Clinical Management When the Environment Can Be Changed

Clinical Management Can Be Changed*

When the Environment

Charles E. Reed, M.D., F.C.C.P.

HDI = heumethylene cliisoeyanate; HEPA = high-elliciency particle &Iter; MDI= methane diisocyanate; BAST= radioallergosorben test; RIA= radioimmunoassay;

=

TDI tolueoe diisocyanate

W

hen the question of changing the environment as a means of treating occupational asthma is considered, the factory is the patient and the concern is not the disease pathophysiology but the manufacturing process. Industrial hygiene is the discipline that treats factories, and a fundamental principle of this discipline is that the toxicity of an airborne chemical is related to its concentration in the air. Furthermore, successful recognition of the risk and longterm control of occupational exposure require measurement of the concentration at appropriate work sites and monitoring clumges in the concentration over time. Traditionally, industrial hygiene has focused on toxic chemicals and has developed exquisitely sensitive assays using gas chromatography and mass spectroscopy. Application of these analytic techniques to chemicals that cause occupational asthma, for example, toluene diisocyanate (TDI), has enabled investigators to correlate air concentration with disease and to establish threshold limit values for the toxic effects of TDI in normal subjects and to estimate the concentrations, I to 20 ppb, that may elicit symptoms of asthma in patients who are sensitized.• Equipment for monitoring diisocyanate concentrations is widely used. One approach to reducing the problem of TDI-induced asthma has been to substitute less volatile diisocyanate, such as diphenyl methane diisocyanate (MDI) and hexamethylene diisocyanate (HDI). Thus, in the plastics and paint industries, it has proved feasible in many applications to substitute MDI or HDI for TDI in an attempt to reduce the risk of occupational asthma. Although this approach is intuitively plausible and anecdotally seems effective, there is as yet no convincing evidence that these other diisocyanates are less sensitizing. Certainly they can cause asthma or hypersensitivity pneumonitis. a.• These analytic principles of industrial hygiene apply to all occupational lung diseases, not only those associated with organic chemicals. It is quite feasible to quantify the concentrations in the air of high molecular weight aeroallergens. The 3 technical requirements for these measurements are (I) a high volume air sampler, (2) a filter medium that permits high ftow rates and efficient elution of the allergens in small volumes of buffer, and (3) sensitive RIAs for the allergen. In recent years, we have refined all 3 of these components into a practical system suitable for area sampling. 4 •5 Fbr convenience and to avoid overloading the filter, an automated cassette for changing the filter at appropriate *From the Department of Medicine, Mayo Clinic, Rochester, MN. &print requem: Dr. Reed, Mayo Clinic, Rochester; MN 55905

218S

intervals is available. If airborne concentrations of the allergens ~ high and ifsensitive, 2-site RIAs are available, it is quite possible to employ personal samplers to measure individual exposures during particular tasks. In principle, any allergen can be assayed by RAST inhibition providing that reference standards can be prepared and IgE antibodycontaining sera identified. Similar inhibition assays can use either IgG or human or rabbit polyclonal antibody.• ~ have used them for humidifier scum antigens, Aspergillus fumigatus, and storage mites. 8 Two-site immunoassays with monoclonal antibody to different epitopes of the allergen are available for a few allergens. The advantages of RAST inhibition assays are assurance that the allergens responsible for the sensitization are being measured and that the antibody usually is available for the asking from sensitized workers. The advantages of 2-site assays using either polyclonal or monoclonal antibodies are greater sensitivity and a greater working range of concentrations, and, for monoclonal antibodies, continuity of a consistent, dependable reagent with appropriate specificity. Assays for many occupational allergens have been applied to specific work sites as an aid to confirming exposure and controlling the environment (Thble I).

