Occupational asthma Moira
Chan-Yeung,
md, mrcp,
frcp[c]; Stefan Grzybowski,
Occupational asthma is probably much more common than is generally realized. Though many causes have been described, undoubtedly many more are yet to be recognized. One of the diagnostic difficulties
lies in the fact that in most forms of this disease a late asthmatic reaction occurs in the evening rather than at work. The pathogenetic mechanisms differ in various forms of occupational asthma. In some, an immunologic mechanism is likely; in others, a "pharmacologic" action of the offending agent is implicated. Asthma due to inhalation of dusts of western red
cedar, isocyanates, detergent enzymes
and textiles is considered in detail. Periodic examination of workers at risk is of value for early diagnosis and prevention of irreversible airway obstruction.
L'asthme dont la
cause est
professionnelle est probablement beaucoup plus repandu qu'on ne le croit generalement. En depit du grand nombre de causes deja decouvertes,
il est incontestable que nombre d'autres causes restent a decouvrir. Une des difficultes du diagnostic reside dans le fait que, dans la majorite des formes de cette pathologie, la reaction asthmatique tardive se manifeste le soir plutot qu'au cours du travail de la journee. Dans les diverses formes de I'asthme professionnel les mecanismes pathogenes sont variables. Dans certaines formes un mecanisme immunologique est fort probable. Dans d'autres formes c'est l'action "pharmacologique" de I'allergene qui est
impliquee.
Nous passons
en revue
detaillee les formes d'asthme relevant de I'inhalation de poussiere de cedre rouge
occidental, d'isocyanates,
From the department of medicine, University of British Columbia, Vancouver Reprint requests to: Dr. Moira Chan-Yeung, Department of medicine, The Vancouver General Hospital, 855 12th Ave. W, Vancouver, BC V5Z 1M9
MD, FRCP,
d'enzymes de detersifs et de textiles. Si on cherche a porter un diagnostic a prevenir une occlusion irreversible des voies aeriennes, il
precoce et
importe d'examiner periodiquement les travailleurs particulierement exposes.
Only in recent years have we realized occupational asthma occurs fre¬ quently and is therefore of practical clinical importance. Serious research in this field is only just beginning and that
there
little doubt that in the not we will discover many more causes of this group of diseases and their varied pathogenetic mechanisms. seems
too distant future
frcp[c] Exposure to fumes of a polyvinyl chloride film cut with a hot wire gives rise to asthmatic symptoms among meat
ma.
wrappers.41
In this review
will discuss in to inhalation of dusts of western red cedar, isocy¬ anates, detergent enzymes and textiles. These conditions differ in both clinical picture and pathogenesis and serve as examples of most forms of occupational asthma. we
greater detail asthma due
Models of
occupational asthma
Western red cedar
Western red cedar (Thuja plicata), of the seven species of cedar grow¬ ing in North America, is important commercially. The durability of this wood makes it ideal for both outdoor and indoor construction. Respiratory symptoms due to occupational exposure to western red cedar were first recog¬ nized in England in 1949.10 The clinical picture was described in detail 20 years later by Milne and Gandevia in Aus¬ tralia.11'12 In British Columbia, red cedar asthma is fairly common: in the last few years we have seen more than 80 patients and described various as¬ pects of this condition.13'14 This type of asthma is seen in sawmill workers, carpenters, cabinet workers, construction workers and wood earvers; it is not seen in loggers. The clinical picture is characteristic. The majority of patients have been ex¬ posed to a variety of wood dusts for years without having respiratory symp¬ toms. After a period of steady exposure to western red cedar, usually between 6 weeks and 3 years, they begin to cough and wheeze and become breathless. A few may have burning and run¬ ning of the eyes and rhinorrhea several weeks before the onset of chest symp¬ toms. Initially the respiratory symptoms occur after work in the evening or night; later they occur also during the working hours and the nocturnal sympone
Occupations
associated with asthma Asthma is associated with a large number of occupations. Inhalation of substances of animal origin gives rise to asthma in shepherds, grooms, farm¬ ers, laboratory technicians and others. Enzymes of Bacillus subtilis cause asth¬ ma among workers in the detergent industry.1"7 The problems of sensitivity to insects, particularly mayflies, affect¬ ing workers in power plants along the Mississippi River,8 have been studied extensively. A high prevalence of asth¬ ma was reported among culture-oyster workers in Japan.9 Inhalation of substances of vegetable origin is another common cause of asthma in industry. Exposure to dusts of woods such as western red cedar,10"15 Iroko,16 cedar of Lebanon,17 mahogany and oak18 has been shown to give rise to asthma. Occupational asthma has been recognized among workers in the textile industry (byssinosis),1926 among bakers and flour mill workers27 and among grain elevator workers.28 Dusts of organic and inorganic chem¬ icals such as toluene diisocyanate,29"37 piperazine,88 complex salts of platinum,39 and vapours from aminoethyl ethanolamine in aluminum soldering flux40 have been shown to cause asth¬
CMA JOURNAL/MARCH 6, 1976/VOL. 114 433
toms become more distressing. Symp¬ toms are usually partially or completely
relieved during weekends and holidays. With continuous exposure, persistent breathlessness develops, with no relief on weekends. Only a few patients complain of asthma immediately after ini¬ tial exposure to red cedar dust. After cessation of exposure the symp¬ toms usually clear over a period of weeks but may persist for months. The nocturnal symptoms are the last to dis¬ appear. When, after clearing of symp¬ toms, the patient returns to work, it is not unusual for the symptoms to reappear slowly, after 1 or 2 weeks of exposure. About half of the patients
have persistent rhinorrhea. The incidence of atopy in
patients
with red cedar asthma is the same as that in the general population (about 10%). Eosinophilia is common. Chest radiographs are either normal or show evidence of overinflation; there is no evidence of allergic alveolitis. When these patients have routine pulmonary function studies (spirometry, measure¬ ment of lung volume and diffusing ca¬ pacity) some weeks after cessation of exposure the results either are normal or show mild to moderate airway ob¬
struction. Skin testing with extracts of western red cedar is not helpful in diagnosis.
ally within 24 hours, although in some diisocyanate (MDI), naphthalene diiso¬ patients the reaction may last for 3 to cyanate (NDI) and hexamethylene di¬ 4 days. A dual asthmatic reaction has isocyanate (HDI). Of these, TDI is the most volatile and most toxic. two components an immediate one, Two types of clinical response to occurring within a few minutes of chal¬ lenge, with spontaneous recovery with¬ TDI have been described, the first due in 1 to 2 hours, and a second reaction to irritation24 and the second due to 3 to 4 hours later. Late and dual asth¬ matic reactions are much more com¬ mon than immediate reactions. Systemic symptoms and leukocytosis do not occur. In general there is a good correlation between inhalation reaction and the clinical features of the patients: those who complain of immediate symptoms on exposure have an imme¬ diate asthmatic reaction; those who have symptoms after work have a late asthmatic reaction.
Isocyanates The industrial value of isocyanates lies in their reactivity with certain com¬ pounds containing active hydrogen ions, with which they form addition com¬ pounds containing hydroxylic groups, such as urethane, or in their ability to form polymerization products. Products made from isocyanates include flexible foam (mattresses, piltows, seat cushions and packing material), rigid foam (insulation), surface coating (varnish and paints), adhesives and plastics. There are four primary isocyanates: toluene
"allergy".29'30 Irritative effects occur on exposure to high concentrations of TDI: burning of eyes, sore throat, cough and dyspnea usually appear 4 to 8 hours after onset of exposure and may persist for 3 to 7 days. The "allergic" response occurs in a minority of individuals after a period of exposure: the onset is insidious, with a nocturnal cough that may progress to severe asthma on ex¬ posure to even minute concentrations of isocyanate. Other features, such as the lack of diagnostic skin and serologic tests and the value of inhalation chal¬ lenge in confirming the diagnosis,33'34 are similar to those described for red cedar asthma. Some investigators have suggested that, in addition to the acute asthmatic syndrome, there might be a more insidious, chronic deterioration in lung function in workers exposed to TDI.85'36 These observations, however, have not been confirmed by others.37 Although there are many similarities between asthma due to western red cedar and that due to isocyanates, there are certain differences, notably that atopic subjects may be affected more frequently by isocyanates30 than by red cedar dust.
