Medical Unit - Treatment guidelines occupational asthma

(adopted July 20, 1995)

Asthma related to workplace exposures can be classified into the following two major types:

1. Occupational asthma
2. Work-aggravated asthma

Occupational asthma is a condition characterized by respiratory symptoms, variable airflow limitation and/or airway hyperresponsiveness caused by exposure to an agent(s) in the workplace. Occupational asthma can be due either to sensitizer or irritant agents. Work-aggravated asthma occurs when asthma that was present prior to employment at a specific job is aggravated by exposure to an agent(s) in the workplace.

Asthma is a condition that is characterized by recurrent exacerbations interspersed with periods of relative remission. The dynamic nature of the disease must be considered both at the time of initial assessment and during treatment. The primary principle of management of occupational asthma or work-aggravated asthma is prevention of exposure to the causative or aggravating agent(s) at the workplace.

Scope of the guideline: This guideline deals with the assessment and treatment of occupational asthma and work-aggravated asthma. Because causation and work-relatedness are fundamental to the diagnosis of either occupational asthma or work-aggravated asthma, this guideline will deal with these issues.

A physician may vary from these rules if in the judgment of the physician, variance is warranted to meet the health care needs of the patient and that variance remains within the standards of practice generally accepted by the health care community, and the physician documents the need for the variance in the evaluation report or the medical treatment record in the manner that is generally accepted by the health care community.

Not every medical situation can be addressed in these regulations and medical standards change constantly. The documentation required of the physician is necessary to monitor and explain the use of variances.

I. Initial assessment

A. Purpose

The purpose of the initial assessment is to establish the clinical database upon which the diagnosis of asthma and the likelihood of work-relatedness will be based. The essential elements to the initial assessment include the following: 1) the presenting symptoms; 2) a detailed understanding of the circumstances of the onset of the illness; 3) the course of the illness; 4) past medical history, including risk factors for airways disease; 5) occupational and environmental exposure history; 6) physical examination; 7) selection of appropriate laboratory or field tests; 8) information about exposure(s) from the workplace or other sources.

B. Appropriate assessment methods

1. History and physical

A key feature of the history in patients with asthma is the generally episodic nature of respiratory symptoms. The most common symptoms are cough (productive or nonproductive), wheezing, chest tightness, and shortness of breath. Some patients with occupational asthma who have been exposed to the causative agent(s) in the workplace for a long time may have chronic symptoms. Even these patients will generally experience some improvement of their symptoms when removed from exposure to the causative agent(s) for a period of several weeks. Nonspecific airway hyperresponsiveness to a variety of stimuli such as exercise, cold air, and irritants is characteristic of asthma and simple questions about the effects of such stimuli should be asked.

Another feature of the history is whether a latent period occurred (i.e., an asymptomatic period of weeks, months, or even years after exposure started before the onset of the illness). Sensitizer-induced occupational asthma typically involves a latent period, while asthma induced by high-level irritant exposure does not involve such a period.

Patients and their health care providers may not always recognize the early symptoms of occupational asthma. The temporal relationship between an exposure and the onset of symptoms is highly variable (see Appendix 1). Evidence for remittance of symptoms with weekends, vacations, or change of job tasks should be sought.

In addition to asking the patient about his/her past medical history, every effort should be made to obtain copies of previous medical records, including records of workplace medical surveillance programs. The patient should be questioned about childhood respiratory problems, frequency of "colds" or episodes of "bronchitis," childhood asthma, allergies (including eczema and "hay fever"), previous pneumonia, or other serious respiratory illness. The smoking history should include the packs per day and the years smoked. The cumulative tobacco smoke exposure should be expressed in terms of total pack-years. The patient also should be questioned as to any history of cardiovascular problems and whether or not the patient currently has cardiovascular symptoms.

A complete chronological occupational history is desirable since previous jobs may have involved sensitizing or irritant exposures. A more detailed understanding is needed of the job held by the patient at the time of the onset of his/her respiratory illness and of all processes at the workplace. Particular attention should be paid to processes that transfer materials from one contained space to another, that disturb a potential allergen reservoir, and that involve two-component paints, coatings, adhesives, foams, or products that must be mixed immediately before use. Recognized exposures should be listed along with the presence and type of ventilation and/or respiratory protective equipment. The effects of work process changes on symptoms should be explored, as well as the occurrence of fires or spills. Routine tasks such as maintenance and clean-up should be clarified, in addition to episodic tasks.

