Bronchial asthma of occupational origin: a review.

There are immediate benefits when one can establish the diagnosis of occupationally induced asthma. It is a man-made disease and is thus reversible. Diagnosis depends on knowledge of the source and types of exposure which can be correlated with the clinical, physiological and immunologic patterns of affected workers. The discovery of one case can often lead more readily to recognition of others. Individuals with asthma of an occupational origin should be removed from work. Equally as important is the initiation of proper industrial hygiene procedures which would improve the occupational environment and periodic medical surveillance of workers for the identification of early disease or individuals with few or no symptoms.

Bronchial asthma is a disease characterized by increased responsiveness of the trachea and bronchi to various 'stimuli; it is manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy (3). Occupational asthma is a respiratory disorder characterized by reversible obstruction of the airways and caused by the inhalation of substances or materials which are manufactured or directly used by a worker or are incidentally present at the work site (84). This definition encompasses a variety of airway disorders, regardless of the action, and includes processes which result from both an immunologic and nonimmunologic basis. Occupational asthma is manifested clinically by chest tightness, cough, wheezing and shortness of breath and physiologically by temporal alterations in pulmonary mechanics. While airway obstruction is initially intermittent and reversible, continued exposure to the inciting agent may, in some instances, lead 1 to irreversible obstructive airway disease and chronic respiratory symptoms.
While the diagnosis of bronchial asthma is based largely on clinical and physiological characteristics, it must be differentiated from other obstructive pulmonary diseases such as chronic bronchitis. This latter disorder is characterized clinically by excessive production of bronchial mucus and is manifested by chronic productive cough (3,22). For epidemiologic purposes "chronic" refers to the presence of these 'symptoms on most days for at least three months of the year during two or more successive years. Physiologically, chronic bronchitis is associated with irreversible obstruction of the airways. Emphysema, another type of chronic obstructive pulmonary disease, is defined in terms of its pathological characteristics as an abnormal and permanent enlargement of respiratory air spaces (the structure beyond the terminal bronchiole) that is accompanied by destructive changes (3). Bronchial asthma, chronic bronchitis, and emphysema can occur together, and many patients with chronic airway obstruction have combined features of two or even all three of the diseases. When chronic bronchitis and bronchial asthma occur together, the resultant clinical syndrome is often called "asthmatic bronchitis." Bronchial asthma and emphysema can also be encountered together, especially in older patient'S. A rational formulation of diagnosis, therapy and prognosis for an individual suspected of having airway obstruction of occupational origin requires precise identification of the disorder or the combination of disorders afflicting the worker.

EPIDEMIOLOGY
According to the results of a health interview survey conducted by the National Center for Health Statistics (89), 6,031,000 persons in the United States were afflicted with bronchial asthma in 1970. This number represents approximately 3 to 3.5°/0 of the population.
The prevalence of occupational asthma is hard to determine. Bernstein reported that, in a recent survey of the United States, occupational asthma was not recognized as a reportable entity in a single state (8). In 1970 the state of California noted that the designation "noninfectious chronic respiratory disease" accounted for 4 010 of all reported occupational diseases (8). Thirty per cent of these respiratory conditions could be attributed to agents capable of causing obstructive pulmonary disease. The incidence of respiratory symptoms due to wood and paper dusts was 4°/0, isocyanates 4°/0, various chemicals 8.8 {11o, and proteolytic enzymes 3°/0. An estimate of the prevalence of specific types of occupational asthma in the United States for the years 1969-1970 indicated that in the cotton industry the prevalence of byssinosis was approximately 25 010 among the workers in the carding process and 12 010 among spinning workers (8). About 5°/0 of the workers exposed to volatile isocyanates develop asthma. The prevalence of asthma among workers exposed to proteolytic enzymes was estimated to be between 10 and 45 010. Epidemiologic studies of workers exposed to grain dust, including millers and bakers, have reported asthma prevalences between 2 and 40 010 (84).
It lS clear, however, that in any individual plant or industry, prevalence depends on factors such as type, source and concentration of occupational exposure, work conditions, industrial hygiene factors, climactic influences, and individual characteristics of host response. Wada et al. 54 reported on approximately 2,000 oyster workers from 500 plants in the Hiroshima Bay and found 18.1 010 with bronchial asthma (129). Nakashima conducted a questionnaire survey which included 66.2 {11o of the 9,326 residents of Saka town in Japan, where 70 oyster shops were located, and found a history of bronchial asthma in 2.7 010 of the males and 2.6 1,) 10 of the females (88). The results strongly suggest that the presence of bronchial asthma in Saka town was influenced by the particular type of asthma prevalent among cultured oyster workers.
In certain instances especially high percentages of persons exposed to an occupational inhalant can develop a'sthma. For instance, it has been reported that almost every worker in the power plants along the Mississippi River eventually becomes sensitized to river flies (31). Approximately 70 010 of flight crews dispersing irradiated sterile male screwworm flies develop allergic symptoms (43).
In some cases prevalence may be influenced by economic factors. Ishizaki et al. were able to demonstrate an association between the numbers of reported cases of allergic symptoms in workers exposed to western red cedar dust and the quantity of western red cedar imported into Japan (51). Up to 1960, as little as 10,000 m 3 of western red cedar had been imported into Japan and the imports were limited mainly to the Tokyo and Yokohama-Kawasaki ports. By 1968 imports had increased to 440,000 m 3 and the wood was widely distributed among various ports throughout Japan. Coincidentally with the wide distribution of the wood, cases of western red cedar asthma were reported from all over Japan.