Japanese investigators15 have reported diisocyanate (TDI), diphenylmethane greater success with this method of in¬ 5.o n )> vestigation; however, we were unable to DISODIUM CROMOGLYCATE their results with extracts reproduce io prepared as they described. Serologic gO INITIAL TEST I J 1 Detergent enzymes tests have not proven helpful in diag¬ .\ nosis; thus far, attempts to detect anti¬ Enzymes of B. subtilis were added to household laundry detergents in Europe bodies have failed.14 in 1965 and in the United States in Inhalation provocation tests are the 1967. Respiratory disease as a result definitive method of confirming the of An of aerosol extract of west¬ exposure to these enzymes was found diagnosis. a few years later among workers manuern red cedar or of plicatic acid the active compound in the red cedar ex¬ facturing these detergents.1"4 The clin¬ ical picture is characteristic. After a tract14 is inhaled under controlled conditions to reproduce the symptoms period of exposure the patients begin to have dyspnea, wheezing and fatigue, and to obtain objective evidence of typically several hours after a day's airway obstruction. Control tests in¬ work or at night. The dyspnea is usu¬ halation of the diluent of the extracts (carbol saline) or an extract of Douglas ally out of proportion to the wheezing. The patients feel better in the morning fir should be performed on the and return to work and the pattern is previous day to exclude any nonspecific 22 repeated. Malaise is prominent and response and to ascertain the degree of some weight loss may occur but fever diurnal variation of observations. A is uncommon. The symptoms often im¬ positive reaction has been defined as Hrr- t.i.I.I.r4 6 8 10 12 a response in which, after inhalation prove when exposure ceases but this challenge, the forced expiratory volume FIG. 1.^Dual asthmatic reaction following may take weeks or months. in 1 second (FEVi) decreases more challenge with red cedar extract. The Eosinophilia may be found; chest than 15% from the control value. immediate component occurs within have revealed no abnorma¬ radiographs lities. Pulmonary function tests show Three patterns of bronchial reactions minutes and subsides spontaneously in the late component appears are seen immediate, late and dual 31 hour; airway obstruction in almost all patients to 4 hours later and is still evident but restrictive changes and diffusion de¬ asthmatic reactions (Fig. 1). An imme¬ at 24 hours. Disodium cromoglycate fects are also found in some patients. diate asthmatic reaction occurs within blocked the immediate and late 5 to 10 minutes of inhalation and sub¬ reactionsboth when this patient was challenged Skin tests with extracts of B. subtilis are useful as supporting evidence of sides usually in 1 to 2 hours. A late on another occasion with the same dose asthmatic reaction develops 3 to 4 of extract. (Units of horizontal axis, allergy to the enzyme. Patients with hours after challenge and subsides usu¬ hours.) enzyme-induced respiratory disease in.
-I-
434 CMA JOURNAL/MARCH 6, 1976/VOL. 114
O
uj
variably have immediate wheal and flare skin reactions when tested with appropriate antigens. In a screening of workers in the detergent industry a close correlation was found between skin sensitivity and a history of respira¬ tory symptoms.1,3'5 It is not clear at present whether atopic subjects have a higher incidence of positive skin tests and respiratory symptoms.6 Inhalation provocation tests have shown a dual asthmatic reaction in all patients;2'7 some had a reduction in diffusing capa¬ city that persisted for at least 3 months.7 No correlation between the presence of respiratory disease and precipitating antibodies has been estab¬ lished.5'7 The long-term sequelae of this
disease are unknown. This condition differs from the pre¬ vious two in several respects: there are systemic symptoms and possible alveolar involvement in some patients, and skin tests with appropriate extracts are useful in detecting sensitized workers. Textile dusts Byssinosis is a respiratory disease as¬ sociated with the inhalation of dusts of cotton, flax and soft hemp. The work¬ ers may have a cough for a while and then suddenly notice an aggravation of the cough, with attacks of breathlessness and wheezing. These attacks usu¬ ally occur on the 1st day of the workweek ("Monday tightness") and disap¬ pear an hour or so after work is left, but they may recur each Monday after a weekend away from dust exposure. With continued exposure the symptoms also occur on Tuesdays and may occur on other days of the week. Eventually there is irreversible airway obstruc¬ tion.19 Patients with byssinosis usually have decreased ventilatory function on Mondays after 3 to 4 hours of exposure to
dust.20
physical and radiologic findings in patients with byssinosis are initially normal. When irreversible airway ob¬ struction develops, the findings are those of chronic bronchitis and em¬ physema. It appears that smokers are The
more
likely to acquire byssinosis.22'23
There is no correlation between posi¬ tive results of skin testing with extracts of cotton, hemp and flax and the pres¬ ence of disease.24,25 Precipitating anti¬ bodies against textile antigens have not been demonstrated.25 Inhalation provo¬ cation tests with an extract of cotton bracts showed acute bronchoconstriction 20 to 30 minutes after inhalation, lasting for 1 to 2 hours, in patients with byssinosis and in some healthy
subjects.26
This condition differs from the three discussed above in both its clinical fea¬ tures and the timing of the bronchial response on inhalation challenge.
Pathogenesis The pathogenesis of most forms of occupational asthma is unknown. In pa¬ tients with asthma due to western red cedar and isocyanates, immediate, late and dual asthmatic reactions occurring on inhalation challenge suggest an al¬ lergic origin. Similar reactions have been described in conditions such as allergic bronchopulmonary aspergillosis42 and avian allergy,43 in which the immediate asthmatic reaction was found to be mediated by reaginic anti¬ body and the late asthmatic reaction was closely correlated with the presence of Arthus skin reaction and precipitat¬ ing antibodies. However, in asthma due to red cedar and isocyanates it is not possible to elicit an allergic skin re¬ sponse or to detect circulating anti¬ bodies with the antigens causing the bronchial reactions. While it is likely that compounds such as plicatic acid in red cedar dust act as haptens, we may be dealing with a nonimmunologic reaction. In asthma due to detergent enzymes, skin tests with appropriate antigens are
in all patients with symptoms and in some asymptomatic workers. There is no correlation between the presence of symptoms and precipitating antibodies. In byssinosis the consensus is that bronchoconstriction is due to the pres¬ ence in the textile dust of "histaminereleasing substances". The pathogenesis of occupational asthma therefore varies with different conditions. Gandevia44 has proposed the following classification of the possible mechanisms: 1. Reflex bronchoconstriction due to inhalation of particulate matter, irritant gases and vapours. 2. Allergic bronchoconstriction, usu¬ ally associated with bronchial hyper-
positive
medical history. Occupational asthma should be suspected when symptoms occur after working hours and at night, with improvement over the weekends and holidays. In the cotton industry the history of "Monday tightness" is char¬ acteristic. Evidence of an adverse working en¬ vironment can be obtained by a "stopresume" work test, during which the patient's lung function is monitored; it should be remembered, however, that bronchospasm may persist for weeks or months after cessation of exposure. Measurement of ventilatory function before and at the end of a work shift is occasionally useful: a decrease in FEVi of more than 15% suggests oc¬ cupational asthma. Skin tests and serologic examination can be done when the antigen has been identified. Unfortunately, positive re¬ actions indicate exposure rather than disease, and false-negative responses are common.