Non-occupational environmental exposures such as the presence of pets in the home or the use of potentially sensitizing or irritant materials in hobbies or crafts should be discussed.

The physical examination should be directed to both the upper and lower respiratory tract. Rhinitis and/or sinusitis frequently coexist with asthma, whether the asthma is sensitizer or irritant-induced. Thus, the nasal mucous membranes and pharynx should be inspected and the sinuses palpated. The presence of conjunctivitis may be due to either sensitizer or irritant exposure. Pharyngitis is more likely to be a sign of irritant exposure. The neck should be auscultated for stridor. Auscultation of the chest during quiet breathing and forced exhalation should be performed with notation made of wheezes, rhonchi, or crackles.

Examination of the cardiovascular system should be performed to rule out a non-respiratory cause of the patient's symptoms. The skin should be inspected for evidence of thermal or chemical burns and for eczematous dermatitis which can accompany allergic asthma. The extremities should be inspected for clubbing, cyanosis, and edema. Examination of other organ systems should be guided by the history.

It is important to recognize that the physical examination of a patient with occupational or work-aggravated asthma is often normal when the patient is away from the causative or aggravating workplace exposure.

2. Laboratory or field testing

Objective evaluation of asthma should begin with the first visit.

a. Spirometry

Spirometry should be performed before and after inhaled beta-agonist bronchodilator administration to look for reversible airflow limitation at the time of the initial assessment. A greater than 12 percent improvement in forced expiratory volume in 1 sec (FEV1) with an absolute value increase of greater than 200 ml after bronchodilator is considered evidence of reversibility of airflow limitation. Spirometry should be performed using equipment and techniques that meet the criteria of the American Thoracic Society.

If available, spirometry performed before and after the workshift ("cross-shift" spirometry), or at the end of a period off work and again after a period back at work, may document work-relatedness of occupational asthma or work-aggravated asthma. Cross-shift spirometry, although specific, is not always sensitive for occupational asthma, in part because late asthmatic reactions which occur after work will not be detected across a single shift.

b. Nonspecific challenge testing

If spirometry shows no airflow limitation and asthma is suspected, a methacholine or histamine challenge test to look for nonspecific airway hyperresponsiveness is indicated. When the baseline FEV1 is below 70 percent of the predicted value, response to inhaled bronchodilator rather than measurement of airway responsiveness is the appropriate test to establish the diagnosis of asthma. It is imperative that standardized methods be used in the performance of nonspecific challenge tests. The results should be expressed as the provocative concentration to cause a decline in FEV1 of 20 percent (PC20). Airway hyperresponsiveness is present when the PC20 is less than 8 mg/ml methacholine.

If necessary, serial (repeated) nonspecific challenge testing, similar to serial spirometry, can be used to document work-relatedness of occupational asthma or work-aggravated asthma. Airway responsiveness should increase during a period of exposure to the causative agent(s) and to decrease when the exposure ceases.

c. Peak expiratory flow rate

The serial measurement of peak expiratory flow rate (PEFR) is useful in confirming the work-relatedness of occupational asthma or work-aggravated asthma. Measurements should be made at least four times per day for at least two weeks, including both days at work and days off work. With some patients, it may take up to seven to ten days away from work before PEFR improvement occurs. Patients must be trained in peak flow measurement. A minimum of three forced expiratory maneuvers should be recorded and the two best readings should be within 20 L/min of each other or further readings should be made. The best peak expiratory flow rate should be recorded and used for analysis. A greater than 20 percent diurnal variability in PEFR is supportive evidence for the diagnosis of asthma.

d. Specific challenge testing

Specific challenge testing with the putative agent should only be done when the diagnosis cannot be confirmed by other measures. When necessary, specific challenges should be performed in a hospital setting where there are physicians experienced in this type of testing. The possibility of late asthmatic reactions must always be considered when specific challenges are performed.

e. Exercise challenge testing

Most people with asthma have nonspecific airway hyperresponsiveness that leads to exercise-induced asthma (EIA). Therefore, this condition should be anticipated in patients with occupational asthma or work-aggravated asthma. A history of cough, wheezing, chest tightness, shortness of breath, or lack of endurance during or after exercise suggests EIA. Exercise testing should not be done routinely in the investigation of occupational asthma or work-aggravated asthma. However, when doubt about the presence of EIA exists, an exercise challenge can establish the presence of this condition. Spirometry is performed before and after exercise; if a patient has a greater than 15 percent decline in FEV1 from baseline after exercise, then EIA is present.

