu 1, SF-00290 Helsinki 29, Finland.
de&de. sitization of the respiratory tract by Airway obstruction and acute effects airways have been reported in workers exposed to urea- or phenol-formaldehyde re~ins.*~-~” Owing to the design of these studies, the findings could not bes~?@ifically attributed to formaldehyde. Fo sidered the cause of asthma in case repo@s on a rubber tire worker,24 a laboratory technician,ag and a spray painter. 26 Hendrick and Ianez7* 2* reported on two nurses who responded to bronchial provocation with formaldehyde. Our report concerns 12 cases of fo~~hyde asthma diagnosed during the period January 1, 1977, to May 3 I , 1983. Five are described in more detail. 91
92
Nordman
TABLE
I. Some
Case
Sex
1 2 3 4 5 6 7 8 9 10 11 12
F F M F F F F F F F M M
Lung
J ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al. characteristics
Exposure source
Furniture lacquer Ironing textiles Chipboard House paint Gluing plywood Gluing plywood Ironing textiles Laboratory chemicals Gluing plywood Footwear glue Heating polyethene House paint
of 12 subjects
with formaldehyde
Time of exposure before symptoms
Atow
2mo 1 mo 6yr 19 yr 4 mo 8 yr 6 mo 5yr 4 yr 5 Yr 4 yr 13 yr
+ + -
PEF diurnal variation (%I
8 15 14 5 9 6 14 5 14 18 7 25
asthma
FEV, (U
FVC (L)
2.84 2.06 4.41 2.70 2.22 2.60 2.50 2.81 2.93 2.0 3.78 2.80
3.47 2.90 4.92 3.17 2.80 3.43 2.99 3.25 3.67 2.7 4.65 4.48
FEV% deviation from predicted
-2 -8 + 10 +5 +2 -6 -3 +5 -4 -0.5 +8 -18
FEV, response bronchodilation (%I
0 +8 +3 0 +8 + 10 i-24 +6 +9 0 +6 0
function measured on admission to hospital and without medication.
SUBJECTS AND METHODS During 6% yr 230 patients were investigated because of suspected formaldehyde-induced bronchial asthma. The patients were referred to the Institute of Occupational Health from all over Finland. All subjects had been exposed to formaldehyde and were suffering from respiratory symptoms compatible with asthma attacks. The definition of asthma adopted here was that recommended by the joint committee of the American Thoracic Society and the American College of Chest Physicians.2s Clinical examinations included a detailed medical and occupational history, skin prick testing with common allergens, recording the spontaneous diurnal variations of the PEF, spirometry with a bronchodilation test, a histamine provocation test, an exercise test (when it was considered appropriate), and bronchial challenge with formaldehyde and a negative control. Serologic tests, including determination of eosinophil count and total serum IgE, were also performed. Skin sensitivity to about 20 common allergens including animal epithelia, pollens, house dust, and mite was tested with the skin prick technique according to the method of Aas and Belin.30 Atopy was defined as at least one reaction equal to or larger than the reaction to histamine. Routine epicutaneous testing with formaldehyde was performed by use of the occlusive Finn Chambers method,31 and a formaldehyde solution of 1 .O%. Dilution series (2% to 1% to 0.5%) were used when irritant reactions were suspected and in all patients with a positive test to exclude such reactions. The spirograms were recorded with a water-sealed spirometer (Kifa, Sweden). FVC and FEV, were expressed as a percentage of the predicted values,32j 33 and the FEV% (100 X FEV,,,/FVC) was calculated. Salbutamol (two puffs of 0.1 mg each) or rimiterol hydrobromide (three puffs of 0.2 mg each) was used in the bronchodilation test after spirometry. An increase of at least 15% and 1.50 ml in FEV, was regarded as significant. The PEF was measured with a
Wright peak flow meter. All PEF measurements were recorded by a nurse at the bed ward. In the determination of spontaneous diurnal variations, the PEF was recorded every 3 hr for at least 24 hr before the inhalation testing started. The best of three measurements was recorded. The degree of bronchial hyperreactivity was assessed with a histamine challenge test modified from the one described by Laitinen. 