3
Agents, Sources, Source Controls, and Diseases

The indoor environment contains many allergens that can be airborne. They derive from various organic and inorganic sources and may be inhaled as particles, vapors, or gases. Chemically, most are proteins, but low-molecular-weight (LMW) reactive chemicals in industrial settings have also caused allergy. Indoor allergens can be derived from the outside, from the structure or furnishings of a building, or from the humans, animals, and plants within it. Similarly, microbiological aerosols can originate in outside air or in sources within the building.

Biological sources of allergens are surprisingly diverse: they range from domestic animals that shed allergen-containing particles to such sources as food substances dropped on the floor, fungi growing on walls or under carpets, plant materials brought into the house, microorganisms within the air-conditioning system, and a variety of arthropods (in particular, the house dust mite) that may grow within the structure of the house or in the furniture (Table 3-1). Homes, apartment buildings, schools, offices, hospitals, stores, and factories each have unique features that affect the types and quantities of allergens that are present. The major allergenic protein molecules—and in some cases, even the allergenic epitopes—have been identified and characterized in the case of house dust mites, cats, dogs, and certain fungi.

DUST MITE, COCKROACH, AND OTHER ARTHROPODA

House dust (called house dust because most studies have focused on houses—but it also occurs in schools, offices, and other buildings) is made



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Indoor Allergens: Assessing and Controlling Adverse Health Effects 3 Agents, Sources, Source Controls, and Diseases The indoor environment contains many allergens that can be airborne. They derive from various organic and inorganic sources and may be inhaled as particles, vapors, or gases. Chemically, most are proteins, but low-molecular-weight (LMW) reactive chemicals in industrial settings have also caused allergy. Indoor allergens can be derived from the outside, from the structure or furnishings of a building, or from the humans, animals, and plants within it. Similarly, microbiological aerosols can originate in outside air or in sources within the building. Biological sources of allergens are surprisingly diverse: they range from domestic animals that shed allergen-containing particles to such sources as food substances dropped on the floor, fungi growing on walls or under carpets, plant materials brought into the house, microorganisms within the air-conditioning system, and a variety of arthropods (in particular, the house dust mite) that may grow within the structure of the house or in the furniture (Table 3-1). Homes, apartment buildings, schools, offices, hospitals, stores, and factories each have unique features that affect the types and quantities of allergens that are present. The major allergenic protein molecules—and in some cases, even the allergenic epitopes—have been identified and characterized in the case of house dust mites, cats, dogs, and certain fungi. DUST MITE, COCKROACH, AND OTHER ARTHROPODA House dust (called house dust because most studies have focused on houses—but it also occurs in schools, offices, and other buildings) is made

