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Damp Indoor Spaces and Health (2004)

Chapter:5 Human Health Effects Associated with Damp Indoor Environments

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5 Human Health Effects Associated with Damp Indoor Environments INTRODUCTION Various human health effects have been attributed to damp or moldy indoor environments. Respiratory symptoms are most often researched, but other symptoms and clinical outcomes have also been examined in studies and anecdotal reports. Previous chapters of this report have addressed the scientific literature regarding the biologic and chemical agents encountered in damp indoor environments: the factors influencing their presence or release, actions that can be taken to prevent or remediate contamination by them, the means available to characterize human exposure to them, and their toxic proper- ties. This chapter evaluates the strength of the scientific evidence concern- ing the possible association between the agents and adverse health out- comes. Although it does not review all such literature1—an undertaking beyond the scope of this report—it attempts to cover the most recent stud- ies and other work that the committee believed to be influential in shaping scientific understanding at the time it completed its task in late 2003. The chapter is organized by health outcome. Each major section describes the characteristics or symptoms of the health outcome, discusses the evidence 1Several surveys and reviews of the literature regarding damp indoor spaces and health or of specific exposures related to damp indoor spaces have been published in recent years, including Bornehag et al. (2001), Fung and Hughson (2003), Kolstad et al. (2002), Kuhn and Ghannoum (2003), Peat et al. (1998), Piecková and Jesenská (1999), and Robbins et al. (2000). 183

184 DAMP INDOOR SPACES AND HEALTH of possible association between the outcome and the presence of dampness or dampness-related microbial agents, and presents the committee’s conclu- sions regarding the evidence of the association. (Chapter 1 describes the methodologic considerations underlying the evaluation of the evidence and definitions of the categories used to summarize the committee’s findings.) Because there are great differences between specific health outcomes in the amount and type of information available, the sections vary in their depth and focus. This chapter, like other parts of the report, focuses on studies that examine the health effects of dampness or of fungi and bacteria associated with damp indoor spaces. Other exposures that may be found in such environments—notably, house dust mites, viruses, and environmental to- bacco smoke (ETS)—are not addressed here, although their presence may have important effects on occupants. The health effects of those agents are covered in detail in the Institute of Medicine reports Clearing the Air (IOM, 2000), as related to asthma, and Indoor Allergens (IOM, 1993), as related more generally to allergic responses. Smoking and ETS in particular are established confounding factors in studies of respiratory health outcomes and serve as sensitizing agents and potentiators of effect (IOM, 2000; Scien- tific Committee on Tobacco and Health, 1998; U.S. EPA, 1992). Larger organisms, such as cockroaches, also inhabit damp spaces and may be responsible for some of the health problems attributed to these spaces and are addressed in the previously cited IOM reports. Studies of such microbial infections as tinea pedis (athlete’s foot) that are associated with moisture but not the damp indoor conditions addressed in this report are excluded. An extensive literature examines the influence on occupants’ health of various agents found indoors—such as pesticides (Lewis, 2000), nitrogen dioxide (NO2) from gas appliances (Neas et al., 1991), and volatile organic compounds and formaldehyde outgassing from furnishings or construction materials (Norbäck et al., 1995; U.S. EPA, 1989)—or characteristics of indoor environments, including ventilation rate, temperature, and the use of circulated air and sealing measures to improve energy efficiency (Engvall et al., 2003; Seppänen and Fisk, 2002). When reading this chapter, one should remember that many of the health effects attributed to the presence of mold or other dampness-related agents in the papers cited here have also been attributed to other factors. Not all papers that address damp indoor spaces control for those other factors, just as dampness-related agents are not always examined as possible factors in studies of the health effects of indoor spaces. This weakness in the literature underlines the importance of the committee’s recommendations for research on improved methods of exposure assessment. Indoor environments are complex. They subject occupants to multiple exposures that may interact physically or chemically with one another and

HUMAN HEALTH EFFECTS 185 with the other characteristics of the environment, such as humidity, tem- perature, and ventilation. Synergistic effects—interactions among agents that result in combined effects greater than the sums of the individual effects—may take place. Information on the combined effects of multiple factors and on synergist effects among agents is cited wherever possible. However, as was noted in Clearing the Air, little information is available on this topic and it remains one of active research interest. Finally, some factors may influence people’s exposure to indoor agents, their ability to respond to circumstances in which indoor exposure may increase the risk of adverse health outcomes, and their health in general. Notable among those is socioeconomic status (SES). Low SES may be a contributory or independent factor in some of the health outcomes ad- dressed below, affecting their incidence of severity. Thus, when the committee draws conclusions about the association between damp indoor environments and health outcomes, it is not impos- ing the assumption—and readers should not presume—that these outcomes are necessarily associated with exposure to a specific microbial agent or to microbial agents in general. When an association between a particular indoor dampness-related agent and a particular health outcome is addressed, it is specified in the text. However, even in those cases, it is likely that people are being exposed to multiple agents. The following sections draw conclusions about the state of the scien- tific literature regarding association of health outcomes with two circum- stances: exposure to a damp indoor environment and the presence of mold or other microbial agents in a damp indoor environment. As noted in Chapter 2, the term dampness has been applied to a variety of moisture problems in buildings that include high relative humidity, condensation, and signs of excess moisture or microbial growth. Most of the studies considered by the committee did not specify which microbial agents were present in the buildings occupied by subjects, and this likely varied between and even within study populations. The conclusions presented here qualify the term mold with quotation marks to indicate the uncertainty regarding the agents that may be involved. To fulfill their charge to evaluate the effect of damp indoor spaces on health, the committee conducted a review of epidemiologic studies. The committee began their evaluation presuming neither the presence nor the absence of association. They sought to understand the strengths and limita- tions of the available evidence. These judgments have both quantitative and qualitative aspects. They reflect the nature of the exposures, health out- comes, and populations exposed; the characteristics of the evidence exam- ined; and the approach taken by the study’s authors to evaluate this evi- dence. Because of the great differences among the studies reviewed, the committee concluded it was inappropriate to use quantitative summary

186 DAMP INDOOR SPACES AND HEALTH techniques such as meta-analysis. Instead, as detailed in Chapter 1, the committee summarized their judgment of the association between damp- ness or mold and particular health outcomes by using a common format to categorize the strength of the scientific evidence. Fungi and other microbial agents are omnipresent in the environment, and the committee restricted its evaluation to circumstances that could be reasonably associated with damp indoor environments. Studies regarding homes, schools, and office buildings were considered; such other indoor environments as barns, silos, and factories—which may subject people to high occupational exposures to organic dusts and other microbial contaminants—were not. EVALUATING HEALTH EFFECTS Most of the research about the health effects resulting from damp indoor spaces is the result of epidemiologic investigations of associations between self-reported symptoms or clinical outcomes and the presence of dampness (however it might be defined or termed) or “mold,” either re- ported or measured. The studies examined in this report primarily ad- dressed dampness or mold in the home, reflecting the focus of researchers working in this field. A small number of studies of office or school environ- ments were also evaluated. As detailed in Chapters 2 and 3, many of the studies use reports of current or past signs of dampness and mold or general measures of it as a proxy for the agents of interest. A few have considered dampness as a risk factor separate from the presence of microbial agents indoors. There are thought to be more than one million species of fungi, but humans are routinely exposed to only about 200 (IOM, 2000), and fewer than 50 are commonly identified and described in epidemiologic studies of indoor environments (Asero and Bottazzi, 2000). Many health studies that evaluate the presence of mold do not formally identify species. Instead, they use “mold” as a generic term to describe microbial growth. From a practi- cal standpoint, that means that fungi—perhaps several species—are grouped with fungus-like bacteria (such as thermophilic actinomycetes) when the health consequences of microbiologic agents are being investigated. Epide- miologic studies that examine particular mold species or strains often fail to factor or minimize the possible influence of other mold species and bacteria and other agents associated with damp indoor environments. Only a hand- ful of researchers have explicitly examined chemical emissions from water- damaged materials. Their studies are discussed in Chapter 2. Clinical studies and case reports are additional sources of information on some health outcomes, but they are often limited by the small number of subjects examined. Clinical studies may involve exposure scenarios (such as intentional installation) that are not encountered outside the laboratory,

HUMAN HEALTH EFFECTS 187 and case reports often address unusual or unusually high potential expo- sures that are not representative of those experienced in homes, schools, or office buildings. Some clinical studies and case reports are cited below; their results were considered by the committee with the understanding of their inherent limitations. Anecdotal reports of health problems attributed to mold indoors often dominate mass-media attention, but they are not a source of reliable infor- mation. Good epidemiologic and clinical practice in investigations of po- tential environmental health problems requires—to the extent possible— the evaluation of all suspect environmental agents, valid measures of exposures and health outcomes, and thorough consideration of alternative explanations for observed signs, symptoms, and diseases. Those criteria can be difficult to completely fulfill in scientific studies, and they are sel- dom met in outlets where information is not subject to rigorous scientific standards. Epidemiologists most commonly use questionnaires to collect informa- tion about symptoms, signs, and diseases. Exposures are often character- ized through self-reports or expert-reports of the presence of dampness or visible mold. While self-reports are often the only way to gather informa- tion from large numbers of subjects in a cost-efficient manner, they have disadvantages that must be considered when evaluating studies that use them. A self-report of dampness or visible mold, for example, may indicate rather a wide range of potential exposures: particular molds, endotoxin, gram-negative bacteria, microbial VOCs, house dust mites, and dampness- related chemical releases from building materials, among others. Except in cases where studies carefully separate dampness-related exposures or where specific biomarkers of exposure exist, it can be difficult to identify the responsible agent and even then the identification of the agent may be problematic. It is not always possible to determine whether a specific health outcome examined in a study is caused by an allergic reaction versus an infectious agent, an irritant stimulus, a toxic agent, or some other cause. The clinical literature and to a lesser extent, toxicological studies, inform the interpretation of some epidemiological findings—especially those stud- ies that are carried out under carefully controlled conditions. However, confident attribution of an outcome to a particular pathological mechanism is often limited by the observational (rather than experimental) nature of epidemiological studies and more than one mechanism may be responsible for the results in a particular study. Studies reviewed by the committee examined populations from across the United States and numerous foreign countries including Canada, Australia, New Zealand, and the nations of Europe. Differences in such factors as climate, predominant mycoflora, building practices, the genetic make up of subjects, and cultural traditions may affect results. Despite these limitations, epidemiological studies pro-

188 DAMP INDOOR SPACES AND HEALTH vide useful information for studying patterns of disease in populations and drawing conclusions about possible environmental influences. Clinical measures are sometimes used in smaller-scale studies. For res- piratory disease outcomes, these include lung-function testing based on spirometry or peak expiratory flow measures. Challenge testing with inha- lation of methacholine, histamine, or other substances designed to induce bronchospasm in susceptible people has been used to measure the extent of bronchial hyperresponsiveness in clinical settings and epidemiologic stud- ies. The thorax has been imaged radiographically with chest x-rays and computed tomographic (CT) scans to evaluate individual patients in clinical studies. Lung biopsy may be indicated to confirm or rule out the diagnosis of particular diseases, such as hypersensitivity pneumonitis. Direct objec- tive means of measuring nasal function have not been widely applied to the evaluation of complaints related to damp indoor spaces. Similarly, objec- tive clinical measures have not been widely used to investigate gastrointes- tinal, dermatologic, rheumatologic, or neurologic complaints. A variety of biologic markers of inflammation are increasingly being applied to measure the effects of exposure to dampness and dampness- related agents in indoor environments (Purokivi et al., 2001; Roponen et al., 2001a; Trout et al., 2001; Wålinder et al., 2001). Circulating immuno- globulin G (IgG) antibodies to microbial agents that can cause hypersensi- tivity pneumonitis have been shown to have limited prognostic significance as markers of the chronic form of this disorder (Cormier and Bélanger, 1989; Guernsey et al., 1989; Marx et al., 1990), but it has been asserted that these markers are more useful as indicators of recent high-level expo- sure to specific molds and thermophilic actinomycete antigens (Lacasse et al., 2003). A 2003 study suggests that stachylysin—a proteinaceous hemolysin—may be a useful indicator of human exposure to Stachybotrys chartarum (Van Emon et al., 2003). Immunologic markers that have been examined in relation to indoor environmental exposures include cytokines, other mediators of inflammation, and antibodies to mycotoxins measured in nasal lavage fluids and in serum. Exhaled nitric oxide (NO) is a biomarker of respiratory tract inflammation that is elevated in some inflammatory lung conditions but not in others (Robbins et al., 1996). Measurement of substances in induced sputum samples and exhaled-breath condensate samples has not yet been applied to dampness or mold in indoor spaces but might be used to investigate them (Mutli et al., 2001). Variability in indi- vidual susceptibility as mediated by genetic risk factors is beginning to be explored by investigators. Chapter 3 addresses the use of biomarkers in exposure assessment. Although this report focuses on health effects associated with excessive indoor dampness, excessive dryness may also be a problem. An indoor environment is typically considered to be dry if the relative humidity level

HUMAN HEALTH EFFECTS 189 falls below 30% (Nagda and Hodgson, 2001). Low indoor relative humid- ity conditions are more likely in winter when cold outdoor air, which is less able to hold moisture, is drawn indoors and warmed. Health complaints associated with indoor dryness include skin irritation, drying of the lining (mucous membranes) of the nose, mouth, and throat, nosebleeds, eye irrita- tion, sore throat, and minor respiratory difficulties (Arundel et al., 1986; Berglund, 1998). A 2003 study by Reinikainen and Jaakkola found that, in dry conditions, increasing the humidity level alleviated some of these symptoms. RESPIRATORY SYMPTOMS Respiratory symptoms—possible indications of disease rather than dis- ease itself—have been ascribed to numerous agents found in and character- istics of indoor environments. This section divides them between upper respiratory tract (URT) and lower respiratory tract (LRT) symptoms. Stud- ies reviewed vary in which symptoms and sets of symptoms they examine. Upper Respiratory Tract Effects The URT comprises the nose, mouth, sinuses, and throat. The commit- tee identified numerous studies that examine either individual URT symp- toms (such as nasal congestion or sore throat) or groups of symptoms. Rhinitis, an inflammatory condition that involves the nasal mucosa, consti- tutes one such group: nasal congestion, sneezing, and runny or itchy nose (Jaakkola et al., 1993; Koskinen, 1999). Allergic rhinitis (“hay fever”) is rhinitis caused by IgE-mediated inflammation. Sinusitis symptoms are simi- lar to those of the common cold; they result from the inflammation of the paranasal sinuses. Ear and eye symptoms related to URT infections are sometimes grouped with them. Sinus disease related specifically to Aspergil- lus is discussed later in this chapter. Overview of the Evidence Table 5-1 summarizes results of studies that address URT symptoms. Because these symptoms often occur together, the table includes papers that address several different outcomes. Among the studies summarized in the table is an investigation by Rylander and Mégevand (2000) of risk factors for respiratory infections. The investigation, which examined 304 Swiss children 4–5 years old, reported associations between humidity in the home and colds (odds ratio [OR], 2.71; 95% confidence interval, 1.07–6.91), sore throats (3.02; 1.14–7.98), and ear infections (2.78; 1.13–6.80) after adjusting for mother’s age and allergy status. The ORs for the association

TABLE 5-1 Selected Epidemiologic Studies—Upper Respiratory Tract Symptoms and Exposure to Damp Indoor 190 Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Cross-sectional studies Engvall et al., 2002 3,241 adults in Self-reported moldy odor and 1.92 (1.78–2.07) multifamily buildings water leakage in preceding 5 for nasal symptoms; years 4.42 (4.09–4.77) for throat irritation Kilpeläinen et al., 2001 10,667 students Self-reported visible mold 1.29 (1.01–1.66) (18–25 years) for allergic rhinitis; 1.48 (1.17–1.88) for common cold ≥ 4 times per year Self-reported visible mold or 1.30 (1.12–1.51) damp stains or water damage for allergic rhinitis 1.28 (1.09–1.47) for common cold ≥ 4 times per year Rylander and 304 children Self-reported humidity 2.71 (1.07–6.91) Mégevand, 2000 (4–5 years old) for cold; 3.02 (1.14–7.98) for sore throat Self-reported mold at home 2.27 (.082–6.33) for cold; 2.57 (0.86–7.71) for sore throat Zacharasiewicz et al., 2,849 children Self-reported dampness at home 1.51 (1.31–1.74) 2000 (6–9 years old) for nasal symptoms