34 This involves inhaling a 1% solution of histamine diphosphate through a nebulizer in three stages involving one, four, and 16 inhalation(s), respectively. The nebulizer used was a De Vilbiss No. 40 (De Vilbiss Co., Somerset, Pa.) through which air flowed at a rate of 5 L per minute. Each stage was followed by a PEF measurement. A drop in PEF of 15% or more at any stage was considered significant, and the test was discontinued. A positive reaction after a single inhalation was classified as “strong” bronchial hyperreactivity, a reaction after four inhalations as “intermediate,” and a reaction after 16 inhalations as “slight. ” If a histamine or metacholine test had been performed during the previous 3 mo, the histamine test was not always considered necessary. The metacholine test was done according to Hargreave et al.35 The technical procedures of the bronchi provocation tests were close to those outlined by Pepys et a1.36 and Newman Taylor and Davies. 37 Exposure to formaldehyde was achieved by evaporating 35 or 70 ~1 of an aqueous solution (35%) of formaldehyde in an exposure chamber measuring 10 m3. Temperature and humidity could not be regulated. The standardized procedure was calibrated to generate concentrations as close to 1.2 mg/m3 (1 ppm) and 2.5 mg/m3 (2 ppm) as possible without exceeding these levels that correspond to the new and the old nationally recommended exposure limits. The formaldehyde concentrations were measured four times annually by use of the chromotropic assay.38 According to these measurements evaporation of 35 ~1 of formalin caused concentrations in
VOLUME 75 NUMBER 1. PART 1
TABLE
II. The results
Formaldehyde
of bronchial
provocation
tests in 12 subjects
with
asthma-Rare
formaldehyde ---
Bronchial
Case 1
2 3 4 5 6 7 8 9 10 11
12/l
Bronchial hyperreactivity
None Metacholine + None Slight Intermediate Slight Not done Slight None Metacholine + Slight Slight
Placebo provocation
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative
Immediate PEF change (%I
-25 -24
provocation
with
Late PEF change (%I (latency)
-43 -31
(16 hr) (16 hr)
-22 -21
(14 hr) (14 hr)
-49 - 36t
- 19 -14$ -35 -213
-29 -47
(I6 hr) (1.5 hr)
or overlooked
asthma __.-. .-.-..--
formaldehyde -..-_-_.Response Wheeze on bronchod#lation* auscultation (%I
93
--
2.5 mg/m3
+ t+ t .-
to
t?ij t I4 t 58 . -.. -.+67 -+ 30
*Dash indicates that no bronchodilator was administered. fchallenged with 1.2 mg/m’. $A 30-minute bronchial challenge done with the patient’s own glue resulted in an immediate 20% decrease in PEF. Formaldehyde concentrations were not measured. #Welding polyethene boxes (about 450” C) resulted in ‘an immediate 17% decrease in PEF. J/Reported in 1977.” Reacted to the house paint with a drop of 42% at 3 hr and 59% at 12 hr.
the range of 0.98 to 1.07 mg/m3; 70 11 of formalin caused 2.09 to 2.44 mg/n?. The higher concentration was routine up to May 1982. Since then the concentration in the first challenge has been 1.2 mg/m3. A negative response to 1.2 mgim” was followed by a provocation test with 2.5 mg/m”. A few patients who had suffered severe asthma attacks were challenged on the first occasion with a concentration of 0.3 to 0.5 mg/m3. Although in some instances the work place conditions were simulated in the exposure chamber, specific provocations with formaldehyde were always undertaken as well. Each provocation test began between 9:00 and 1l:OO A.M. and lasted for 30 min during which there was no tumover of air inside the chamber. The PEF was used as the indicator of ventilatory response. It was measured every 15 min during the first hour after the onset of exposure and longer if it was necessary. After the first hour the PEF was recorded hourly for 8 hr and thereafter at 3-hour intervals until the next morning. A 15% immediate and a 20% late drop in the PEF compared with the preexposure level was regarded as a positive reaction. The prerequisites for a provocation test were that the patient managed without drugs and had a spontaneous variation preferably not exceeding 1.5%#,i.e., the asthma was satisfactorily stable. Some exceptions from the latter criterion were made. Medication was discontinued not later than 3 days before the hospitalization. If it was needed, patients were sent home on sick leave for 2 to 3 wk with appropriate medication, including oral steroids when they were required. The next challenge was not performed until the preexposure PEF level had been achieved. A negative control test was always done with
Dome’s* base solution, following the same procedwes as with formaldehyde or with lactose pawdef .3’fSimulating the work tasks sometimes afforded s&q&z p&e&o tests, such as ironing fabrics treated or untreated with formaldehyde.