Methacholine challenge is more sensitive than exercise challenge, even in patients with a history suggestive of exercise-induced asthma (EIA). If it is clinically important to confirm the clinical suspicion that exercise induces bronchospasm, exercise challenge should be performed under standardized conditions of exercise intensity and duration and ambient temperature and humidity in a laboratory with experience in exercise testing; the sensitivity of the test can be enhanced by having the patient orally inhale cold, dry air during exercise.

f. Lung volumes, diffusing capacity and pulmonary exercise

Measurement of lung volumes, diffusing capacity for carbon monoxide, and standard pulmonary exercise testing should be obtained only if indicated by the patient's history or physical findings.

g. Blood work

Certain specific blood tests should be obtained but only if indicated by the patient's history or physical findings. When the physician considers it necessary to obtain certain blood tests, the purpose should be stated clearly. (e.g. Alpha 1-antitrypsin for non-smoker with suspected coexisting chronic obstructive pulmonary disease; arterial blood gasses for patients in whom hypoxemia or hypoventilation with hypercapnea is suspected based on the physical examination; or a complete blood count and/or a sputum culture with sensitivities for patients in whom complicating acute bronchitis is suspected.)

h. Chest imaging studies

Chest radiographs or chest CT scans should be obtained only if indicated by the patients history or physical findings.

3. Information from the workplace

Information that should be requested from the workplace includes Material Safety Data Sheets (MSDSs), industrial hygiene records (including environmental monitoring data), and employee health records. Such information is often valuable in the determination of work-relatedness of asthma symptoms.

C. Inappropriate initial assessment methods

1. Routine blood work

Blood chemistries are not indicated. The total IgE may be elevated but is neither sensitive nor specific.

2. Routine immunologic tests

Skin prick testing with a specific antigen suspected of causing occupational asthma may be useful to document sensitization, but blindly testing the patient with a panel of available antigens is not indicated, unless his/her history suggests the likelihood of multiple allergies. "In vitro " testing for the presence of IgE antibodies against a specific antigen suspected of causing occupational asthma may also be useful to document sensitization, but blindly testing the patient?s serum against a panel of available antigens is not indicated.

D. Diagnosis of occupational asthma or work-aggravated asthma

The diagnosis of occupational asthma or work-aggravated asthma should be based on the following features: 1) the presence of airflow limitation and its reversibility 2) in the absence of airflow limitation, the presence of nonspecific airway hyperresponsiveness and 3) the demonstration of work-relatedness.

1. Requirements for the diagnosis of occupational asthma

a. Diagnosis of asthma

b. An association between symptoms of asthma and work

c. One or more of the following criteria:

i. Workplace exposure to an agent known to cause occupational asthma (see list in reference 9)

ii. Work-related change in FEV1 (greater than 12 percent decline from the pre-shift baseline value) or PEFR (greater than 20 percent diurnal variability on work days but not on days off work)

iii. Work-related change in nonspecific airway responsiveness (a decrease in PC20 that is two or more doubling doses lower than the pre-exposure baseline value)

iv. Positive response to specific inhalation challenge (greater than 15 percent decline in FEV1 from the pre-challenge baseline value)

v. Onset of asthma with a clear association with a symptomatic exposure to an irritant agent in the workplace

Occupational asthma should be diagnosed when a + b + c(ii) or c(iii) or c(iv) or c(v) are present. When a + b + c(i) are present, occupational asthma is likely.

Work-aggravated asthma should be diagnosed when a + b + c(ii) or c(iii) are present and the patient was symptomatic or required medication to control his/her asthma at the time of starting the job in question. When a + b are present and the patient was symptomatic or required medication at the time of starting the job in question, work-aggravated asthma is likely.