Chilled-water air conditioner or humidi&er slime: textile manufacturing plants, office buildings Insects Honey bees: honey packing houses Blowflys: research laboratories Cockroaches: research laboratories Mites Storage mites: dairy barns, grain dust Animals Rats, mice, guinea pigs: laboratory animal quarters Cows: dairy barns Parakeets: bird breeding rooms Hen's egg protein: egg processing plants Microorganisms Aspergillus fumigatw: dairy barns Thermophilic actinomycetes: dairy barns Enzymes Esperase: detergent packaging Papain: meat packing Bromelain: clinical laboratory Plants Ragweed: dairy barns Grass Soybean: grain dust 'lbmato pollen: greenhouses

Workshop on Envllonmenlal and OocupellonaJ Alit-.

of the pollutant and the rate of its removal . The general mass balance equation describing the ratio is: C = PQ,C.+S " E,Q. + K + NEdQd en represents steady-state concentrations; the numerator represents the rate of generation of allergen; the denominator represents the rate of removal. PQ,.C. is the outdoor source term; P is an empirically derived penetration factor, which for respirable-sized particles can be assumed to be I. Q. equals ventilation rate; C. is outdoor concentration. For occupational allergens, the outdoor source term is 0. S is indoor source substance generation rate . It has two components, ck novo generation into the air and resuspension of settled allergen from dust. E.Q. is removal by ventilation. E, is ventilation efficiency, calculated from the ratio of the concentration in the exhaust air to concentration in the occupied space divided by a mixing factor. In spaces where air is recirculated and mixing is good, E. can reasonably be assumed to be I. Q. is ventilation rate. K is natural decay rate (settling for particulates). NEdQd is removal rate by air cleaning; N is cleaner removal efficiency; Ed is device ventilation efficiency analogous to E.; and Qd is device flow rate . Reduction in steady-state concentrations can be achieved by 3 different strategies: (1) reduced source generation or aerosolization, (2) increased ventilation, and (3) air filtration. The choice of 1 of these strategies or of a combination of them depends on the particular situation. Several examples

FIGURE 1. Spray wash air conditioner at a nylon plant at time of intervention.

The aim of controlling exposure is to reduce the concentration of the allergen in the air below the level that causes disease. Control also requires identification of the allergen to be controlled, but discussion of identifying the allergen is beyond the scope of this presentation. In principle, 2 levels of allergen need to be considered: the level that initiates the sensitization in the first place and the level that elicits reactions in already sensitized subjects. Unfortunately, reliable information about either of these levels is still unavailable for most allergens, but it appears that in general, sensitizing levels are considerably higher, and occasional very high levels (for example, spills of TDI) are particularly likely to sensitize. After sensitization has occurred, much lower levels can elicit reactions. For diisocyanates and similar chemicals, the eliciting level is of the order of I to 30 ng/m3 . From what we know about protein allergens, they appear to fall in this same order of magnitude. Therefore, the goal of allergen abatement is to control both the occasional peak concentrations and the usual steadystate concentration. Preventing spills or other accidental reasons for occasional high concentrations is usually a matter of design of the manufacturing, cleaning, and air-handling equipment and its proper maintenance. The main focus of this presentation is on control of steady-state concentration of allergens. The steady-state concentration of any indoor air pollutant is determined by the ratio between the rate of production

FIGURE

2. The same spray wash air conditioner after intervention. CHEST I 98 I 5 I NOVEMBER, 1990 I Supplement

217S

Air-Borne Antigen (11/77-11/79)

these changes were effected, no new cases of hypersensitivity pneumonitis developed and newly hired workers did not develop antibody, although the original workers' antibody levels declined very slowly. From these observations, it is possible to estimate roughly the allergen concentrations required to sensitize (100 to 1,000 n!¥m3) and to elicit symptoms (1 to 10 n!¥m3 ). Eradication of the source was possible in this and similar cases because the allergen was not necessary to the purpose of the plant. 7 •8 When the allergen is an integral part of the product, such as Bacillus subtilis enzyme in the detergent industry, eradication is not an option, and other means of reducing the amount of airborne allergen must be sought. Th reduce the concentration of the enzyme, the process was altered to reduce dust generation, and although it was not possible to eliminate the allergen from the air entirely, concentrations were greatly reduced. •

1.5 1.3 1.1 .9

.7 .5 .3

.1 1979

1978

Date

VENTILATION AND AIR FILTRATION

FIGURE 3. Airborne levels of slime allergen during the period after intervention in November 1978 at a similar plant with the same design of air conditioners as in Figures 1 and 2.