RESULTS Twelve patients were considered to have bronchial asthma speci6cally caused by ~o~~~~y~. Some characteristics of the ascertained cases are demon-
strated in Table I. All had been exposed occupationally . Some of the patients had been exposed while they wefe using formaldehyde en&&g glues or paints (eight), ironing textiles treated wit% resin containing formaldehyde (two), using f~~~~~ solut&ns in a laboratory (one), using fu~~~b~de ~~~ta~~g detergents (one), and welding ~l~~y~~~e boxes at a temperature of 450” (one). CMy two patients displayed atopy. The patients had beam exposed for a period of time between 1 mo and 19 yr before the onset of symptoms; six had been exposed for more than 5 yr, whereas four noted symIMms within 6 mo of exposure. The results of the bronchial provocation tests are illustrated immediate
. ts denzanstrated an in Table Il. Eight reaction, i.e., within 30 mirr of the begin-
*Division of Mites Laboratories Ltd., England.
94
Nordman
J. ALLERGY CLIN. IMMUNOL JANUARY 1985
et al.
o----abase
PfZF L/min
+--+
line PEF
Case reports
lactose cant ro1 formaldehyde 2 5 mg/m’
Five casesrepresenting typical histories, different reaction patterns, and various responses to drugs are presented below. The number of the cases corresponds to the numbering in Tables I and II. Case 1
minutes
FIG.
1. Results
PEF L/mill I
hours time from beginning of Prov0catlonS
of bronchial
provocation
tests
e-----o
bss* line PEF
k----d
a----a
control ironing
l
*
FIG.
2. Results
of bronchial
provocation
in case
1.
ironi textile with “pormaldehyda formald.hydau~’ isofwnaline inhabtton 0.18mg ssltut~mol inhalation 02 mg
tests
in case
2.
A 31-yr-old woman was referred to us by an insurance company for further examination. She had started her employment in the furniture industry in 1980. Two of the varnishes that she used regularly for 1 yr contained ureaformaldehyde resin. There was no atopy in her personal or family history. She had been smoking for 8 yr. About 2 mo after she had started using the varnishes, she experienced rhinitis and a nonproductive cough at work, which improved over weekends. She was completely free from symptoms during vacations. On admission she had been unexposed for 2 mo and had no symptoms. There was no blood eosinophilia, and total IgE was 13 U/ml. Skin prick tests were negative. The results of spirometry demonstrated a slight obstruction (Table I). The histamine challenge did not indicate any bronchial hyperreactivity, and the spontaneous PEF diurnal variation was 8%. Lactose powder did not cause any bronchial reaction. The bronchial provocation test with 1.2 mg/m3 of formaldehyde did not cause a drop in PEF. When the patient was challenged with 2.5 mg/m3, she reacted with an immediate 25% decrease of PEF starting within 15 min of the beginning of the exposure (Fig. 1). Her symptoms were subjectively similar to those she had experienced at work.
Case 2 ning of exposure. Six late reactions, two of which were preceded by immediate drops in PEF, were recorded. The formaldehyde concentration used in 11 cases was 2.5 mg/m3 and in one case 1.2 mg/m3. Three patients did not react at all on provocation to histamine, indicating the absence of bronchial hyperreactivity. The bronchial provocation with formaldehyde was interpreted as negative in 218 patients; the diagnosis was bronchial asthma in 96 patients. The histamine provocation test was positive in 71 patients and negative in 127 of the 218 patients not reacting to formaldehyde. Ten workers had not been challenged with histamine or metacholine, and results wel;e not available for nine patients. Fifteen of the positive tests and seven of the negative tests had been done before admission to our institute. The histamine reactions of the 175 histamine tests performed at our institute on subjects not reacting when they were exposed to formaldehyde demonstrated seven patients reacting after one inhalation, 20 patients reacting after four inhalations, and 29 patients reacting after 16 inhalations, whereas 119 patients did not react.
The subject was a 51-yr-old woman who had been working in the textile industry for 11 yr. She had been ironing formaldehyde-treated textiles for about 1% yr before examination. There was no atopy in her personal or family history. During the 50s she had suffered from pulmonary tuberculosis. Within 1 mo of ironing textiles, she experienced urticaria and 1 mo later experienced spells of breathlessness and a productive cough. At a pulmonary disease unit her asthmatic symptoms had been associated with her work place, although formaldehyde had not been suspected as the cause. Before the specific provocation tests two attempts to return to work failed because the symptoms reappeared immediately: however, on admission she had no symptoms. The diurnal vatialion of PEF was 15%. There was a slight obstruction (Table I), no blood eosiriophilia, and the total serum IgE was 13 U/ml. Skin prick tests with common allergens were negative.The histamine provocation test was discontinued because of nausea. A metacholine provocation test caused a 15% drop in PEF. In the placebo test the patient ironed a textile without any formaldehyde content. This did not affect the PEF. Ironing a textile from her work place for 44 hr resulted in an immediate 17% decrease of PEF accompanied by a wheeze. A late reaction with a maximum of 38% decrease of FEF occurred 16 hr after the onset of provocation. A provocation
VOLUME 75 NUMBER 1, PART 1
FIG. 3. Results
Formaldehyde
of bronchial
provocation
tests
in case
3.