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Indoor Allergens: Assessing and Controlling Adverse Health Effects up of fibers from carpets and furniture, grit and sand particles, human skin scales, and food debris. This mixture is combined with allergens from domestic animals, insects, and a variety of microscopic arthropods, bacteria, algae, and fungi growing within the house and other buildings. In addition, air coming into these buildings can carry pollen and molds from outside that then become part of the dust. Because the occupants of a house are inevitably exposed to house dust, any source of foreign protein in the dust is a potential cause of sensitization. Skin testing of patients with asthma or rhinitis initially utilized extracts made from dust collected from their own house (i.e., autologous dust; Kern, 1921); now, however, commercial extracts of house dust are widely used for diagnosis and immunotherapy. In 1980 the U.S. Food and Drug Administration (FDA) estimated that at least 10 million injections of "house dust" extract were administered annually in the United States. Until 1967, house dust allergenicity was attributed to animal dander, insects, and fungi (Spivacke and Grove, 1925; Vannier and Campbell, 1961). In that year, however, Voorhorst and his colleagues in the Netherlands observed large numbers of mites in dust samples and demonstrated that dust TABLE 3-1 Biological Sources of Allergens in Houses Acarids Fungi* Dust mites Dermatophagoides pteronyssinus Dermatophagoides farinae Euroglyphus maynei Blomia tropicalis Storage mites Inside Multiple species including Penicillium, Aspergillus, Rhizopus, Cladosporium (growing on surfaces or wood) Spiders Outside Entry with incoming air, multiple species Insects Pollens Cockroaches Blattella germanica (German) Periplanetta americana (American) Blatta orientalis (Oriental) Derived from outside Other Crickets, flies, beetles, fleas, moths, midges Sundry Horsehair in furniture, kapok Food dropped by inhabitants Domestic Animals Rodents Cats, dogs, ferrets, skunks, horses, rabbits, pigs Wild: mice, rats Pets: mice, gerbils, guinea pigs * Fungal spores may contain very little allergen and may require germination to produce significant exposure.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects mites of the genus Dermatophagoides were a major source of house dust ''atopen" (Voorhorst et al., 1967). They also developed techniques for growing mites in culture, which made it possible to produce extracts commercially for skin testing. Most patients with positive skin tests to house dust have specific immunoglobulin E (IgE) antibodies to dust mite allergens (Johansson et al., 1971). Sensitization thus can be detected either by skin tests or measurement of serum IgE antibodies. Dust mite sensitivity was found to be strongly associated with asthma by J. M. Smith and colleagues (1969) and Miyamoto and coworkers (1968). Indeed, in some countries (e.g., Brazil, Australia, New Zealand, Japan, the Netherlands, Denmark, and England), sensitivity to dust mites appears to be so common among young asthmatics that other sources of indoor allergens are relatively unimportant (see Arruda et al., 1991; Clarke and Aldons, 1979; Sears et al., 1989; and Sporik et al., 1990). In dry climates, however, such as in northern Sweden and central Canada, and in high-altitude areas (e.g., Colorado), mite growth is poor and domestic animals predominate as the major source of indoor allergens. Humidity enhances the growth of mites in carpets, mattresses, and other household items (Korsgaard, 1983a). In some inner-city areas, cockroach debris or rodent urine may be the dominant sources of allergens in house dust (Bernton et al., 1972; Hulett and Dockhorn, 1979; Kang et al., 1979; Twarog et al., 1976). Many different protein sources thus contribute to house dust allergenicity (see Table 3-1). Heavy exposure to house dust can give rise to sneezing in anyone, and it has been suggested that endotoxins or other substances in dust can be directly toxic. The association between exposure to house dust and diseases such as asthma, chronic rhinitis, and atopic dermatitis, however, has been shown only in individuals who have developed hypersensitivity. The symptoms produced by house dust allergens in sensitized (i.e., allergic) individuals include asthma, perennial rhinitis, and atopic dermatitis. For each disease the symptoms range from severe to very mild; moreover, some individuals, despite their having IgE antibodies, suffer no discernible symptoms. In some cases, the correlation between exposure to a specific indoor allergen and symptoms is obvious; certainly, many individuals who are allergic to cats experience the rapid onset of symptoms on exposure to cat allergens. In contrast, most symptoms related to exposure to house dust are nonspecific and not temporally related to exposure. Thus, in general, it is not possible to distinguish the role of different specific indoor allergen sources solely on the basis of an individual's medical history. Indeed, many patients with asthma are not aware of any other symptoms that would be recognized as allergic. Because their histories are not specific and in many cases exposure to house dust allergens is perennial, understanding the relationship between exposure and disease has required both measurement of exposure and documentation of sensitization.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Dust Mites as a Source of Indoor Allergens Many different species of dust mites have been found in house dust, but the predominant ones in most parts of the world belong to the family Pyroglyphidae: Dermatophagoides pteronyssinus, D. farinae, and Euroglyphus maynei. In Florida, Central America, and Brazil (see Hughes, 1976; Van Bronswijk, 1981; Voorhorst et al., 1967; and Wharton, 1976), several species of storage mites and Blomia tropicalis are important sources of allergens. It is probably best to reserve the term dust mites for pyroglyphid mites and to use the term domestic mites to cover any species of mites that are found in houses (Platts-Mills and de Weck, 1989). Mites are eight-legged and sightless, and they live on skin scales and other debris. They absorb water through a hygroscopic substance extruded from their leg joints and are thus entirely dependent on ambient humidity. In addition, they have a narrow optimal growth temperature range of between 65° and 80° F. As humidity falls, mites will withdraw from surfaces, but even in very dry conditions it may take months for mites in sofas, carpets, or mattresses to die or for allergen levels to fall (Arlian et al., 1982; Platts-Mills et al., 1987). Mites excrete partially digested food and digestive enzymes as a fecal particle surrounded by a peritrophic membrane (Tovey et al., 1981a). Large quantities of fecal particles are found in mite cultures, and they are a major form of the mite allergen in house dust. The peritrophic membrane probably keeps the particles intact; however, chitin is not waterproof; consequently, allergens elute from fecal particles quite rapidly (Tovey et al., 1981b). Mite fecal pellets are similar to pollen grains in size (10–35 μm in diameter), in the quantity of allergen they carry (i.e., ~0.2 ng), and in their rapid release of proteins. Dust mites are approximately 0.3 mm in length. Moving mites can be seen by light microscopy, but the great majority of mites in dust are dead and are therefore difficult to identify without separating them from other dust particles (Arlian et al., 1982; Wharton, 1976). DUST MITE ALLERGENS The first mite allergen to be purified, D. pteronyssinus allergen I (or Der p I; Chapman and Platts-Mills, 1980), is a 24,000-MW glycoprotein that has been sequenced and cloned; it has sequence homology with papain and functional enzymatic activity (Chua et al., 1988). In 1984, high-affinity monoclonal antibodies to Der p I were reported, opening the door to the development of assay systems that would improve the sensitivity and specificity of measurement (Chapman et al., 1984). A second major allergen (MW 15,000) was first identified in 1985 and has now been fully defined,