IMMUNOLOGY OF BRONCHIAL ASTHMA
The term "atopy" was first introduced by Coca and Cooke in 1923 to describe a population of patients in which disorders such as allergic rhinitis, asthma, and atopic dermatitis were common (23). Atopic patients were found to have a unique response to intranasal immunizations with certain protein and carbohydrate antigens. They produced high concentrations of skin-sensitizing antibodies which resulted in an immediate type response to skin testing with these antigens (64,105,106,107,108,109,110). Such a reaction was rarely observed in normal (nonatopic) subjects immunized by the same schedule. When the same antigens were given parenterally, both atopics and controls had similar serum antibody responses. Atopic individuals seem more likely to develop allergy to many industrial materials, e.g., enzymes of B. subtilis and gum acacia, than nonatopic subjects. On occasion, however, nona-topics may be more sUISceptible to sensitization (20).
The critical role of immunoglobulin E (IgE) in the pathogenesis of many cases of asthma has been demonstrated by surveys of patients with allergic asthma who show significantly elevated concentrations of IgE, whereas serum IgE is often normal in patients with rhinitis without asthma (49,53,54,61,64,65,119). In 1966 Reid and associates reported skin-fixing antibody activity in the IgG fraction of the sera of several atopic patients (103). It appears that some allergic patients possess a non-IgE antibody which may contribute to tissue changes noted in chronic allergic reactions. It is not clear, however, if they are directly related to acute asthmatic reactions.
Immunologic reactions have been classified into four types (44). In type I, or anaphylactic reaction, IgE antibody binds by its Fc fragment to specific receptor sites on the surface of the mast cell or basophil. Antigen reacts with the cell-bound antibody to form bivalent complexes, and these in turn trigger a series of enzymatic reactions that ultimately result in the release of mediators such as histamine, serotonin, the slow-reacting substance of anaphylaxis (SRS-A), and the eosinophil chemotactic factor of anaphylaxis (ECF-A), which causes the asthmatic reaction. Type II, or cytotoxic type reaction, is mediated by a reaction of the antibody with the surface antigen of cells and the formation of an immune complex. There ts no evidence to suggest that this type of immunologic reaction takes place in asthma. Type III, or Arthus reaction, involves circulating antibodies and depends on the presence of immune complexes capable of activating the complement system and generating certain chemotactic fragments. It is not clear what role this type of reaction has in the pathogenesis of occupational 3JSthma. Type IV, delayed hypersensitivity or "tuberculin reaction," is cellmediated immunity. This type of immunologic mechanism may play some role in certain types of occupationally induced asthma (14).
Different types of asthmatic reactions can be observed following bronchial provocation conducted with specific antigens and under carefully controlled conditions (96,97). The types of reaction fall into three main groups: immediate; nonimmediate or late; and dual or combined reactions, during which both immediate and late reactions occur ( fig. 1). To date at least two forms of immediate and three forms of late asthmatic reaction have been described. The immediate reactions are rapid in development (within 15-30 min) and are relatively short in duration. The immunologic mechanisms regarded as responsible for immediate asthmatic reactions are type I, IgE (long-term homocytotropic) and type I, IgG (short-term homocytotropic) antibody-mediated allergy. The three types of nonimmediate or late asthmatic reaction consist of a reaction beginning about 1 h after antigen challenge and lasting for 2-3 h, (b) a reaction starting after about 3-4 h, maximal 5-8 h, and lasting about 24-36 h, in which there is evidence of a type III precipitating antibody, immune-complex allergic reaction, and (c) a reaction beginning early in the morning which can be recurrent for several days after the challenge even though measurements of forced expiratory volume in 1 s return to pretest levels during the day. These various patterns of late reaction occur in the absence of IgE antibody. The responses of immediate and late asthmatic reactions to therapeutic agents are different. Isoproterenol inhalation causes reversal of the immediate reactions. Corticosteroids have little effeot on immediate asthmatic reactions, whether given systemically or by inhalation, but they are effective in inhibiting late asthmatic reactions. Disodium cromoglycate inhibits immediate asthmatic reactions and may also inhibit certain late reactions or those associated with immediate asthmatic reactions.