FIG. 4. Results
asthma-Rare
of bronchial
provocation
of overiooked
tests
in case
95
4.
test with 2.5 mg/m3 of formaldehyde produced an almost identical pattern of PEF reaction (Fig. 2). Isoprenaline had no effect on the attack, which may have been due to technical errors in the administration of the drug. However, isoprenaline has been reported to increase airway resistance in some individuals.3e Salbutanol reversed the reaction completely. Six hours after the formaldehyde provocations, the patient complained of headache. Six months later she was almost free from symptoms. Unspecific agents such as dust and certain odors occasionally caused asthmatic symptoms, but she did not have to use bronchodilators regularly. She still had not returned to work. The results of spirometry were within predicted limits, and there was no response on bronchodilation. The diurnal PEF variations did not exceed 15%.
beclomethasone di-isoproprionate was successful; the formaldehyde concentration of 2.5 mg/m” did not produce a decrease in PEF (Fig. 3). Both provocation testS with the higher concentration were followed by headache during the night. When he was reexamined 16 mo Later, he was virtually no longer being exposed to formaldehyde. He had stopped working as a carpenter, and the itadoor concentrations at home were 0.1 mg/m3. On rare occasions he had had symptoms from unspecific stimuli, such as the smell of paint. He needed bronchodilators once or twice a month. The results of spirometry with broncbodilation and the maximum midexpiratory flow were normal. The result of the histamine provocation test was negative. The bronchial provocation tests were repeated. Both the placebo test and a test with 2.5 mgim” of formaldehyde were negative.
Case 3
Case 4
The subject was a 32-yr-old male carpenter who had been panelling indoor walls with chipboard for 6 yr. Formaldehyde concentration of 0.4 mg/m3 had been measured in his own house where the walls were laid with chipboard; the exposure level at his work place was unknown. He was a smoker without any atopy in his personal or family history. On admission he had been suffering for 3 mo from hoarseness, cough, and breathlessness in relation to his work with chipboard. He had been free from symptoms at weekends. The results of spirometry and of the histamine provocation test were normal. The PEF demonstrated a diurnal variation of 14%. Skin prick tests indicated no atopy. The scratch test with formaldehyde was negative. A metacholine provocation and an exercise test performed 1 mo earlier at the local hospital for pulmonary diseases had failed to reveal any bronchial hyperreactivity. He was first challenged with a formaldehyde concentration of 0.4 mg/m3, which elicited a 17% decrease in PEF and a sensation of breathlessness about 17 hr after exposure. A challenge with a concentration of 2.5 mg/m3 caused a drop of 31% in PEF at the same time during the night, indicating an exposure-effect relationship. A wheeze was audible on auscultation. An attempt to block the late reaction by the administration of four puffs (25 pg each) of
A 45-yr-old nonsmoking woman who had been cleaning buildings before and after they were painted for 22 yrs was examined in 1978. Some of the detergents and polish that she regularly used contained formd&hy&. She had no previous history of atopy herself, but her sisters suffered from atopic dermatitis and asthma. She had been suffering from rhinitis at work since starting the job as a cleaner. Periods of breathlessness at work had started about I yr before our examinatians. The patient related her respiratory symptoms to the smell of a certain paint, which proved to have a formaldehyde content. On adm&ion she was symptomless. There was no blood eosinophilia, and the total serum IgE was 95 U/ml. The only positive skin reaction was to cat; the RAST test was also positive to cat. Skin tests with plaster and formaldehyde were negative. FEV, and FVC were within predicted values. The his&mine provocation test revealed slight bronchial hyperreactivity . The baseline PEF demonstrated a diurnal variation of 5%. A bronchial provocation test with lactose powder was negative. A concentration of 2.5 mg/n? of formaldehyde produced an immediate 49% drop in FEF acLmmpanied by a wheeze. The patient was then administered two isoprenaline inhalations (0.08 mg each), which reversed the reaction completely (Fig. 4).
96
Nordman
o------a .--~.-w....~.* *-
PEF Llmin I
t
J. ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al.
I
-
ba88 line PEF lactose control fcfmaldehyde 1.2mg/m3 formaldehyde 1.2mslm’ +chromoglycate (Lomudal’)
hours minutes from beginning of provocaticas
FIG.
5. Results
of bronchial
provocation
tests
in case
5.