Dales and Miller, 1999 403 elementary school Self-reported mold or mildew 1.81(1.02–3.24) for children itchy eyes, rash or itch, nose irritation Wan and Li, 1999 1,113 workers in Self-reported mold 0.94 (0.50–1.77) for 19 office buildings nasal congestion or runny nose Self-reported flooding 1.55 (0.79–3.06) for nasal congestion or runny nose Wieslander et al., 1999 95 staff members in Measured dampness in concrete 1.10 (1.15–1.45) 4 hospitals floor for irritated, stuffy, or runny nose 1.29 (1.02–1.18) for itching, burning, or irritated eyes Koskinen et al., 1999a 699 adults (16+ years) Surveyor-assessed moisture 1.06 (0.71–1.59) in 310 households for rhinitis; 1.92 (1.11–3.30) for sinusitis; 1.46 (1.03–2.08) for sore throat Self-reported mold 1.89 (1.15–3.11) for rhinitis; 1.36 (0.78–2.39) for sinusitis; 2.40 (1.56–3.69) for sore throat (continued on next page) 191

TABLE 5-1 continued 192 Reference Subjects Dampness or Mold Measure Risk Estimate Koskinen et al., 1999b 204 children (7–15 Surveyor-assessed moisture 4.31 (1.80–10.34) years old) in 310 for rhinitis; households 0.75 (0.19–2.98) for sinusitis; 2.34 (1.13–4.86) for sore throat Thorn and Rylander, 129 adults Measured airborne glucan 1.23 (0.85–1.77) for 1998a (18–83 years old) (> 2–4 ng/m3) irritation in nose Pirhonen et al., 1996 1,460 adults Self–reported damp or mold 1.68 (0.97–2.89) (25–64 years old) problem for dry or sore throat Jaakkola et al., 1993 2,568 preschool Self-reported mold odor in 2.39 (1.15–4.98) for children preceding year nasal congestion; 2.38 (1.13–4.99) for nasal excretion Self-reported water damage 4.60 (2.57–8.22) for >1 year ago nasal congestion; 3.19 (1.64–6.19) for nasal excretion Brunekreef, 1992 2,685 adult parents of Self-reported damp stains or 1.03 (0.79–1.35) among children 6–12 years mold growth (last 2 years) women (for allergy); old 1.24 (0.95–1.73) among men (for allergy) Brunekreef et al., 1989 4,625 children Self-reported molds (ever) 1.57 (1.31–1.87) (7–11 years old) for hay fever Self-reported dampness (ever) 1.26(1.06–1.50) for hay fever

HUMAN HEALTH EFFECTS 193 between visible mold in the home and colds, bronchitis, and sore throats were also greater than 1.0 but did not achieve statistical significance. Koskinen and colleagues (1999a) studied 699 adults in Finland and found that those who reported moisture in their homes were more likely to have common colds (1.62; 1.08–2.41), hoarseness (1.44; 0.99–2.10), sore throat (2.40; 1.56–3.68), rhinitis (1.89; 1.15–3.11), and eye irritation (1.43; 0.84–1.83) in the preceding 12 months, after adjusting for smoking, age, sex, allergy, indoor pets, and atopic predisposition. A companion study of children in the same residences (Koskinen et al., 1999b) yielded ORs greater that 1.0 for some URT symptoms (cold, hoarseness, sore throat, rhinitis, and eye irritation) but not others (sinusitis and otitis). However, the num- ber of observations was relatively small, and the confidence intervals were wide. Kilpeläinen et al. (2001) surveyed over 10,000 college students and observed an association between incidence of common colds (≥ 4 per year) and visible mold by itself (1.48; 1.17–1.88) and “visible mold or damp stains or water damage” (1.28; 1.09–1.47). An association was also found with allergic rhinitis and visible mold (1.29; 1.01–1.66) and “visible mold or damp stains or water damage” (1.30; 1.12–1.51). No association was observed between allergic conjunctivitis and either exposure surrogate. The analyses controlled for parental education, smoking, presence of second- hand smoke, pets, wall-to-wall carpeting, place of residence (farm, rural nonfarm, or urban), and type of residence (apartment vs other building types). Wieslander et al. (1999) found that damp concrete floors were associ- ated with an increased risk of irritated, stuffy, or runny nose (1.10; 1.02– 1.18) and itching, burning, or irritated eyes (1.29; 1.15–1.45). The re- searchers, who were investigating the influence of building characteristics on URT symptom incidence, hypothesized that the health outcomes were the result of exposure to the emission of 2-ethyl-1-hexanol due to alkaline degradation of octylphthalates in floor materials. The concentrations of total and viable molds and bacteria were low in the buildings evaluated in the study. A study of 4,625 children by Brunekreef et al. (1989) found significant relationships between rates of hay fever and “mold” or “dampness” in homes (ORs, 1.57 and 1.26, respectively), although neither finding corre- lated with fungal counts (Su et al., 1989, 1990). Some other studies reviewed by the committee examined less common symptoms or focused on particular dampness-related agents. Subjects in moldy environments sometimes report an impaired sense of smell (Koskinen et al., 1999b; Nevalainen et al., 2001). The ability to smell can be tested and measured, but the method has not been applied in studies of dampness or mold in indoor environments, so interpretation of results is problematic. A 2000 study showed an association between nasal polyposis and skin

194 DAMP INDOOR SPACES AND HEALTH reactivity to Candida albicans in a study of 15 patients but did not specifi- cally examine whether the exposure had indoor sources (Asero and Bottazzi, 2000). Of the studies summarized in Table 5-1, only Thorn and Rylander (1998a) measured a specific dampness-related agent—airborne (1→3)-β-D- glucan concentrations. Conclusions Several epidemiologic studies address the association between one or more URT symptoms—nasal congestion, sneezing, runny or itchy nose, and throat irritation—and indoor dampness or microbial contamination. Studies are uniform in showing an increased risk of those symptoms; some, although not all, of the studies report statistically significant associations. The commit- tee did not conduct an empirical investigation of the possible effect of publi- cation or respondent bias; as indicated in Chapter 1, it does not believe either to be the determining factor in the results. It concludes as follows: • There is sufficient evidence of an association between exposure to a damp indoor environment and upper respiratory tract symptoms. • There is sufficient evidence of an association between the presence of “mold” (otherwise unspecified) in a damp indoor environment and upper respiratory tract symptoms. Lower Respiratory Tract Effects The major passages and structures of the lower respiratory tract (LRT) include the windpipe (trachea) and within the lungs, the bronchi, bronchi- oles, and alveoli. Although a number of LRT symptoms are reported when people are exposed to agents or particular environmental conditions in the home and other indoor spaces, limitations of study design sometimes pre- clude conclusions to be drawn regarding whether symptoms reported by participants indicate of the presence of defined disease entities. LRT symp- toms include cough with or without production of phlegm, wheeze, chest tightness, and shortness of breath (dyspnea). Cough Cough can be triggered by a variety of means, including exposure to allergens or irritants. It may either be a nonspecific complaint or be associ- ated with a clinical syndrome. Overview of the Evidence Among the more recent studies reviewed in Table 5-2 is a 2003 effort by Belanger and colleagues that prospectively examined

TABLE 5–2 Selected Epidemiologic Studies—Cough and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Cross-sectional studies Belanger et al., 2003)a 593 infants (1–12 months Reported persistent mold or 1.53 (1.01–2.30) old) with asthmatic sibling mildew in previous 12 months for persistent cough Measured fungal colonies 0.99 (0.89–1.10) (species not specified) for persistent cough 256 infants with asthmatic Reported persistent mold or 1.91(1.07–3.42) sibling + asthmatic mother mildew in previous 12 months for persistent cough Measured fungal colonies 1.04 (0.87–1.24) (species not specified) for persistent cough Gunnbjörnsdottir et al., 1,853 young adults Self-reported water damage or 2.23 (1.24–4.00) 2003 visible mold in home (n = 74) for long-term cough Gent et al., 2002 880 infants (1–12 months Measured Penicillium 1.01 (0.80–1.28) old) with asthmatic sibling low (1–499 CFU/m3) Measured Penicillium 1.62 (0.93–2.82) medium (500–999 CFU/m3) Measured Penicillium 2.06 (1.31–3.24) high ≥ 1,000 CFU/m3) Measured Cladosporium 1.03 (0.79–1.35) low (1–499 CFU/m3) Measured Cladosporium 1.45 (0.99–2.12) medium (500–999 CFU/m3) Measured Cladosporium 0.72 (0.42–1.24) high ≥ 1,000 CFU/m3) “Other mold” 1.05 (0.83–1.33) low (1–499 CFU/m3) (continued on next page) 195

TABLE 5–2 continued 196 Reference Subjects Dampness or Mold Measure Risk Estimate “Other mold” 0.78 (0.42–1.45) medium (500–999 CFU/m3) “Other mold” 1.18 (0.63–2.21) high (≥ 1,000 CFU/m3) Water leaks 1.17 (0.91–1.49) Humidifier use 1.26 (1.01–1.56) Engvall et al., 2001 3,241 adults in Self-reported moldy odor and 3.97 (3.74–4.22) multifamily buildings signs of high humidity Self-reported moldy odor and 3.78 (3.46–4.12) major water leakage Dales and Miller, 1999 403 elementary-school Self-reported mold or mildew 1.28 (0.74–2.23) for children nocturnal cough or wheeze Koskinen et al., 1999a 699 adults (16+ years old) Surveyor-assessed moisture 2.11(1.21–4.98) for in 310 households nocturnal cough; 1.42 (0.92–2.19) for cough without phlegm; 1.15 (0.78–1.69) for cough with phlegm Self-reported mold 2.30 (1.32–4.01) for nocturnal cough; 1.60 (1.01–2.53) for cough without phlegm; 1.44 (0.95–2.19) for cough with phlegm Koskinen et al., 1999b 204 children (≤ 15 years Surveyor-assessed moisture 5.72 (1.22–26.83) for old) in 310 households nocturnal cough; 3.23 (1.43–7.31) for

cough without phlegm; 0.94 (0.47–1.87) for cough with phlegm Taskinen et al., 1999 622 children (7–13 years Self-reported dampness 2.3 (1.3–4.1) old), 101 cases total (school) Self-reported dampness 4.7 (2.1–10.8) (school, home) Andriessen et al., 1998 1,614 children Self reported moisture stains 1.01 (0.89–1.16) (5–13 years old) Self reported molds 1.01(0.87–1.18) Jędrychowski and Flak, 1,129 children (age 9) Self-reported molds or 1.13 (0.64–2.02) 1998 dampness Rylander et al., 1998 347 children in 2 schools Problem school vs control 26.1% vs 10.3% (1 with previous mold school (p = 0.024) in problem) nonatopics, for dry cough; 54.5% vs 7.1% (p = 0.003) in atopics, for dry cough; 23.1% vs 8.2% (p = 0.012) in nonatopics, for dry cough at night without cold 58.3% vs 6.5% (p < 0.001) in atopics, for dry cough at night without cold; 17.0% vs 7.5% (p = NS) in nonatopics, (continued on next page) 197

TABLE 5–2 continued 198 Reference Subjects Dampness or Mold Measure Risk Estimate for cough with phlegm; 40.0% vs 7.1% (p = 0.031) in atopics, for cough with phlegm Thom and Rylander, 129 adults Measured airborne glucan 1.05 (0.72–1.52) 1998a (18–83 years old) (>2–4 ng/m3) for dry cough Measured airborne glucan 1.08 (0.74–1.56) (>4 ng/m3) for dry cough Austin and Russell, 1997 1,537 children (12–14 Self-reported damp 1.62 (1.06–2.48) years old) Self-reported mold 1.78 (1.10–2.89) Pirhonen et al., 1996 1,460 adults Self-reported damp or mold 1.37 (0.99–1.88) (25–64 years old) problem Jaakkola et al., 1993 2,568 preschool children Self-reported mold odor in 3.88 (1.88–8.01) for past year persistent cough Self-reported water damage 2.54 (1.16–5.57) for >1 year ago persistent cough Brunekreef, 1992 2,685 adult parents of Self-reported damp stains or 1.75 (1.30–2.36) children 6–12 years old mold growth (last 2 years) among women 2.56 (1.94–3.38) among men Dales et al., 1991a 13,495 children Self-reported dampness or 1.89 (1.63–2.20) (5–8 years old) mold Self-reported flood 1.38 (1.16–1.65) Self-reported moisture 1.91 (1.60–2.27) Self-reported mold site 1.61 (1.36–1.89)

Self-reported mold sites 2.26 (1.80–2.83) (2 vs 0) Dijkstra et al., 1990 775 children Self-reported damp stains or 0.57 (0.13–2.56) (6–12 years old) mold Self-reported damp stains, 3.62 (1.57–8.36) mold Brunekseef et al., 1989 4,625 children Self-reported molds (ever) 2.12 (1.64–2.73) (7–11 years old) Self-reported dampness (ever) 2.16 (1.64–2.84) Waegemaekers et al., 164 men Self-reported damp homes 1.35 (nonsignificant; no 1989 CI reported) 164 women Self-reported damp homes 3.48 (nonsignificant; no CI reported) 190 children Self-reported damp homes 2.99 (1.28–6.97) for morning cough; 1.54 (0.77–3.10) for day or night cough Author-measured airborne 1.98 (no CI reported) fungi Case-control studies Verhoeffet al., 1995 Children (6–12 years old): Self-reported dampness 1.70 (0.94–3.09) 84 chronic cough cases, Self-reported mold 1.90 (1.02–3.52) 247 controls Surveyor-observed dampness 1.18 (0.70–1.99) Surveyor-observed mold 1.26 (0.70–2.25) aSame population studied by Gent et al., 2002. 199

200 DAMP INDOOR SPACES AND HEALTH persistent cough and wheeze in a cohort of 849 infants (up to 1 year old) who had at least one sibling with physician-diagnosed asthma. Telephone inter- views were used to ascertain symptoms and home characteristics; indoor allergens (house dust mites, cockroaches, cats, and dogs), airborne fungal spores, and NO2 were measured. In models that controlled for allergen con- centrations, the presence of a gas or wood stove, maternal education, ethnicity, the sex of the child, and smoking in the home, measured mold or mildew was associated with persistent cough both in infants whose mothers had asthma (1.91; 1.07–3.42) and in those whose mothers did not have asthma (1.53; 1.01–2.30). A study of the same cohort by Gent et al. (2002) classified airborne concentrations of Penicillium, Cladosporium, and “other mold”2 as low, medium, and high. It found an association between high Penicillium and greater incidence of persistent cough (p < 0.05 for trend) in an analysis that accounted for the influence of socioeconomic factors and housing characteristics; neither Cladosporium nor “other mold” showed such a relationship. The authors concluded that susceptible infants in homes with high Penicillium were at greater risk for cough but noted that the study was limited by the fact that a single airborne sample was used to represent expo- sure and that samples were taken at different times of the year and some molds exhibit seasonality. Gunnbjörnsdottir et al. (2003) found an association between “self- reported mold and water damage” and long-term cough (2.23; 1.24–4.00) in a study of young adults that controlled for age, sex, smoking history, environmental tobacco smoke, total serum IgE, and sensitization to a num- ber of environmental agents. However, no relationship was found for mold or water damage alone or for nocturnal cough. The Engvall et al. (2001) study of 3,241 people in multifamily buildings found a significantly in- creased risk of cough where there was either self-reported moldy odor and signs of high humidity (3.97; 3.74–4.22) or moldy odor and major water leakage (3.78; 3.46–4.12). Their analyses accounted for subject age, sex, current smoking, number of subjects per room, and type of ventilation. Two large studies of children are included in Table 5-2. Dales et al. (1991a) used questionnaires to gather data on the health and home charac- teristics of over 13,000 children 5–8 years old in 30 communities across Canada. Cough was associated with parent-reported basement flooding, water damage, or leaks in the preceding year (1.38; 1.16–1.65); wet or damp spots in rooms other than the basement (1.91; 1.60–2.27); having mold in two or more sites in the home (2.26; 1.8–2.83); or having at least one of the dampness-mold indicators (1.89; 1.63–2.20). Those estimates 2No other mold was found in a sufficient number of households to permit separate analysis. The “other mold” spore count was determined by subtracting Penicillium and Cladosporium from the total.