II. Initial Treatment

A. Purpose

The most important feature of the treatment of occupational asthma or work-aggravated asthma is to prevent further exposure to the causative agent(s). The medical treatment of patients with occupational asthma or work-aggravated asthma is not different from treatment of patients with nonoccupational asthma. The recommendations of the National Asthma Expert Panel should be followed and are summarized below. Effective management of asthma depends on both pharmacologic and nonpharmacologic measures. In addition to prevention of further exposure to the causative or aggravating agents(s) at the workplace, patient education, a step-care approach to pharmacologic therapy, and objective measures to monitor the severity of disease and response to therapeutic interventions (including serial monitoring of PEFR). The goals of asthma management include the following: 1) to maintain normal activity levels (including exercise) 2) to maintain (near) "normal" pulmonary function 3) to prevent chronic and troublesome symptoms (e.g., coughing or breathlessness at night, in the early morning, or after exercise) 4) to prevent recurrent exacerbations of asthma and 5) to avoid adverse effects from asthma medications. With some patients, it may take several months to achieve these goals.

B. Appropriate initial treatment methods

1. Prevention of further exposure to the causative agent(s)

a. When occupational asthma is caused by a sensitizing agent, the affected worker should be removed from all further exposure to the agent because of the risk of severe bronchospam and even death. Early diagnosis and cessation of exposure have been documented to increase the likelihood of a favorable outcome. Job transfer within the same workplace may be recommended only if low-level secondary exposure that may cause exacerbations of asthma is not anticipated.

b. When occupational asthma is caused by an irritating agent or there is work-aggravated asthma, removal of the affected worker from further exposure is preferred, but exposure control measures such as product substitution, process enclosure, increased local exhaust ventilation, and/or respiratory protective gear may be appropriate on a trial basis. Monitoring of symptoms, medication use, and PEFR should be done during such a trial.

2. Education

Health education is an essential tool in the management of asthma. Patient education should begin at the time of diagnosis and be integrated with follow-up care. A management partnership between the patient and the health care provider should be established, and the patient should be encouraged to understand asthma and to learn and practice the skills necessary to manage his/her disease. The essentials of asthma patient education include the following: 1) key points about the symptoms and signs of asthma 2) characteristic airway changes in asthma (inflammation, bronchospasm, excessive and thick mucus) 3) asthma triggers and how to avoid them 4) how medications work and potential adverse effects 5) demonstration of the correct use of metered-dose inhalers 6) criteria for pre-medicating to prevent onset of symptoms and for initiating treatment after onset of symptoms 7) indications for emergency care; and 8) optimal use of serial PEFR monitoring.

3. Medications

Appropriate medications for the treatment of asthma include inhaled beta-agonist bronchodilators, inhaled corticosteroids, cromolyn sodium, nedocromil sodium, theophylline, and oral corticosteroids. The following step-care approach to the use of these medications has been recommended in non-emergent cases:

a. Step 1 -- inhaled beta-agonist as needed

b. Step 2 -- inhaled beta-agonist as needed and either an inhaled corticosteroid or cromolyn sodium or nedocromil sodium. Inhaled steroids should be used in low doses; i.e. less than 800 mcg of beclomethasone diprionate (BDP) or the equivalent.

c. Step 3 -- in addition to Step 2; higher doses of inhaled corticosteroids (in doses greater than 800 mcg of BDP or the equivalent) should be used plus oral theophylline. Short courses of oral corticosteroids may be used as required for acute exacerbations.

d. Step 4 -- the addition of an oral corticosteroid for maintenance therapy on a daily, or preferably alternate day, schedule.

4. Exercise

The presence of EIA is important to consider when advising patients about work and recreational activities. EIA can be prevented by pre-medication with inhaled beta-agonist bronchodilators or cromolyn sodium or nedocromil. Patients with occupational asthma or work- aggravated asthma should be encouraged to exercise in order to stay physically fit. Their asthma needs to be effectively managed so that they are able to do so.

5. For a more detailed discussion of the staging of asthma and and treatment modalities, the reader is referred to Primary Reference item # 22 (Kleerup,E. and Tashkin, D.).

6. Respiratory therapy modalities when clinically indicated and upon prescription by an M.D. or D.O.

C. Inappropriate initial treatments include, but are not restricted, to:

1. Antibiotic therapy if the patient shows no signs of infection

2. Supplemental home oxygen unless the patient shows signs of hypoxemia (i.e. PaO2 less than 60)

3. Allergy hyposensitization injections

4. Sublingual hyposensitization treatments

5. Oral anti-fungal therapy for "intestinal candidiasis"

6. Chelation therapy

7. Sauna treatments (so-called Hubbard therapy)

8. Home nebulizer administration of bronchodilator medications

9. Acupuncture

10. Other treatment modalities offered or recommended by non-M.D., non-D.O. health care providers .

III. Secondary Assessment

A. Purpose

The purpose of early reassessment is to make sure that the patient with occupational asthma or work-aggravated asthma is being optimally managed according to the guidelines of the National Asthma Expert Panel described above.