In some occupations, the source of the allergen cannot be controlled. An example is laboratory animal handling where the source is the animal itsel£ In this occupation, ventilation and filtration techniques are the only ones that are feasible. Our measurements indicate that male rats shed very large amounts of urinary allergens into the air, about 20 nwmin per animal. In a typical animal care room with ventilation above the recommended ventilation rate of 15 changes of air per hour, the concentration of rat urinary protein allergen ranged around 100 n!¥m3 • In a room with only 30 animals and relatively low concentrations of allergen, doubling the air exchange ratio by recirculating air through a highefficiency particle filter (HEPA) reduced the concentration 50%. In a similar room with 300 animals, however, the HEPA filter bad a negligible effect because the allergen production rate was so high, about 6 IJ.Wmin. To reduce the steady-state allergen concentration in such a room effectively required increasing the filtration with laminar ftow isolation cages to 172 changes of air per hour ('Thble 2). This is about 100 times the air exchange rate in most homes and offices. It appears that it will rarely be feasible to remove allergen by increasing ventilation or air filtration rates in laboratory animal quarters to provide levels that will not elicit symptoms in sensitized workers. Instead, workers can use indi-

will illustrate the application of these principles. ELIMINATING THE SouRcE

An outbreak of hypersensitivity pneumonitis occurred in employees of nylon manufacturing plants who worked in areas supplied by air from a chilled wateN:OOiing and humidification system. 7 They and most of their fellow workers developed antibody to allergens extracted from the slime growing in the water reservoirs of this system (Fig 1). Inhalation challenge with these allergen preparations reproduced an acute episode of the disease. A number of engineering changes were made, including carefully controlled chlorination of the water. The slime was eradicated (Fig 2). Airborne concentrations of the slime allergens declined rather slowly because of considerable residual material in inaccessible ducts, but eventually the concentration inside the plant was reduced, and the goal of keeping indoor levels below outdoor levels was achieved (Fig 3). Parenthetically, these allergens, which arise from a variety of organisms, are ubiquitous, being detectable at low concentrations in outdoor air and any stagnant water. After

Table 2-Calculated tmd Meaaured Airborne Bat UrintJry Allergen (fl(!/rrr)

Room No

Rat Count

1034 1023 1031C 1031C 1022 1022 1022

300 300 30 30 275 275 275

Room Size (m•) 100 80

34 80

Air flow (m3/min)*

Rat Urinary Allergen

v

F

75 43:j: 16 16 43 43 43

212 0 0 17 0 17 34

Air Changeslh

Calculatedt (X±SD)

Measured (X±SD)

172 30 18

20 146:j: 57 29 134 94 72

18±7.2 803±282.0 47±25.7 26± 12.5 216±56 208±217 114±92

36

30 43 56

*V =ventilation, F = <ration (HEPA) tCalculated from the fOrmula C = S + V + F, when S, the source, is the number of male rats X 20 nglmin, V is ventilation rate, and F is <ration rate. See text. :j:Indicates designed ventilation; actual ventilation was much less because exhaust vents were inadvertently occluded.

2185

Workshop on Environmental and Occupational Asthma

Table 3-Maimum Concentrationa of Aeroollergana in \&rioua LocGtiona

Agent

Micropolyspora foeni Thermooctinomyces vulgaris Aspergillus fumigatm l.ollum perennae Lepidoglyphus tlestructa

Approximate Concentration (IJ.!Vm•) 2,700 187

1.2 0.085 12

Location Dairy barn during

bedding chopping Dairy barn during bedding chopping Quiet dairy barn in winter Quiet dairy barn in winter Quiet dairy barn in winter

{storage mite)

Mus musculus urinary

0.06

Animal quarter

protein

Rattus norvegicus

1.2

Animal quarter

urinary protein Guinea pig urinary protein

17

Animal quarter

Bos domesticus

16

Quiet dairy barn in winter

epithelium Egg albumin Papain Esperase Humidifier slime protein

50 5 0.18 15

Egg processing plant Meat processing plant Detergent packing plant Nylon production plant