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 3-2 Defined Indoor Allergens Allergen   Molecular Weight (kDa) Sequence Function Monoclonal Antibodiesa Assay House Dust Mite Group I Der p I Der f I Eur m I 25 25 25 cDNA cDNA Nucleotide Cysteine protease ++ ++ + ELISA ELISA — Group II Der p II Der f II 14 14 cDNA N-terminal Unknown ++ ++ ELISA ELISA Group III Der p III Der f III 29 29 N-terminal N-terminal Serine proteases - ++ RIAb RIAb Cat—Felis domesticus Fel d I   35 cDNA Unknown ++ ELISA Albumin   68 — — ± RIAb Dog—Canis familiaris Can f I   27 — Unknown ++ ELISAb Cockroach Blattella germanica Bla g I   20–25 — Unknown + ELISAb Bla g II   36 N-terminal Unknown ++ ELISA Periplanetta americana Per a I   20–25 — Unknown - — Rodent Mus musculus   19 Protein sequence alpha-2U- + ELISAb Rattus norvegicus   19 cDNA globulin + RIAb NOTE: kDa, kilodaltons; cDNA, complementary DNA; ELISA, enzyme-linked immunosorbent assay; and RIA, radioimmunoassay. a "++" Indicates that more than one epitope has been defined. b Assays in research use.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects cloned, and named Der p II (Chua et al., 1990; Heymann et al., 1989; Lind, 1985). There are homologous cross-reacting allergens produced by D. farinae (Dandeau et al., 1982; Haida et al., 1985; Heymann et al., 1986; Yuuki et al., 1990); see Table 3-2 for current groupings of allergens. The group II mite allergens show greater than 90 percent sequence homology and are very strongly cross-reacting. They are also relatively stable in relation to heat and pH, but they have no enzymatic activity and their function in the mites is not known. Researchers assume that the group I proteins are digestive enzymes because they are found in glands surrounding the gut and are present in high concentrations in fecal pellets (Tovey, 1982). Currently, simple, sensitive monoclonal antibody-based assays are widely used for quantitating group I allergens (Horn and Lind, 1987; Luczynska et al., 1989). Assays for group II (and also group III) are in development. COMMERCIALLY AVAILABLE ALLERGEN EXTRACTS House dust extracts for use either in skin testing or for in vitro assays of IgE antibodies are made from vacuum cleaner bags collected outside the pollen seasons from houses without animals. Other sources for dust (e.g., schools, offices) are not commercially available. The quantity of dust mite allergen in commercial house dust extracts varies from 0.05 to 2.0 µg of Der p I/ml.1 Commercial dust mite extracts can be made from either whole mite culture or from isolated mite bodies. At present, the FDA requires that mite extracts be made from isolated mites. Mites are photophobic; they can be separated by using a light source to "drive" them out of the culture material. Horse dander or human shavings contained in the same media that are used for growing mites may expose recipients of the extract to these proteins. Extracts made from bodies of D. pteronyssinus typically contain 30 µg of Der p I and 20 µg of Der p II. Insects as a Source of Indoor Allergens Many insects have been identified as sources of inhalant allergens in case reports or small outbreaks; these include moths, crickets, locusts, beetles, nimitti flies, lake flies, and houseflies (Ito et al., 1986; Kay et al., 1978; Kino et al., 1987; Koshte et al., 1989). Yet the only insect that has been repeatedly recognized as a common source of indoor allergens is the cockroach (Bernton et al., 1972; Kang et al., 1991; Pollart et al., 1989, 1991). 1   Cat allergen (Fel d I; see later discussion) in house dust extract varies from less than 0.01 to 2 µg of Fel d I/ml; in general, there is no detectable cockroach allergen and little in the way of fungal allergens.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Sources of insect allergens are diverse and may include skin scales from moths and hemoglobin from lake flies or river flies (Mazur et al., 1987). For domestic cockroaches, fecal material and saliva may contribute to the allergen reservoir, and large quantities of allergen can be washed off the outside of the roach. DOMESTIC COCKROACHES The German cockroach Blattella germanica is very common in crowded cities, in the southern United States, and in tropical countries of the world. As early as 1964, Bernton and his colleagues recognized that many patients with asthma who sought treatment at indigent care clinics had skin tests positive for cockroach (Bernton et al., 1964). Positive skin tests have been reported in several urban clinic populations including Boston, New York, Kansas City, Detroit, Chicago, and Washington, D.C. (Call et al., 1992; Hulett and Dockhorn, 1979; Kang et al., 1979). Subsequently, Kang and her colleagues reported positive bronchial provocation and good responses to immunotherapy with cockroach extract (Kang et al., 1979, 1991). In most suburban clinics, few or no patients have positive skin tests to cockroach extracts. A case-control study of emergency room patients confirmed the significant association of cockroach sensitivity with asthma (Pollart et al., 1989). An unpublished study on cockroach allergen levels in houses in different parts of a town showed that the correlation between cockroach sensitization and asthma was restricted to that part of the town in which cockroach allergen was present in the houses (Gelber et al., in press). Researchers have identified two cockroach allergens, Bla g I (MW ∼ 30 kilodaltons [kDa]) and Bla g II (MW 36 kDa; see Table 3-2), and have developed monoclonal antibodies and assays specific for these allergens (Pollart et al., 1991). Details regarding the sources of these allergens, their cross-reactivity with those derived from Periplaneta americana, and the nature of the particles that become airborne are not well established (Swanson et al., 1985). Cockroach allergen can be found throughout the house, but the highest levels are generally found in kitchens. Further work is needed to define the nature of insect allergens, the nature of the particles that become airborne, and their role as indoor allergens. Measuring Exposure to House Dust Allergens The major outdoor allergens are components of well-defined particles (i.e., pollen grains or fungal spores) that are disseminated by wind and that can be identified microscopically. In contrast, indoor allergens come from a variety of particles that are not naturally airborne and that cannot be identified

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Indoor Allergens: Assessing and Controlling Adverse Health Effects microscopically. Thus, evaluation of airborne indoor allergens depends on sensitive immunoassays and requires a method for collecting particles. This can be done either with a filter or with a multistage impactor (Solomon and Matthews, 1988; see also the discussion in Chapter 6). In 1981, Tovey and colleagues (1981b) showed that fecal particles were a major form in which the allergen Der p I becomes airborne and that very little or no (i.e., <1 ng per cubic meter of air) mite airborne allergen was detected in undisturbed rooms (de Blay et al., 1991b; Platts-Mills et al., 1986; Swanson et al., 1989; Yasueda et al., 1989). Furthermore, airborne mite allergen falls rapidly after disturbance. These results support the view that mite allergen is predominantly airborne on particles that are larger than or equal to 10 µm in diameter. The levels found in the air during disturbance depend critically on the form of the disturbance and vary from 5 to 200 ng of Der p I/m3. Assuming that airborne Der p I is carried predominantly on fecal particles, it is possible to estimate the number of particles that become airborne and to an estimate of the number of particles that could enter the lung, since the mean allergen content of the particles is known. Chapter 6 discusses methods of assessing exposure and risk. Thresholds: The Relationship Between Exposure, Sensitization, and Disease Voorhorst and his colleagues (1967) found that dust from the houses of symptomatic allergic patients generally had more than 500 mites/g of dust. During the 1980s, further data accumulated demonstrating a dose-response relationship between exposure to mite allergens (or mites) and both sensitization and asthma (Bernton et al., 1972; Kang et al., 1991; Pollart et al., 1989, 1991). From these results, it also appeared that there were levels of exposure (or thresholds) below which the risk of sensitization or asthma was much less. This finding notwithstanding, the results suggest that in areas in which all houses contain high levels of mite allergen, sensitivity to mites is a major risk factor, not only for wheezing but for hospitalization of children with asthma. Fewer data are available on the levels of exposure associated with sensitization or disease for allergens other than dust mite. However, there are data about the levels of cat allergen present in house dust. Dust from all houses with a cat contains at least 8 µg of Fel d I/g (the levels range as high as 1.5 mg of Fel d I/g). In houses without a cat, levels vary from less than 0.2 µg/g to 80 µg/g; it is thought that this allergen is transported into the houses on the clothes of inhabitants. Levels of cat allergen of less than 1 µg of Fel d I/g of dust appear not to give rise to sensitization or disease. For cockroach allergen the rarity of sensitization among suburban patients suggests that the levels found in suburban houses (i.e., less than 1