HUMAN HEALTH EFFECTS 201 were not adjusted for confounders, but the authors stated that analyses that adjusted for age, sex, race, parental education, presence of environmental tobacco smoke (ETS), presence of gas appliances, and hobbies that generate airborne contaminants yielded similar results. Questionnaires were also used by Brunekreef et al. (1989) to obtain information on 4,624 children 7–11 years old living in homes that were part of the Harvard Six Cities Study. Similar ORs were estimated for the relationship between cough and the presence of mold (2.12; 1.64–2.73) or dampness (2.16; 1.64–2.84) in sub- jects’ homes. Estimates were slightly higher for nonasthmatic wheezers (OR = 1.73) and nonwheezers (1.59) than for asthmatics (1.50); no confi- dence intervals were reported, but the relationships were all statistically significant (p < 0.05). Conclusions Despite the variations in methods used to collect informa- tion, studies report a remarkably consistent association between cough and damp indoor conditions. Statistically significant associations between cough and visible signs of dampness or mold have been described by a number of investigators, with ORs of 1.3 to over 5.0. The committee concludes • There is sufficient evidence of an association between exposure to a damp indoor environment and cough. • There is sufficient evidence of an association between the presence of “mold” (otherwise unspecified) in a damp indoor environment and cough. Wheeze Wheeze is a musical or whistling sound, typically accompanied by labored breathing, produced when a person exhales; it may be accompa- nied by a feeling of tightening in the chest. It is a subjective finding that may be a sign or symptom of asthma but can also occur in persons who are not considered to be asthmatic. Before the age of about 3 years, children may exhibit wheeze or other symptoms that are characteristic of asthma, but they might not exhibit persistent asthmatic symptoms or other related con- ditions, such as bronchial reactivity or allergy, later in life. Wheeze in these children may thus signify a non-allergic inflammatory process. In adults and older children, wheeze in the presence of dampness or mold more likely signifies an allergic response, although high level exposure to microbial agents may trigger an irritant response. Several agents found indoors and several indoor characteristics have been associated with increased likeli- hood of wheeze, including high relative humidity, low temperatures, gas heating, and the presence of smokers (Ross et al., 1990).

202 DAMP INDOOR SPACES AND HEALTH Overview of the Evidence Studies of wheeze that examined direct or indi- rect measures of the presence of dampness or mold are summarized in Table 5-3. Many of the studies cited in the table also examined the LRT health outcomes reviewed above. Among the others is the Zock et al. (2002) meta-analysis of 18,873 adult subjects in a wide-ranging multicenter asthma study. The researchers found increased ORs for the associations between self-reported wheeze apart from colds in the last year (characterized as an asthma symptom in the study) and home water damage in the last year (1.23; 1.06–1.44), water on the basement floor (1.26; 0.81–1.98), and visible mold or mildew in the last year (1.44; 1.30–1.60). The analyses controlled for sex, age, and smoking status. Maier et al. (1997) surveyed parents of 925 children 5–9 years old in Seattle to obtain information on home characteristics and wheezing in the preceding 12 months in children without a previous diagnosis of asthma. Data on four measures of household dampness were analyzed: household water damage, visible mold, water in the basement, and wall or window dampness. Reported household water damage was associated with an OR greater than 1.0 for current wheezing (1.7; 0.9–3.0) in an analysis that adjusted for sex, ethnicity, allergy history, SES, and parental asthma; a combined “any wetness or no water damage” measure was not (1.0; 0.6– 1.8). The authors suggested that household water damage might be an indicator of poorer housing quality and thus a surrogate for lower SES, noting that they found a stronger nonadjusted risk of current wheezing among children in lower SES categories. Alternatively, they proposed that household water damage might simply have been more easily recognized than other forms of household dampness by study participants. When data were separated by subjects’ race, household water damage was associated with current wheezing among both blacks (prevalence ratio, 3.2; 1.0–9.9; nonadjusted) and other nonwhites (2.5; 0.7–8.3). Jędrychowski and Flak (1998) examined the influence of outdoor and indoor air quality on respiratory-health outcomes in 1,129 children 9 years old in Cracow, Poland. Surveys of parents were used to obtain information on the children’s health and home characteristics; questionnaire data and measurements of suspended particulate matter and sulfur dioxide (SO2) were used to construct an outdoor air-pollution index score. After adjust- ment for outdoor air pollution, sex, parental education, type of home heat- ing system, ETS, and the presence of a physician-diagnosed allergy, home mold or dampness was found to be associated with wheezing (1.63; 1.07– 2.48). When subjects were separated by allergic status, nonallergic children of nonallergic parents were found to be at increased risk for two or more respiratory symptoms in the presence of home mold or dampness (2.27; 1.07–4.82).

TABLE 5-3 Selected Epidemiologic Studies—Wheeze and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Adolescents and adults Cross-sectional studies Gunnbjömsdottir et al., 1,853 young adults Self-reported water damage or 1.4 (0.78–2.52) 2003 visible mold in home Zock et al., 2002 18,872 adults in 38 Self-reported water damage 1.16 (1.00–1.34) for centers of European in last year wheeze, breathlessness Community Respiratory 1.23 (1.06–1.44) for Health Survey wheeze apart from colds Self-reported water on 1.46 (1.07–2.01) for basement floor wheeze, breathlessness 1.26 (0.81–1.98) for wheeze apart from colds Self-reported mold or mildew 1.34 (1.18–1.51) for in last year wheeze, breathlessness 1.44 (1.30–1.60) for wheeze apart from colds Nicolai et al., 1998 155 adolescents Self-reported dampness 14.3% exposed vs. (mean age, 13.5 years) 5.3% nonexposed (p = 0.06) Self-reported dampness 5.77 (1.17–28.44) (adjusted for mite allergen concentrations) Brunekreef, 1992 2,685 parents of Self-reported damp stains or 1.43 (1.15–1.77) children 6–12 years old mold growth (last 2 years) in women; 1.63 (1.30–2.06) in men (continued on next page) 203

TABLE 5-3 continued 204 Reference Subjects Dampness or Mold Measure Risk Estimate Waegemaekers et al., 164 men Self-reported damp homes 4.06 (p < 0.01; no CI 1989 reported) 164 women Self-reported damp homes 4.79 (p < 0.01; no CI reported) Case-control studies Norbäck et al., 1999 98 cases and 357 Self-reported water damage or 1.6 (1.03–2.6) controls nested among flooding Swedish adult (20–45 Dampness in floor 2.8 (1.4–5.5) years old) cohort Visible mold on indoor 2.4 (1.4–4.3) surfaces Moldy odor 1.5 (0.74–3.1) At least one sign of dampness 2.2 (1.5–3.2) Infants and children Cross-sectional studies Belanger et al., 2003 a 849 infants with Reported persistent mold or 2.51 (1.37–4.62) asthmatic siblings mildew in previous 12 months mother with asthma 1.22 (0.80–1.88) mother without asthma Measured fungal colonies 1.23 (1.01–1.49) (species not specified) mother with asthma 1.10 (0.99–1.23) mother without asthma Gent et al., 2002 880 infants (1–12 Measured Penicillium 1.11(0.87–1.42) months old) with low asthmatic siblings Measured Penicilliurn 1.29 (0.65–1.48) medium Measured Penicillium 2.15 (1.34–3.46) high

Measured Cladosporium 0.92 (0.69–1.22) low Measured Cladosporium 0.95 (0.61–1.49) medium Measured Cladosporium 0.91 (0.53–1.56) high Other mold low 0.97 (0.75–1.26) Other mold medium 0.91 (0.49–1.68) Other mold high 1.02 (0.49–2.11) Water leaks 1.18 (0.90–1.55) Humidifier use 1.41 (1.11–1.79) Park et al., 2001 499 infants with at least Family-room dust endotoxin 1.33 (0.99–1.79) one parent with asthma ≥ 100 EU/mg for any wheeze or allergy 1.55 (1.00–2.42) for repeated wheeze Taskinen et al., 1999 622 children (7–13 Self-reported dampness 3.8 (1.8–8.3) years old); 76 cases (school) total Self-reported dampness 3.4 (0.8–14.2) (home) Self-reported dampness 3.8 (1.3–11.3) (school and home) Jędrychowski and Flak, 1,129 children (9 years Self-reported molds or 1.63 (1.07–2.48) 1998 old) dampness Rylander et al., 1998 347 children in 2 Problem school vs control 13.5% vs 2.8% schools (1 with previous school (p = 0.014) in mold problem) nonatopics; 36.4% vs 13.3% (p = NS) in atopics (continued on next page) 205

206 TABLE 5-3 continued Reference Subjects Dampness or Mold Measure Risk Estimate Slezak et al., 1998 1,085 children in Head Self-reported dampness or 2.01 (1.38–2.93) Start programs (3–5 mold years old) Maier et al., 1997 925 children (5–9 years old) Self-reported mold 1.2 (0.7–1.9) Self-reported water damage 1.7 (1.0–2.8) Self-reported basement water 1.0 (0.6–1.7) Self-reported water 1.3 (0.8-2.1) condensation Any of above 1.1 (0.7–1.8) Jaakkola et al., 1993 2,568 preschool Self-reported moldy odor in 4.31 (1.61–11.6) for children preceding year persistent wheeze Self-reported water damage 8.67 (3.87–19.4) for >1 year ago persistent wheeze Dales et al., 1991a 13,495 children Self-reported dampness or 1.58 (1.42–1.76) (5–8 years old) mold Self-reported flood 1.25 (1.10–1.41) Self-reported moisture 1.74 (1.53–1.98) Self-reported mold site 1.42 (1.26–1.59) Self-reported mold sites 1.73 (1.45–2.06) (2 vs 0)

Dijkstra et al., 1990 775 children Self-reported damp stains or 1.13 (0.45–2.88) (6–12 years old) mold Self-reported damp stains and 1.54 (0.59–4.00) mold Strachan et al., 1990 1,000 children (7 years old) Self-reported mold 3.70 (2.22–6.15) Brunekreefet al., 1989 4,625 children Self-reported molds (ever) 1.79 (1.44–2.32) (7–11 years old) Self-reported dampness (ever) 1.23 (1.10–1.39) Waegemaekers et al., 190 children Self-reported damp homes 2.80 (1.18–6.64) 1989 Author-measured airborne 1.28 (includes shortness fungi of breath, asthma) aSame population studied by Gent et al., 2002. 207

208 DAMP INDOOR SPACES AND HEALTH Conclusions Studies demonstrate a consistent association between wheeze and various indications of indoor dampness, although the association of wheeze with exposure to indoor allergens (notably, house dust mite) in damp environ- ments somewhat complicates the evaluation. Studies addressing infants and children and those addressing adolescents and adults yield similar relative risk estimates. The committee concludes on the basis of its review that • There is sufficient evidence of an association between exposure to a damp indoor environment and wheeze. • There is sufficient evidence of an association between the presence of “mold” (otherwise unspecified) in a damp indoor environment and wheeze. Shortness of breath (Dyspnea) Dyspnea is the medical term for shortness of breath. It is a common complaint in persons suffering from a variety of respiratory illnesses and can also be a symptom in persons suffering from cardiac disease. Acute inhalation of high concentrations of endotoxin may also cause dyspnea (Jagielo et al., 1996; Reed and Milton, 2001). Overview of the Evidence Clinicians and some investigators routinely perform lung-function testing as an objective measure of respiratory physi- ology in persons with dyspnea. Results from the epidemiologic studies that address dyspnea are summarized in Table 5-4. Conclusions Available studies consistently report an association between exposure to dampness or the presence of mold (otherwise unspecified) and dyspnea. However, the small number of studies lessens the confidence with which conclusions can be drawn. Taken together, • There is limited or suggestive evidence of an association between exposure to a damp indoor environment and episodes of dyspnea (short- ness of breath). • There is inadequate or insufficient evidence to determine whether an association exists between the presence of mold or other agents in damp indoor environments and episodes of dyspnea (shortness of breath). RESPIRATORY TRACT DISORDERS Sinusitis Sinusitis is a common clinical problem that consists of an inflammation of the paranasal sinuses of the face (Braunwald et al., 2001). It is usually

TABLE 5-4 Selected Epidemiologic Studies—Dyspnea and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Cross-sectional studies Koskinen et al., 1999a 699 adults (16+ years Surveyor-assessed moisture 2.33 (1.09–4.98) for old) in 310 households nocturnal dyspnea Self-reported mold 1.58 (0.74–3.39) for nocturnal dyspnea Norbäck et al., 1999 98 cases and 357 Self-reported water damage or 2.2 (1.4–3.7) daytime controls nested among flooding 2.2 (1.4–3.5) nocturnal Swedish adult (20–45 Dampness in floor 3.1 (1.5–6.2) daytime years old) cohort 2.7 (1.3–5.4) nocturnal Visible mold on indoor 2.2 (1.2–4.0) daytime surfaces 2.5 (1.4–4.5) nocturnal Jędrychowski and Flak, 1,129 children (9 years Self-reported molds or 2.01 (1.24–3.28) 1998 old) dampness Waegemaekers et al., 164 men Self-reported damp homes 9.38 (nonsignificant; no 1989 CI reported) 164 women Self-reported damp homes 2.25 (nonsignificant; no CI reported) 190 children Self-reported damp homes 0.92 (0.32–2.61) 209

210 DAMP INDOOR SPACES AND HEALTH caused by infectious organisms, including viruses, bacteria, and, less often, fungi. It may also be caused by the inhalation of irritant substances. The inflammatory process that is common to the various etiologies of sinusitis leads to the presence of increased amounts of mucus and mucosal edema that prevent drainage of mucus through the ostia of the sinuses. This ob- structive process helps to cause or perpetuate microbial infection of the sinuses. Sinusitis can be an acute process that resolves spontaneously, can lead to a serious infection of the soft tissues surrounding the sinuses, and can become chronic and result in mucosal thickening and nasal polyps. The immune status of the patient helps to determine the course of the disease. Signs and symptoms of sinusitis are similar to those of allergic rhinitis and viral URT infections, and this can make diagnosis difficult. Overview of the Evidence Fungal sinusitis can present in a variety of ways (Schubert, 2000). The clinical syndromes that result from the presence of fungi in the paranasal sinuses include acute invasive fungal sinusitis, chronic invasive fungal si- nusitis, mycetoma, and allergic fungal sinusitis. Fungi are commonly isolated from the nasal secretions of patients with chronic rhinosinusitis and from healthy people. The presence of the fungi is indicative of colonization or noninvasive infection in most cases. In one study, 91% of healthy volunteers had positive fungal cultures; separately, 91% of patients with chronic rhinosinusitis were also found to have posi- tive cultures (Braun et al., 2003). Some 33 genera of fungi were isolated, with a mean of 3.2 species per subject. Persons with chronic rhinosinusitis had eosinophilic mucin, which was not present in the normal control sub- jects. The presence of such allergic mucin is characteristic of the disorder termed allergic fungal rhinosinusitis (AFS). Marple (2002) states that fun- gal exposure alone is thought to be insufficient to initiate AFS and that instead it is a multifactorial event that results from exposure to specific fungi, an IgE-mediated atopy, specific T-cell HLA receptor expression, and aberration of local mucosal defense mechanisms. Invasive fungal sinusitis almost always occurs in persons who are immunocompromised by diabetes, hematologic malignancies, or immu- nosuppressive treatments after transplantation or chronic glucocorticoid therapy (Malani and Kaufman, 2002). It may present as an acute, fulmi- nant process that ends in death. If the host is immunocompetent, it is more likely to be a subacute disorder. Conclusions It is not known whether the organisms that cause the various clinical syndromes of fungal sinusitis come from the indoor or the outdoor environ-

HUMAN HEALTH EFFECTS 211 ment. The committee did not identify any studies that associated the condi- tion specifically with damp or moldy indoor spaces. As noted above, fungal colonization is often found in the sinuses of both healthy persons and those who have sinusitis or nasal symptoms. Available information does not indicate that exposure to a damp indoor environment or the presence of agents associated with them places other- wise-healthy people at risk for the various forms of sinusitis. Airflow Obstruction Overview of the Evidence Airflow obstruction can be easily measured with a spirometer and can be seen in the context of asthma, chronic obstructive pulmonary disease (COPD), and other lung disorders that are more uncommon and less clearly linked to environmental exposures. Relatively little research has examined whether indoor dampness- related agents are associated with changes in FEV1 or FEV1:FVC,3 the most reliable measures of obstructed airflow. Strachan et al. (1990) noted that total mold counts were nonsignificantly higher in the homes of children who exhibited a 10% or greater decline in FEV1 after exercise. The Thorn and Rylander (1998b) experimental study of the response of healthy adult volunteers to 40 µg of inhaled lipopolysaccharide (endotoxin)—a rather large amount—under controlled conditions found relatively small but sta- tistically significant decrements in both measures; the FEV1:FVC ratio re- mained almost unchanged. Norbäck et al. (1999) noted that FEV1 was lower and peak expiratory flow (PEF) variability higher in subjects whose dwellings had floor damp- ness. Sunyer et al. (2000) found—after adjusting for bronchial hyper- responsiveness, respiratory symptoms, and smoking—that specific immuno- response to Alternaria alternata was associated with a lower baseline FEV1. In contrast, Gunnbjörnsdottir et al. (2003) did not observe any difference in FEV1 or FVC measurements between subjects who reported water damage or visible mold and those who did not. An association between a reduction in FEF25–754 and living in a damp or mold-contaminated home was identi- fied in one study in children (Brunekreef et al., 1989). 3Forced vital capacity (FVC) is the total volume of air that can be expired after deep inhalation. Forced expiratory volume in (FEV1) is the volume of air that can be expired in the first second of FVC; the normal value is at least 80% of FVC (an FEV1:FVC ratio of 0.8). 4Forced expiratory flow 25%–75% (FEF 25-75) is the average forced expiratory flow at the middle part of the FVC maneuver. It is used as an indication of the state of the lower airways. Normal values vary with sex, age, and height.