Case 5 For the last 2 yr the tasks of a 56-yr-old woman who had been working in the plywood industry for 27 yr had entailed regular use of glue containing formaldehyde. According to determinations on a single occasion, the formaldehyde concentration in the air at her work place was 1.2 mg/m3. After 6 mo of exposure, she noticed that she was coughing and occasionally wheezing at work, and she herself related the symptoms to the use of the glue. She had no symptoms during vacations. Her brother suffered from bronchial asthma, but there was no atopy in her own history. The exercise test and a histamine provocation test performed at the local hospital for pulmonary diseases 3 mo before our examinations indicated exercise-induced asthma and intermediate bronchial hyperreactivity, respectively. She was referred to us in January 1983, having been free from symptoms after 3 mo of sick leave during which she had received asthma therapy including a short oral steroid cure. She had no symptoms on admission. Her blood eosinophils were normal, and total serum IgE was 12 U/ml. Skin prick tests with common allergens were negative. The epicutaneous test with formaldehyde yielded a positive reaction; hoyvever, she had no history of dermatitis. The baseline PEF displayed slight diurnal variations (9%) and the WV, and FVC were within predicted values without any response on bronchodilation. A bronchial provocation test with lactose powder did not cause any drop in PEF. Challenged with 1.2 mg/m3 of formaldehyde, she reacted with an immediate 36% drop in PEF accompanied by a wheeze. The reaction was reversed by two puffs of rimiterol hydrobromide (0.2 mg each). An attempt to block the reaction by administering inhalations of sodium chromoglycate at 7:00, ll:OO, and 11:45 A.M. before renewed provocation with 1.2 mg/m3 (starting at 11:55 A.M.) failed; a.n identical bronchial reac-
tion was triggered with an immediate 29% decreasein PEF (Fig. 5).
DlSbJSSlON The diagnosis of formaldehyde asthma in the 12 cases was justified by the medical history and clinical examinations, including a positive inhalation test to
formaldehyde.
The diagnosis
hinges
heavily
on the
bronchial provocation test, which is still the only way of demonstrating the causal specificity of the disease.23, *K $s, 4o The possibility of false positive cases cannot entirely be ruled out. For instance, cases 10 and 12 demonstrated PEF variability strong enough to
obscure the interpretation of the provocation tests. The variability in these, as in the other cases, was due to a morning dip. Case 10 reacted immediately on formaldehyde. The reaction of Case 12 concurred with that of the morning dip but was 39% stronger. He also reacted when he was challenged with formaldehyde emitting house paint with a 42% drop in PEF at 3 hr that deepened to 59% at 12 hr after the provocation. Moreover, the symptoms as perceived by these patients were similar to those experienced at work. On such grounds we interpreted the provocation test as clearly positive. In cases 1 and 3 an exposure-effect relationship was suggested by increasing the challenge level of formaldehyde from 1.2 to 2.5 mg/m3 and 0.4 to 2.4 mg/m3, respectively. The concentrations of formaldehyde were, however, not measured in conjunction with each test. This may have affected the claimed dose-response relationships because variability in humidity as well as fluctuations in the temperature in the chamber may have caused greater variability in concentrations than the control measurements four times a year revealed. However, measurements performed over the last 7 yr and during all seasons suggest that the variability in fact was rather small. The controlled exposure tests demonstrated that concentrations of about 1.2 and 2.5 mg/m3 (1 and 2 ppm) of formaldehyde are enough to trigger the attacks in individuals already sensitized; in case 3 there was a clear indication that 0.4 mg/m3 (0.3 ppm) may be sufficient. These levels frequently occur in work places where formaldehyde is handled, whereas 0.4 mg/m3 is not uncommon in homes and offices.41 Simulating the patients’ work tasks (case 2) and a specific provocation test with 2.5 mg/m3 of formaldehyde produced identical PEF reactions. This demonstrated that the reaction was reproducible, which was corroborated in case 5, who reacted identically to formaldehyde despite preadministration of sodium chromoglycate. The difficulty of finding a suitable placebo for formaldehyde has been discussed by Hendrick et al.42 Ironing a formaldehyde-free textile constituted an acceptable placebo test in case 2. In contrast, patients could easily distinguish lactose powder and Dome’s base solution from formaldehyde. These substances therefore merely served to identify subjects reacting to totally unspecific stimuli. Evaluating the outcome
VOLUME 75 NUMBER 1, PART 1