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Indoor Allergens: Assessing and Controlling Adverse Health Effects unit of Bla g II/g of dust) are insufficient to sensitize individuals. By contrast, the levels found in inner-city houses (i.e., more than 10 units of Bla g II/g of dust) are clearly sufficient to induce sensitization and appear to be associated with asthma (Gelber et al., 1992; Pollart et al., 1991). There is a general misconception that levels of allergen will be (or should be) higher in the houses of patients with allergic disease than in the homes of nonallergic individuals living in the same area. It is equally likely, however, that levels of exposure are similar for individuals with and without allergic disease in a given region and that differences in individual responses are a function of individual susceptibility. It is important to understand the actual findings. (Chapter 2 presents a brief discussion of exposure to allergens as a risk factor for sensitization.) Because the common allergens are thought to cause or exacerbate asthma by the inhaled route, measurement of inhaled allergen might seem to be the best method for determining exposure (Price et al., 1990; Swanson et al., 1985; Tovey et al., 1981b). There are several reasons, however, why current threshold levels for indoor allergen exposure are based on measurements of allergen in dust collected from carpets, mattresses, sofas, and other such items. First, the quantities that become airborne (commonly, 5–50 ng/cubic meter of air) are too small to measure in epidemiological surveys. Second, the relevance of airborne levels depends on particle size, which is technically difficult to determine. Third, the quantities of these allergens that become airborne in a house depend critically on domestic disturbance. Thus, at present, overwhelming practical reasons exist for basing threshold levels on the measurement of a representative allergen in "reservoir" dust. An index of exposure using these measurements of reservoir dust assumes that they are positively correlated with inhaled exposure. Chapter 6 addresses issues related to assessing exposure and risk and presents a risk assessment for sensitization related to dust mite exposure as an example. Reducing Exposure to Dust Mites Reducing exposure to so-called "trigger factors," i.e., factors that trigger an allergic response, has been a standard part of the treatment of allergic disease for many years, and for many years it was normal practice to recommend avoidance measures to patients who had skin tests that were positive for house dust. This practice was strongly supported by the experiments of Storm van Leeuwen (Storm van Leeuwen et al., 1927) and Rost (1932), who demonstrated benefits to patients with asthma and atopic dermatitis, respectively, from living in a "climate chamber." Until recently, there has been only limited clinical use of avoidance measures in treating allergic diseases associated with dust mite sensitivity, in part because the control measures that were originally proposed were not

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Indoor Allergens: Assessing and Controlling Adverse Health Effects effective in controlling mite allergens (Burr et al., 1980; Korsgaard, 1982). In addition, several general medical tests have suggested that avoidance measures should be considered in patients who have a certain typical history. As discussed earlier, however, many allergic patients are not aware of an association between dust exposure and their symptoms (particularly the association between dust and asthma or atopic dermatitis). Today, there is considerable evidence that full avoidance (i.e., 95 percent reduction of mite allergen) can be achieved and can reduce both symptoms and bronchial reactivity. For example, moving patients to a hospital room or sanatorium has been consistently effective (Dorward et al., 1988; Ehnert et al., 1991; Platts-Mills et al., 1982; Warner and Boner, 1988); these units generally have very low levels of mites (i.e., less than 20 mites/g of dust) and mite allergen (less than 0.4 µg of Der p I/g). Recently, four controlled studies of the effects of avoidance measures conducted in the homes of patients have found significant improvement in both asthma symptoms and bronchial hyperreactivity (Dorward et al., 1988; Ehnert et al., 1991; Murray and Ferguson, 1983; Walshaw and Evans, 1986). Avoidance measures can be divided into those for use in the bedroom and those for use in the rest of the house (Box 3-1). In the bedroom, the following have been shown to be effective: covering mattresses and pillows with impermeable covers; washing bedding at 130°F once per week BOX 3-1 Avoidance Measures for Mite Allergen A. Bedrooms ▪ Cover mattresses and pillows with impermeable covers ▪ Wash bedding regularly at 130° F ▪ Remove carpets, stuffed animals, and clutter from bedrooms ▪ Vacuum clean weekly (wearing a mask)* B. Rest of the House ▪ Minimize carpet and upholstered furniture; do not use either in basements ▪ Reduce humidity below 45 percent relative humidity or 6 g/kg ▪ Treat carpets with benzyl benzoate or tannic acid * There is a temporary increase in potential exposure to allergens associated with the vacuuming process. The net potential for exposure should be reduced by vacuuming, however, and is considerably less than the cumulative effects of not vacuuming. Wearing a mask while vacuuming should help reduce exposure while vacuuming.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects (Miller et al., 1992; Owen et al., 1990); and removing carpets (although Rose and colleagues [1992] have shown that the use of acaricides or tannic acid treatment can also reduce mite allergen). Other control strategies for the bedroom are designed to eliminate sites in which mites can grow and to reduce dust collectors to make cleaning easier. The recent report from NHLBI (1991) is an excellent source of information regarding allergen avoidance. (See also Box 8-1 in Chapter 8.) Three different approaches are possible for control of mite growth in the rest of the house: Design the house with polished floors and wooden, vinyl, or leather furniture to eliminate sites where mites can grow. Maintain indoor relative humidity at below 50 percent (absolute humidity below 6 g/kg). Korsgaard (1983a) has shown that in some areas of the world this can be accomplished by simply increasing ventilation. In other areas, it would be necessary to use air conditioning during the humid months. Use acaricides to treat carpets or furniture, including pyrethroids (D. Charpin et al., 1990b), natamycin (an antifungal), pirimiphos methyl (Mitchell et al., 1985), and benzyl benzoate (Bischoff et al., 1990). In each case the chemicals are effective in killing the mites, although methods for applying the agents may present problems (de Saint-Georges-Gridelet et al., 1988; Platts-Mills et al., 1992). Several different chemical treatments (as in approach 3 above) have been shown to achieve 90 percent reduction in allergen levels for a month or more. In addition, 1 or 3 percent solutions of tannic acid have been recommended for denaturing mite allergens (Green et al., 1989). Again, this method achieves a 90 percent reduction of mite allergen, but because tannic acid does not kill mites, the effect is temporary (i.e., approximately 6 weeks to 2 months). Carpets fitted onto unventilated floors—for example, in basements or on the ground floor of a house built on a concrete slab—are particularly difficult to treat. Under these circumstances water can accumulate either because of condensation onto the cold surface of the concrete or because of leakage (either domestic or rainwater from outside). In either case, once the carpet is wet, it will stay wet and become an excellent environment for the growth of fungi and mites. Avoidance Measures for Other Allergens For most other allergens, only case reports are available as guidance regarding the clinical effectiveness of avoidance measures. Removal is certainly the logical approach to management for most domestic animals or rodents (Wood et al., 1989); if sensitivity to insects (cockroach or others) is