BRONCHIAL SMOOTH MUSCLE TONE AND HYPERREACTIVE AIRWAYS
Bronchial smooth muscle tone is maintained through a regulatory mechanism involving the adrenergic and cholinergic nervous pathways. One proposed theory for the development of bronchial asthma suggests the presence of partial or complete blockage (acquired or inherited) of the beta-adrenergic nervous system with resultant bronchoconstriction from unopposed alpha-adrenergic and cholinergic innervations (2,122). Cholinergic innervation through the vagus seems to have the most influence over normal bronchial smooth muscle tone (17). The increased airway resistance produced in sensitized dogs challenged with allergen can be prevented by blockage of either the efferent or afferent nerves of the vagus (45).
Stimulating various receptors causes a striking reflex effect in bronchial motor tone. Damage to the bronchial epithelium, by toxic gases or chemicals, has been shown to expose sensory nerves of airways and result in a lowering of the threshold for activation of their sensory nerve endings (87). Inhaling certain chemicals (e.g., TDI), gases (e.g., S02), or chemically inert dust or mechanically stimulating the mucosa of the airways may stimulate subepithelial (irritant) receptors and cause reflex bronchoconstriction which can be abolished by or prevented by cutting the vagus nerves of animals or by administering atropine sulfate to healthy human subjects (86,87). Histamine also produces bronchial smooth muscle contraction which is abolished by ganglionic blockade or by atropine; this action suggests that cholinergic mechanisms are involved (45,87). Bronchoconstriction will develop to proportionally smaller concentrations of certain inhaled chemicals such as methocholine and histamine in asthmatics than in healthy individuals (45,87,92,93). It has been suggested that increased sensitivity of the "irritant" receptors could be the cause of airway hyperreactivity and it may continue even after exposure has ended. Paine and associates reported evidence of bronchial hyperreactivity in some patients with occupational asthma (94). Seven patients with asthma induced by either western red cedar or isocyanate fumes were greatly benefited by removal from their occupational exposure. Reexamination, however, after a period of up to three years of freedom from exposure showed that their response to the inhalation of methacholine aerosol was still abnormal. ThiJS finding indicated persistent hyperreactive airways that were similar to "nonoccupational" asthma.

INTRACELLULAR NUCLEOTIDES
The beta-adrenergic receptor is closely associated with adenyl cyclase, an enzyme which is present in the plasma membrane of many cells and which indirectly controls processes such as active secretions, transport and the storage of carbohydrate (5, .57). Evidence suggests that stimulating the beta-adrenergic receptor results in a series of intracellular biochemical events which involve the activation of the receptor enzyme, adenyl cyclase, and the production of adenosine 3', 5' monophosphate (cyclic AMP) from adenosine triphosphate (ATP). Cyclic AMP levels are regulated by another enzyme, phosphodiesterase, which degrades cyclic AMP to adenosine 5' monophosphate.
It has been proposed that asthmatic patients do not respond normally to betaadrenergic stimulating agents (5, 122). Consequently, they have lower levels of intracellular cyclic AMP that result in the release of mediators which cause the asthmatic reaction. Additionally, in vitro studies demonstrate cholinergic receptors which regulate a different intracellular cyclic nucleotide pool, cyclic guanosine 3', 5' monophosphate (cyclic GMP) (5). Cholinergic agents such as carbachol or methacholine cause mediator release by augmenting intracellular concentrations of cyclic GMP without any concurrent effect on cyclic AMP. Thus the balance of smooth muscle tone is maintained by the reciprocal activity of the sympathetic and parasympathetic nerve pathways and is influenced by intracellular homeostasis mediated by two different intracellular cyclic nucleotide pools, one being influenced by adrenergic stimulation, the other by cholenergic stimulation. Fig. 2 is a summary of the mechanisms which enhance mediator release.

DISPOSITION AND CLEARANCE OF PARTICLES FROM THE LUNG IN ASTHMA
The site at which aerosol particles contact responding tissue is an important determinant of the nature and severity of resulting damage. With particles 20 fh in diameter, deposition takes place mainly in the upper respiratory tract and secondary bronchi primarily by inertial deposition.

57
nearly evenly between the upper respiratory tract and bronchi, sedimentation by gravity being important in the deeper penetration. Tracheobronchial depositions of particles 1-5 /1, in diameter were found to be higher in asthmatic and bronchitic patients than in nonsmoking subjects, and most of the increase was found in airways distal to the trachea (66). Studies on healthy subjects and subjects with chronic bronchitis have demonstrated that inhaled particles 5 /1, in diameter penetrate deeper in healthy subjects than in bronchitic subjects (125). The nose, with its narrow tortuous passages, is ideally constructed to remove larger aerosol volumes. For particles larger than 10 ,u nasal deposition can approach nearly 100 % provided that flow rate is greater than 18 l/min (48). It has been estimated that there is also a substantial removal of particles in the 2-5 p range. In the larger bronchi, the mucociliary blanket propels particles toward the mouth. Inhaled particles resting on alveolar surfaces are engulfed by macrophages and are passively transported into this film (48). Other lung clearance mechanisms have also been described (48,125).
In asthma the site of deposition of inhaled particles depends on the degree of airway obstruction that is present at any time. In the presence of bronchospasm, airway radius decreases and the deposition is more by impaction, which results in a net effect of more central deposition of all inhaled ma,terial. As bronchial constriction subsides, the particles reach more peripheral airways. During an asthmatic attack the normal pulmonary defenses may be impaired by environmental and occupational agents such as cigarette smoke, air pollution chemicals, and dust. This phenomenon could result in the persistence of antigen within the lung.