of the bronchial provocation tests, it may be advocated that a preexisting bronchial hyperreactivity is the reason for the obstruction after the inhalation of the irritant formaldehyde vapor. However, three of the I2 did not react at all when histamine was administered. The histamine test was “old-fashioned” in not demonstrating the actual dose of histamine administered and may not totally rule out some degree of reactivity. It should, however, well suffice for the purposes of this study as it is doubtful whether formaldehyde, when it is inhaled at the concentrations administered (0.4 to 2.5 mg/m3), would reach the bronchial tree in concentrations high enough to cause any irritation at all. It has been demonstrated experimentally in dogs receiving high doses (about 180 mg/m”) of formaldehyde that less than 5% reaches the lungs.4” This is supported by the fact that 71 subjects with bronchial hyperreactivity demonstrated in a histamine or metacholine test did not react at all when they were exposed to 2.5 mg/m3 of formaldehyde. Thus, a finding of hyperreactivity in patients suspected of having formaldehyde asthma does not preclude the diagnosis. It is plausible that the hyperreactivity is often secondary to sensitization to formaldehyde as it is in other forms of extrinsic asthma. From the above arguments we considered that the 12 cases were caused by specific sensitization to formaldehyde rather than by nonspecific irritation. The mechanism leading to formaldehyde asthma is, however, unknown. Some features of the disease suggest a background of allergy: very few individuals in an exposed population contract the disease, a variable period of exposure to formaldehyde preceded the symptoms in each case confirmed, and the attacks were provoked by low concentrations that, apart from slight irritation of the eye, nose and throat, should cause little irritation of the bronchial tree. A similar conclusion was reached by Hendrick and Lane.z8 Beclomethasone inhalations before the exposure in case 3 blocked the late reaction totally. This was consistent with one of the cases reported by Hendrick and Lanez8 who, however, reported another case whose reaction could not be blocked by inhalation of bethametsone 7-valerate. Whether the inconsistency indicated different underlying mechanisms remained a matter of speculation. An attempt to block the immediate reaction of case 5 with sodium chromoglycate failed completely in contrast to other immediate, especially IgE-mediated, asthma reactions.“4 All our subjects with formaldehyde asthma had been exposed occupationally. No cases caused by domestic exposure have been reported to date. However, domestic exposure to urea-formaldehyde foam
Formaldehyde
asthma-4are
or overlooked
97
has caused one case of asthma, although the causative agent was not formaldehyde.“” In the provocation tests four of the 12 patients reacting specifically to formaidehyde compJained of headache during the afternoon. This may be worth noting as headache is one of the symptoms frequently complained of in occupational or domestic exposure to formaldehyde.“‘, ‘S -17None of the four patients experienced headache in conjunction with the placebo tests. The conspicuous discrepancy between the paucity of well documented cases of formaldehyde asthma and the vast global use of formaldehyde, both industrially and domesticaliy,4s evoked the question in the title as to whether formaldehye asthma is a rare disease or merely overlooked. The figures presented above answer the latter part of the question: 12 positive cases implies that the disorder is at Xeast under reported. However, the 230 patients subjected to bronchial provocation tests represented a highly selected material. They were referred to the institute, being the only place conducting routine specific formaldehyde provocation tests in Finland, from all over the country. The reason for their referral was either the suspicion of formaldehyde-induced asthma or an unspecified occupational asthma with an exposure history that raised such a suspicion at the Institute. Still, only 12 of 230 suspected cases could be confirmed with specific bronchial provocation tests. Jr can be concluded that respiratory sensitization to formaldehyde, although it certainly occurs, is a rare disease. This agrees with the opinion expressed by Hendrick et a1.12and is very similar to the finding by Wallenstein et a1.40 who reported that only two persons reacted to formaldehyde out of 13 1 who were exposed and had symptoms from the respiratory tmCt The removal from exposure of case 2 and 3 led to almost total recovery; in case 3 the bronchial reaction to 2.5 me/m3 of formaldehyde could not be repeated after 16 mo. However, as demonstrated in asthma caused by red cedar4g and isocyanate,SOthe symptoms in occupational asthma may continue. although the exposure is discontinued. The reaction of case 3 to 0.4 mg/m3 of formaldehyde implies that domestic exposures may suffice to maintain symptoms in occupationally acquired formaldehyde asthma. Although asthma as a result of domestic exposure to formaldehyde has not been reported to date, we should be well advised to pay special attention to exposure in the homes of persons suffering from occupational formaldehyde asthma. We thank Ms. H. Hahlman who superwed most of the provocation tests and Ms. A. Tolkki who tirew the figures.
98
Nordman
J. ALLERGY CLIN. IMMUNOL. JANUARY 1985
et al.