Provocation
testing
with the appro¬ is the most definitive way to establish the diagnosis. This is not devoid of danger and should be performed in a hospital, where frequent observations can be made and resuscita¬ tion facilities are available.
priate inhalant
Treatment Treatment of acute episodes of occu¬ pational asthma does not differ from that of any acute attack of asthma. Symptomatic relief in mild attacks is often produced by aerosol bronchodila¬ tors such as salbutamol (Ventolin) or orciprenaline sulfate (Alupent). Xanthine derivatives such as aminophylline and theophylline are also useful. Corti¬ costeroids may be necessary for severe and prolonged attacks. Removal from exposure should be recommended; complete recovery may take many months. It is possible that in patients with severe disease irre¬ versible airway obstruction may even¬ tually develop. When a change of job is not feasible or exposure is occasional, the use of special masks or respirators is often recommended; however, such masks may not be effective and are often not worn because of discomfort. In some patients the use of disodium
reactivity. 3. Pharmacologic bronchoconstric¬ tion; the best example is byssinosis. 4. Acute inflammatory bronchocon¬ striction due to exposure to high con¬ centrations of irritant gases and va¬ pours (sulfur dioxide, nitrogen dioxide, ozone, ammonia, ete). Diagnosis The important first step in diagnosis cromoglycate or corticosteroids (sys¬ of occupational asthma is to think of it temic or topical) may help prevent the when asthmatic symptoms develop in occurrence of symptoms; however, this may not prevent the development of an industrial worker. The taking of a irreversible airway damage. is essential. good occupational history Careful enquiry is necessary not only Prevention into the substances the patient is work¬ More than 12 000 toxic chemicals ing with but also into those present in the working environment. In addition are used in United States industry but to the many agents known to cause the threshold limit value (TLV) has been asthmatic symptoms, there are undoub¬ established for only 400 of them and tedly a great many yet to be described. little is known about the remainder There are certain diagnostic clues in the (R.L.H. Murphy: personal communiCMA JOURNAL/MARCH 6, 1976/VOL. 114 435
cation). Establishment of the TLV gives practical guidelines for the control of products that are health hazards because of direct toxicity. The value is less useful when sensitization occurs, because symptoms may develop in susceptible individuals exposed to a concentration of sensitizing agent well below the TLV. On the other hand, it is likely that the greater the concentration of such an agent, the greater the proportion of those exposed who will become sensitized. In prevention, therefore, environmental control is essential. Measures to reduce the amount of exposure, such as improved ventilation, alteration of work practices or substitution of a nonhazardous substance, should be taken. Delineation of host factors is important in the prevention of occupational asthma. It would be possible to prevent the disease if one could identify susceptible individuals during pre-employment examination and exclude them from a particular industry. Little is known about these factors. Atopy seems important in some industries (e.g., enzyme detergents) but not in others (e.g., textiles and western red cedar). Deficiency in a1-antitrypsin has not been shown to be a predisposing factor in a survey of cedar mills.'5 Studies into the genetic and immunologic profiles of workers during preemployment examination and subsequent follow-up may delineate more important susceptibility factors. Periodic examination of workers at risk is therefore necessary; it is also of great value in early diagnosis of occupational asthma and prevention of potential irreversible airway obstruction. References 1. FLINDT MLH: Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet 1: 1177, 1969 2. PaPvs J, HARGREAVE FE, LONGBOTTOM JL, et al: Allergic reactions of the lungs to enzymes of Bacillus subtilis. Lancet 1. 1181 1969 3. Nawiiousa ML, TAGO B, PococK .J, et al: An epidemiological study of workers producing enzyme washing powders. Lancet 1: 689, 1970 4. GREENBERG M, MILNE JF, WATr A: Survey of workers exposed to dusts containing derivatives of Bacillus subtilis. Br Med J 2: 629, 1970 5. DoLovicis J, Lrrma DC: Correlates of skin test reactions to Bacillus subtilis enzyme preparations. J Allergy Clin immunol 49: 43, 1972 6. MITCHELL CA, GANDEvIA B: Respiratory symptoms and skin reactivity in workers exposed to proteolytic enzymes in the detergent industry. Am Rev Resp Dis 104: 1, 1971 7. Fiio.z T, McMuluL&IN KD, BROOKS 5, et al: Clinical, immunologic and physiologic observations in factory workers exposed to B. subtilis enzyme dust. J Allergy 47: 170, 1971 8. FIGLEY KD: Mayfly (Ephemeride) hypersensitivity. J Allergy 11: 376, 1940 9. WADA 5, NIsHIMOTO Y, NAKASHIMA T, et al: Clinical observation of bronchial asthma in culture-oyster workers. Hiroshima J Med Sci 16: 255, 1967 10. DoIG AT: Other lung diseases due to dust. Postgrad Med J 25: 639, 1949 11. MILNE J, GANDEvIA B: Occupational asthma and rhinitis due to western (Canadian) red cedar (Thuja plicata). Med J Aust 2: 741. 1969 12. GANDEvIA B, MILNE J: Occupational asthma and rhinitis due to western red cedar (Thuja plicata) with special reference to bronchial reactivity. Br J md Med 27: 235, 1970
13. CHAN-YEUNG M, BARTON GM, MACLEAN L,
et al: Bronchial reactions to western red cedar (Thuja plicata). Can Med Assoc J 105: 56, 1971 14. CHAN-YEUNG M, BARTON GM, MACLEAN L, et al: Occupational asthma and rhinitis due to western red cedar (Thu/a placata). Am Rev Resp Dis 108: 1094, 1973 15. ISHIZAKI T, SHIDA T, MIYAMOTO T, et al: Occupational asthma from western red cedar
dust
(Thuja
plicata)
in
furniture
factory
workers. .1 Occup Med 15: 580, 1973 16. PICKERING GAG, BArrEN JC, PEPYs J: Asthma due to inhaled wood dusts, Western red cedar and Iroko. Clin Allergy 2: 213, 1972
17. GREENBERG M: Respiratory symptoms following brief exposure to cedar of Lebanon (Cedra libani) dust. Gun Allergy 2: 219, 1972 18. SOSMAN AJ, SCHLUETER DP, FINK JN, et al: Hypersensitivity to wood dust. N Engl J Med 281: 977, 1969 19. HARRIS TR, MERCHANT JA, KILBURN KH, et al: Byssinosis and respiratory disease of cotton mill workers. J Occup Med 14: 199, 1972 20. BouHuva A, VAN DE WOESTIJNE KP: Res-
piratory mechanics and dust exposure in byssinosis. J Clin Invest 49: 106, 1970
21. BERRY G, MOLYNEUX MK: The correlation of cotton dust exposure and physiological re-
sponse, in Proceedings of an International Conference on Respiratory Disease in Textile
Workers, Alicante, Spain, 1968, p 184 22. BOUHUYS A, WoLFsoN R, HORNER DW, et al: Byssinosis in cotton textile workers; respiratory survey of a mill with rapid labour
turnover. Ann Intern 23. ZUsKIN E, WoLFsoN Byssinosis in carding Arch Environ Health
Med 71: 257, 1969 R, HARPEL G, et al: and spinning workers. 19: 666, 1969
24. CAYTON HR, FuRNass G, MAITLAND HB: Studies in cotton dust in relation to byssinosis. Part II: Skin tests for allergy with extracts of cotton dust. Br J md Med 9: 186, 1952 25. POPA V. GAYRILE5CU N, PREDA N, et al: An investigation of allergy in byssinosis - sensi-
tization to cotton, hemp, flax and jute antigens. Br J md Med 26: 101, 1969 26. BouHuYs A: Byssinosis, in Breathing, Physiology, Environment and Lung Diseases, New York, Grune, 1974, p 416 27. BONNEvIE P: Occupational allergy in bakery, in Netherlands Society of Allergy. Occupational Allergy, Springfield, IL, CC Thomas, 1958, p 161 28. WARREN P, CHERNIACK RM, Tsa KS: Hypersensitivity reactions to grain dust. J Allergy Clin Immunol 53: 139, 1974 29. MUNN A: Hazards of isocyanates. Ann Occup Hyg 8: 163, 1965 30. BRUCKNER HC, AvERY SB, STETsON DM, et al: Clinical and immunologic appraisal of workers exposed to diisocyanate. Arch Environ Health 16: 619, 1968 31. SwaNssoN
A,
HOLMQUIST
CF,
LUNDOREN
KD: Injury to the respiratory tract by isocyanates used in making lacquers. Br J md Med 12: 50, 1955 32. BRUGSCH HG, ELKIN HB: TDI toxicity. N Engl I Med 268: 353, 1963 33. WEILL H: personal communication 34. Pas'Ys J, PICKERING CA, BRESLIN ABX, et al: Asthma due to inhaled chemical agents tolylene dilsocyanate. Clin Allergy 2: 225, 1972 35. PETERS JM: Cumulative pulmonary effects in workers exposed to tolylene diisocyanate.