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Indoor Allergens: Assessing and Controlling Adverse Health Effects TABLE 3-4 Characteristics of Syndromes Related to Inhalation of TMA Characteristic Rhinitis and Immediate-Type Asthma LRSS Pulmonary Disease-Anemia Irritant Syndromes Latent period (duration of exposure prior to onset of symptoms) Weeks to months of work exposure Weeks to months of work exposure Weeks to months of work exposure Occurs on first high-work dose exposure Onset of symptoms after work exposure Immediate (minutes) 4–12 hours Progressive with further work exposure Variable, depending on exposure Degree (type) of exposure TMA dust (mild) or fumes TMA dust (moderate) or fumes TMA fumes (heavy) Fumes or dust (great) Skin tests (TM-HSA) Positive immediate-type Negative Not done Negative Total antibody to TM-HSA Present High Very high Variable IgE to TM-HSA Present Absent Absent Absent NOTE: TMA, trimellitic anhydride; LRSS, late respiratory systemic syndrome; TM-HSA, trimellitic anhydride-human serum albumin. SOURCE: Zeiss et al., 1982.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects including penicillin, sulfa, and spiramycin, are known to induce specific IgE, positive skin tests, and asthma (Davies and Pepys, 1975; Davies et al., 1974). Other pharmacologic agents including cimetidine and alpha-methyldopa can cause asthma on an immunologic basis, that is, as a result of an antigen being recognized by specific antibody or sensitized cells (Butcher et al., 1989). Metal salts of nickel, platinum, and chromates can cause rhinitis, conjunctivitis, or asthma (Block and Chan-Yeung, 1982; Cromwell et al., 1979; Dolovich et al., 1984; Malo et al., 1982; McConnell et al., 1973; Novey et al., 1983; Pepys et al., 1972, 1979; Pickering, 1972). Positive skin tests, specific IgE, and positive bronchial challenges have all been reported. Exposure occurs in processing or plating facilities. Some investigators believe that sensitization to platinum is virtually universal, given a large enough exposure. Acid anhydrides are used as curing agents in the manufacture of epoxy resins. Exposure may occur in a variety of industries including those that manufacture curing agents, plasticizers, or anticorrosive coating agents. In addition to allergic rhinitis, conjunctivitis, and asthma, two other allergic reactions or diseases, LRSS and PDA, described above, may result from TMA. Other anhydrides, including phthalic anhydride and tetrachlorophthalic anhydride, have also caused asthma (D. I. Bernstein et al., 1982; Topping et al., 1986). Isocyanates are used to produce a number of products including paints, surface coatings, and polyurethane foam. They are also found in some home improvement products such as refinishing agents. In contrast to people who react to TMA, many individuals affected by isocyanates do not have specific IgE or positive skin tests (I. L. Bernstein, 1982). Isocyanate asthma is a major cause of LMW chemical-induced asthma, but to date, the mechanism (i.e., allergy versus nonimmunologic sensitivity) is unknown. In addition to asthma, reports have linked isocyanates with hypersensitivity pneumonitis and an immunologically mediated hemorrhagic pneumonitis (Patterson et al., 1990). Research has shown that ethylenediamine induces asthma in individuals exposed to shellac or lacquer (Gelfand, 1983; Lam and Chan-Yeung, 1980). Positive skin tests and positive bronchial responses, both immediate and delayed, have been reported. Azo-dyes, such as azodicarbonamide, can also cause asthma (Park et al., 1991; Slovak, 1981). These studies describe positive skin tests and changes in pulmonary functions after a work shift. Exposure to such chemicals may occur in plants that manufacture or weigh dyes. Formaldehyde is a chemical that is often found at very low levels in homes, offices, and schools and at higher levels in workplaces that use the substance. Asthma is sometimes reported following gaseous formaldehyde