REFERENCES 1. Swenberg JA, Kerns WD, Mitchell RI, Gralla EJ, Pavkov KL: Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor. Cancer Res 40:3398, 1980 2. The health hazards of formaldehyde. Lancet 1:926, 1981 (editorial) 3. Bryson DD: Health hazards of formaldehyde. Lancet 1:1263, 1981 4. Berger JM, Lamm SH: Health hazards of formaldehyde. Lancet 1:1264, 1981 5. Morgan WKC: Health hazards of formaldehyde. Lancet 2:981, 1981 6. lnfante PF, Ulsamer AG, Groth D, Chu KC, Ward J: Health hazards of formaldehyde. Lancet 2:980, 1981 7. Pirill V, Kilpiii 0: On dermatitis caused by formaldehyde and its compounds. Ann Med lnt Fennial 38:38, 1949 8. Roths WC? Palmar and plantar eczema caused by steam ironing clothes containing formaldehyde. Berufs-Dermatosen 17: 263, 1969 9. Kerfoot EJ, Mooney TF: Formaldehyde and paraformaldehyde study in funeral homes. Am lnd Hyg Assoc J 36:533, 1975 10. Blejer HP, Banotes JT: Occupational health report of formaldehyde concentrations and effects on workers at the Bayly Manufacturing Company, Visalia, Calif., 1966. Study report number S-1806. Los Angeles, State of California Health and Welfare Agency, Dept. of Public Health, Bureau of Occupational Health. 11 Radar J: Reizwirkungen von Formaldehyde in Priipariersalen: analytische und experimentelle Untersuchungen. Inaugural Dissertation. W&burg University, 1974 1-J 1L. Andersen I, Molhave L: Controlled human studies with formaldehyde. In Gibson JE, editor: Formaldehyde toxicity. New York, 1983, Hemisphere Publishing Corp, pp 154-65 13. Andersen I: Formaldehyde in the indoor environment-health implications and the setting of standards. In Proceedings of International Climate Symposium SBl , Copenhagen, 1979 14. Marzulli FN, Maibach HI: Contact allergy: predictive testing in humans. In Marzulli FN, Maibach HI, editors: Dermatotoxicology and pharmacology. Hemisphere Publishing Corp, Washington, D.C., 1977, pp 353-72 15. Magnusson B, Kligman AM: Allergic contact dermatitis in the guinea pig. Springfield, Bl., 1970, A Thomas 16. Cronin E: Formaldehyde. In Cronin E, editor: Contact dermatitis. London, 1982, Churchill Livingstone, pp 788-94 17. Parkes WR: Occupational lung disorders, ed 2. London, 1982, Butterworths, pp 415-53 18. Pepys J: Occupational asthma: an overview. J Occup Med 24534, 1982 19. Brooks SM: Bronchial asthma of occupational origin. A rcview. Stand J Work Environ Health 3:53, 1977 20. Gandevia B: Occupational asthma. Part I. Med J Aust 57(suppl 2):332, 1970 21. Harris DK: Health problems in the manufacture and use of plastics. Br J lnd Med 10~255, 1953 22. Schoenberg JB, Mitchell ChA: Airway disease caused by phenolic (phenol-formaldehyde) resin exposure. Arch Environ Health 30:574, 1975 23. Gamble JF, McMichael AJ, Williams T, Battigelli M: Respnatory function and symptoms: an envitonmental-epidemiological study of rubber workers exposed to a phenol-formaldehyde type resin. Am Ind Hyg Assoc J 37:499, 1976 24. Popa V, Teculescu D, Stanescu D, Gavrilescu N: Bronchial
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asthma and asthmatic bronchitis, determined by simple chemicals. Dis Chest 56:395, 1965 Sakula A: Formalin asthma in hospital laboratory staff. Lancet 1:816, 1975 Alanko K, Keskinen H, Saarinen L: Ammattiastma. Duodecim 93:306, 1977 Hendrick DJ, Lane DJ: Formalin asthma in hospital staff. Br Med J 1:607, 1975 Hendrick DJ, Lane DJ: Occupational formalin asthma. Br J Ind Med 34:11, 1977 ACCP-ATS Joint Committee on Pulmonary Nomenclature: pulmonary terms and symbols. Chest 67:383, 1975 Aas K, Belin L: Standardization of diagnostic work in allergy. lnt Arch Allergy Appl lmmunol 45:57, 1973 Phil& V: Chamber test versus patch test for epicutaneous testing. Contact Dermatitis 1:48, 1975 Berglund E, Birath G, Bjure J, Grimby G, Kjellmer J, Sandqvist L, Soderholm B: Spirometric studies in normal