MECHANISMS PROPOSED FOR OCCUPATIONAL ASTHMA
Patients with occupational asthma may have wheezing and bronchospasm on the basis of nonallergic as well as allergic processes. Either type of mechanism will cause the airways to become hyperreactive. This airway hyperreactivity can persist for a variable period of time even 58 after termination of exposure to the offending substance. The development of airway hyperreactivity by nonallergic mechanisms has been documented. For instance, Boushey reported that preexposure to the thermal degradation products of polyvinyl chloride meat-wrapping film resulted in hyperreactivity in subsequent challenges to histamine aerosol (11).
Occupational asthma on an allergic basis may develop in an atopic worker with preexisting nonoccupational asthma. Once occupational exposure is terminated in this individual, symptoms will improve, but because of the underlying disease they may not disappear completely. On the other hand, symptoms of nonatopic workers who have no underlying disease and develop asthma at work usually disappear when exposure is terminated. The time frame for the disappearance of clinical and physiological changes may depend on the duration of airway hyperreactivity which was part of the original asthmatic response. Asthma on a nonallergic or irritant basis (mechanical, chemical, reflex, pharmacological) can occur in both atopic and nonatopic individuals (38,84). Terminating exposure will lead. to cessation of asthma in this group after some period of time.
Clinically, occupational asthma can be present in one of several forms. (a) Purely allergic asthma occurs paroxy,smally but is usually associated with symptom-free intervals. The attacks are precipitated by exposure to specific allergens in the workplace and may be immediate, late or dual reactions. (b) Nonallergic asthma is caused by reflex, pharmacological or inflammatory mechanisms (38,84). (c) Complicated asthma includes pulmonary processes such as emphysema or chronic bronchitis in a patient with occupational asthma. There may be other medical complications such as cardiac disease or chronic cor pulmonale. In complicated asthma there is, in addition to reversible airway obstruction, a significant irreversible component. (d) Preexisting nonoccupational asthma may be aggravated by nonspecific irritants at work. (e) Status asthmaticus is a severe form of asthma which does not respond to usual treatment and may lead to acute respiratory insufficiency. It is a medical emergency and requires hospitalization.

PULMONARY PHYSIOLOGY
Pulmonary function testing is essential for the diagnosis of obstructive airway disease. One of the most common tests for measuring changes in expiratory air flow is forced vital capacity (FVC), or the volume of air that can be expired with a forced expiration after a deep inspiratory vital capacity maneuver is made. The volume of air that is expired by the first second is the forced expiratory volume at 1 s (FEV!). Both FEV! and FVC are decreased with obstructive airway disease. FEV! and FVC may also be decreased in restrictive lung disease, but because of a generalized decrease in lung volume and not because of a reduction in air flow. For this reason, FEV! must be related to FVC (FEV\/FVC 0/0). FEV/FVC Ofo is decreased with airway obstruction, but is "normal" in restrictive lung disease. In general most subjects show a FEV\/FVC Ofo of 75 Ofo or greater. This figure may vary with age so that older individuals may have values between 70  of the airways such as asthma and bronchitis and disease associated with the loss of lung elasticity such as emphysema.
Recent evidence suggests that physiological tests which detect air flow changes in the small airways (less than 2 mm internal diameter) may be useful in identifying early disease (69). The resistance of airways smaller than 2 mm in diameter is a small fraction of the total pulmonary resistance, and considerably increased resistance must be present in these airways before any Isignificant change in FEV\ and FVC occurs. Measuring air flow during the latter part of vital capacity has been reported to aid in detecting small airway disease (75). A spirogram formed from these events suggests that the traditional measurement moot likely to be affected would be the maximum midexpiratory flow (MMF), since it is a measure of flow taken at a relatively low lung volume ( fig. 3). The screening tests of 53 smokers showed the only abnormal values to be a reduced MMF and an increased residual volume (75). Airway resistance, specific conductance, FEV\> total lung capacity, and maximum expiratory flow rates were within predicted norms. Other tests used for detecting small airway disease have included measurements of expiratory flow volume curves, closing volumes, and expiratory flows utilizing different density gases (16,70). The sine qua non of bronchial asthma is the reversibility of airway obstruction. The degree of reversibility is assessed by inhalation of a bronchodilator. Reversibility is defined as at least a 15 Ofo improvement in the FEV] , as compared to the baseline value.
OCCUPATIONAL ASTHMA WITH AN ALLERGIC BASIS Many allergenic substances in the work environment cause sensitivity and are associated with reversible obstructive airway disease. Most of these substances are organic in nature and include animal and vegetable compounds. Inorganic chemicals are usually primary irritants in nature, but they can become allergenic perhaps by acting as haptenes. While the exact cause may be identified, the relative importance of specific agents on the overall incidence of occupational asthma is scant. It is likely that many cases are either unrecognized or unrecorded.
of these individuals worked as hairdressers. A detailed examination of five subjects indicated that all reacted to. human dander and two had a positive nasal provocation test to human dander extract. There was a good correlation between the degree of skin reactions in patients and peripheral eosinophila. Positive skin reactions to human dander, even in high dilutions, appeared more frequently in atopic patients, about as frequent as to house dust. There appeared to be no crossallergy with danders derived from dogs, cats, and other animals.
Occupational asthma to proteolytic enzymes have been documented in a variety of workers (32,35,52,83,90,95,98,115,130). Proteases (subtilisins or subtilopetidases) obtained from strains of B. subtilis exhibit enzyme activity over a wide pH and temperature range and are therefore ideally suited for incorporation into household cleaning agents. Occupational exposure may occur among workers handling drums or paper sacks