vidual protective equipment, which has been reported to reduce allergic symptoms and anecdotally is useful in many situations. 10 Also, it is possible to provide work stations with air flow characteristics that minimize exposure during specific tasks. In theory at least, full protective equipment with an outside air supply could be useful but does not seem a practical solution. A third example illustrates the problem more than the solution. \\brkers in plants where raw eggs are processed into liquid or powdered egg products may develop asthma from allergy to inhaled egg white protein. 11 •12 These plants process 1.5 million eggs a day. In a continuous operation, the eggs are cracked, the shells blown away, and the whites separated from the yolk. Uquid whole egg or the separated egg white and yolk are pumped to refrigerated storage. Subsequently, the liquid is pumped through high-pressure spray nozzles into a drying oven. The dried product is picked up by a vacuum and transported to a cyclone separator, sifted, and packaged. Workers are exposed to aerosolized liquid egg products in the transfer and breaker rooms and to powdered egg dust in the drying area and packaging room. Immunoassay of air samples in such a plant showed extraordinarily high levels of egg protein, 50 J.Lg/m3 of ovalbumin, 11 J.Lg/m3 of ovomucoid, and 2 J.Lg/m3 oflysozyme. Concentrations of various allergens in other environments are listed in Thble 3. In egg processing plants, appropriate means of reducing exposure have not yet been devised. The plants supply filtered air to the breaking and packaging rooms to maintain positive pressure in accordance with US Department of Agriculture guidelines. Total dust levels are in accord with accepted values for nontoxic nuisance dusts but are clearly much too high for a potent allergen. Even increasing ventilation tenfold is not likely to be able to keep

up with this extraordinary source. Major changes in the design of the egg cracking and transferring equipment will be required to prevent aerosolization of the egg proteins into the working environment. CoNCLUSION

The principles of dealing with working environments where occupational respiratory disease occurs are no different when the disease is asthma than when the disease is pneumonoconiosis or any other respiratory illness. The choice of abatement strategies depends on the particular process, the physical structure of the equipment, and the rate of aerosolization of the allergen. When feasible, primary effort should be placed on preventing aerosolization. Increased ventilation and air filtration are feasible only when allergen production rate is low or localized to areas where exhaust fans can remove it before it reaches the workers' breathing zone. REFERENCES

1 National Institute for Occupational Safety and Health. Criteria for a recommended standard. Occupational exposure to diisocyanates. US Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control, 1978:78215 2 Grammer LC, Eggum P, Silverstein M, Shaughnessy MA, Liotta JJ, Patterson R. Prospective immunologic and clinical study of a population exposed to hexamethylene diisocyanate. J Allergy Clin Immunol1988; 82:627-33 3 Malo JL, Ourmet JL, Cartier A, Levitz D, Zeiss CR. Combined alveolitis and asthma due to hexamethylene diisocyanate (MDI). J Allergy Clio Immunol1983; 72:413-19 4 Swanson MC, Agarwal MK, Reed CE. An immunochemical approach to indoor aeroallergen quantitation with a new volumetric air sampler: studies with mite, roach, cat, mouse, and guinea pig antigens. J Allergy Clio Immunoll985; 76:724-29 5 Reed CE, Swanson MC, Agarwal MK, Yunginger jw. Allergens that cause asthma: identification and quantification. Chest 1985; 87S:40S-44S 6 Campbell AR, Swanson MC, Reed CE, May JJ, Pratt DS. Aeroallergens in dairy barns near Cooperstown, NY and Rochester, MN. Am Rev Respir Dis 1989; 140:317-20 7 Reed CE, Swanson MC, Lopez M, Ford AM, Major J, Witmer WB, et al. Measurement of IgG antibody and airborne antigen to control an industrial outbreak ofhypersensitivity pneumonitis. J Occup Med 1983; 25:207-10 8 Woodard ED, Friedlander B, Lesher RJ, Font W. Kinsey R, Hearne Fr. Outbreak of hypersensitivity pneumonitis in an industrial setting. JAMA 1988; 259:1965-69 9 Agarwal MK, Ingram .Jw. Dunnette S, Gleich GJ. Immunochemical quantitation of an airborne proteolytic enzyme, esperase 14, in a consumer products factory. Am Ind Hyg Assoc J 1986; 47:136-43 10 Muller-Wening D, Repp H. Investigation on the protective value of breathing masks in farmer"s lung using an inhalation provocation test. Chest 1989; 95:100.00 11 Smith AB, Bernstein DI, 1lu-Ching AW, Gallagher JS, London M, Kopp S, et al. Occupational asthma from inhaled egg protein. AmJ Ind Med 1987; 12:205-18 12 Bernstein DI, Smith AB, Moller DR, Gallagher JS, lili'-Ching AW, London M, et al. Clinical and immunologic studies among egg-processing workers with occupational asthma. J Allergy Clin lmmunol1987; 80:791-97

CHEST I 98 I 5 I NOVEMBER, 1990 I Supplement

219S