212 DAMP INDOOR SPACES AND HEALTH Bronchial hyperresponsiveness (BHR), also known as bronchial hyper- reactivity, is a clinical finding defined by a fall in FEV1 of more than 20% in response to inhalation of methacholine, histamine, or other substances known to cause bronchospasm. Such substances include common air pol- lutants, such as sulfur dioxide and ozone, and inhaled allergens (Tilles and Bardana, 1997). The excessive responsiveness presents as cough and wheeze. Bronchial hyperresponsiveness is seen not only in persons with asthma and other chronic inflammatory diseases of the airways but also in persons with allergic rhinitis and in many otherwise healthy people (O’Byrne and Inman, 2000). Measurement of BHR is an important research tool in epidemiologic studies and clinical evaluations. BHR has been associated with exposure to organic dust in occupational environments (Carvalheiro et al., 1995), and some researchers have reported an association with sensitization to molds in the indoor environment or the presence of visible mold in the home (Chinn et al., 1998; Dharmage et al., 2001; Nelson et al., 1999; Zock et al., 2002). Conclusions Airflow obstruction is a prominent clinical finding of symptom exacer- bation in people with asthma or COPD. The following conclusions apply to persons who do not suffer from those diseases, which are addressed sepa- rately in this chapter: • There is inadequate or insufficient evidence to determine whether an association exists between exposure to a damp indoor environment and airflow obstruction in otherwise healthy people. • There is inadequate or insufficient evidence to determine whether an association exists between the presence of mold or other agents in damp indoor environments and airflow obstruction in otherwise healthy people. Mucous Membrane Irritation Syndrome Overview of the Evidence Mucous membrane irritation syndrome (MMI) consists of symptoms such as rhinorrhea (runny nose), nasal congestion, and sore throat that are secondary to irritation of the nose, eyes, and throat (Richerson, 1990). The symptoms often occur with cough and other LRT complaints. MMI is most commonly associated with exposures in agricultural environments (Von Essen and Romberger, 2003) but studies have shown that the symptoms also occur in people exposed to damp buildings with or without visible mold growth. Rudblad et al. (2001, 2002) found persis-

HUMAN HEALTH EFFECTS 213 tent mucosal hyperreactivity in adult subjects exposed to a damp indoor environment. The mechanisms by which these effects might occur in humans include release of proinflammatory cytokines—including tumor necrosis factor al- pha (TNF-α), interleukin-1 (IL-1), and IL-6—and nitric oxide (NO) (Hir- vonen et al., 1999; Purokivi et al., 2001). Mold spores have been shown to stimulate the release of proinflammatory cytokines from macrophages (Hir- vonen et al., 1997). Studies indicate that indoor-air fungi activate leuko- cytes to produce oxidative stress (Ruotsalainen et al., 1995) and that molds can be directly toxic to macrophages (Murtoniemi et al., 2001). The find- ings from studies done in humans are supported by studies of laboratory animals (Jussila et al., 2002a,b; Shahan et al., 1998). Chapter 4 discusses the results of several experiments performed by exposing animals to fungal spores or mycotoxins; they suggest that such exposures could cause MMI symptoms and other respiratory and nonrespiratory symptoms. Difficulties in performing the necessary exposure assessment have prevented a more direct evaluation of whether mycotoxins from indoor microbial agents might have that effect on humans. Interestingly, one study found that high- level nasal exposure to fungal spores in an occupational setting was not associated with high NO or proinflammatory cytokines in nasal lavage fluids; this suggests that microbial exposure does not always result in in- flammatory changes detectable by this method (Roponen et al., 2002), although such changes were detected in people who worked in damp school and office environments (Hirvonen et al., 1999; Roponen et al., 2001b). Conclusions Mucous membrane irritation syndrome is one of the respiratory prob- lems associated with high-level exposure to organic dust. Little attention has been paid to it as a health outcome possibly associated with nonagricul- tural indoor exposure to microbial agents. The committee concludes that there is inadequate or insufficient information to determine whether an association exists between indoor dampness or dampness-related agents and mucous membrane irritation syndrome. Chronic Obstructive Pulmonary Disease The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as “. . . a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases” (Pauwels et al., 2001). Smoking is regarded as the primary cause of COPD; other agents that have been implicated include

214 DAMP INDOOR SPACES AND HEALTH ETS, air pollutants, and a variety of organic and inorganic dusts (Blanc et al., 2003). Symptoms include cough that is often productive of sputum, persistent dyspnea, wheeze, and diminished exercise tolerance. Spirometry often shows chronic airflow limitation, usually with limited reversibility by bronchodilator medication. Little is known about the heritability of COPD, although it is being actively investigated (Wilk et al., 2003). Overview of the Evidence There is some evidence that persons with COPD symptoms are more likely than those without to experience an exacerbation of their symptoms when exposed to damp indoor spaces (Brunekreef, 1992). There is also a recognized association between bronchial hyperresponsiveness, atopy, and COPD (IOM, 1993). Several studies (reviewed above) address COPD symptoms, but rela- tively little research examines an association between dampness-related agents and diagnosed COPD. Thorn and Rylander (1998a) measured air- borne (1→3)β-D-glucan in the homes of 129 adults and reported an in- creased risk of chronic bronchitis at both lower concentrations (>2–4 ng/m3: OR, 7.99; CI, 0.65–98.05) and higher concentrations (>4 ng/m3: 2.51; 0.23–27.83). (Studies of exposure to glucans and other health out- comes are discussed below in the section titled “Severe Respiratory Infec- tions.”) Although some of the homes surveyed had experienced water dam- age, they were, according to the researchers, “not particularly damp” when the study was conducted. In a case study of two critically ill patients who were receiving high-dose corticosteroid medication for COPD symptoms, Kistemann et al. (2002) suggest that they may have acquired aspergillosis because of exposure to airborne Aspergillus conidia (>102 CFU/m3) re- leased during reconstruction activities near the intensive-care unit where they were housed. Other studies have also reported Aspergillus infections in COPD patients who were undergoing chronic corticosteroid therapy (Bulpa et al., 2001). Conclusions Studies identified by the committee indicate that immunocompromised people with COPD are at increased risk for fungus-related illness. How- ever, there is inadequate or insufficient information to determine whether an association exists between indoor dampness or dampness-related agents and chronic obstructive pulmonary disease itself. Symptoms experienced by those diagnosed with COPD are addressed in the section titled “Respira- tory Symptoms” earlier in the chapter.

HUMAN HEALTH EFFECTS 215 Asthma Definition of Disorder Asthma, like COPD, is a disorder of airflow obstruction. As was noted in the 2000 Institute of Medicine report Clearing the Air, finding a widely accepted definition for this disease has proved problematic. The definition adopted by the committee responsible for that report states that (pp. 23– 24) . . . asthma is understood to be a chronic disease of the airways character- ized by an inflammatory response involving many cell types. Both genetic and environmental factors appear to play important roles in the initiation and continuation of the inflammation. Although the inflammatory re- sponse may vary from one patient to another, the symptoms are often episodic and usually include wheezing, breathlessness, chest tightness, and coughing. Symptoms may occur at any time of the day but are more commonly seen at night. These symptoms are associated with widespread airflow obstruction that is at least partially reversible with pharmacologic agents or time. Many persons with asthma also have varying degrees of bronchial hyperresponsiveness. Research has shown that after long peri- ods of time this inflammation may cause a gradual alteration or remodel- ing of the architecture of the lungs that cannot be reversed with therapy. Objective information about the presence and severity of asthma can be obtained by demonstrating airflow obstruction with spirometry. Alterna- tively, evidence of airflow obstruction can be obtained by measuring peak expiratory flow. Asthma is distinguished from other airway disorders in part by reversibility of the airflow obstruction, which may be spontaneous or induced by bronchodilator medications. Role of Sensitization Asthma may be allergic or nonallergic. Allergic asthma is IgE-medi- ated.5 A number of cell types play an important role in asthma, including eosinophils, macrophages, and T lymphocytes. Basophils and neutrophils are also present in increased numbers in the inflammatory infiltrates of asthma. The interactions of those cell types with one another and the substances they release are complex; they are addressed in Chapter 4 of Clearing the Air (IOM, 2000) and elsewhere (Oh et al., 2002; Wills-Karp 5Douwes and Pearce (2003) note that “molds are known to produce immunoglobulin E- inducing allergens, and some studies have shown a higher prevalence of mold sensitization among subjects living in damp buildings (Norbäck et al., 1999) and among severe asthmatics (Black et al., 2000).”

216 DAMP INDOOR SPACES AND HEALTH and Chiaramonte, 2003). It is now recognized that there are at least two distinct variants of atopic diseases: an extrinsic allergic variant that occurs in the context of sensitization to environmental allergens and an intrinsic, nonallergic variant with no detectable sensitization and with low IgE con- centrations. A third form, a combination of the first two, has also been described (Novak and Bieber, 2003). Nonallergic asthma may be mediated by irritant responses. Mecha- nisms of irritant asthma are largely unknown, but there is evidence that a localized airway response and activation of neural pathways are involved (Balmes, 2002). It has been proposed that neutrophilic airway inflamma- tion may also play a role in causing asthma (Douwes et al., 2002). Other Asthma Issues Allergic responses to fungi have been well documented (Halonen et al., 1997; Norbäck et al., 1999). However, the difficulty of performing popula- tion-based surveys to assess subjects for allergies to molds is compounded by the relative lack of standardized mold antigens for use in skin-prick testing. Clearing the Air (IOM, 2000) notes that about 6–10% of the population are sensitized to fungal allergens; Mari et al. (2003) found that 19% of atopics reacted to at least one of seven fungal extracts—Alternaria, Aspergillus, Candida, Cladosporium, Penicillium, Saccharomyces, and Tri- chophyton—administered via skin-prick test. Skin-test surveys most often focus on broad panels of allergens, including fungi as a single representative extract (usually Alternaria), two or three extracts, or mixtures of several fungi. However, Galant et al. (1998), in a survey of California allergy patients, revealed that nine fungal extracts were necessary to detect 90% of mold-allergic patients. Most studies that focus specifically on fungal sensi- tivity also use only a few extracts, Alternaria again being the dominant type. A 2002 study of IgG and IgE antibodies in Finnish children who attended a water-damaged school found that the number of positive IgG antibodies did not correlate with respiratory symptoms or illnesses although the mean number of positive IgG findings was higher in the exposed group (Savilahti et al., 2002). Fungal skin-sensitivity rates increase with age (Erel et al., 1998). Pro- duction of IgG antibodies as a result of allergen exposure may block the skin-test response even in patients who clearly are experiencing symptoms on exposure (Witteman et al., 1996). Fungal allergens can produce a strong IgG response and possibly make reported incidences of skin reactivity underestimates. Asthma has an important genetic component (Burke et al., 2003). Cur- rent evidence indicates that the clinical syndrome of asthma is a diverse

HUMAN HEALTH EFFECTS 217 group of related conditions that require multiple genes to be expressed for the clinical syndrome to become apparent (Blumenthal, 2002; Cookson, 2002). In addition to the presence of genes that predispose persons to asthma, some exposures may be required for the symptoms to appear. The nature of the gene-environment interactions relevant to damp indoor envi- ronments is a topic of a great deal of research and is not completely under- stood. For example, studies about genetic susceptibility to the inflamma- tory effects of endotoxin are yielding interesting findings, but no firm conclusions can yet be drawn that can be applied directly to the issue of endotoxin exposure in damp indoor spaces (Vercelli, 2003). Substances in the damp indoor environment other than endotoxin could be identified as important in the future. As discussed in Chapter 4, animal studies have shown that exposure to fungal spores causes a profound inflammatory response in the LRT (Jussila et al., 2001, 2002a,b; Shahan et al., 1998). Intratracheal exposure of mice to Streptomyces californicus resulted in release of TNFα and IL-6 and in inflammatory-cell recruitment to the airways (Jussila et al., 2001). A similar inflammatory response was seen when mice were challenged with other fungi commonly found in damp indoor spaces: Aspergillus versicolor and Penicillium spinulosum (Jussila et al., 2002a,b). Inflammatory-cell recruit- ment to the airways and release of TNFα and IL-6 were also seen in mice experimentally exposed to the nonfungal contaminant Mycobacterium ter- rae isolated from a moisture-damaged building (Jussila et al., 2002c). It must be determined whether other mediators of inflammation are also involved in the inflammatory response of the respiratory tract after expo- sure to fungi and other microorganisms that are present in large numbers in damp indoor spaces. High indoor humidity has been associated with increased endotoxin concentrations, and this might help to explain why damp indoor spaces cause symptoms (Park et al., 2001). Contaminated humidifiers can spray spores, fragments, fungal components (including endotoxins) and dis- solved allergens into the air (Baur et al., 1988; Burge et al., 1980; McConnell et al., 2002; Tyndall et al., 1995) and may contribute to exposure in some instances. Exposure to high concentrations of endot- oxin has been associated with a lower FEV1 in asthmatic people (Michel et al., 1996). There is evidence from animal studies that long-term endot- oxin exposure results in chronic lung inflammation (Vernooy et al., 2002), but it is not known whether that occurs in humans. Some studies (Böttcher et al., 2003; Braun-Fahrländer et al., 2002; Gehring et al., 2002) suggest that indoor exposure to endotoxin protects against allergic sensitization and allergic wheeze, but the notion remains controversial (Maziak et al., 2003; Weiss, 2002).

218 DAMP INDOOR SPACES AND HEALTH Exacerbation of Asthma Overview of the Evidence Studies of asthma can be divided into those dealing with factors that lead to the development of asthma and those dealing with factors that lead to the onset or worsening of symptoms— some combination of shortness of breath, cough, wheeze, and chest tight- ness—in someone who has already developed asthma. Multiple indoor environmental factors are thought to exacerbate asthma. Table 5-5 summarizes the conclusions reached in Clearing the Air on the state of the scientific evidence (as of the middle of 1999) regarding the association between various indoor agents and asthma exacerbation. Conclusions regarding microbial agents that are addressed in the present report are omitted from the table. Some investigators have examined the association between self-reports of asthma symptoms in people who identify themselves as asthmatic and their presence in damp or moldy indoor environments. The health outcome that is evaluated varies but typically involves two components: a self-report of physician-diagnosed asthma as evidence of the disorder and a self-report of one or more of the asthma symptoms listed above or use of asthma medication. The outcome is variously labeled current asthma, asthma symp- toms, symptomatic asthma, or exacerbations. Exacerbation is used here as an umbrella term for consistency with the 2000 IOM report Clearing the Air, but it should be noted that the studies reviewed do not in general ask whether the subject experienced a worsening of symptoms or of symptom frequency in the presence of dampness or mold—a more customary defini- tion of exacerbation. It is thus not always clear whether subjects are expe- riencing their typical level of symptoms or an adverse reaction in response to a trigger. The discussion and conclusions in this section should be inter- preted with that caveat in mind. The committee did not review the literature regarding outdoor fungal levels. It notes that some (Dales et al., 2003, 2004; Delfino et al., 1997) but not all (Lierl and Hornung, 2003) studies of hospital admissions suggest an association between increased levels and asthma exacerbations. Table 5-6 summarizes the results of studies that addressed asthma symptoms in asthmatic people and exposure to a damp indoor environment or the presence of mold or other agents in damp indoor environments. The studies reviewed in the table include a 2002 paper by Zock et al. that drew data from nearly 19,000 adult subjects in Europe, Australia, New Zealand, India, and the United States who participated in a multicenter asthma study. A meta-analysis of data from the centers—adjusted within study centers for sex, age group (20–29, 30–39, 40–45 years), and smoking status—yielded a statistically significant relationship between “current asthma” (defined as asthma symptoms, medication use, or both within