Substances of animal origin
Workers may come in contact with substances of animal origin that result in asthma (table 1). These substances include animal hair, epidermal squamae, mites, small insects, molds, dander, bacteria, and protein dust (50,79,84,102).
Workers such as shepherds, farmers, jockeys, laboratory and research technicians, animal handler,s, veterinarians, and grooms who come in contact with animals, particularly in poorly ventilated areas, may develop asthma on an allergic basis (4,36,47,79,84). Animal hair and dander or epidermal squamae in themselves can be the causal agents, but mites and other small insects, as well as mold, in the work environment have been implicated (84). Voorhorst reported on a group of workers with human dander allergy (128 of the enzyme and during the preparation or packing of the powders, and the risk of sensitization may also be present during industrial and, rarely, domestic use (7,95). Asthma caused by sensitization to these substances is associated with positive scratch and interdermal tests to the enzyme extract and the presence of specific IgE antibodies (35,84,95). In some studies between 40 and 50 % of workers with moderate to heavy exposure to enzyme dust have become sensitized according to positive scratch or interdermal skin tests. Atopic individuals more often develop asthma or positive skin tests to enzyme extract, but symptoms also occur in nonatopic individuals and those who do not develop skin test reactivity (130).
No evidence of permanent lung damage, as revealed by pulmonary function tests, has been detected in exposed workers whether sensitized or not, but some reduction of gas transfer for carbon monoxide and an increase in alveolar-arterial oxygen tension, supposedly due to small airway obstruction, has been described in a small group of workers (35,95). Recently Musk and Gandevia have reported a loss of pulmonary elastic recoil in workers formerly exposed to proteolytic enzyme {alcalase) in the detergent industry (85).
Adequate dust suppression and preventive measures reduce the prevalence of respiratory symptoms in sensitized workers (131). There is a clear relationship between sensitization and the level of exposure to the powder (90,112). When the condition is recognized, changes in production techniques are indicated. Dust sources can be enclosed, ventilation must be increased, and vacuum cleaning should be used instead of sweeping. Effective respirators have been provided for exposed workers and have substantially reduced the frequency of sensitization.
Inhalation of papain, another proteolytic enzyme, causes emphysema in experimental animals (18). Milne and Brand investigated four food technologists who were occupationally exposed to heavy concentrations of papain dust and developed asthma (80). In two subjects an immediate asthmatic reaction occurred following exposure and symptoms persisted for some months. Pulmonary function tests of the four subjects 1.5 years later showed that two had minimal abnormalities related to bronchial reactivity and the distribution of ventilation.

Other substances of animal origin
A variety of insects such as mushroom fly, aphid, bedbug, locust, bee, housefly, moth, daphnia, Mexican bean weevil, and sewage filter flies have been implicated as causing rhinitis and bronchial asthma (4,30,31,33,43,47,79,84,127). Sensitizing materiaLs include scales and hair which have been rubbed off in flight from the wings or body and have become airborne. Occupational exposure to insect emanations occurs for entymologists, beekeepers, laboratory workers, and mushroom workers. In some instances the majority of workers exposed to insect products can be sensitized. This was the case for workers in power plants along the Mississippi River; they became sensitized to river flies and developed rhinitis or asthma (31).
Sensitization to irradiated male screwworm flies have been reported in 70 0J0 of the flight crews dispersing the flies into infested areas (43). Other sources of occupational exposures include weevils in grain dust, moths in fish bait, mites in house dust, and trypsin dust (33,34,67,120,127,134). Asthma from primitive organisms which live in the sea and attach themselves to the surfaces of oyster shells has been reported in seasonal workers who crush oyster shells in order to obtain the meat (88,129).
The clinical picture of western red cedar asthma has received a great deal of attention. Western red cedar is characteristically different from other woods in its unusually high content of water soluble compounds, including a variety of materials such as tannin, dyes, pitch, resins, and lignins (20). Plicatic acid, a major fraction, is a unique component of western red cedar and has not been identified in any other wood. In provocation tests, plicatic acid produces bronchial reactions similar to that produced by the whole extract and is probably the causative agent (20). Usually the exposed worker first complains of eye and nose irritation with rhinorrhea and nasal obstruction. After some weeks, a cough develops which is usually worse at the end of the day or at night. Subsequently there may be episodes of nocturnal cough or wheezing. Characteristically the symptoms, especially those occurring at night, persist for days or weeks after the cessation of exposure. Symptoms may recur on the first day or evening after return to work but sometimes they do not reappear for a week or more. Diagnosis may be more difficult for workers who have continued exposure with a clinical picture of persistent airway obstruction showing no change over weekends and only partial recovery during absences of 2---4 weeks from work. Diagnosis is not aided by skin testing since immediate and delayed skin reactions to cedar extracts have been inconsistent (40). At present, inhalation tests are the best method for confirming the diagnosis.
Asthma due to grain allergy is found principally in millers and bakers, although it may occur in farm workers handling grain (4,62,67,84,91,95,101). Outbreaks of asthma have occurred in people exposed to a prevailing wind carrying grain dust from neighboring mills (95). The specific antigens responsible for wheat allergy are not known, although it may be a component of the wheat, parasitic fungi such as smut or rust, saprophytes such as aspergillus, or organisms such as wheat weevil and the mite (84,95). Many mill workers have positive skin reactions to mixed flour or weevil extracts but only a minority complains of asthma and a few react to inhalation with weevil extract (95). Prevalence of asthma has ranged from 2.10/0 in a study from The Netherlands to 30 IJ/o in Yugoslavian employees of a mill and some bakeries (84). Other studies have indicated rates of sensitization up to 50 0/0. Often asthma is sufficiently mild to allow workers to continue work. Since in almost 50 % symptoms improve or even disappear, spontaneous desensitization may occur. Pepys has reported dual types of asthmatic reactions in two bakers (96,97). These patients were given immediate prick tests and had serum precipitin antibodies.