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Indoor Allergens: Assessing and Controlling Adverse Health Effects exposure; bronchial provocation studies are usually negative but on occasion they may be positive (Hendrick and Lane, 1977; Nordman et al., 1985). Two studies that investigated immunologic sensitization reported negative challenges even in those individuals with specific IgE to formaldehyde (Dykewicz et al., 1991; Grammer et al., 1992). Thus, immunologically mediated asthma resulting from formaldehyde exposure has yet to be proved. Other volatile organic chemicals such as toluene and turpentine can act as irritants but are not specific sensitizers. Exposure and Risk Various air sampling and personal monitoring techniques are used to measure chemical exposures (Eller, 1984), but they are not without limitations. For example, intermittent samples may not reflect an individual's actual exposure because of variations in the exposure levels of the chemical. In addition, only a few allergenic chemicals such as TDI and TMA have threshold limit values (TLVs) set by the American Conference of Governmental Industrial Hygienists (ACGIH, 1986) or permissible exposure limits (PELs) set by the Occupational Safety and Health Administration (OSHA; CFR, 1991). TLVs and PELs are generally established to help prevent chemical toxicity among workers. Thus, they may have no relevance to levels of chemicals that may sensitize an individual or provoke allergic responses and that may be many orders of magnitude below toxic levels. Very few studies report threshold levels for human exposure to chemicals that elicit allergic responses, and those that do describe exposure concentrations present them only as estimates. A Japanese study of 41 workers exposed to two enzymes and three antibiotics showed that the incidence of occupational allergy was correlated with the frequency and concentration of exposure to allergens (Chida, 1986). In other studies, approximately 50 TMA workers were evaluated in a facility that reduced worker exposure over time by improved ventilation, work practices, and respiratory protection. The levels of antibody in workers decreased with decreasing exposure to TMA (Boxer et al., 1987; Grammer et al., 1991b). In a study of isocyanate workers, the group with the highest exposure had the highest prevalence of positive antibody (Grammer et al., 1991a). In a study of 500 workers at a TMA manufacturing facility, five categories of exposure were identified (Zeiss et al., 1992). Only workers in the highest exposure categories developed specific antibody and allergic reactions to TMA. In contrast to human studies, estimates of exposure in animal models are considerably more accurate. Studies have reported a concentration-dependent immunologic response in a guinea pig model of TDI asthma (Karol, 1983) and a threshold concentration and concentration-immunologic

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Indoor Allergens: Assessing and Controlling Adverse Health Effects response relationship in a rat model of immunologic TMA disease (Zeiss et al., 1989). It is likely that such relationships also exist in humans, but there are no data to illuminate such linkages. (Quantitative exposure data from animal experiments may not necessarily translate to humans.) Other than exposure, risk factors for the development of sensitization to a given chemical have not been defined. In studies of risk factors for development of sensitization to chemicals such as TDI, atopy and airway hyperreactivity were either not predictive or only weakly so (I. L. Bernstein, 1982; Chester and Schwartz, 1979; Nicholas, 1983). Control by Avoidance and Exposure Reduction Although some of the control measures used in industrial settings may not be directly applicable to the indoor air environment, the model of reduced exposure that results in reduced sensitization rates is applicable to indoor aeroallergens. Prospective studies of TMA workers (Grammer et al., 1991b; Zeiss et al., 1983, 1992) have reported that serial immunologic studies are useful in predicting which individuals are likely to develop immunologically mediated disease. With careful monitoring, those workers who develop specific antibody can be removed from exposure at the onset of any allergic symptoms. Alternatively, if the development of disease seemed very likely, the worker could be relocated at the onset of serologic positivity. In TMA workers, there is evidence that development of specific antibody is predictive of allergic disease, but this finding has not been confirmed in a definitive manner in populations of workers exposed to other chemical allergens. The timing of removal from exposure relative to disease onset is important. Some data suggest that early removal of workers who develop asthma as a result of chemical exposure will allow most of them to return to normal pulmonary function. In contrast, asthma tends to persist among workers who have had the disease for several years before they are removed from exposure (Chan-Yeung, 1990). This is especially true for workers who already have abnormal pulmonary function. With respect to reducing exposure, there is evidence that decreasing airborne concentrations of a chemical such as TMA reduces disease prevalence (Boxer et al., 1987; Chan-Yeung, 1990). As outlined earlier, other evidence in animals and in humans suggests the existence of environmental exposure concentration thresholds and environmental concentration exposure-immunologic response relationships. If these thresholds and relationships could be defined for chemical allergens, reducing exposure could be the best approach to preventing allergic disease caused by these substances. Exposure reduction measures would include improved ventilation, work practices, and protective equipment.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects Conclusions and Recommendations Many of the protein allergens have long been recognized, but a lengthening list of newly recognized allergenic chemicals is developing. Allergic diseases caused by these chemicals can differ from those caused by protein allergens in terms of symptoms, mechanisms of action, and appropriate treatment. The diseases can differ also in terms of etiology and exposure, i.e., often occurring at the work site. A better understanding of these differences will assist in the formulation of improved measures of prevention and treatment. Research Agenda Item: Determine the types of allergic diseases caused by reactive allergenic chemicals, their prevalence rates, and the mechanisms responsible for the resulting airway reactions. A body of knowledge about chemical allergens is available, but many areas have not been well studied. Other chemicals besides those already reported to cause allergic reactions may provoke responses. Thus, as new chemicals are introduced, the list of agents that elicit allergic reactions is likely to grow. Research Agenda Item: Identify the risk factors, such as a specific immunologic response, that are predictive of the development of chemically induced sensitization or allergic disease, and as soon as possible after their introduction, determine the sensitizing potential of new chemical entities. This knowledge will facilitate the development of primary and secondary preventive strategies. The allergic rhinitis, conjunctivitis, and asthma that arise from exposure to chemicals appear to be due to classic immunologic reactions. However, late respiratory systemic syndrome (LRSS) and immunologic hemorrhagic pneumonitis occur only in response to chemical exposures and are not the result of response to the usual protein allergens; the mechanisms of immunologic damage in these two cases are not entirely known. The mechanism of non-IgE-mediated isocyanate asthma is also unclear. Research Agenda Item: Determine the disease mechanisms of chemically induced LRSS, of immunologic hemorrhagic pneumonitis, and of non-IgE-mediated isocyanate asthma. Appropriate in vitro or in vivo models should also be developed. LMW reactive allergenic chemicals can cause immunologic sensitization and consequent allergic reactions. At a minimum, hundreds of thousands of U.S. workers are exposed to chemicals that can form haptens with airway proteins and induce allergic diseases. The goal of reducing the