HUMAN HEALTH EFFECTS 219 TABLE 5-5 Selected Findings from Clearing the Air (IOM, 2000) Regarding Association Between Biologic and Chemical Exposures and Exacerbation of Asthma in Sensitive Persons Biologic Agents Chemical Agents Sufficient Evidence of a Causal Relationship Cat ETS (in preschool-age children) Cockroach House dust mite Sufficient Evidence of an Association Dog NO 2, NOx (high-level exposuresa) Rhinovirus Limited or Suggestive Evidence of an Association Domestic birds ETS in school-age and older children and in adults Chlamydia pneumoniae Formaldehyde Mycoplasma pneumoniae Fragrances Respiratory syncytial virus (RSV) Inadequate or Insufficient Evidence to Determine Whether an Association Exists Cow and horse Pesticides Rodents (as pets or feral animals) Plasticizers Chlamydia trachomatis Houseplants Pollen exposure in indoor environments Insects other than cockroaches Limited or Suggestive Evidence of No Association (no agents met this definition) (no agents met this definition) aAt concentrations that may occur only when gas appliances are used in poorly ventilated kitchens. preceding 12 months in persons who reported that a physician had diag- nosed asthma) and mold or mildew in the home in the preceding year (1.28; 1.13–1.46). The increased ORs for current asthma and self-reported water damage in the last year (1.13; 0.94–1.35) and water on the basement floor (1.54; 0.84–2.82) were nonsignificant. Those observations were homoge- neous across centers and stronger in subjects sensitized to Cladosporium species. A study by Engvall et al. (2001) used a questionnaire to gather informa- tion on 3,241 people living in randomly selected units in 231 multifamily buildings in Stockholm. Their analyses—which controlled for age, sex, current smoking, number of subjects per room, and type of ventilation— found relationships between self-reported “asthma symptoms” and a number

TABLE 5-6 Selected Epidemiologic Studies—Asthma Symptoms in Asthmatic People and Exposure to Damp Indoor 220 Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Adults Cross-sectional studies Zock et al., 2002 18,872 adults in 38 study Self-reported water damage in 1.13 (0.95–1.35) centers of European last year for “current asthma” Community Respiratory Self-reported water on 1.54 (0.84–2.82) Health Survey basement floor for “current asthma” Self-reported mold or mildew 1.28 (1.13–1.46) in last year for “current asthma” Kilpeläinen et al., 2001 10,667 college students Self-reported visible mold 2.21 (1.48–3.28) (18–25 years old) for “current asthma symptoms” Self-reported visible mold, 1.66 (1.25–2.19) for damp stains, water damage “current asthma symptoms” Engvall et at., 2001 3,241 persons randomly At least one sign of dampness 2.28 (2.19–2.37) sampled in multi-family for “asthma symptoms” buildings At least one dampness-related 2.38 (2.30–2.47) odor for “asthma symptoms” Reports of at least one odor 3.59 (3.37–3.82) and structural building for “asthma symptoms” dampness Hu et al., 1997 2,041 young adults Self-reported water leaking 1.6 (0.7–3.5), (20–22 years old) physician-reported 1.6 (0.7–3.8), self-reported

Self-reported indoor dampness 1.2 (0.8–1.9), physician-reported 1.3 (0.7–2.2), self-reported Self-reported visible mold 1.5 (1.0–2.4), physician-reported 2.0 (1.2–3.2), self-reported Pirhonen et al., 1996 1,460 adults Self-reported damp or mold 1.02 (0.60–1.72) (25–64 years old) problem Brunekreef, 1992 2,685 adult parents of Self-reported damp stains or 1.25 (0.94–1.66) children 6–12 years old mold growth (last 2 years) among women 1.29 (0.92–1.81) among men Waegemaekers et al., 164 men Self-reported damp homes 1.15 (nonsignificant) 1989 164 women Self-reported damp homes 4.16 (p<0.05) Case-Control Studies Norbäck et al., 1999 98 cases and 357 Self-reported water damage or 1.9 (1.2–2.9) for at least controls nested among flooding one asthma symptom Swedish adult (20–45 Dampness in floor 3.3 (1.6–6.8) for at least years old) cohort one asthma symptom Visible mold on indoor 2.9 (1.6–5.3) for at least surfaces one asthma symptom Moldy odor 1.8 (0.9–3.8) for at least one asthma symptom At least one sign of dampness 2.2 (1.5–3.2) for at least one asthma symptom 221 (continued on next page)

TABLE 5-6 continued 222 Reference Subjects Dampness or Mold Measure Risk Estimate Williamson et al., 1997 102 asthmatics; 196 Self-reported dampness or 1.93(1.14–3.28), matched controls (5–44 condensation in present home physician-diagnosed years old) asthma Self-reported dampness in 2.55 (1.49–4.37), previous home physician-diagnosed asthma Observed severe dampness 2.36 (1.34–4.01), physician-diagnosed asthma Observed significant mold 1.70 (0.78–3.71) Children Cross-sectional studies Wever-Hess et al., 2000 113 infants (0–1 years Self-reported damp housing 7.6 (2.0–28.6) old) 3.8 (1.1–12.8) for “recurrent exacerbations” Taskinen et al., 1999 622 children (7–13 Self-reported dampness 1.0 (0.4–2.3) for years old); 28 cases (school) symptomatic asthma total Self-reported dampness (home) 1.9 (0.4–10.4) for symptomatic asthma Self-reported dampness 1.1 (0.2–5.5) for (school and home) symptomatic asthma Jędrychowski and Flak, 1,129 children (9 years Self-reported molds or 2.65 (0.96–7.13) for 1998 old) dampness diagnosed asthma Nicolai et al., 1998 155 adolescents (mean Past or present self-reported 61.5% exposed vs age, 13.5 years) Dampness in the home 37.7% non-exposed (p<0.05) for ≥5 asthma attacks in previous year

Rönmark et al., 1999 3,431 children (7–8 Parent-reported dampness at 1.40 (0.8 1–2.42) for years old) in northern home atopic asthma Sweden 1.78 (1.10–2.89) for nonatopic asthma Yang et al., 1997 4,164 primary-school Self-reported home dampness 1.73 (1.20–2.49), children (3–15 years physician confirmed old) asthma Jaakkola et al., 1993 2,568 preschool Self-reported water damage 2.52 (0.93–6.870 children >1 year ago Self-reported mold odor in last 1.46 (0.34–6.29) year Dales et al., 1991a 13,495 children Self-reported flood 1.29 (1.06–1.56) (5–8 years old) Self-reported moisture 1.58 (1.29–1.94) Self-reported dampness or 1.45 (1.23–1.71) mold Self-reported mold site 1.40 (1.16–1.68) Self-reported mold sites 1.67 (1.27–2.19) (2 vs 0) Dijkstra et al., 1990 775 children Self-reported damp stains or 1.16 (0.38–3.52) (6–12 years old) mold Self-reported damp stains and 1.56 (0.50–4.87) mold Brunekreefet al., 1989 4,625 children Self-reported dampness (ever) 1.42 (1.04–1.94) (7–11 years old) Waegemaekers et al., 190 children Self-reported damp homes 2.80 (0.39–20.02) 1989 (continued on next page) 223

TABLE 5-6 continued 224 Reference Subjects Dampness or Mold Measure Risk Estimate Case-control studies Yazicioglu et al., 1998 597 controls, 85 Self-reported home dampness 2.62 (1.13–6.81) asthmatics Dekker et al., 1991 13,495 children Self-reported dampness or 1.46 (1.22–1.74) (5–8 years old) visible mold Mohamed et al., 1995 77 child cases and 77 Author-observed damp damage 4.9 (2.0–11.7) controls (9–11 years old) in child’s bedroom

HUMAN HEALTH EFFECTS 225 of dampness indicators. Where both damp odor and structural building dampness were reported, the adjusted OR was 3.59 (3.37–3.82). Kilpeläinen et al. (2001) analyzed the results of 10,667 surveys re- turned by university students 18–25 years old. The researchers observed an OR of 2.21 (1.48–3.28) between “current asthma” (defined as self-reported, physician-diagnosed asthma with symptoms during the preceding year) and visible mold and an OR of 1.66 (1.25–2.19) between “current asthma” and visible mold, damp stains, or water damage. The analyses controlled for parental education, smoking, ETS, pets, wall-to-wall carpeting, place of residence (farm, rural nonfarm, or urban), and type of residence (apartment vs other building types). After controlling for the effects of genetic predis- position to asthma or allergies, this relationship was significant only in those whose parents were asthmatic or had atopic disease, and the p value for the interaction between atopic heredity and dampness was statistically significant (0.033). Norbäck et al. (2000) reported an association between current asthma symptoms (bronchial hyperresponsiveness and either wheezing or dyspnea in the preceding 12 months) and building dampness at work (8.6; 1.3–56.7) in a study of 87 personnel working in four geriatric hospitals during the winter months. The authors suggested that the result might be a conse- quence of exposure to the emission of 2-ethyl-1-hexanol due to alkaline degradation of octylphthalates in damp floor materials. Dharmage et al. (2001) measured home allergen concentrations and performed skin-prick and lung-function tests in 485 adults in Melbourne, Australia. Dust samples in subjects’ bedrooms and beds were evaluated for dust mites (Der p 1) and cat allergen (Fel d 1); ergosterol was used as a proxy of fungal biomass. Air samples were screened for five allergenic fungi—Cladosporium, Alternaria, Epicoccum, Penicillium, and Aspergil- lus—and for Der p 1 and Fel d 1, and questionnaires were used to gather personal and sociodemographic characteristics of the cohort. The authors reported that high ergosterol was associated with an increased risk of cur- rent asthma after adjustment for potential confounders, but the relation- ship was not statistically significant (data not provided). Among studies of children, the Taskinen et al. (1999) analysis of 622 children (7–13 years old) found no relationship between physician-diag- nosed, parent-reported asthma and moisture problems in the home (1.9; 0.4–10.4), school (1.0; 0.4–2.3), or both combined environments (1.1; 0.2– 5.5). Dales et al. (1991a), however, did identify a relationship between home dampness or mold and physician-diagnosed asthma (1.45; 1.23– 1.71) in a survey of the parents of 13,495 children 5–8 years old. Conclusions Numerous studies of adults and children uniformly report odds ratios over 1 for the association between exposure to dampness or the

226 DAMP INDOOR SPACES AND HEALTH presence of mold or other agents in damp indoor environments and self- reports of symptoms in people with physician-diagnosed asthma. Most of the observed associations are statistically significant. From the reviewed body of evidence, the committee concludes that • There is sufficient evidence of an association between exposure to a damp indoor environment and asthma symptoms in sensitized asthmatic people. • There is sufficient evidence of an association between the presence of “mold” (otherwise unspecified) in a damp indoor environment and asthma symptoms in sensitized asthmatic people. Studies used to draw this conclusion use self-reports or parent reports of physician-diagnosed asthma in combination with self-reports of asthma symptoms or medication use as their measure of health outcome. Development of Asthma Overview of the Evidence The other asthma outcome reviewed by the committee was development—that is, the initial onset of the illness. Asthma is defined by the manifestation of a set of symptoms rather than by any one objective test. With asthma symptoms ranging from clearly episodic to nearly continuous, from mild to severe, and from coughing without other respiratory symptoms to a loud wheeze, the initial diagnosis of the illness can be complicated and subject to controversy. It is thus difficult to study the determinants of and influences on asthma development. An additional complication arises in interpreting studies of infants and younger children. Before the age of about 3 years, children may exhibit symptoms that are characteristic of asthma, but they might not exhibit persistent asthmatic symptoms or other related conditions, such as bronchial reactivity or al- lergy, later in life. Table 5-7, excerpted from Clearing the Air, shows the conclusions drawn on the state of the scientific evidence (as of the middle of 1999) regarding the association between the development of asthma and various agents indoors. Conclusions regarding microbial agents that are addressed in the present report are omitted from the table. Studies of damp indoor environments or dampness-related agents and asthma development are summarized in Table 5-8. The table includes stud- ies of LRT illnesses in infants and young children thought to be at risk for allergic sensitization to microbial agents and asthma development. A 2002 study examined the possible relationship between the presence of indoor molds and development of asthma in adulthood with a population- based indirect case-control design (Jaakkola et al., 2002a,b). The authors

HUMAN HEALTH EFFECTS 227 TABLE 5-7 Selected Findings from Clearing the Air (IOM, 2000) Regarding Association Between Indoor Biologic and Chemical Exposures and Development of Asthma Biologic Agents Chemical Agents Sufficient Evidence of a Causal Relationship House dust mite (no agents met this definition) Sufficient Evidence of an Association (No agents met this definition) ETS (in preschool-age children) Limited or Suggestive Evidence of an Association Cockroach (in preschool-age children) (no agents met this definition) Respiratory syncytial virus (RSV) Inadequate or Insufficient Evidence to Determine Whether an Association Exists Cat NO 2, NOx Cow and horse Pesticides Dog Plasticizers Domestic birds Formaldehyde Rodents Fragrances Cockroaches (except for preschool-age ETS (in school-age and older children) children, and in adults) Chlamydia pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae Houseplants Pollen Limited or Suggestive Evidence of No Association Rhinovirus (adults) (no agents met this definition) concluded that there was an association between visible mold or mold odor in the workplace and adult-onset asthma (1.54; 1.01–2.32) in an analysis that controlled for the possible confounding influences of sex, age, parental atopy or asthma, education, smoking, ETS, pets, work indoors, self-reported occu- pational exposures, and signs of dampness or water damage (Jaakkola et al., 2002a). An earlier case-control study of adult asthma and self-reported damp- ness-related agents in the home (Thorn et al., 2001) reached like conclusions, finding an association with visible mold (2.2; 1.4–3.5) but not with visible dampness (1.3; 0.9–2.0). Similar results for males and females were obtained when the data were analyzed separately. That study, which examined 174 adult cases and 870 referents, controlled for age, sex, smoking habits, and atopy. Longitudinal study of birth cohorts is the best research design to exam- ine the onset of asthma in relation to environmental conditions. There is

228 DAMP INDOOR SPACES AND HEALTH TABLE 5-8 Selected Epidemiologic Studies—Asthma Development and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Dampness or Reference Subjects Mold Measure Risk Estimate Adults Population-based nested case-control studies Jaakkola et al., 521 newly diagnosed Visible mold or odor 1.54 (1.01–2.32) 2002a adult cases; 932 (work) controls Damp stains or paint 0.84 (0.56–1.25) peeling (work) Water damage (work) 0.91 (0.60–1.39) Visible mold or odor 0.98 (0.68–1.40) (home) Damp stains or paint 1.02 (0.73–1.41) peeling (home) Water damage (home) 0.90 (0.61–1.34) Thom et al., 174 adult (20–50 Self-reported visible 1.3 (0.9–2.0) 2001 old) asthma cases dampness diagnosed in last 15 Self-reported visible 2.2 (1.4–3.5) years; 870 referents mold growth Self-reported 1.8 (1.1–3.1) dampness or visible prevalence mold growth Children Nested and incident case-control studies Øie et al., 172 children <2 years Surveyor-verified 2.4 (1.25–4.44) 1999 old with bronchial for bronchial obstruction; 172 obstruction matched controls from population- based sample of 3,754 newboms (same population as Nafstad et al., 1998) Nafstad et al., 251 children <2 years Parent-reported 2.5 (1.1–5.5) 1998 old with bronchial dampness for bronchial obstruction and 251 obstruction controls (0–2 years Surveyor-verified 3.8 (2.0–7.2) old) from population- dampness for bronchial based sample of obstruction 3,754 newboms Inspector-observed 3.8 (2.0–7.2) dampness for bronchial obstruction first diagnosed

HUMAN HEALTH EFFECTS 229 TABLE 5-8 continued Dampness or Reference Subjects Mold Measure Risk Estimate Yang et al., 86 cases with first- Parent-reported 1.77 (1.24–2.53) 1998 time diagnosis of home dampness asthma and 86 controls (3–15 years old) Infante-Rivard, 457 newly diagnosed Parent-reported 1.89 (1.30–2.74) 1993 infant cases and 457 humidifier use controls (3–4 years old) Cohort Studies Slezak et al., 1,085 children in Head Self-reported 1.94 (1.23–3.04) 1998 Start programs (3–5 dampness self-reported, years old) or mold physician- diagnosed asthma Maier et al., 925 children (5–9 Water damage 1.7 (1.0–2.8) for 1997 years old) followed physician- prospectively for diagnosed asthma 1 year Other wetness 1.1 (0.6–1.8) for or no water physician- damage diagnosed asthma evidence that some environmental factors, such as ETS and allergens from house dust mites and cockroaches, cause allergic disease in genetically pre- disposed subjects (IOM, 2000). In a 2-year-long birth-cohort study of 3,754 children born in Oslo (Nafstad et al., 1998), exposure to indoor dampness problems increased the risk of development of clinically confirmed bron- chial-obstruction signs and symptoms (3.8; 2.0–7.2) in children 0–2 years old, even when the presence of house dust mites was controlled for. The association was observed regardless of whether the parents or trained in- spectors reported the dampness, but it was enhanced if both parents and trained inspectors reported it. A later paper on the same cohort (Øie et al., 1999) found that the adjusted OR for bronchial-obstruction signs and symptoms was higher in low-ventilation-rate homes (9.6; 1.05–87.45) than in high-ventilation-rate homes (2.4; 1.25–4.44); low-ventilation-rate homes had total air change rates of less than 0.5/hr while high were anything above that. The authors observed that the results were consistent with the hypothesis that low ventilation rates strengthen the effects of indoor air pollutants. Yang et al. (1998) examined the influence of indoor environmental factors on the development of asthma in children 3–15 years old. They drew 86 cases and 86 controls from patients at a teaching hospital in