Cotton
Byssinosis represents a complex of respiratory symptoms due to exposure to the dust of cotton, flax, or soft hemp; it may vary clinically from acute dyspnea and chest tightness on one or more days of Table 3. Causes of occupational asthma of chemical origin. chromium, vanadium, platinum, tannic acid, gum arabic, traganth, karaya aliphatic polyamines, piperazin, ethylene diamine, penicillin, ampicillin, spiramycin, phenylglycerine, pthalic anhydride, epoxy resins, and isocyanates (4,6,13,14,15,19,26,36,37,38,41,42,55,58,59,63,68,74,99,100,104,111,112,113,121,123,124,132). a work week to chronic and permanent obstructive airway disease (8,10,39,77,78,84,95,101,112). The chief sources of dust occur in the ginnery where seeds are removed from the cotton after it has been picked, in the "mixing room," during the opening of cotton bales, in the "blow room" where the cotton is beaten and blown for the elimination of dust and short fibers, and in the "card room" where carding engines comb the fibers and remove dirt and defective materials (95). Other dusty operations are "stripping," which consists of removing dust and cotton fibers adherent to the wire teeth of the carding engine, and "grinding" the teeth. Respiratory problems are noted in industries employing flax in the manufacture of linen and yarn for rope or in the manufacture of rope, twine, thread, hose pipes, tarpaulins, fishing nets, and clothing (95). Jute is used in the manufacture of carpets, felt, wadding, and in combination with flax for various types of cloth. Sisal is employed chiefly in rope manufacturing.
The diagnosis of byssinosis rests on (a) a history of occupational exposure to cotton or dust of related material, (b) a typical history of chest tightness or ,shortness of breath, particularly on the first day of the work week, and (c) a fall in FEV 1 during the workday or work week (84). The prevalence of the symptom complex seems to be related to dust level and, in particular, to the coarse protein particles rather than to the mineral or cellulose portion of the cotton (84). While it is not clear whether an immunologic response is working in thiJs type of occupational asthma, a pharmacologically active substance which causes constriction of smooth muscles in animal preparations has been identified (29,72,84).

Substances of chemical origin
A variety of chemicals, both simple and complex, is associated with occupational asthma (table 3). In general those with molecular weights of less than 1,000 (micromolecules) are included, for example, paraphenylene diamine, formalin, chloramine, formaldehyde, and sulfathiazole (84 Isocyanates. Isocyanates are widely used in the production of polyurethane, which has application in the manufacture of plastics, foam, surface coating and elastomers, adhesives, and fibers (6,14,15,26,63,84,95,100,110,113,123,124). The four most common isocyanates are toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), naphthalene diisocyanate (NDI) , and hexamethylene diisocyanate (HDI). Occupational exposure to TDI, by far the most significant commercially and toxicologically, may occur during its production in the vicinity of foam-producing machines, during spraying and molding operations, from accidental leakage or spillage of liquid TDI, during bulk or drum handling or drum emptying or leakage from pumps, during disposal of TDI waste, the welding of polyurethane covered wires, the burning of polyurethane products or during the use of polyurethane floor varnish with a TDI activator (95). Exposure to high concentrations, which may occur with accidental spillage, is irritating and causes shortness of breath, chest tightness, cough, wheezing, and occasionally rales. Usually low concentrations are encountered in industry. The mechanism for the development of asthma has not been demonstrated, and it is not completely clear whether the reaction is mediated by a true allergic mechanism, although it seems likely. There does not appear to be any correlation between atopic status and the development of clinical sensitivity. Both reaginic and complement fixing antibodies have been reported in affected subjects, and specific lymphocyte transformation to TDI has been demonstrated (14,63,123). Pepys has described an immediate, late and dual response in workers. The late bronchial reaction was inhibited by cromolyn sodium (96).
Apart from the asthmatic reactions in apparently sensitized subjects, a progressive fall in FEV 1 and FVC through the week and over periods of up to two years has been shown in workers exposed !o levels of TDI below the threshold limit value of 0.02 ppm (100,112). In addition, a high prevalence of cough and sputum production has been demonstrated in workers exposed both acutely to high con-64 centrations and repeatedly to low concentrations (112).
Other chemicals. Pthalic anhydride is an essential chemical reagent in the manufacturing process of a variety of industrial products which include plasticizers, epoxy resins, and paints (59,68). Although the prevalence of sensitization to this chemical is unknown, the occurrence of asthma in exposed workers is cited as an important toxic effect by chemical safety data sheets 1ssued by the Manufacturing Chemists Association (71). Maccia and coworkers reported on clinical sensitization in a worker who developed symptoms of rhinorrhea, lacrimation, and wheezing after exposure to this chemical (68). Positive immediate skin tests and bronchial challenge to pthalic anhydride, as well as a high serum titer of specific IgE (by the radioallergosorbent test), corraborated clinical hypersensitivity.