The timing of the reassessment depends on the severity of the patient's asthma at the time of the initial assessment. The more severe the disease, the earlier the reassessment should be scheduled. The severity of the patient's asthma should be classified according to the similar guidelines of the National Asthma Expert Panel or the American Thoracic Society.

B. Appropriate secondary assessment methods

The first step of reassessment is a history and directed respiratory tract physical examination. The second step is to review the patient's serial PEFR log/symptom diary, if available. The third step is to perform spirometry. Based on the results of the reassessment, the severity of the patient's asthma should again be classified according to the National Asthma Expert Panel or the American Thoracic Society guidelines.

C. Inappropriate secondary assessment methods (see I.C. above)

IV. Secondary Treatment

A. Purpose

Because occupational asthma or work-aggravated asthma may not resolve with cessation of exposure to the causative agent(s), and asthma, in general, may improve or worsen with time, periodic reevaluation of the management strategy is necessary. The purpose of secondary treatment is to help the patient whose asthma is slow to resolve.

B. Appropriate secondary treatment methods

Depending on the severity of asthma, efforts to improve control of symptoms and improve pulmonary function should be undertaken. Such efforts may include further recommendations regarding the workplace, job transfer or relocation, avoidance of nonoccupational trigger factors, continued patient education, and changes in medications. Medications should be changed following the step-care approach recommended by the National Asthma Expert Panel (see II.B.2 above).

The use of a spacer device may enhance efficacy and reduce adverse effects of inhaled medications.

Effective evaluation and treatment of rhinitis/sinusitis may help to improve control of asthma symptoms.

C. If the asthmatic condition has not resolved or is not under good clinical control with medical management, and all necessary steps to eliminate workplace exposure to the offending agent have been taken, the injured worker should be referred to a pulmonary specialist.

D. Inappropriate secondary treatments (see II.C above)

V. Prevention

A. Purpose

Symptomatic occupational asthma and work-aggravated asthma can only be prevented at the present time through avoidance of exposure to sensitizing or irritating agents and through medical surveillance for early signs of disease.

B. Appropriate preventive measures

1. Avoidance of workplace exposure to asthma-inducing or asthma- aggravating materials.

The list of materials used in a workplace should be periodically reviewed for potential sensitizing or irritating agents. Substitution of other materials that do not contain such agents should be encouraged. If it is necessary to use materials containing known sensitizing or irritating agents, then efforts should be made to reduce exposure of workers by process enclosure, local exhaust ventilation, and/or respiratory protective gear.

If materials containing known sensitizing or irritating agents are used, then environmental monitoring by an industrial hygienist should be performed to document the level of exposure in the workplace. If the measured level is high, then appropriate control measures to reduce exposure should be taken.

2. Medical surveillance

Medical surveillance programs for the detection of early evidence of asthma are appropriate for workplaces where exposure to known sensitizing or irritating agents is likely to occur (e.g., a small animal care facility or a polyurethane foam packing facility). Tests that have been proposed for the surveillance of occupational asthma and work-aggravated asthma include the following: respiratory questionnaires, serial PEFR monitoring, serial nonspecific challenge testing. The predictive value of these proposed surveillance tests has not been adequately studied, but there are some data to support the use of serial PEFR monitoring.

If a medical surveillance program is instituted in a workplace, appropriate intervention to reduce the exposure of workers with early evidence of work-related disease must be incorporated into the program.

3. Public health responsibility of physicians diagnosing occupational asthma

There may be additional workers at risk for occupational asthma in a workplace where one worker has been diagnosed to have the disease. Evaluation of exposures at the workplace and medical screening of other workers may prevent further cases of occupational asthma. Contacting the employer to arrange a visit to the workplace (or to recommend that this be done by a qualified occupational medicine physician or industrial hygienist) is an appropriate first step in this regard.

VI. Primary References

1. American Thoracic Society. Guidelines for the Evaluation of Impairment/Disability in Patients with Asthma. Am Rev Respir Dis 1993, 147:1056-61.