Proc R Soc Med 63: 14, 1970
36. MCKERROW CB, DAvIES JH, PARRY JONES A: Symptoms and lung function following acute and chronic exposure to tolylene dilsocyanate. Ibid, p 18 37. FERRIS BG: Effect of working with toluene dilsocyanate. Paper presented at Respiratory Symposium, Vancouver, Nov 29, 1974 38. PEPYS J, PICKERING CA, LOUDON HWG: Asthma due to inhaled chemical agents; piperazine dihydrochloride. Clin Allergy 2:
189, 1972
39. Pal'vs J, PICKERING CA, HUGHES EG: Asthma
due to inhaled chemical agents - complex salts of platinum. Ibid, p 391 40. PEPYs J, Pickering CA: Asthma due to inhaled chemical fumes - aminoethyl ethanolamine in aluminum soldering flux. Ibid, p 197 41. SoKOL WN, AELONY Y, BEALL GN: Meat-
wrapper s asthma. A 226: 639, 1973 42. Pa.vs J, HARGREAvE Inhibitory effects of on allergen-inhalation
1968
new syndrome? JAMA
FE, CHAN M, et al: disodium cromoglycate tests. Lancet 2: 134,
43. HAROREAvE FE, PEPYS J: Allergic respiratory reactions in bird fanciers provoked by allergen inhalation provocation tests. I Allergy
Clin Immunol 50: 157, 1972
44. GANDEvIA B: Occupational asthma, Part I.
.DemuIen® ethynodiol diacetate ethinyl estradiol Indication - Oral Contraception. ContraIndications - Malignant tumors of the breast or genital tract, estrogen dependent neoplasia, signiticant liver dystunction, history ot cholestatic jaundice, during breast teeding, undiagnosed vaginal bleeding, history ot CVA, coronary thrombosis, classical migraine, thrombophlebitis or thromboembolic disease, ocular lesions such as partisl or complete loss ot vision: detect in visual fields, diplopia: suspect pregnancy. Warnings - Discontinue medication at the earliest manifestation of: thromboembolic disorders such as thrombophlebitis, cerebrovascular disease, pulmonary embolism, myocardial schemia, retinal thrombosis: visual defects, proptosis, diplopia, undiagnosed severe headache, classical migraine, papilledema, ophthalmic vascular lesions, psychiatric disturbances. Rule out pregnancy after two consecutive periods are missed or after the first missed period if the prescribed regimen has not been followed. Demulen may cause metabolic imbalance; observe carefully in epilepsy, asthma, cardiac and renal dysfunction. Precautions - Before use, a thorough history should be taken and a thorough physical esamination performed, including the breasts and pelvic organs and a Papanicolaou smear. Follow up examination ahould be within six months and at least yearly thereafter. Liver, thyroid and other endocrine function tests should not be considered accurate unless therapy has been discontinued. Withdrawal of medication for 2 to 4 months is necessary before alteration in thyroxine binding reverta to normal. Similar precautions apply to liver function studiex and other tests of protein binding (e.g. plasma cortixol). Follow diabetic patients or those with a family hiatory of diabetes closely for decrease in glucose tolerance. Persistent irregular vaginal bleeding requires investigation. In metabolic or endocrine disease and when metabolism of calcium and phosphorus is involved, careful clinical evaluation should precede medication. Possible influence of prolonged therapy on pituitary, ovarian, adrenal, thyroid, hepatic or uterine function awaits further atudy. Risks of complications due to adrenocortical insufficiency appear to be minimal, but may occur. Treatment may mask the onset of the climacteric. Advise the pathologist of therapy with Demulen with relevant specimens. Uterine tibroids are subject to the same complications as may occur in pregnancy. Sudden enlargement, pain or tenderness require discontinuance of medication. Patients with a history of emotional disturbance, especially the. depressive type, are prone to recurrence. It this occurs, discontinue medication. Discontinue medication in patients who develop transient aphasia, paralysis, or loss of consciousness. Give Demulen to patients with signs of essential hypertension only under close superviaion. Elevation of blood pressure may occur at any time and even if asymptomatic necessitates cessation of medication. Give with great care and under close supervixion to patients with a history of jaundice. Do not preacribe to those with a history of cholestatic jaundice, especially associated with pregnancy. In those patients who develop severe generalized pruritus or icterus, consider hepatic dysfunction and withdraw medication. It the jaundice is of the cholestatic type, do not resume medication. Conaidering the 'oversuppression syndrome' patients may be advised to discontinue medication after approximately two years and resume only after normal ovulatory cycles have been re-established. Avoid prescribing to patients with a history of prolonged episodes of amenorrhea or infertility. Assess adolescent patients for adequate skeletal development prior to medication. Oral contraceptives may accelerate epiphyseal closure. After discontinuing Demulen, the patient should await the resumption of normal ovulating cycles before attempting to become pregnant. Use special judgment in prescribing to women with recurrent fibrocystic disease of the breast. Estrogen-progestogen combinations may increase plasma lipoproteins. Use with caution in women with pre-exixtent hyperlipoproteinemia. Adverse Effects - The following have been noted with varying incidence: nausea, vomiting, other GI symptoma, breakthrough bleeding, spotting, change in menatrual flow, amenorrhea, edema, suppression of lactation, migraine, cholestatic jaundice, rash (allergic), rise in blood preasure and mental depression. Disturbances in bleeding patterns are usually most pronounced during the firat cycle and usually disappear after several cycles. The following have been reported, although no cause and effect relationship has been established: anovulation poettreatment, premenstrual-like syndrome, changes in libido and appetite, cystitis-like syndrome, headache, nervousness, hemorrhagic eruption, and itching. Thrombophlebitis, pulmonary embolism and neuro-ocular lesions have been observed, although a cause and effect relationship has neither been established nor disproved. Various laboratory results may be altered particularly BSP, coagulation factors, tests of thyroid function, metapyrone, pregnanediol and corticosteriod determinations. Dosage - Demulen 21 - One tablet daily. Cyclic administration 3 weeks on tablets and one week oft. Demulen 28 One tablet daily. Continuous administration 21 active tablets followed by 7 inert tablets. Availability - Each white, round tablet with Searle on one side and 71 on the other contain ethynodiol diacetate 1.0 mg., and ethinyl estradiol 0.05 mg. Available in 21 and 28 day Compack dispensers (on green toil).