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Indoor Allergens: Assessing and Controlling Adverse Health Effects incidence and severity of allergic disease caused by chemical exposure is achievable, although it may not be possible to prevent all such disease. Research Agenda Item: Determine the number of workers exposed to allergenic chemicals in various industrial and non-industrial settings and the prevalence of allergic disease resulting from such exposure. Populations in close contact with reactive allergenic chemicals and highly potent sensitizers would be logical candidates for study. For those individuals who develop allergic disease from exposure to chemicals, it is important to determine their long-term prognosis. In particular, if immune responses that are predictive of allergic disease can be identified, and reduced exposure can be shown to result in resolution of disease (and disappearance of immunologic sensitization), then reduced exposure may represent the most practical approach for preventing allergic disease arising from chemical exposure. Research Agenda Item: Conduct dose-response studies in humans to determine both the relationship between allergen concentration and immunologic response, and a threshold environmental exposure concentration for sensitization. In addition to studies of the threshold concentrations necessary for sensitization, thresholds for elicitation of allergic reactions to chemicals once sensitization has occurred also require study. Such thresholds exist but vary markedly from individual to individual, as shown by bronchoprovocation tests performed with high-molecular-weight allergens. This is probably also the case with chemical allergens, but the issue has not been systematically studied. If threshold concentration levels do exist but are highly variable, and in some cases very low, the only practical way to manage sensitized individuals is to terminate the exposure. PLANTS AND PLANT PRODUCTS It is well known that plants produce substances, materials, or products that are allergenic in humans. The best understood are pollen from trees, grasses, and weeds and the oils or resins from the leaves of poison ivy and poison oak. Airborne pollen can produce allergic rhinitis or asthma, or both, in the susceptible atopic population. The oils from poison ivy can produce allergic contact dermatitis; susceptibility is not limited to atopic individuals. Pollen production is seasonal and varies in quantity, depending on geographic location and climatic conditions. Local pollen production also varies annually, depending on weather conditions. Outdoor pollen can enter the indoors with ventilation air and can also

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Indoor Allergens: Assessing and Controlling Adverse Health Effects be transported indoors on people and their clothing as well as on pets. Clothing that was previously hung outdoors to dry is another source of pollen. Studies have shown that indoor pollen concentrations can be quite high during the pollen production season (O'Rourke et al., 1990; Platts-Mills et al., 1987; Pollart et al., 1988). Reports of indoor pollen concentrations have ranged from 0 to 5.5 million pollen grains per gram of house dust (O'Rourke and Lebowitz, 1984). Elevated concentrations of pollen in indoor air are found under open window conditions (in one case 600 grains per cubic meter in a room) (O'Rourke et al., 1989). These high airborne pollen concentrations are rare, but 30 pollen grains per cubic meter are not uncommon. Since people spend a majority of their time indoors (NAS, 1981; Quackenboss et al., 1991a,b), over 20 pollen grains can be inhaled in a typical household each day (on average, over all seasons). During the spring, when average outdoor pollen concentrations approach 400 grains per day, indoor exposure can approach 40–80 grains per day (O'Rourke, 1989). Indoor plants are commonly found in office or school environments and in the home. Most are grown for their green foliage and accommodate low light or a lack of direct sunlight. As such, most do not flower in these environments and therefore are not pollen sources. Indeed, most plants grown indoors are not highly allergenic. Nevertheless, as more plants are used indoors, especially in large numbers in office settings, those considered not allergenic or only slightly allergenic may need to be reexamined. For example, Axelsson and colleagues (1987b, 1991) report that the leaves of Ficus benjamina (weeping fig) can produce airborne IgE-mediated rhinitis and asthma. They estimate that the risk of sensitization among truly atopic individuals is 6 percent. Hausen and Schulz (1988) report on a woman who developed conjunctivitis, rhinitis, and asthma from the nectar secretions of an ornamental plant, Abutilon striatum (flowering maple). Ford and co-workers (1986) report the development of IgE antibodies to pollen allergens from Parietaria judaica, an outdoor allergenic member of the nettle family found in the Mediterranean region but not likely to be found indoors. Most recent reports in the literature regarding allergic reactions to indoor plants involve contact dermatitis produced by airborne allergens. Plants provoking such reactions include Allium (garlic), chlorophora (iroki; Fernandez de Corres et al., 1984, 1985), Chrysanthemum , citrus, Coleus (Van Hecke et al., 1991), common ferns (Geller-Bernstein et al., 1987), Compositae (daisy), Frullania (Pecegueiro and Brandao, 1985), lichens, Lilium (lily), Pelargonium (geranium), Philodendron, Pinus (pine), Platycodon grandiflorum (balloon flower; Nagano et al., 1982), Primula (primrose), Typha latifolia (cattail), and Umbelliferae (family name for parsley, carrots, coriander, etc.). Because many of these studies report the effects of mixtures of houseplants and garden plants, it is difficult to determine which house or indoor plants are truly allergenic.

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Indoor Allergens: Assessing and Controlling Adverse Health Effects The types of plants grown in the home will frequently differ from those grown in the office or workplace, in that the home gardener may well experiment with different types of plants grown in different locations at various times of the year (e.g., growing herbs in an indoor window box with a southern exposure). Similarly, home gardeners with a greenhouse may grow a wide variety of allergenic plants. Although there is only limited knowledge of the extent of allergic disease from allergenic indoor plants, it seems logical to assume that if increased use is made of indoor plants that are pollen producers, atopic individuals may find indoor environments as unpleasant as the outdoors during the traditional pollen season. In addition, indoor blooming patterns are sometimes manipulated to be different from outdoor ''normal" seasonal patterns. Plant Products In addition to the plants themselves, plant materials such as Psyllium and latex can be brought indoors in a variety of consumer products. Psyllium is a grass from India used as a fiber and bulk supplement for bowel control. There are reported cases of severe anaphylactic reactions among workers who produce this product, as well as among those who use it. Airborne exposure to the product can also produce allergic reactions among susceptible individuals during use in the home. Plant sources of allergens that have been shown to produce asthma in selected occupationally-exposed populations are presented in Chapter 2 (Table 2-4). Some of these plant materials can be present in residential and other indoor environments because of the activities of the occupants. Whether they will pose a hazard to the occupant depends on many factors including the amount of airborne exposures. Dried flowers are another example of a potentially allergenic product that can be brought indoors. LATEX Latex allergy has recently received substantial attention because of increasing reports of its occurrence and its potential, in certain individuals, to produce life-threatening anaphylactic reactions. The latex (or sap) of the Havea brasiliensis plant is the source of natural rubber (cis-1,4-polyisoprene). Although rubber production yields a product that is 93–95 percent polyisoprene, the final product may be as much as 2–3 percent protein by weight (Windholz et al., 1983). The protein component of the latex contains allergens that are responsible for numerous recent reports of latex allergy. Exposure occurs by direct contact or by inhalation of dust or powder that is often used for packaging. Patient reactions to latex have ranged from contact urticaria to systemic anaphylaxis. Persons at increased risk include patients with congenital