2. American Thoracic Society. Lung Function Testing: Selection of Reference Values and Interpretational Strategies. Am Rev Respir Dis 1991, 144:1202-18.

3. American Thoracic Society. Standardization of Spirometry - 1987 Update. Am Rev Respir Dis 1987, 136:1285-98.

4. Balmes John R., M.D. Surveillance for Occupational Asthma. Occupational Medicine: State of the Art Reviews 1991, 6 (No.1):101-110.

5. Balmes John R., M.D.: Occupational Asthma. West J Med 1992, 157:169.

6. Bernstein David I. Clinical Assessment and Management of Occupational Asthma. In: Asthma in the Workplace. New York: Marcel Dekker.1993, 103-19.

7. Bernstein, I.L., Chan-Yeung, M., Malo, J-L, Bernstein, D.I. Definition and Classification of Asthma. In: Asthma in the Workplace. New York: Marcel Dekker Inc., 1993:1-4.

8. Chan-Yeung, M., Malo, J-L. National History of Occupational Asthma. In: Asthma in the Workplace. New York: Marcel Dekker, Inc., 1993:299-322.

9. Chan-Yeung, M., Malo, J-L. Compendium I - Table of the Major Inducers of Asthma.

In: Asthma in the Workplace. New York: Marcel Dekker, Inc., 993: 595-623.

10. Clark, Noreen M., Ph.D.: Asthma Self-Management Education: Research and

Implications for Clinical Practice. Chest 1989, 95:1110-13.

11. Fabbri, L.M., Danieli, D., Crescioli, S., et al. Fatal Asthma in a Subject Sensitized to Toluene Disocyanate. Am Rev Respir Dis 1988, 137:1494-8.

12. Feldman, C.H., Clark, N.M., Evans, D.: The role of health education in medical management in asthma. Clin Rev Allergy 1987, 5:195-205.

13. Lam,S., Wong, R., Chan-Yeung, M. Nonspecific bronchial reactivity in occupational asthma. J Allerg Clin Immunol 1979, 63:28-34.

14. Liss, G.M., Tarlo, S.M. Peak Expiratory Flow in Possible Occupational Asthma. Chest 1991, 100:63-9.

15. Malo, J-L., Cartier, A., Ghezzo, H., et al. Patterns of Improvement in Spirometry, Bronchial Hyperresponsiveness, and Specific Ige Antibody Levels After Cessation of Exposure in Occupational Asthma Caused by Snow Crab Processing. Am Rev Respir Dis 1988, 38:807-12.

16. Malo, J-L., C?te, J., Cartier, A., et al. How many times per day should peak expiratory flow rates (PEFR) be assessed when investigating occupational asthma. Thorax 1993, 48:1211-7.

17. Malo, J-L., Ghezzo, H., L'Archeveque, J., et al. Is the Clinical History a Satisfactory Means of Diagnosing Occupational Asthma? Am Rev Respir Dis 1991, 43:528-32.

18. Matte, T.D., Hoffman, R.D., Rosenman, K.D., Stanbury, M. Surveillance of Occupational Asthma under the SENSOR Model. Chest 1990, 98(Suppl):173S-8S.

19. National Asthma Education Program Expert Panel. Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung and Blood Institute. National Institute of Health Publication No. 91-3042A, 1991.

20. Sterk PJ, Fabbri LM, Quanjer PHL, et al. Airway Responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J 1993, 6(Suppl 16):53-83.

21. The Occupational and Environmental Health Committee of the American Lung Association of San Diego and Imperial Counties; San Diego, California. Taking the Occupational History. Ann Intern Med 1983, 99:641-51.

22. Kleerup, EC and Tashkin, DP. Outpatient Therapy of Adult Asthma. Western J Med.1995, 63(No. 1):49-63.

Appendix 1: Symptom patterns of asthma suggesting work-relatedness

1. Do symptoms of asthma develop after a worker starts a new job or after new materials are introduced on a job (a substantial period of time may elapse between initial exposures and development of symptoms)?

2. Do symptoms develop within minutes of specific activities or exposure at work?

3. Do delayed symptoms occur several hours after exposures or during the evenings of workdays?

4. Do symptoms occur less frequently or not at all on days away from work and on vacations?

5. Do symptoms occur more frequently on returning to work?