Med I Aust 15: 332, 1970
45. CHAN-YEUNG M, WILLSON G, MELVILLE M: Prevalence of respiratory symptoms in red cedar mill workers (in preparation for publication)
436 CMA JOURNAL/MARCH 6, 1976/VOL. 114
Searle Pharmaceuticals Oakville, Ontario L6H 1M5
Chan-Yeung,
md, mrcp,
frcp[c]; Stefan Grzybowski,
Occupational asthma is probably much more common than is generally realized. Though many causes have been described, undoubtedly many more are yet to be recognized. One of the diagnostic difficulties
lies in the fact that in most forms of this disease a late asthmatic reaction occurs in the evening rather than at work. The pathogenetic mechanisms differ in various forms of occupational asthma. In some, an immunologic mechanism is likely; in others, a "pharmacologic" action of the offending agent is implicated. Asthma due to inhalation of dusts of western red
cedar, isocyanates, detergent enzymes
and textiles is considered in detail. Periodic examination of workers at risk is of value for early diagnosis and prevention of irreversible airway obstruction.
L'asthme dont la
cause est
professionnelle est probablement beaucoup plus repandu qu'on ne le croit generalement. En depit du grand nombre de causes deja decouvertes,
il est incontestable que nombre d'autres causes restent a decouvrir. Une des difficultes du diagnostic reside dans le fait que, dans la majorite des formes de cette pathologie, la reaction asthmatique tardive se manifeste le soir plutot qu'au cours du travail de la journee. Dans les diverses formes de I'asthme professionnel les mecanismes pathogenes sont variables. Dans certaines formes un mecanisme immunologique est fort probable. Dans d'autres formes c'est l'action "pharmacologique" de I'allergene qui est
impliquee.
Nous passons
en revue
detaillee les formes d'asthme relevant de I'inhalation de poussiere de cedre rouge
occidental, d'isocyanates,
From the department of medicine, University of British Columbia, Vancouver Reprint requests to: Dr. Moira Chan-Yeung, Department of medicine, The Vancouver General Hospital, 855 12th Ave. W, Vancouver, BC V5Z 1M9
MD, FRCP,
d'enzymes de detersifs et de textiles. Si on cherche a porter un diagnostic a prevenir une occlusion irreversible des voies aeriennes, il
precoce et
importe d'examiner periodiquement les travailleurs particulierement exposes.
Only in recent years have we realized occupational asthma occurs fre¬ quently and is therefore of practical clinical importance. Serious research in this field is only just beginning and that
there
little doubt that in the not we will discover many more causes of this group of diseases and their varied pathogenetic mechanisms. seems
too distant future
frcp[c] Exposure to fumes of a polyvinyl chloride film cut with a hot wire gives rise to asthmatic symptoms among meat
ma.
wrappers.41
In this review
will discuss in to inhalation of dusts of western red cedar, isocy¬ anates, detergent enzymes and textiles. These conditions differ in both clinical picture and pathogenesis and serve as examples of most forms of occupational asthma. we
greater detail asthma due
Models of
occupational asthma
Western red cedar
Western red cedar (Thuja plicata), of the seven species of cedar grow¬ ing in North America, is important commercially. The durability of this wood makes it ideal for both outdoor and indoor construction. Respiratory symptoms due to occupational exposure to western red cedar were first recog¬ nized in England in 1949.10 The clinical picture was described in detail 20 years later by Milne and Gandevia in Aus¬ tralia.11'12 In British Columbia, red cedar asthma is fairly common: in the last few years we have seen more than 80 patients and described various as¬ pects of this condition.13'14 This type of asthma is seen in sawmill workers, carpenters, cabinet workers, construction workers and wood earvers; it is not seen in loggers. The clinical picture is characteristic. The majority of patients have been ex¬ posed to a variety of wood dusts for years without having respiratory symp¬ toms. After a period of steady exposure to western red cedar, usually between 6 weeks and 3 years, they begin to cough and wheeze and become breathless. A few may have burning and run¬ ning of the eyes and rhinorrhea several weeks before the onset of chest symp¬ toms. Initially the respiratory symptoms occur after work in the evening or night; later they occur also during the working hours and the nocturnal sympone
Occupations
associated with asthma Asthma is associated with a large number of occupations. Inhalation of substances of animal origin gives rise to asthma in shepherds, grooms, farm¬ ers, laboratory technicians and others. Enzymes of Bacillus subtilis cause asth¬ ma among workers in the detergent industry.1"7 The problems of sensitivity to insects, particularly mayflies, affect¬ ing workers in power plants along the Mississippi River,8 have been studied extensively. A high prevalence of asth¬ ma was reported among culture-oyster workers in Japan.9 Inhalation of substances of vegetable origin is another common cause of asthma in industry. Exposure to dusts of woods such as western red cedar,10"15 Iroko,16 cedar of Lebanon,17 mahogany and oak18 has been shown to give rise to asthma. Occupational asthma has been recognized among workers in the textile industry (byssinosis),1926 among bakers and flour mill workers27 and among grain elevator workers.28 Dusts of organic and inorganic chem¬ icals such as toluene diisocyanate,29"37 piperazine,88 complex salts of platinum,39 and vapours from aminoethyl ethanolamine in aluminum soldering flux40 have been shown to cause asth¬
CMA JOURNAL/MARCH 6, 1976/VOL. 114 433
toms become more distressing. Symp¬ toms are usually partially or completely
relieved during weekends and holidays. With continuous exposure, persistent breathlessness develops, with no relief on weekends. Only a few patients complain of asthma immediately after ini¬ tial exposure to red cedar dust. After cessation of exposure the symp¬ toms usually clear over a period of weeks but may persist for months. The nocturnal symptoms are the last to dis¬ appear. When, after clearing of symp¬ toms, the patient returns to work, it is not unusual for the symptoms to reappear slowly, after 1 or 2 weeks of exposure. About half of the patients
have persistent rhinorrhea. The incidence of atopy in
patients
with red cedar asthma is the same as that in the general population (about 10%). Eosinophilia is common. Chest radiographs are either normal or show evidence of overinflation; there is no evidence of allergic alveolitis. When these patients have routine pulmonary function studies (spirometry, measure¬ ment of lung volume and diffusing ca¬ pacity) some weeks after cessation of exposure the results either are normal or show mild to moderate airway ob¬
struction. Skin testing with extracts of western red cedar is not helpful in diagnosis.
ally within 24 hours, although in some diisocyanate (MDI), naphthalene diiso¬ patients the reaction may last for 3 to cyanate (NDI) and hexamethylene di¬ 4 days. A dual asthmatic reaction has isocyanate (HDI). Of these, TDI is the most volatile and most toxic. two components an immediate one, Two types of clinical response to occurring within a few minutes of chal¬ lenge, with spontaneous recovery with¬ TDI have been described, the first due in 1 to 2 hours, and a second reaction to irritation24 and the second due to 3 to 4 hours later. Late and dual asth¬ matic reactions are much more com¬ mon than immediate reactions. Systemic symptoms and leukocytosis do not occur. In general there is a good correlation between inhalation reaction and the clinical features of the patients: those who complain of immediate symptoms on exposure have an imme¬ diate asthmatic reaction; those who have symptoms after work have a late asthmatic reaction.
Isocyanates The industrial value of isocyanates lies in their reactivity with certain com¬ pounds containing active hydrogen ions, with which they form addition com¬ pounds containing hydroxylic groups, such as urethane, or in their ability to form polymerization products. Products made from isocyanates include flexible foam (mattresses, piltows, seat cushions and packing material), rigid foam (insulation), surface coating (varnish and paints), adhesives and plastics. There are four primary isocyanates: toluene
"allergy".29'30 Irritative effects occur on exposure to high concentrations of TDI: burning of eyes, sore throat, cough and dyspnea usually appear 4 to 8 hours after onset of exposure and may persist for 3 to 7 days. The "allergic" response occurs in a minority of individuals after a period of exposure: the onset is insidious, with a nocturnal cough that may progress to severe asthma on ex¬ posure to even minute concentrations of isocyanate. Other features, such as the lack of diagnostic skin and serologic tests and the value of inhalation chal¬ lenge in confirming the diagnosis,33'34 are similar to those described for red cedar asthma. Some investigators have suggested that, in addition to the acute asthmatic syndrome, there might be a more insidious, chronic deterioration in lung function in workers exposed to TDI.85'36 These observations, however, have not been confirmed by others.37 Although there are many similarities between asthma due to western red cedar and that due to isocyanates, there are certain differences, notably that atopic subjects may be affected more frequently by isocyanates30 than by red cedar dust.