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Indoor Allergens: Assessing and Controlling Adverse Health Effects problems of the spinal cord (e.g., myelomeningocele), patients with recurrent bladder catheterizations, or any patient with a history of rash, swelling, or itching after blowing up balloons, wearing rubber gloves, or using other latex-containing products. On rare occasions, latex condoms can cause allergic reactions. Most cases of allergy to latex are mediated by IgE antibodies. However, because of varying source materials, the heterogeneity of immune response, and a variety of test methods, the identities of the specific protein allergens remain to be determined (Jones et al., 1992). Case reports of latex allergy began to appear in the literature in 1979 (Nutter, 1979). Most early reports were of contact urticaria (Forstrom, 1980; Meding and Fregert, 1984; Nutter, 1979); reports of allergic rhinitis (Carrillo et al., 1986), anaphylaxis (Axelsson et al., 1987a; Slater, 1989; Turjanmaa et al., 1984), and asthma (Seaton et al., 1988) followed. Occupational asthma related to latex hypersensitivity has also been described; the response has been attributed to inhalation exposure to cured latex during the inspection and packaging of finished gloves (Tarlo et al., 1990). Fisher (1987) has also reported contact urticaria and anaphylactoid reaction as a result of exposure to cornstarch surgical glove powder. Swanson and colleagues (1992) support the conclusion that dust from latex gloves is a significant occupational aeroallergen, reporting 28 medical center employees diagnosed with rhinitis or asthma caused by exposure to dust from latex gloves. In addition to health care workers and manufacturers, children with spina bifida are at increased risk for latex allergy, and credible evidence supports an IgE-mediated mechanism (Slater, 1989; Slater et al., 1990a, 1991; Spanner et al., 1989; Turjanmaa, 1987). One prospective study reported that 5 out of 12 spina bifida patients (41 percent) have IgE antibody specific for rubber proteins (Slater et al., 1990a). Another report suggested that IgE titers to latex allergen might be due to parenteral exposure to latex surgeon's gloves during primary closure of the meningomyelocele and that early initial exposure and frequent reexposures may predispose children with spina bifida to rubber allergy (Slater et al., 1990b). Recent episodes of fatal and life-threatening anaphylaxis have made it increasingly urgent to identify the specific allergen(s) responsible for these reactions (Kelly et al., 1991). Jones and others (1992) and Turjanmaa and colleagues (1988) have reported large variations in the latex allergen content of gloves from different manufacturers; powder-free gloves were significantly less allergenic in this survey. Slater and Chhabra (1992) reported that all patients with latex-specific IgE had antibodies to a 14-kDa peptide present in an extract made from nonammoniated latex; many sera recognized a 20-kDa peptide as well. They concluded that current data are insufficient to identify definitively the major allergen(s) and suggested that

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Indoor Allergens: Assessing and Controlling Adverse Health Effects studies of latex extract would be useful in further characterizing the immune response to natural rubber. With recent increases in the production and use of latex gloves and other rubber products, clinical sensitivity may be more common than in previous years, and the regulatory, research, and medical communities are responding accordingly. A current regulatory review by the FDA may result in relabeling of latex products—including latex gloves, condoms, catheters, dental dams, and enema kits—to highlight the risks of latex hypersensitivity. The FDA has already issued a Medical Alert (MDA91-1, March 29, 1991) containing recommendations to health professionals regarding the use of latex products. The American College of Allergy and Immunology has also issued interim guidelines on latex allergy. As noted by Slater (1989), and others, and described in the medical alert and guidelines, patients with a history of rubber-induced allergic reactions, as with all life-threatening allergy, should practice avoidance as the main form of treatment. Health care workers should use nonrubber gloves when treating these patients, and appropriate care should be taken to avoid exposing latex-sensitive patients to either direct or aerosolized contact (e.g., from the cornstarch dust used in packaging latex gloves). It has also been suggested that latex allergen may be carried on syringe needles from the rubber stoppers of multiuse vials (Silverman, 1989). Finally, it is important that sensitive individuals be recognized prior to surgery so that proper precautions can be taken to avoid latex exposure and minimize the potential for experiencing the associated adverse reactions. In addition to allergen avoidance strategies, some authors believe that latex-sensitive patients should be premedicated according to protocols for the prevention of anaphylactic reactions in surgery (Bielory and Kaliner, 1985; Greenberger et al., 1985; Lasser et al., 1987). CONCLUSIONS AND RECOMMENDATIONS Indoor plants are commonly found in offices, schools, and the home. Although most indoor plants do not produce aerosols of allergen-containing particles, as more plants are used indoors, especially in large numbers in office settings, the risk of exposure to plant allergens increases. Research Agenda Item: Assess the significance of workplace exposures to indoor plants, including the contribution to the overall magnitude of indoor allergic disease. Latex allergy has recently received substantial attention because of increasing reports of its occurrence and its potential, in certain individuals, to produce life-threatening anaphylactic reactions. In addition to health care

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Indoor Allergens: Assessing and Controlling Adverse Health Effects workers and manufacturers, children with spina bifida are at increased risk for latex allergy. Research Agenda Item: Conduct research to further characterize the immune response to natural rubber. This effort should include studies of the incidence and prevalence of natural-rubber-related allergic disease.