Metals
Chromium, a potent sensitizer that is us~d in the manufacture of pigments and m tanning, has been reported to cause bronchial asthma (19,27,56,84,116). The hexavalent compound is the most active one chemically and the most widely encountered in occupational health problems. Complex salts of platinum, used in the manufacture of catalysts, in electroplating, in the production of fluorescent screens, in work with jewelry, and in platinum refinery operations, can cause a syndrome of asthma, urticaria, and rhinitis that is known as "platinosis" (37,112). The a,sthmatic reaction may be immediate, late or dual in type and it can be repro-duc~d by inhalation challenge tests (Skin prick tests with low concentrations of chloroplatinates give immediate positive reactions, and late asthmatic reactions are inhibited by cromolyn.) Asthma resulting from nickel sulfate has been reported in nonatopic workers involved in nickel plating (74). The inhibition of tanned red cell hemoagglutination reactions indicated the presence of a specific antibody in the patient's serum.

ASTHMA WITH NO ALLERGIC BASIS
Occupational asthma may occur on a nonallergic basis, either by reflex, pharma-<:ological or inflammatory mechanisms (38,84). Extracts of cotton, hemp, sisal, and flax contain an active bronchoconstrictor or histamine-releasing substance (84,95,112). Histamine-releasing agents and other vasoactive substances have been identified in wheat dust (38,84). Histamine liberation has been proposed as one mechanism by which proteolytic enzymes produce clinical effects (84). Acute bronchospasm as a result of reflex or inflammatory mechanisms has been noted following occupational exposures to sulfur dioxide, ammonia, hydrochloric acid, ozone, nitrogen dioxide, hydrogen sulfide, piperazine, and thermal degradation products of polyvinyl chloride meat-wrapping film (12,38,84). Boushey et al. noted increased bronchial reactivity to histamine aerosol in subjects preexposed to polyvinyl chloride pyrolysis products (11). After a severe inflammatory reaction to an irritating gas such as chlorine, attacks of bronchospasm may occur on subsequent days after exposure to very low concentrations of this gas (74). Other substances causing bronchoconstriction include urea formaldehyde, used in molding sands in metal foundries, and organic phosphate insecticides.