230 DAMP INDOOR SPACES AND HEALTH southern Taiwan. Cases had a first-time physician diagnosis of asthma. The study found a statistically significant association between parent-reported home dampness and asthma (1.77; 1.24–2.53) when they controlled for age, sex, parental education, parental asthma, physician-confirmed allergy to food, breast-feeding, and even the presence of mold or dust. Infante-Rivard observed (1993) significant associations between first- time diagnosed asthma and the parent-reported use of a humidifier in the child’s bedroom (1.89; 1.30–2.74) after adjusting for maternal smoking and presence of an electric home-heating system in a case-control study of 914 children 3–4 years old. A 2001 study found an association between age and IgE sensitization to Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, and Penicillium chrysogenum in atopic children 0–15 years old, with maximal sensitization prevalence at about 8 (Nolles et al., 2001). A second study showed that children who attended a water-damaged school and had in- creased respiratory complaints were more likely to have high IgE values to a variety of common indoor allergens than were children who attended a reference school (Savilahti et al., 2001). However, Taskinen et al. (2002) did not find an association between asthma and IgG antibodies to molds in the schools of 126 screened children. In a 1997 study, Taskinen et al. compared 133 children in two schools— one with “moisture problems,” the other without—and observed that eight of nine asthma-diagnosed children attended the moisture-problem school. No data were provided on the date of diagnosis, but skin-prick tests re- vealed positive mold tests in six of the eight asthmatic children in the moisture-problem school. Two studies that were previously summarized in the discussions of wheeze and cough above also provide information related to asthma devel- opment. Gent et al. (2002) and Belanger et al. (2003) evaluated a cohort of 849 infants (<1 year old) who had at least one sibling with physician- diagnosed asthma. Belanger et al. (2003) used models that controlled for allergen concentrations, the presence of a gas or wood stove, maternal education, ethnicity, the sex of the child, smoking in the home, and respira- tory illness; measured mold or mildew was associated with wheeze (2.51; 1.37–4.62) and persistent cough (1.91; 1.07–3.42) in infants whose moth- ers had asthma. Gent et al. examined airborne concentrations of Penicil- lium, Cladosporium, and “other mold” in the cohort. (No other mold was found in enough households to allow separate analysis; the “other mold” spore count was determined by subtracting Penicillium and Cladosporium from the total.) They found an association between higher Penicillium concentrations and greater incidence of wheeze and persistent cough (p < 0.05 for trend) in an analysis that accounted for the influence of socioeco-

HUMAN HEALTH EFFECTS 231 nomic factors and housing characteristics. Neither Cladosporium nor “other mold” showed such a relationship. Persistent cough and wheeze in infancy is associated with a greater risk of asthma development. Research by Stark et al. (2003)—also cited below under “Respiratory Infections”—is related to this issue as well. Those investigators examined the incidence of croup, pneumonia, bronchitis, and bronchiolitis in a cohort of 499 infants genetically predisposed to asthma. They found associations between the illnesses and high concentrations of some microbial agents commonly found indoors in the United States (Penicillium, Cladosporium, Zygomycetes, and Alternaria). An independent association was found with measures of indoor dampness. There is an association between infection with one respiratory virus, respiratory syncytial virus, and later develop- ment of asthma (IOM, 2000). Other respiratory viruses cause exacerba- tions of acute severe wheeze in persons with established asthma but are not associated with the development of incident asthma (Gern et al., 1999). Conclusions In summary, studies reviewed by the committee indicate that • There is limited or suggestive evidence of an association between exposure to a damp indoor environment and the development of asthma. It is not clear whether this association reflects exposure to fungi, bacteria or their constituents and emissions, such other agents related to damp indoor environments as house dust mites and cockroaches, or some combination thereof. The responsible factors may vary among individuals. • There is inadequate or insufficient evidence to determine whether an association exists between the presence of mold or other agents in damp indoor environments and the development of asthma. The expo- sure-assessment problems in the papers examined and the small number of longitudinal studies performed limit the confidence that can be placed in their results. Hypersensitivity Pneumonitis Overview of the Evidence Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveo- litis, is a granulomatous lung disease that is the result of exposure and sensitization to antigens inhaled with a variety of organic dusts (Terho, 1982). Symptoms of acute HP include dry cough, dyspnea, and fever expe- rienced several hours after the causative exposure (Fraser et al., 1999). Acute bronchospasm may also be present. A subacute form of the disease has been described, and there is a chronic form of HP that may present with

232 DAMP INDOOR SPACES AND HEALTH pulmonary fibrosis (Yi, 2002). More detail on the diagnosis and etiology of HP are available in literature reviews on the disorder (Lacasse et al., 2003; Wild and Lopez, 2001). HP is diagnosed by collecting information from multiple sources. There is no single characteristic finding; clinicians need several pieces of evidence that make HP the most likely diagnosis before subjects are described as having it. These include a careful clinical and exposure history, environ- mental sampling for the presence of microorganisms known to cause HP, chest x-ray pictures and high-resolution CT scanning of the thorax, lung- function and serologic tests, and lung biopsy specimens. Circulating immu- nologic antibodies have been shown to have little value as markers for chronic HP (Cormier and Bélanger, 1989; Guernsey et al., 1989; Marx et al., 1990), but it is generally agreed that they are better used as indicators of recent high exposure to specific molds and thermophilic actinomycete anti- gens (Lacasse et al., 2003). HP has been described in case reports after environmental exposures to buildings contaminated with fungi in a variety of settings, including show- ers and home ultrasonic humidifiers (Hogan et al., 1996; Lee et al., 2000; Suda et al., 1995). Bacteria contaminating an ultrasonic cold-air home humidifier have been implicated as a causative agent (Kane et al., 1993), as have bacteria (thermophilic actinomycetes) that are able to tolerate very warm environments. A seasonal form of building-related HP caused by the fungus Trichosporon cutaneum is found mainly in Japan (Ando et al., 1995). Management of building-related HP includes standard medical therapy and removing sources of fungal contamination from the environment. In some cases, efforts to remove mold from a building are unsuccessful in relieving symptoms, and moving to another home or office may be neces- sary (Apostolakos et al., 2001). It is not uncommon for building-related illness to occur when, despite careful investigation, it is not clear whether the respiratory illness observed is HP or another clinical syndrome that is not yet defined (Trout et al., 2001). The possible role of mycotoxins in causing this type of respiratory illness was raised by Trout and colleagues. They found IgG antibodies to roridin-A, a tricothecene mycotoxin, in a person who had an illness sus- pected of being HP but whose clinical findings were not classic for this disorder. However, the test was not useful for distinguishing persons who were probably exposed to mold indoors from those who were not. Their paper raises the question of whether mycotoxins may have a role in acute and chronic lung injury in humans. Further exploration of the subject is needed, including research to find biomarkers that can be used to assess exposure to mycotoxins reliably. Exposure to disease-mediating organic material clearly is not the sole

HUMAN HEALTH EFFECTS 233 factor in determining whether a person will develop HP. Only a small minority of exposed people manifest the disease, and those who do are not necessarily the most highly exposed. Genetic factors also have a role, and research suggests that some polymorphisms may modify a person’s risk of the disease (Schuyler, 2001). Conclusions HP is a relatively rare immune-mediated condition, and only suscep- tible people exposed to a sensitizing antigen develop clinically significant disease. It has thus been studied with relation to specific agents rather than dampness in general. Studies reviewed by the committee indicate that there is sufficient evidence of an association between the presence of mold and bacteria in damp indoor environments and hypersensitivity pneumonitis in such people. Others are not at risk for this disease. Inhalation Fevers Inhalation fever is the general name given to any one of a number of influenza-like, self-limited syndromes caused by a heterogeneous group of stimuli (Blanc, 1997). Two that have been potentially associated with damp indoor environments are briefly addressed here. Humidifier fever is an illness that consists of a febrile reaction accom- panied by respiratory tract symptoms and fatigue. It does not manifest the radiographic or laboratory abnormalities consistent with HP and it is thought to be a nonimmunologic reaction (Baur et al., 1988). Organic dust toxic syndrome (ODTS) is a self-limiting noninfectious fe- brile illness that occurs after heavy organic-dust exposure by inhalation (Emanuel et al., 1975; Marx et al., 1981; Von Essen et al., 1990). Common symptoms include malaise, myalgia, headache, nonproductive cough, fever and nausea—symptoms that resemble those of acute HP. However, unlike HP, prior sensitization is not required in ODTS, serum precipitin antibodies against fungi are negative, the chest x-ray picture usually does not show infiltrates, there is no hypoxemia, there is no restriction or low CO diffusing capacity on lung-function testing. ODTS shares with HP the laboratory finding of leukocy- tosis with a predominance of neutrophils and a left shift during the acute phase. Overview of the Evidence Humidifier fever has been reported most commonly in industrial set- tings where workers are exposed to microorganisms—notably, thermo- philic actinomycetes but also including other bacteria and protozoa—grow- ing in humidification systems. However, humidifier fever has also been

234 DAMP INDOOR SPACES AND HEALTH reported in an office building where a culture of the water from the humidi- fier yielded Pseudomonas spp. (Forsgren et al., 1984) and may occur in offices where a humidifier in the air-conditioning system is in operation (Robertson et al., 1985). It is a short-term ailment, and removal of the individual from the environment or the contaminant from the air-handling system is effective. Little research has been published on humidifier fever in recent years, perhaps because increased attention to the health effects of contamination in humidifying systems has resulted in decreased incidence and decreased use of such systems. ODTS is well established as an ailment associated with occupational exposures in agricultural environments (Seifert et al., 2003a). Although it has been referred to as pulmonary mycotoxicosis (May et al., 1986), the relevant exposure is a complex mixture of bacteria, fungi, their byproducts, and other contaminants; the components responsible for the syndrome are not known (Blanc, 1997). As this chapter notes, some studies describe subjects who experience headache, nausea, or fatigue after exposure to damp indoor environments (Dales et al., 1991a,b; Hyndman, 1990; Koskinen et al., 1999a,b; Norbäck and Edling, 1991; Thorn and Rylander, 1998a,b; Wan and Li, 1999). ODTS has been identified as posing a risk for workers performing renovation work on building materials that are contaminated with fungi (NYCDOH, 2000) but has not, to the committee’s knowledge, been explored as a possible explanation of symptoms experienced by some occupants of highly contami- nated indoor environments. A paper by Kolmodin-Hedman et al. (1986) did describe a case of ODTS in a museum worker who had high airborne expo- sure from moldy books. Evidence indicates that ODTS is underrecognized as a diagnosis (Seifert et al., 2003b). Although concentrations of organic dust consistent with the development of ODTS are very unlikely to be found in homes or public buildings, clinicians should consider the syndrome as a possible explanation of symptoms experienced by some occupants of highly contaminated indoor environments. Conclusions Inhalation fevers are associated with occupational exposure to high concentrations of organic materials, including bacteria, fungi, and their associated constituents and emissions. Humidifier fever, which may have been a problem in the past in some industrial environments and office buildings, has not been identified in damp home environments. The com- mittee concludes that there is inadequate or insufficient evidence to deter- mine whether an association exists between indoor dampness or the pres- ence of mold or dampness-related agents and inhalation fevers in nonoccupational environments.

HUMAN HEALTH EFFECTS 235 Respiratory Infections Overview of the Evidence Immune-Compromised Persons Serious respiratory infections resulting from exposure to a variety of fungi, including Aspergillus spp. and Fusarium spp., are common in persons who undergo high-dose cancer chemotherapy, are recent recipients of a solid-organ transplant, or are otherwise immuno- compromised (DeShazo et al., 1997; Fridkin and Jarvis, 1996; Iwen et al., 2000; Patterson, 1999; Young et al., 1978). It is likely that many of these fungal infections are contracted through contact with fungi in some indoor environment because poor health leads people with severely impaired im- mune systems to spend most of or all their time indoors. It is less clear that the fungal exposure is related to the presence of moisture problems in the indoor spaces. Signs of water intrusion or damage are not typically noted in case reports of life-threatening fungal infections in severely immunocom- promised patients, but such reports rarely indicate that there was a specific investigation of potentially problematic environmental conditions or possible mold growth. Not all forms of immune compromise are the same: the suscep- tibility of hosts to different fungal infections or other fungal processes de- pends on the nature of their deficit. Further, fungal infections experienced by immune-compromised persons do not always involve genera and species that are typically associated with damp indoor environments. The lungs of persons with some chronic pulmonary disorders—such as cystic fibrosis, asthma, and COPD—may become colonized and potentially infected with Aspergillus. Clinical manifestations vary, depending on the status of the host’s immune system (Marr et al., 2002). In a cystic fibrosis or asthma patient, the presence of Aspergillus may result in worsening of the airway disease secondary to the hypersensitivity response called allergic bronchopulmonary aspergillosis (Greenberger, 2002). This disorder occurs predominantly in atopic subjects, and its manifestations include wheeze, pulmonary infiltrates, bronchiectasis, and fibrosis (Kauffman, 2003). Atopic persons may also develop sinus disease secondary to the presence of As- pergillus organisms (Stevens et al., 2000). The proposed mechanism of this disorder is damage to the epithelium and underlying tissue by the exagger- ated inflammatory response (Kauffman et al., 1995). It is usually not clear whether the exposure to Aspergillus occurred in the indoor environment or outdoors. Persons with COPD can develop respiratory failure secondary to invasive or semi-invasive pulmonary aspergillosis (Bulpa et al., 2001; Franquet et al., 2000). This outcome can also occur in persons with a variety of conditions that compromise the immune system, such as some malignancies (Stevens et al., 2000). The third disease process caused by Aspergillus is pulmonary aspergilloma, which is defined as a conglomera-

236 DAMP INDOOR SPACES AND HEALTH tion of Aspergillus hyphae matted together with fibrin, mucus, and cellular debris in a pulmonary cavity or ecstatic (stretched) bronchus (Stevens et al., 2000). Persons with this problem may be without symptoms or may suffer from clinically significant hemoptysis (coughing up blood or bloody spu- tum). Pulmonary aspergillosis can also lead to the invasive form of the disease. Otherwise-Healthy Persons A few studies have examined the association of the presence of fungi or other agents in damp indoor spaces with respira- tory infections or illnesses in otherwise-healthy children. Comparable stud- ies of adults were not identified. Studies reviewed by the committee are summarized below. A 1989 paper by Brunekreef et al. describes a study of 4,624 children 7–11 years old in homes in six U.S. cities. In analyses that controlled for other predictors of respiratory symptoms and illnesses, statistically signifi- cant associations were observed between parent-reported household mold and several respiratory illnesses (bronchitis: 1.48; 1.17–1.87; “chest ill- ness”: 1.40; 1.11–1.78; “lower respiratory illness”: 1.57; 1.31–1.87). Simi- lar results were obtained for the association with parent-reported home dampness (bronchitis: 1.32; 1.05–1.67; “chest illness”: 1.52; 1.20–1.93; “lower respiratory illness”: 1.68; 1.41–2.01). Dales and Miller (1999) evaluated parent-reported “chest illness” (otherwise unspecified) during the winter months in 403 elementary-school children in Wallaceburg, Ontario. Air and dust samples from the children’s bedrooms and living areas were analyzed for endotoxin; dust samples from those locations were also tested for the dust-mite allergens Der p 1 and Der f 1. After controlling for the presence of these factors and a set of child and family characteristics (child’s age and sex, parental allergies, parental edu- cation, and the presence of pets or smokers in the home), an OR of 1.51 (0.76–3.02) was reported for the association between parent-reported mold or mildew in the preceding 12 months and chest illness in the subjects. Stark and colleagues (2003) examined the incidence of four lower res- piratory illnesses—croup, pneumonia, bronchitis, and bronchiolitis—in a cohort of 499 infants of asthmatic or allergic parents (that is, a birth cohort at risk for asthma). Samples were taken in the infants’ bedrooms and ana- lyzed for four airborne and 11 dustborne fungal taxa at the start of the study. The risk of lower respiratory illnesses in the year after the sampling was associated with high (>90th percentile) indoor concentrations of Peni- cillium (airborne, RR, 1.73; 1.23–2.43), Cladosporium (dustborne, 1.52; 1.02–2.25), Zygomycetes (dustborne, 1.96; 1.35–2.83), Alternaria (dust- borne, 1.51; 1.00–2.28), or any fungus (1.86; 1.21–2.85). When the out- comes were separated by the presence or absence of wheeze, the relative risk of lower respiratory illness was greater without wheeze (3.88; 1.43–