Japanese investigators15 have reported diisocyanate (TDI), diphenylmethane greater success with this method of in¬ 5.o n )> vestigation; however, we were unable to DISODIUM CROMOGLYCATE their results with extracts reproduce io prepared as they described. Serologic gO INITIAL TEST I J 1 Detergent enzymes tests have not proven helpful in diag¬ .\ nosis; thus far, attempts to detect anti¬ Enzymes of B. subtilis were added to household laundry detergents in Europe bodies have failed.14 in 1965 and in the United States in Inhalation provocation tests are the 1967. Respiratory disease as a result definitive method of confirming the of An of aerosol extract of west¬ exposure to these enzymes was found diagnosis. a few years later among workers manuern red cedar or of plicatic acid the active compound in the red cedar ex¬ facturing these detergents.1"4 The clin¬ ical picture is characteristic. After a tract14 is inhaled under controlled conditions to reproduce the symptoms period of exposure the patients begin to have dyspnea, wheezing and fatigue, and to obtain objective evidence of typically several hours after a day's airway obstruction. Control tests in¬ work or at night. The dyspnea is usu¬ halation of the diluent of the extracts (carbol saline) or an extract of Douglas ally out of proportion to the wheezing. The patients feel better in the morning fir should be performed on the and return to work and the pattern is previous day to exclude any nonspecific 22 repeated. Malaise is prominent and response and to ascertain the degree of some weight loss may occur but fever diurnal variation of observations. A is uncommon. The symptoms often im¬ positive reaction has been defined as Hrr- t.i.I.I.r4 6 8 10 12 a response in which, after inhalation prove when exposure ceases but this challenge, the forced expiratory volume FIG. 1.^Dual asthmatic reaction following may take weeks or months. in 1 second (FEVi) decreases more challenge with red cedar extract. The Eosinophilia may be found; chest than 15% from the control value. immediate component occurs within have revealed no abnorma¬ radiographs lities. Pulmonary function tests show Three patterns of bronchial reactions minutes and subsides spontaneously in the late component appears are seen immediate, late and dual 31 hour; airway obstruction in almost all patients to 4 hours later and is still evident but restrictive changes and diffusion de¬ asthmatic reactions (Fig. 1). An imme¬ at 24 hours. Disodium cromoglycate fects are also found in some patients. diate asthmatic reaction occurs within blocked the immediate and late 5 to 10 minutes of inhalation and sub¬ reactionsboth when this patient was challenged Skin tests with extracts of B. subtilis are useful as supporting evidence of sides usually in 1 to 2 hours. A late on another occasion with the same dose asthmatic reaction develops 3 to 4 of extract. (Units of horizontal axis, allergy to the enzyme. Patients with hours after challenge and subsides usu¬ hours.) enzyme-induced respiratory disease in.
-I-
434 CMA JOURNAL/MARCH 6, 1976/VOL. 114
O
uj
variably have immediate wheal and flare skin reactions when tested with appropriate antigens. In a screening of workers in the detergent industry a close correlation was found between skin sensitivity and a history of respira¬ tory symptoms.1,3'5 It is not clear at present whether atopic subjects have a higher incidence of positive skin tests and respiratory symptoms.6 Inhalation provocation tests have shown a dual asthmatic reaction in all patients;2'7 some had a reduction in diffusing capa¬ city that persisted for at least 3 months.7 No correlation between the presence of respiratory disease and precipitating antibodies has been estab¬ lished.5'7 The long-term sequelae of this
disease are unknown. This condition differs from the pre¬ vious two in several respects: there are systemic symptoms and possible alveolar involvement in some patients, and skin tests with appropriate extracts are useful in detecting sensitized workers. Textile dusts Byssinosis is a respiratory disease as¬ sociated with the inhalation of dusts of cotton, flax and soft hemp. The work¬ ers may have a cough for a while and then suddenly notice an aggravation of the cough, with attacks of breathlessness and wheezing. These attacks usu¬ ally occur on the 1st day of the workweek ("Monday tightness") and disap¬ pear an hour or so after work is left, but they may recur each Monday after a weekend away from dust exposure. With continued exposure the symptoms also occur on Tuesdays and may occur on other days of the week. Eventually there is irreversible airway obstruc¬ tion.19 Patients with byssinosis usually have decreased ventilatory function on Mondays after 3 to 4 hours of exposure to
dust.20
physical and radiologic findings in patients with byssinosis are initially normal. When irreversible airway ob¬ struction develops, the findings are those of chronic bronchitis and em¬ physema. It appears that smokers are The
more
likely to acquire byssinosis.22'23
There is no correlation between posi¬ tive results of skin testing with extracts of cotton, hemp and flax and the pres¬ ence of disease.24,25 Precipitating anti¬ bodies against textile antigens have not been demonstrated.25 Inhalation provo¬ cation tests with an extract of cotton bracts showed acute bronchoconstriction 20 to 30 minutes after inhalation, lasting for 1 to 2 hours, in patients with byssinosis and in some healthy
subjects.26
This condition differs from the three discussed above in both its clinical fea¬ tures and the timing of the bronchial response on inhalation challenge.
Pathogenesis The pathogenesis of most forms of occupational asthma is unknown. In pa¬ tients with asthma due to western red cedar and isocyanates, immediate, late and dual asthmatic reactions occurring on inhalation challenge suggest an al¬ lergic origin. Similar reactions have been described in conditions such as allergic bronchopulmonary aspergillosis42 and avian allergy,43 in which the immediate asthmatic reaction was found to be mediated by reaginic anti¬ body and the late asthmatic reaction was closely correlated with the presence of Arthus skin reaction and precipitat¬ ing antibodies. However, in asthma due to red cedar and isocyanates it is not possible to elicit an allergic skin re¬ sponse or to detect circulating anti¬ bodies with the antigens causing the bronchial reactions. While it is likely that compounds such as plicatic acid in red cedar dust act as haptens, we may be dealing with a nonimmunologic reaction. In asthma due to detergent enzymes, skin tests with appropriate antigens are
in all patients with symptoms and in some asymptomatic workers. There is no correlation between the presence of symptoms and precipitating antibodies. In byssinosis the consensus is that bronchoconstriction is due to the pres¬ ence in the textile dust of "histaminereleasing substances". The pathogenesis of occupational asthma therefore varies with different conditions. Gandevia44 has proposed the following classification of the possible mechanisms: 1. Reflex bronchoconstriction due to inhalation of particulate matter, irritant gases and vapours. 2. Allergic bronchoconstriction, usu¬ ally associated with bronchial hyper-
positive
medical history. Occupational asthma should be suspected when symptoms occur after working hours and at night, with improvement over the weekends and holidays. In the cotton industry the history of "Monday tightness" is char¬ acteristic. Evidence of an adverse working en¬ vironment can be obtained by a "stopresume" work test, during which the patient's lung function is monitored; it should be remembered, however, that bronchospasm may persist for weeks or months after cessation of exposure. Measurement of ventilatory function before and at the end of a work shift is occasionally useful: a decrease in FEVi of more than 15% suggests oc¬ cupational asthma. Skin tests and serologic examination can be done when the antigen has been identified. Unfortunately, positive re¬ actions indicate exposure rather than disease, and false-negative responses are common.