DIAGNOSIS OF OCCUPATIONAL ASTHMA
A careful history is essential for the diagnosis of occupational asthma. Clues for suspecting the possibility of a work-related disease include the abrupt onset of asthma in an adult with no previous history of allergic disease. The worker may note that asthma tends to develop toward the evening and is often better by the next morning. Sometimes the symptoms are only nocturnal, and the clockwork regularity of a nocturnal symptomatology is frequently the only clue. The subject generally improves over the weekend or during vacations. Although the patient may be aware of substances at work that affect him and fellow workers, in some industries complex chemical and engineering processes may liberate substances which the worker is unaware of.
The fact that other workers are not symptomatic does not, in itself, differentiate between a direct irritant effect and an allergic phenomenon. It is helpful to differentiate between an irritant and allergic process. Asthma on an allergic basis more often appears after repeated exposure to the offending allergen. There is a delayed period of exposure at work which lasts several months or several years before the onset of asthma. Only a small proportion of exposed workers is affected if the process is allergic in basis. Once sensitization has occurred, reactions are elicited with very small concentrations of the substance, below those which produce irritation and below those noted for threshold limit values. There may be difficulty in diagnosing a late asthma reaction since the time lapse between development of symptoms and exposure to the provoking agent may obscure the relationship and lead to a diagnosis of nonoccupational asthma or bronchitis.
Physical examination of the worker in the office may not be helpful, but examination at work during exposure can lead to the diagnosis. The patient complains of tightness in the chest, and inspiratory and expiratory wheezes become audible shortly after exposure begins. It is important to remember that chest examination may be normal, particularly for workers whose only symptoms are cough and chest tightness and whose exposure took place several hours previously.
The chest X-ray is usually normal in a vast majority of subjects with occupationally induced asthma. The most frequent positive findings that are not related to complications include hyperaeration, changes in thoracic configuration, decrease in size of heart associated with attenuation of peripheral pulmonary vessels, and prominence of the main hilar arteries.
Peripheral blood or sputum eosinophilia are useful for diagnosis. When airway obstruction becomes chronic, the presence of eosinophilia is helpful in confirming obstructive airway disease on an allergic basis. In a study of patients in a respiratory disease clinic with peripheral blood eosinophil counts greater than 400 cells/ m13 all the patients showed some reversibility of airway disease with bronchodilator drugs and corticosteroids (50). Those with eosinophil counts below 400 cells/mlS had a variable response. Peripheral blood eosinophilia is also present in bronchial asthma caused by nonoccupational sources. Physicians have applied the stop-resume work test in trying to differentiate occupational from nonoccupational causes. After several days away from work the offending allergen will result in a decrease in total blood eosinophil count. This occurrence can be coupled with pulmonary function tests so that the diagnosis will be more definitive. Sputum eosinophils can be recognized rapidly and reliably on unstained specimens (21). It has been reported that bronchial asthma is characterized by 15 0/0 or more of all cells in the sputum being eosinophils (28). In general the presence of eosinophils in the sputum indicates an allergic process, and the numbers possibly bear a rough relationship to the severity of the attack.
Pulmonary function testing is an essential laboratory means for confirming the diagnosis of obstructive airway disease. FVC and FEV\ can be measured on several days while the patient is asymptomatic and not working. Measurements after a work exposure, particularly one associated with wheezing or dyspnea should show a decrement of 10 % or more in FVC or FEV 1 in order to be considered positive, i.e., if a stable base line has been observed. Measurements before and after a work shift, particularly on Mondays or after an absence from work, is frequently revealing. The diurinal variation of FEV 1 is small, perhaps not more than 2-3 0/0. Decreases of 200 ml or more, however, are often seen from 0800 to 1600 in cases of occupational asthma. Malingering can usually be excluded by multiple measurements which vary by less than 50 ml, provided that the test is performed by an experienced technician with a well-calibrated spirometer. Response to bronchodilators such as isoproterenol is also helpful in confirming reversible obstructive airway disease. A 15' % or more improvement in FEV 1 following the administration of bronchodilators suggests rever,sible airway obstruction. Patients 66 with no significant response to bronchodilators generally have an irreversible obstructive pulmonary disease such as chronic bronchitis or emphysema. Thus the bronchodilator response is also helpful in the diagnosis of occupational asthma. In some cases the FEV1 measured before and after work only slightly differs (less than 200 ml). Then a greater change may be noted in MMF. Some investigators feel however that at least a 20-25 0J0 improvement in MMF after bronchodilators is necessary before the diagnosis of reversible airway diseas'e can be confirmed.
Immunologic studies are often not available for specific occupational allergens. It is helpful to establish whether the subject is atopic or not and whether immunologic mechanisms are involved. It may thus be useful to perform skin tests to common allergens such as house dust, danders, grasses, and trees. Skin tests for specific occupational allergens are often unreliable and may result in false positive or false negative results. The3e latter studies are often more useful as corroborative evidence of exposure rather than as specific proof of the etiology of the asthma. Immunologic studies such as a positive Prausnitz-Kustner reaction in the case of ca,stor bean exposure or the demonstration of elevated levels of specific IgE in the presence of pthalic anhydride provides strong confirmation of the allergic nature of the work related asthma (68,76). Complement fixation tests, precipitating antibodies, and lymphocyte studies are other tests reported to be helpful in confirming sensitization (6,123). Unfortunately these may not always be available and are often only performed in university centers.
In cases of doubt, inhalation challenge tests with carefully controlled aerosol concentrations of a suspected agent will establish the diagnosis (1,62,97,118). These tests should be made under hospital conditions when the patient is symptom-free, and a very careful control of dosage is necessary if dangerous bronchial reactions are to be avoided. It is important that the investigator use a reliable control aerosol prior to the administration of a specific occupational allergen in order to assess the contribution of nonspecific bronchoconstriction.
Methacholine challenges may be useful in assessing the bronchial reactivity of symptom-free individuals with occupational asthma. In order to identify workers with underlying hyperreactive airways, one could use a provocation test employing methacholine to screen workers who may be exposed to known asthmaprovoking hazards (38,94). Methacholine hyperreactivity, by itself, should not be regarded as disqualifying, however, since some subjects with asthma can work with allergenic agents without difficulty. The demonstration of exaggerated bronchial reactivity in individuals removed from industrial exposure could indicate a latent asthmatic state and may indicate a need for long-term follow up.
TREATMENT AND PREVENTION Individuals found to have occupational asthma on an allergic basis should be removed from work since even low concentrations below the threshold limit value can provoke an asthmatic reaction. In addition, repeated exposure can, in some cases, lead to irrever,sible obstructive airway disease. High concentrations of allergen could result in acute severe asthmatic reaction and death. Therefore, once sensitization occurs, an individual shouhd be removed from work and have no further exposure. Industrial hygiene considerations are important. Attempts to follow threshold limit values are extremely important to the reduction or prevention of sensitization. It is imperative that safety measures concerning handling procedures, avoidance of spills, protective equipment, and good housekeeping procedures be instituted. Increasing the effective control of environmental inhalants by modern industrial hygiene techniques makes it possible for many workers to remain in an improved occupational environment.
Engineering dust and vapor suppression is the most effective way of lowering the average concentration of the incriminated inhalant. The most difficult exposure to control is a short, intermittent, peak level which generally results from some equipment or occupational malfunction. While respiratory protection is useful, in some instances it is difficult to apply prior to the time that such an exposure occurs. The cotton industry provides an important example of how experimental alterations of manufacturing processes, such as washing and steaming the cotton prior to its early processing, can have an important modifying effect on the production of disease and can lead to its prevention. Changes in product formulation can be used in reducing exposure to inhalants. This method has been employed by the detergent industry where the proteolytic enzyme portion of the product was made less dusty by encapsulation procedures.
Since some agents such as isocyanates can produce a decrease in pulmonary function with chronic exposure, periodic medical surveillance which includes respiratory questionnaires, pulmonary function testing and, possibly, eosinophil counts are necessary for the identification of early disease or individuals with few or no symptoms.
The drug treatment of occupational asthma is similar to the treatment of nonoccupational asthma. Oral and aerosol bronchodilators such as theophylline and isoproterenol are the mainstay. Several new beta-adrenergic agents such as terbutaline and allupent are effective. Corticosteroids may be helpful for the treatment of an acute severe reaction. Cromolyn has proven effective in certain instances.

SUMMARY
There are immediate benefits when one can establish the diagnosis of occupationally induced asthma. It is a man-made disease and is thus reversible. Diagnosis depends on knowledge of the source and types of exposure which can be correlated with the clinical, physiological and immunologic patterns of affected workers. The discovery of one case can often lead more readily to recognition of others. Individuals with asthma of an occupational origin should be removed from work. Equally as important is the initiation of proper industrial hygiene procedures which would improve the occupational environment and periodic medical sur-veillance of workers for the identification of early disease or individuals with few or no symptoms.