HUMAN HEALTH EFFECTS 237 10.52) than with wheeze (1.58; 0.95–2.64). Three more general measures of dampness or microbial agents in the home—water damage (1.30; 0.97– 1.75), mold or mildew (1.33; 0.99–1.77), and either of these (1.32; 0.96– 1.80)—yielded similar ORs. The authors state that “the independent effects of visible mold or mildew suggest that dampness-related factors other than exposure to the common culturable fungi are important” in the outcomes they studied. Healthy persons exposed to damp or moldy indoor environments some- times report that they are more prone to respiratory infections, including the common cold, sinusitis, tonsillitis, otitis, and bronchitis. Some investi- gators have suggested that could be due to an immunosuppressive effect (Johanning et al., 1996). Chapter 4 reviews the evidence regarding myco- toxins and immune response. Other Evidence β(1→3)-glucans (also referred to as (1→3)-β-D-glucans, (1→3)-β- glucans, 1,3-beta-D-glucans, and other variants) have been implicated as a cause of the increased risk of respiratory infections in addition to serving as a marker for the presence of mold (Rylander et al., 1998). They are compo- nents of the cell walls of fungi and some bacteria. Concentrations of β(1→3)-glucans can be high in dust collected from buildings that have moisture problems and housing in which residents have no complaints (Gehring et al., 2001; Rylander, 1997). Airborne β(1→3)-glucans have been implicated in the presence of symptoms consistent with mucous mem- brane irritation syndrome, shortness of breath, other chest complaints, and lethargy and fatigue (Wan et al., 1999). There is also some evidence from animal studies that β(1→3)-glucans can potentiate allergen-induced eosino- phil infiltration (Wan et al., 1999). One study demonstrated a decrease in inflammatory cell numbers after experimental β(1→3)-glucan exposure (Fogelmark et al., 1992). Mouse experiments of Korpi et al. (2003) sug- gested that—with regard to previous fungal sensitization of the animals— inhaled β(1→3)-glucan may cause symptoms of respiratory tract irritation without apparent inflammation. It is not yet clear how those observations in animal studies apply to the risk of infection in humans exposed to β(1→3)-glucans. Fully characterizing their effects in environmental expo- sures of humans has been made more difficult by technical challenges in performing the necessary measurements. Conclusions Exposure to fungi in indoor environments is associated with severe respi- ratory infections in some severely immunocompromised persons. There is

238 DAMP INDOOR SPACES AND HEALTH sufficient evidence of an association between exposure to Aspergillus spp. and pulmonary aspergillosis and aspergillomas in such persons. Several less common fungi and bacteria can also induce characteristic infections; but these are uncommon disorders that have not been specifically associated with a damp indoor environment, and they are mentioned here for completeness. Available studies of respiratory illnesses in otherwise healthy people address children. Only Brunekreef et al. (1989) specifically account for indoor dampness, but its presence may be inferred in the other studies because mold is present. Together the available studies indicate that • There is limited or suggestive evidence of an association between exposure to a damp indoor environment and lower respiratory illness (oth- erwise unspecified) in otherwise-healthy children. • There is limited or suggestive evidence of an association between the presence of “mold” (otherwise unspecified) in a damp indoor environment and lower respiratory illness in otherwise-healthy children. • There is inadequate or insufficient evidence to determine whether an association exists between exposure to dampness or the presence of mold or other agents in damp indoor environments and respiratory illness in otherwise-healthy adults. Pulmonary Hemorrhage or Hemosiderosis Pulmonary hemorrhage or hemosiderosis is a pathologic condition char- acterized by an abnormal accumulation of hemosiderin, an iron-containing pigment, in lung tissue (Boat, 1998). It results from diffuse bleeding or hemorrhage in the alveoli, the portion of the lung where gas exchange occurs. Pulmonary hemorrhage may be reported at any age and in associa- tion with a variety of conditions. In children, those conditions include hypersensitivity to cow’s milk, also known as Heiner’s syndrome (Heiner et al., 1962). Autoimmune conditions—such as Goodpasture’s syndrome, Wegner’s granulomatosis, and celiac disease—may present with pulmonary hemorrhage (Boat, 1998). High-dose chemotherapy for cancer can cause it (Robbins et al., 1989). In some cases no etiology is identified. Pulmonary hemorrhage or hemosiderosis is most common in newborns, infants, especially those born prematurely. It is seen in about 55% of autop- sies performed on infants (van Houten et al., 1992). Pulmonary hemor- rhage can also be a subclinical, chronic condition that presents as iron deficiency, and alternatively, it can be episodically symptomatic or be mas- sive and life-threatening. Usually, the clinical picture is characterized by recurrent episodes of acute pulmonary bleeding with associated fever, tac- hypnea, and leukocytosis. Examination of the chest reveals bronchial breath sounds or diminished breath sounds, crackles, and wheeze. The patient may experience a cough productive of sputum and this sputum characteristically

HUMAN HEALTH EFFECTS 239 contains hemosiderin-laden macrophages. A chest x-ray picture usually demonstrates infiltrates, which are typically fleeting and eventually evolve to a reticulonodular pattern. Treatment of pulmonary hemorrhage or hemosiderosis consists primar- ily of providing supportive care. Drug therapy with high-dose corticoster- oids or immunosuppressive agents may be beneficial. Typically, the disease evolves into a chronic form with interstitial fibrosis, pulmonary hyperten- sion, and right-sided heart failure. The disease can be fatal. At autopsy, hemosiderin-laden macrophages may be found in lung tissue at the site of bleeding. Overview of the Evidence Investigators described eight cases of acute pulmonary hemorrhage or hemosiderosis in infants presenting at a Cleveland children’s hospital in 1993–1994 (CDC, 1994). Milk-protein allergies, congenital heart or vascu- lar malformations, infectious processes, trauma, and other causes of pul- monary hemorrhage in infants were ruled out. The investigators noted that the cluster of cases was characterized by the geographic proximity of the infants’ homes (all were in the eastern metropolitan area of Cleveland) and by the race or ethnicity of the cases (all were black). A later report observed that most homes in the area where the infants lived were more than 60 years old and inadequately maintained and that there was a comparatively high rate of poverty in the area: 48% of all the children in the area lived below the poverty level (Dearborn et al., 1999). A follow-up report (CDC, 1997) and two papers by the Cleveland investigators (Etzel et al., 1998; Montaña et al., 1997) included the findings from a case-control study and an assessment of infant-death cases con- ducted by the county coroner. The case-control study matched 10 case infants (two additional cases were identified after the 1994 report was published)—a case was defined as an episode of acute, diffuse pulmonary hemorrhage of unknown etiology in a previously healthy infant in the first year of life and requiring hospitalization—with 30 control infants matched for age and residence in the same geographic area of Cleveland. All case infants and seven of the 30 control infants lived in homes where “major” water damage had occurred during the preceding 6 months. Later visual inspection of those homes and aggressive air sampling revealed a higher concentration of Stachybotrys atra (now called S. chartarum) in the resi- dences of case infants than in those of control infants (1.6; 1.0–30.8)6 6Research later showed that some strains of S. chartarum can produce mycotoxins, includ- ing hemolysin, tricothecenes, and atranones (Jarvis et al., 1998; Vesper et al., 2000). In animal models, spores of these toxic strains induce pulmonary inflammation and hemorrhage (Flemming et al., 2004; Nikulin et al., 1997; Rand et al., 2002, 2003; Yike et al., 2002). Chapter 4 addresses this literature in greater detail.

240 DAMP INDOOR SPACES AND HEALTH (CDC, 1997). Case infants were also more likely to have been in the pres- ence of environmental tobacco smoke before their illness (7.9; 0.9–70.6). The small numbers of cases and controls limited the statistical confidence with which any associations could be assessed. The 1997 Centers for Disease Control and Prevention (CDC) report noted that “based on the findings of the case-control study, health authori- ties in Cleveland recommended prompt clean-up and disposal of all moldy materials in the water-damaged homes and have designed a prevention program focusing on water-damaged homes.” An editorial note that ac- companied the report concluded, however, that further efforts were needed to identify what association, if any, existed between pulmonary hemor- rhage in infants and exposure to water-damaged building materials. In 1997, CDC convened an internal scientific taskforce and a panel of outside experts was chosen to review the possible association between pul- monary hemorrhage/hemosiderosis in infants and S. chartarum in the in- door environment (CDC External Expert Panel, 1999; CDC Working Group, 1999). The results of those independent investigations were re- viewed in a 2000 issue of Morbidity and Mortality Weekly Report (CDC, 2000). The publication noted that both groups of reviewers considered that the interpretation of an epidemiologic association between household wa- ter damage and the Cleveland cases was hampered by a lack of consistent criteria for defining water damage, an absence of a standardized protocol for inspecting and gathering data on the presence of fungi in individual homes, a failure to distinguish between contamination and clinically signifi- cant exposure to fungi, and a failure to obtain isolates of or serologic evidence of exposure to fungi or mycotoxin from case-infants. Reviewers were also critical of the analytic methods used in the original study. The reported OR associating S. chartarum concentrations for each household was judged to be “unstable” in part because of inconsistent methods for sampling and a “potential misleading” strategy for matching cases and controls. The groups concluded that S. chartarum was not clearly associ- ated with acute pulmonary hemorrhage or hemosiderosis in infants, be- cause of issues concerning environmental sampling methods and statistical methods, the fact that sampling was not performed in a blinded fashion,7 and the small difference in the presence of culturable S. chartarum between water-damaged case and control homes. The Cleveland cases (and cases in a Chicago outbreak mentioned in the 7The 2000 MMWR publication notes (p. 182) that “one investigator correctly inferred the identity of many case homes and wanted to be certain to identify culturable fungi in these homes if they were present. As a result, the investigator collected twice the number of air samples from case homes as were collected from control homes.”

HUMAN HEALTH EFFECTS 241 paper) appeared different from classically described idiopathic pulmonary hemosiderosis, and the term acute idiopathic pulmonary hemorrhage (in infants) (AIPH) was proposed to describe them (CDC, 2000). (CDC later proposed a case definition for “acute idiopathic pulmonary hemorrhage in infants,” or AIPHI [CDC, 2001].) The CDC working group indicated that it did not reject a possible relationship between S. chartarum and AIPH in the Cleveland cluster (CDC External Expert Panel, 1999). However, the editorial note that accompa- nied the 2000 CDC report was highly critical of the original findings in the 1997 report and advised that conclusions regarding the possible asso- ciation between cases of pulmonary hemorrhage/hemosiderosis in infants in Cleveland and household water damage or exposure to S. chartarum are not substantiated adequately by scientific evidence produced in the CDC investigation. . . . The associations should be considered not proven; the etiology of AIPH is unresolved. In noting those shortcomings in the collection, analysis, and reporting of study data, the editorial note indicated that a number of actions would be taken by CDC, including • The continuing investigation of AIPH cases, particularly if clusters of such cases could be identified. • The standardization of protocols for data collection and environ- mental assessment to ascertain the possible association between AIPH and environmental etiologies, such as household water damage and exposure to S. chartarum and other fungi. • The implementation of surveillance of AIPH in infants, either in clusters or in individual cases, and the development of a consistent standard surveillance case definition for reporting. • The development of enhanced sampling and laboratory analytic methods for the assessment of environmental exposures to molds and fungi. The Cleveland researchers posted a response to the 2000 CDC report on the World Wide Web that offered rebuttals to the criticisms (Etzel et al., undated). Separately, a 2003 paper by Etzel argued that available evidence regarding Stachybotrys exposure and AIPHI fulfills the Bradford Hill crite- ria of causality (Etzel, 2003). Dearborn et al. (2002), however, maintain that although the potential role of Stachybotrys toxins is suggested by the data, additional evidence is needed to support causation. “The possibility remains that the presence in the infants’ homes of Stachybotrys, a high water-requiring fungus, may simply be an indicator of water intrusion, and other unknown, related factors (in addition to ETS) may play primary or secondary causative roles.”

242 DAMP INDOOR SPACES AND HEALTH Additional individual cases of acute pulmonary hemorrhage in infants in indoor environments where S. chartarum or other fungi are present have been described in Cleveland and elsewhere (CDC, 1997; Dearborn et al., 2002; Elidemir et al., 1999; Flappan et al., 1999; Knapp et al., 1999; Novotny and Dixit, 2000; Tripi et al., 2000; Weiss and Chidekel, 2002). Toxigenic fungal exposure has been suggested as a factor, but its role is yet to be determined. Conclusions The role of Stachybotrys chartarum in the Cleveland AIPH cluster and other AIPH cases remains controversial. The committee did not undertake to reanalyze the Cleveland outbreak data, and it is not in a position to second-guess either the researchers or those who reviewed their work. It does offer the following observations on the basis of published materials. Toxicologic data (discussed in Chapter 4) indicates that exposure to at least some strains of S. chartarum affects the lungs of young animals, although these observations require validation from more extensive re- search before conclusions can be drawn. The human data are equivocal. S. chartarum is not uncommon, and, although theories have been put for- ward,8 no compelling explanation has been presented for its causing such adverse health outcomes in the Cleveland cluster and some other isolated cases but not elsewhere. The Cleveland case infants lived in homes distin- guished by a number of factors that may have contributed to poor health. The influence of some of those factors was explored in the analysis of the cluster, but the small number of cases and the retrospective nature of the data collection necessarily limited the evaluation. The possible synergistic influence of ETS mentioned by some investigators (Dearborn et al., 2002; Montaña et al., 1997; Novotny and Dixit, 2000) is especially interesting in this regard, given the known adverse effects of ETS on infants. The committee concludes that available case-report information, taken together, constitutes inadequate or insufficient information to determine whether an association exists between AIPHI and the presence of Stachy- botrys chartarum or agents present in damp indoor spaces in general. AIPHI is a serious health outcome, and the committee encourages the CDC to pursue surveillance and additional research on the issue to resolve out- standing questions. Epidemiologic and case studies should take a broad- based approach to gathering and evaluating information on exposures and 8 Vesper and Vesper (2002) have suggested that strain differences may help to explain why pulmonary hemorrhage occurred in some homes infested with S. chartarum and not others. In the absence of information on the ubiquity of the strains found in the Cleveland infants’ homes, it is not possible to evaluate the merit of this suggestion.