Provocation
testing
with the appro¬ is the most definitive way to establish the diagnosis. This is not devoid of danger and should be performed in a hospital, where frequent observations can be made and resuscita¬ tion facilities are available.
priate inhalant
Treatment Treatment of acute episodes of occu¬ pational asthma does not differ from that of any acute attack of asthma. Symptomatic relief in mild attacks is often produced by aerosol bronchodila¬ tors such as salbutamol (Ventolin) or orciprenaline sulfate (Alupent). Xanthine derivatives such as aminophylline and theophylline are also useful. Corti¬ costeroids may be necessary for severe and prolonged attacks. Removal from exposure should be recommended; complete recovery may take many months. It is possible that in patients with severe disease irre¬ versible airway obstruction may even¬ tually develop. When a change of job is not feasible or exposure is occasional, the use of special masks or respirators is often recommended; however, such masks may not be effective and are often not worn because of discomfort. In some patients the use of disodium
reactivity. 3. Pharmacologic bronchoconstric¬ tion; the best example is byssinosis. 4. Acute inflammatory bronchocon¬ striction due to exposure to high con¬ centrations of irritant gases and va¬ pours (sulfur dioxide, nitrogen dioxide, ozone, ammonia, ete). Diagnosis The important first step in diagnosis cromoglycate or corticosteroids (sys¬ of occupational asthma is to think of it temic or topical) may help prevent the when asthmatic symptoms develop in occurrence of symptoms; however, this may not prevent the development of an industrial worker. The taking of a irreversible airway damage. is essential. good occupational history Careful enquiry is necessary not only Prevention into the substances the patient is work¬ More than 12 000 toxic chemicals ing with but also into those present in the working environment. In addition are used in United States industry but to the many agents known to cause the threshold limit value (TLV) has been asthmatic symptoms, there are undoub¬ established for only 400 of them and tedly a great many yet to be described. little is known about the remainder There are certain diagnostic clues in the (R.L.H. Murphy: personal communiCMA JOURNAL/MARCH 6, 1976/VOL. 114 435
cation). Establishment of the TLV gives practical guidelines for the control of products that are health hazards because of direct toxicity. The value is less useful when sensitization occurs, because symptoms may develop in susceptible individuals exposed to a concentration of sensitizing agent well below the TLV. On the other hand, it is likely that the greater the concentration of such an agent, the greater the proportion of those exposed who will become sensitized. In prevention, therefore, environmental control is essential. Measures to reduce the amount of exposure, such as improved ventilation, alteration of work practices or substitution of a nonhazardous substance, should be taken. Delineation of host factors is important in the prevention of occupational asthma. It would be possible to prevent the disease if one could identify susceptible individuals during pre-employment examination and exclude them from a particular industry. Little is known about these factors. Atopy seems important in some industries (e.g., enzyme detergents) but not in others (e.g., textiles and western red cedar). Deficiency in a1-antitrypsin has not been shown to be a predisposing factor in a survey of cedar mills.'5 Studies into the genetic and immunologic profiles of workers during preemployment examination and subsequent follow-up may delineate more important susceptibility factors. Periodic examination of workers at risk is therefore necessary; it is also of great value in early diagnosis of occupational asthma and prevention of potential irreversible airway obstruction. References 1. FLINDT MLH: Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet 1: 1177, 1969 2. PaPvs J, HARGREAVE FE, LONGBOTTOM JL, et al: Allergic reactions of the lungs to enzymes of Bacillus subtilis. Lancet 1. 1181 1969 3. Nawiiousa ML, TAGO B, PococK .J, et al: An epidemiological study of workers producing enzyme washing powders. Lancet 1: 689, 1970 4. GREENBERG M, MILNE JF, WATr A: Survey of workers exposed to dusts containing derivatives of Bacillus subtilis. Br Med J 2: 629, 1970 5. DoLovicis J, Lrrma DC: Correlates of skin test reactions to Bacillus subtilis enzyme preparations. J Allergy Clin immunol 49: 43, 1972 6. MITCHELL CA, GANDEvIA B: Respiratory symptoms and skin reactivity in workers exposed to proteolytic enzymes in the detergent industry. Am Rev Resp Dis 104: 1, 1971 7. Fiio.z T, McMuluL&IN KD, BROOKS 5, et al: Clinical, immunologic and physiologic observations in factory workers exposed to B. subtilis enzyme dust. J Allergy 47: 170, 1971 8. FIGLEY KD: Mayfly (Ephemeride) hypersensitivity. J Allergy 11: 376, 1940 9. WADA 5, NIsHIMOTO Y, NAKASHIMA T, et al: Clinical observation of bronchial asthma in culture-oyster workers. Hiroshima J Med Sci 16: 255, 1967 10. DoIG AT: Other lung diseases due to dust. Postgrad Med J 25: 639, 1949 11. MILNE J, GANDEvIA B: Occupational asthma and rhinitis due to western (Canadian) red cedar (Thuja plicata). Med J Aust 2: 741. 1969 12. GANDEvIA B, MILNE J: Occupational asthma and rhinitis due to western red cedar (Thuja plicata) with special reference to bronchial reactivity. Br J md Med 27: 235, 1970
13. CHAN-YEUNG M, BARTON GM, MACLEAN L,
et al: Bronchial reactions to western red cedar (Thuja plicata). Can Med Assoc J 105: 56, 1971 14. CHAN-YEUNG M, BARTON GM, MACLEAN L, et al: Occupational asthma and rhinitis due to western red cedar (Thu/a placata). Am Rev Resp Dis 108: 1094, 1973 15. ISHIZAKI T, SHIDA T, MIYAMOTO T, et al: Occupational asthma from western red cedar
dust
(Thuja
plicata)
in
furniture
factory
workers. .1 Occup Med 15: 580, 1973 16. PICKERING GAG, BArrEN JC, PEPYs J: Asthma due to inhaled wood dusts, Western red cedar and Iroko. Clin Allergy 2: 213, 1972
17. GREENBERG M: Respiratory symptoms following brief exposure to cedar of Lebanon (Cedra libani) dust. Gun Allergy 2: 219, 1972 18. SOSMAN AJ, SCHLUETER DP, FINK JN, et al: Hypersensitivity to wood dust. N Engl J Med 281: 977, 1969 19. HARRIS TR, MERCHANT JA, KILBURN KH, et al: Byssinosis and respiratory disease of cotton mill workers. J Occup Med 14: 199, 1972 20. BouHuva A, VAN DE WOESTIJNE KP: Res-
piratory mechanics and dust exposure in byssinosis. J Clin Invest 49: 106, 1970
21. BERRY G, MOLYNEUX MK: The correlation of cotton dust exposure and physiological re-
sponse, in Proceedings of an International Conference on Respiratory Disease in Textile
Workers, Alicante, Spain, 1968, p 184 22. BOUHUYS A, WoLFsoN R, HORNER DW, et al: Byssinosis in cotton textile workers; respiratory survey of a mill with rapid labour
turnover. Ann Intern 23. ZUsKIN E, WoLFsoN Byssinosis in carding Arch Environ Health
Med 71: 257, 1969 R, HARPEL G, et al: and spinning workers. 19: 666, 1969
24. CAYTON HR, FuRNass G, MAITLAND HB: Studies in cotton dust in relation to byssinosis. Part II: Skin tests for allergy with extracts of cotton dust. Br J md Med 9: 186, 1952 25. POPA V. GAYRILE5CU N, PREDA N, et al: An investigation of allergy in byssinosis - sensi-
tization to cotton, hemp, flax and jute antigens. Br J md Med 26: 101, 1969 26. BouHuYs A: Byssinosis, in Breathing, Physiology, Environment and Lung Diseases, New York, Grune, 1974, p 416 27. BONNEvIE P: Occupational allergy in bakery, in Netherlands Society of Allergy. Occupational Allergy, Springfield, IL, CC Thomas, 1958, p 161 28. WARREN P, CHERNIACK RM, Tsa KS: Hypersensitivity reactions to grain dust. J Allergy Clin Immunol 53: 139, 1974 29. MUNN A: Hazards of isocyanates. Ann Occup Hyg 8: 163, 1965 30. BRUCKNER HC, AvERY SB, STETsON DM, et al: Clinical and immunologic appraisal of workers exposed to diisocyanate. Arch Environ Health 16: 619, 1968 31. SwaNssoN
A,
HOLMQUIST
CF,
LUNDOREN
KD: Injury to the respiratory tract by isocyanates used in making lacquers. Br J md Med 12: 50, 1955 32. BRUGSCH HG, ELKIN HB: TDI toxicity. N Engl I Med 268: 353, 1963 33. WEILL H: personal communication 34. Pas'Ys J, PICKERING CA, BRESLIN ABX, et al: Asthma due to inhaled chemical agents tolylene dilsocyanate. Clin Allergy 2: 225, 1972 35. PETERS JM: Cumulative pulmonary effects in workers exposed to tolylene diisocyanate.