subjects. I. Forced expirograms in subjects between 7 and 70 years of age. Acta Med Stand 173:186, 1963 Birath G, Kjellmer 1, Sandqvist L: Spirometric studies in normal subjects. II Ventilatory capacity tests in adults. Acta Med Stand 173:193, 1963 Laitinen L: Histamine and metacholine challenge in the testing of bronchial reactivity. Stand J Respir Dis [Supp1]86:1, 1974 Hargreave FE, Ryan G, Thomson NC, O’Byme PM, Latimer Chk, Juniper EF, Dolovich J: Bronchial responsiveness to histamine or metacholine in asthma: measurement and clinical significance. J ALLERGY CLIN IMMUNOL 68:347, 1981 Pepys J, Pickering CAC, Loudon HWG: Asthma due to inhaled chemical agents-piperazine dihydrochloride. Clin Allergy 2:189, 1972 Newman Taylor AJ, Davies RJ: Inhalation challenge testing. In Weill H, Turner-Warwick M, editors: Occupational lung diseases. New York, 1981, Marcel Dekker lnc, pp 143-67 NIOSH Manual of Analytical methods. US Dept of Health, Education, and Welfare. Cincinnati, 1974, HEW Publication No. (NIOSH) pp 75-121 Stanescu D, van de Woestijne KP: Decrease of maximum expiratory flow rates following isoprenaline inhalation in patients with chronic obstructive lung disease. In Communications and abstracts. Meeting on bronchodilatation, Societas Europaea Physiologiae Clinicae Respiratotiae. Dublin, Ireland, 1972, P 46 Wallenstein G, Rebohle E, Bergmann I, Voight U, Schneider WD: Berufliche Erkrankungen des Atmungsorgans durch chemische Stoffe mit potentieller Allergenwirkung. Dtsch Gesundh-Wesen 33(24):1119, 1978 Niemela R, Vainio H: Formaldehyde exposure in work and the general environment. Occurrence and possibilities for prevention. Stand J Work Environ Health 7:95, 1981 Hendrick DJ, Rando RJ, Lane DJ, Morris MJ: Formaldehyde asthma: challenge exposure levels and fate after five years. J Occup Med 24:893, 1982 Egle JL Jr: Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Arch Environ Health 25:119, 1972 Pepys J, Hutchcroft BJ: Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 112:829, 1975 Frigas E, Filley WV, Reed CE: Asthma induced by dust from urea-formaldehyde foam insulating material. Chest 79:706, 1981
VOL.UME 75 NUMBER 1, PART 1
Formaldehyde
-26. Olsen JH. Diissing M: Formaldehyde induced symptoms in day care centers. Am Ind Hyg Assoc J 43:366, 1982 47. Gamble J: Effects of formaldehyde on the respiratory system. In Gibson JE, editor: Formaldehyde toxicity. New York, 1983, Hemisphere Publishing Corp, pp 175.97 48. NIOSH/OSHA: Formaldehyde: evidence of carcinogenicity. Joint NIOSHiOSHA Current Intelligence Bulletin 34:1, 1980
asthma--Rare
or overlooked
49. Chan-Yeung M, Lam S, Koener S- Clinical features and natural history of occupational asthma due to western red cedar (7’hcju p/km) Am J Med 72:JI 1. 1982 50. Adams WGF: Long-term effects on the he&h of men engaged in the manufacture of toluene di-lsocyanaie. Br .I lnd Med 32:72,
L97S
Erratum The following correctionsapply to the article “EicosapentaenoicAcid: Its Effects on Aracbidonic Acid Metabolism by Cells in Culture,” by Levine and Worth, which appeared on page 430 of the September 1984issue, Part 2, of TknzJOURNALOFALLERGYANDCLINJCALIMMLJNOLOGY: 1. The correct spelling of the acronym TPA (abbreviationsbox, page 430) is 12-O-tetradecanoyIphorbol- 13-acetate. 2. The fourth line of the legend to Fig. 1 (page 431) should read: “. . . @g/2 X lo5 (01, or 5 p,g/2 x 105 cells (a), or were not preloaded (1p). EPA treatment is nontoxic as . . ..‘. 3. In Table I (page 432), the sixth and ninth entries under “Stimulus” were misaligned with their values to the right. They should read: Immunoreactive SthllUS
A23 187, 2fiM A23187, 2kM
EPA preloded
3.10 k 0.822 (4) 2.89 + 0.968 (4)
PGE,
99
(nglml) Control
Immu~ EPA
PGiL
Inghd CMltrai
7.63 2 0.65 (4) 0.28 2 0.060 (4) 0.90 + 0.063 (4) 12.69 2 0.925 (4) 0.34 +- 0.055 (4) 1.49 i 0.065 (4)