Proc R Soc Med 63: 14, 1970
36. MCKERROW CB, DAvIES JH, PARRY JONES A: Symptoms and lung function following acute and chronic exposure to tolylene dilsocyanate. Ibid, p 18 37. FERRIS BG: Effect of working with toluene dilsocyanate. Paper presented at Respiratory Symposium, Vancouver, Nov 29, 1974 38. PEPYS J, PICKERING CA, LOUDON HWG: Asthma due to inhaled chemical agents; piperazine dihydrochloride. Clin Allergy 2:
189, 1972
39. Pal'vs J, PICKERING CA, HUGHES EG: Asthma
due to inhaled chemical agents - complex salts of platinum. Ibid, p 391 40. PEPYs J, Pickering CA: Asthma due to inhaled chemical fumes - aminoethyl ethanolamine in aluminum soldering flux. Ibid, p 197 41. SoKOL WN, AELONY Y, BEALL GN: Meat-
wrapper s asthma. A 226: 639, 1973 42. Pa.vs J, HARGREAvE Inhibitory effects of on allergen-inhalation
1968
new syndrome? JAMA
FE, CHAN M, et al: disodium cromoglycate tests. Lancet 2: 134,
43. HAROREAvE FE, PEPYS J: Allergic respiratory reactions in bird fanciers provoked by allergen inhalation provocation tests. I Allergy
Clin Immunol 50: 157, 1972
44. GANDEvIA B: Occupational asthma, Part I.
.DemuIen® ethynodiol diacetate ethinyl estradiol Indication - Oral Contraception. ContraIndications - Malignant tumors of the breast or genital tract, estrogen dependent neoplasia, signiticant liver dystunction, history ot cholestatic jaundice, during breast teeding, undiagnosed vaginal bleeding, history ot CVA, coronary thrombosis, classical migraine, thrombophlebitis or thromboembolic disease, ocular lesions such as partisl or complete loss ot vision: detect in visual fields, diplopia: suspect pregnancy. Warnings - Discontinue medication at the earliest manifestation of: thromboembolic disorders such as thrombophlebitis, cerebrovascular disease, pulmonary embolism, myocardial schemia, retinal thrombosis: visual defects, proptosis, diplopia, undiagnosed severe headache, classical migraine, papilledema, ophthalmic vascular lesions, psychiatric disturbances. Rule out pregnancy after two consecutive periods are missed or after the first missed period if the prescribed regimen has not been followed. Demulen may cause metabolic imbalance; observe carefully in epilepsy, asthma, cardiac and renal dysfunction. Precautions - Before use, a thorough history should be taken and a thorough physical esamination performed, including the breasts and pelvic organs and a Papanicolaou smear. Follow up examination ahould be within six months and at least yearly thereafter. Liver, thyroid and other endocrine function tests should not be considered accurate unless therapy has been discontinued. Withdrawal of medication for 2 to 4 months is necessary before alteration in thyroxine binding reverta to normal. Similar precautions apply to liver function studiex and other tests of protein binding (e.g. plasma cortixol). Follow diabetic patients or those with a family hiatory of diabetes closely for decrease in glucose tolerance. Persistent irregular vaginal bleeding requires investigation. In metabolic or endocrine disease and when metabolism of calcium and phosphorus is involved, careful clinical evaluation should precede medication. Possible influence of prolonged therapy on pituitary, ovarian, adrenal, thyroid, hepatic or uterine function awaits further atudy. Risks of complications due to adrenocortical insufficiency appear to be minimal, but may occur. Treatment may mask the onset of the climacteric. Advise the pathologist of therapy with Demulen with relevant specimens. Uterine tibroids are subject to the same complications as may occur in pregnancy. Sudden enlargement, pain or tenderness require discontinuance of medication. Patients with a history of emotional disturbance, especially the. depressive type, are prone to recurrence. It this occurs, discontinue medication. Discontinue medication in patients who develop transient aphasia, paralysis, or loss of consciousness. Give Demulen to patients with signs of essential hypertension only under close superviaion. Elevation of blood pressure may occur at any time and even if asymptomatic necessitates cessation of medication. Give with great care and under close supervixion to patients with a history of jaundice. Do not preacribe to those with a history of cholestatic jaundice, especially associated with pregnancy. In those patients who develop severe generalized pruritus or icterus, consider hepatic dysfunction and withdraw medication. It the jaundice is of the cholestatic type, do not resume medication. Conaidering the 'oversuppression syndrome' patients may be advised to discontinue medication after approximately two years and resume only after normal ovulatory cycles have been re-established. Avoid prescribing to patients with a history of prolonged episodes of amenorrhea or infertility. Assess adolescent patients for adequate skeletal development prior to medication. Oral contraceptives may accelerate epiphyseal closure. After discontinuing Demulen, the patient should await the resumption of normal ovulating cycles before attempting to become pregnant. Use special judgment in prescribing to women with recurrent fibrocystic disease of the breast. Estrogen-progestogen combinations may increase plasma lipoproteins. Use with caution in women with pre-exixtent hyperlipoproteinemia. Adverse Effects - The following have been noted with varying incidence: nausea, vomiting, other GI symptoma, breakthrough bleeding, spotting, change in menatrual flow, amenorrhea, edema, suppression of lactation, migraine, cholestatic jaundice, rash (allergic), rise in blood preasure and mental depression. Disturbances in bleeding patterns are usually most pronounced during the firat cycle and usually disappear after several cycles. The following have been reported, although no cause and effect relationship has been established: anovulation poettreatment, premenstrual-like syndrome, changes in libido and appetite, cystitis-like syndrome, headache, nervousness, hemorrhagic eruption, and itching. Thrombophlebitis, pulmonary embolism and neuro-ocular lesions have been observed, although a cause and effect relationship has neither been established nor disproved. Various laboratory results may be altered particularly BSP, coagulation factors, tests of thyroid function, metapyrone, pregnanediol and corticosteriod determinations. Dosage - Demulen 21 - One tablet daily. Cyclic administration 3 weeks on tablets and one week oft. Demulen 28 One tablet daily. Continuous administration 21 active tablets followed by 7 inert tablets. Availability - Each white, round tablet with Searle on one side and 71 on the other contain ethynodiol diacetate 1.0 mg., and ethinyl estradiol 0.05 mg. Available in 21 and 28 day Compack dispensers (on green toil).
Med I Aust 15: 332, 1970
45. CHAN-YEUNG M, WILLSON G, MELVILLE M: Prevalence of respiratory symptoms in red cedar mill workers (in preparation for publication)
436 CMA JOURNAL/MARCH 6, 1976/VOL. 114
Searle Pharmaceuticals Oakville, Ontario L6H 1M5