HUMAN HEALTH EFFECTS 243 other factors that would help to elucidate the etiology of acute pulmonary hemorrhage or hemosiderosis in infants, including dampness and agents associated with damp indoor environments; ETS and other potentially ad- verse exposures; and social and cultural circumstances, race/ethnicity, hous- ing conditions, and other determinants of study subjects’ health. OTHER HEALTH COMPLAINTS AND DISORDERS Although the health problems most often associated with dampness and dampness-related agents are respiratory, concerns have also been raised about other health outcomes. This section addresses several of them. Many of the epidemiologic studies cited here are wide-ranging examinations of health complaints rather than specific assessments of particular outcomes. The committee’s judgment about the association between exposure to damp indoor spaces or the presence of mold or other agents in damp in- door environments and these health outcomes is discussed at the end of the section. Skin It is well established that severely immunocompromised patients—for example, those treated with immunosuppressive drugs during transplanta- tion procedures, cancer patients receiving chemotherapy, AIDS patients— can develop opportunistic cutaneous and subcutaneous fungal infections of the skin (Wald et al., 1997). Trichothecenes are established dermal irritants. (The dermal toxicity of mold, bacteria, and their constituents is addressed in Chapter 4.) Questions have been raised about whether eczema (eczematous derma- titis) and atopic dermatitis may be related to damp indoor environments. Eczema is a characteristic inflammatory response of the skin to multiple stimuli. There is usually a primary elicitor of the response (such as an allergen), after which many factors may contribute. The unifying feature of eczema is the occurrence of raised erythematous, scaly skin lesions that are extremely pruritic (that is, they provoke itching). The initial diagnosis is based on the patient’s medical history and the appearance of the skin; occasionally, skin biopsy is used. Atopic dermatitis is associated with IgE allergy and often with a family history of atopy. The striking feature of the disease is severe, spasmodic itching. The diagnosis is based on the patient’s medical history and physical examination and on identification of IgE al- lergy with skin tests for specific antibody in the serum. Table 5-9 summarizes studies that address dermal outcomes in the general population. The outcomes are eczema and dermatitis, which are diagnosed conditions; irritation, a symptom that may be frank; and “skin

244 DAMP INDOOR SPACES AND HEALTH TABLE 5-9 Selected Epidemiologic Studies—Skin Problems and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Dampness or Reference Subjects Mold Measure Risk Estimate Cross-sectional studies Engvall et al., 3,241 adults Self-reported odor 2.45 (2.25–2.66) 2002 and water leakage for facial skin in last 5 years irritation Kilpeläinen 10,667 students Self-reported visible 1.31 (0.96–1.79) et al., 2001 (18–25 years old) mold for atopic dermatitis Self-reported visible 1.29 (1.06–1.56) mold, damp stains, for atopic dermatitis or water damage Koskinen 699 adults (16+ Surveyor-assessed 1.03 (0.71–1.49) et al., 1999a years old) in 310 moisture for eczema households 1.18 (0.76–1.83) for atopic eczema 1.06 (0.64–1.78) for allergic eczema Self-reported mold 1.40 (0.93–2.10) for eczema 1.18 (0.73–1.90) for atopic eczema 0.77 (0.43–1.38) for allergic eczema Wan and Li, 1,113 workers in 19 Self-reported mold 2.97 (1.52–5.82) 1999 office buildings for skin symptoms Li et al., 1997 612 day-care workers Self-reported mold 0.58 (0.21–1.60) for allergic eczema 1.95 (1.30–2.91) for skin symptoms Self-reported water 1.55 (0.58–4.14) damage for allergic eczema 2.04 (1.35–3.08) for skin symptoms Pirhonen 1,460 adults Self-reported damp 1.21 (0.86–1.71) et al., 1996 (25–64 years old) or mold problem for allergic eczema 1.31 (0.97–1.76) for atopic eczema Waegemaekers 190 children Self-reported damp 1.65 (1.11–2.46) et al., 1989 homes for skin irritation

HUMAN HEALTH EFFECTS 245 symptoms,” a nonspecific complaint. It should be noted that eczema and atopic dermatitis are sometimes (incorrectly) used interchangeably. Studies that examine eczema and dermatitis report ORs of 0.58–1.55; the confidence intervals of all but one include unity. The four papers that address less specific outcomes—irritation or “skin symptoms”—note statis- tically significant associations with measures of dampness or mold, but it is difficult to assess the implications of these results in the absence of details on the nature of the skin problem or controls for the possibility that the symptom is a characteristic of some other health outcome. The committee notes that future research examining the possible association of microbial exposure with skin symptoms should include stratification by allergic sta- tus, or by preexisting eczema or allergic disease when possible. Gastrointestinal Tract A review article by Peraica et al. (1999) notes that ingestion of my- cotoxins in moldy foodstuffs can lead to gastrointestinal symptoms in hu- mans. Nausea, vomiting, and diarrhea are sometimes reported by persons exposed to dampness and molds in indoor spaces (Dales et al., 1991a), but relatively few epidemiologic studies have evaluated the association between these symptoms and damp indoor conditions. Table 5-10 summarizes the results of some of the studies that have examined nausea as an outcome. Most of the studies report nonsignificant increases in incidence in self- reported symptoms. An early study by Waegemaekers et al. (1989) yielded a statistically significant increase in parent-reported nausea and vomiting in their children, but the authors note that the sample was self-selected among people who expressed health concerns and that respondent bias might be influencing the results. In a controlled human-exposure study, Thorn and Rylander (1998b) examined the responses of 21 healthy adult volunteers who inhaled 40 µg of lipopolysaccharide (endotoxin) under controlled con- ditions. Four reported nausea 24 hrs later; two, diarrhea. Gastrointestinal complaints have a large differential diagnosis, which complicates analyses. Other causes of the symptoms need to be ruled out before it is concluded that these outcomes are secondary to a dampness- related agent. The independent influence of mold odors, which was not controlled for in many of the cited studies, also needs to be considered. Fatigue Fatigue is a common nonspecific complaint that can be caused by a long list of physical and psychiatric disorders. Lifestyle choices, such as long work hours and irregular sleep habits, can contribute to fatigue. Clini- cians approach this problem by ruling out a variety of disorders.

246 DAMP INDOOR SPACES AND HEALTH TABLE 5-10 Selected Epidemiologic Studies—Nausea and Related Symptoms and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Dampness or Reference Subjects Mold Measure Risk Estimate Cross-sectional studies Koskinen et al., 699 adults Surveyor-assessed 1.23 (0.85–1.80) 1999a (16+ years old) moisture for nausea in 310 households Self-reported mold 1.36 (0.90–2.06) for nausea Koskinen et al., 204 children Surveyor-assessed 1.62 (0.78–3.37) 1999b (≤ 15 years old) moisture for nausea, in 310 households 7–15 years old Self-reported mold 2.11 (1.01–4.42) for nausea, 7–15 years old Pirhonen et al., 1,460 adults Self-reported damp 1.80 (0.87–3.71) 1996 (25–64 years old) or mold problem for nausea 1.65 (1.24–2.20) for recurrent stomach ache Waegemaekers 190 children Self-reported damp 3.13 (1.29–5.26) et al., 1989 homes for nausea, vomiting Table 5-11 summaries the results of studies of people in damp and moldy environments in which fatigue was examined. As evidenced by rather broad confidence intervals, data on relatively small numbers of people were analyzed in some of the studies. There is evidence that exposure to molds causes release of proinflam- matory cytokines, including TNFα and IL-6. (Hirvonen et al., 1999). Thorn and Rylander (1998b) reported that 12 of 21 subjects (p < 0.001) who voluntarily inhaled 40 µg of lipopolysaccharide (endotoxin) reported “un- usual tiredness” 24 hrs later. The researchers speculated that the outcome might have been mediated by TNFα activity. A variety of disorders character- ized by release of cytokines into peripheral blood are associated with fatigue, but it is not known whether the cytokines are the cause of that symptom. Bhattacharyya (2003) reports a coincidence between fatigue and chronic rhinosinusitis, noting that 32% of 322 chronic-rhinosinusitis patients sur- veyed report the symptom (the presence of dampness or mold was not addressed); it is not clear whether this suggests a confounding factor in some reports of fatigue or whether the outcomes might have a common cause.

HUMAN HEALTH EFFECTS 247 Neuropsychiatric Symptoms Self-reported cognitive defects and difficulties in concentrating are sometimes noted by people who occupy damp or moldy buildings (Johan- ning et al., 1996; Koskinen et al., 1999a,b; Sudakin, 1998). Such com- plaints, however, are notoriously difficult to quantify. The committee did not identify any well-defined epidemiologic studies that conducted neuropsychiatric testing of individuals and accounted ex- plicitly for dampness or the presence of mold. It did, however, find three small-sample case studies in the peer-reviewed, medical literature, and they are mentioned here for completeness. (Chapter 4 addresses the literature on the neurologic effects of mycotoxin exposure in animals.) Hodgson et al. (1998) investigated a set of three buildings in which occupant health complaints had been reported. Stachybotrys chartarum and Aspergillus spp. were identified on moisture-damaged interior surfaces and in air samples taken in these structures. Three neuropsychologic tests (in addition to medical testing and a questionnaire) were administered to 14 occupants selected by the building’s insurance carrier and to 47 volunteer occupants. The subjects’ results on trial I of the California Verbal Learning Test (CVLT), the dominant-hand time for the Grooved Pegboard Test, and the CVLT long-delay cued-recall test were better than or similar to results of two sets of undocumented controls. More recently, Baldo et al. (2002) administered the San Diego Neuro- psychological Test Battery to 10 adults who had been involved in litigation regarding their exposure to mold. The type of molds they had been exposed to and the duration and setting of the exposure varied among the subjects. The authors found no consistent pattern of test results among the subjects but noted that deficits (relative to normative data) in visuospatial learning, visuospatial memory, verbal learning, and psychomotor speed were ob- served more frequently than deficits in other assessed functions. There was also a significant correlation (Pearson product moment correlation, one- tailed, 0.47; p < 0.05) between a measure of depression (the Beck Depres- sion Inventory, second edition) and the number of cognitive impairments identified in testing of a subset of seven subjects. Anyanwu et al. (2002) identify a unique disorder that they term acous- tic mycotic neuroma and that they state is frequently observed in their clinic. The authors report that four adolescent boys with a variety of physi- cal and mental symptoms and mold exposure were evaluated with brainstem auditory evoked response testing. Waveform abnormalities were reported in the subjects; specifics varied except for one to three interpeak latencies (a measure of acoustic-nerve dysfunction), which were outside the expected range of results in all subjects. It has been shown that inhalation of odorants can activate the temporal

248 TABLE 5-11 Selected Epidemiologic Studies—Fatigue and Related Symptoms and Exposure to Damp Indoor Environment or Presence of Mold or Other Agents in Damp Indoor Environments Reference Subjects Dampness or Mold Measure Risk Estimate Cross-sectional studies Engvall et al., 2002 3,241 adults Self-reported odor and water 2.54 (2.38–2.71) leakage in last 5 years for tiredness Lander et al., 2001 86 workers in moist Histamine-release test (HRT) 1.81 (0.70–4.65) for buildings with mold positive for 1 or more molds fatigue growth Test positive for Penicillium 3.60 (1.09–11.86) for chrysogenum fatigue Koskinen et al., 1999a 699 adults (16+ years Surveyor-assessed moisture 1.50 (0.88–2.56) for old) in 310 households fatigue Self-reported mold 3.97 (1.67–9.46) for fatigue Koskinen et al., 1999b 204 children (≤ 15 years Surveyor-assessed moisture 0.93 (0.37–2.33) old) in 310 households for fatigue 7–15 years old Self-reported mold 1.48 (0.55–4.01) for fatigue 7–15 years old

Wan and Li, 1999 1,113 workers in 19 Self-reported mold 1.32 (0.81–2.17) for office buildings lethargy/fatigue Self-reported water damage 0.96 (0.56–1.63) for lethargy/fatigue Self-reported flooding 1.12 (0.60–2.03) for lethargy/fatigue Thorn and Rylander, 129 adults Measured airborne glucan 1.11 (0.79–1.55) for 1998a (18–83 years) (>2–4 ng/m3) unusual tiredness Measured airborne glucan 0.95 (0.68–1.33) for (>4 ng/m3) unusual tiredness Li et al., 1997 612 day-care workers Self-reported mold 1.89 (1.25–2.87) for fatigue Self-reported water damage 1.99 (1.35–2.92) for fatigue Pirhonen et al., 1996 1,460 adults Self-reported damp or mold 1.81 (1.37–2.39) (25–64 years) problem for fatigue or tiredness Waegemaekers et al., 1989 190 children Self-reported damp homes 2.40 (1.68–3.44) for tiredness 249

250 DAMP INDOOR SPACES AND HEALTH lobe of the cerebral cortex (Kettenmann et al., 1996), and exposure to odorous emissions from animal operations, wastewater treatment, and re- cycling of biosolids has been associated with stress and alterations of mood (Schiffman et al., 2000). Damp and mold-contaminated buildings com- monly have a musty odor that people find unpleasant, but the neurophysi- ologic effect of such odors has not been studied. Odor perception, however, does offer a possible explanation of some reported problems. Sick Building Syndrome Sick building syndrome (SBS) is a term used to describe a combination of nonspecific symptoms related to residence or work in a particular building. Thörn (1999) identifies the core symptoms associated with SBS as • Irritation of the eyes, nose and throat, cough. • Experience of dry skin, rash, pruritus. • Fatigue, headache, lack of concentration. • High frequency of respiratory tract infections. • Hoarseness, wheezing, shortness of breath. • Nausea, dizziness. • Enhanced or abnormal odor perception. Researchers studying SBS incidence and etiology vary in their require- ments for which or how many symptoms must be present over what period of time in order for a subject to be defined as a case. Chemical contami- nants, biologic contaminants (including molds, bacteria, and viruses), inad- equate ventilation, odor perception, thermal comfort, and psychological factors have all been suggested as putative causes (Ebbehøj et al., 2002; Hodgson, 2002; Seppänen and Fisk, 2002). Because of the lack of consis- tent diagnostic criteria, the committee chose not to address SBS as a sepa- rate clinical outcome. The report does address individual symptoms that have been associated with SBS in the discussions above. Cancers Several common fungi can produce mycotoxins that are carcinogenic in at least some animal species (Rao, 2000). As discussed in Chapter 4, inges- tion of some molds—typically as contaminants in grain—has been associ- ated with cancers in humans. The committee did not identify any peer- reviewed scientific literature that addressed microbial agents found indoors and the inhalation route of exposure. A 2002 study showed that human

HUMAN HEALTH EFFECTS 251 lung cells can activate cytotoxic and DNA-reactive intermediates from afla- toxin (Van Vleet et al., 2002). However, a laboratory study of microbial volatile organic compounds found that DNA damage occurred only in circumstances where cytotoxic effects were also seen; neither clastogenic nor mutagenic effects were observed (Kreja and Seidel, 2002). Reproductive Effects Measuring the effects of exposures on reproductive outcomes is chal- lenging because of the large number of factors that contribute to these outcomes. The committee did not identify any peer-reviewed published data on agents or exposure routes relevant to damp conditions indoors. Rheumatologic and Other Immune Diseases Rheumatologic diseases are characterized by inflammation and stiff- ness or pain in muscles, joints, or fibrous tissue and other symptoms. People suffering from such diseases often note that they are exacerbated by envi- ronmental conditions, including dampness, and changes in weather. Atten- tion has been paid to the possibility that exposure to damp indoor spaces might cause rheumatologic conditions because fungi and their constituents can trigger immune responses that result in inflammation. There is some evidence that cold, damp indoor spaces causes erythema- tous skin lesions known as chilblain lupus erythematosus of Hutchinson, but there is little evidence that this problem is associated with systemic lupus erythematosus (Franceschini et al., 1999). In patients with existing rheumatologic arthritis, damp weather increases complaints of stiffness (Rasker et al., 1986). A 2002 study described a cluster of persons with several different rheumatologic diseases (rheumatoid arthritis, ankylosing spondylitis, Sjogren’s syndrome, and psoriatric arthritis) who worked in a water-damaged building contaminated by microbial growth, including molds (Myllykangas-Luosujärvi et al., 2002). It could not be discerned whether particular agents had accounted for this cluster. A broader study of workers in the building measured a series of potential biomarkers in nasal lavage fluids, induced sputum, and serum of occupants who had rheumatic or respiratory disorders and of controls in the same workplace (Roponen et al., 2001b). It was concluded that IL-4 was significantly higher in cases than in control subjects and in all workers when at work vs away on vacation. That implied that IL-4—which down-regulates Th-1-mediated inflammatory responses and up-regulates Th-2—might play a role in both the respiratory and rheumatologic disorders that were observed. It was also observed that higher exhaled NO concentrations were associated with res-

252 DAMP INDOOR SPACES AND HEALTH piratory symptoms. A follow-up study (Ropenen et al., 2003) monitored concentrations of inflammatory mediators in nasal lavage fluids from 12 healthy volunteers over a 1-year period. Substantial individual and sex variability suggested that the measure was most appropriate when subjects could be used as their own controls. Additional studies are needed to ex- plore the relationship between IL-4, exhaled NO, respiratory and rheu- matologic disease, and microorganism-contaminated indoor spaces. More generally, studies by Hirvonen et al. (2001) and Roponen et al. (2001a) indicate experimentally that the ability of spores of a bacterium found in some damp environments (Streptomyces anulatus) to produce an inflammatory response depended on the building material it grew on. Beijer et al. (2003) examined inflammatory markers in the blood of non- smoking persons in homes with either “high” (>4.0 ng/m3) or “low” (<2.0 ng/m3) airborne concentrations of β(1→3)-D-glucan, which was used as a surrogate of mold exposure. Among nonatopic subjects, the ratio between interferon gamma and IL-4 was significantly higher in the high-airborne- concentration group than in the low-airborne-concentration group. The authors suggest that this effect on inflammatory markers indicates that mold exposure may stimulate some parts of the inflammatory-immuno- logic system. Conclusions Few epidemiologic studies have examined damp or “moldy” environ- ments and skin, gastrointestinal tract, fatigue, neuropsychiatric, cancers, reproductive, and rheumatologic outcomes. Studies that are available have tended to address the outcomes only as a part of a survey of signs, symp- toms, and diseases. In some cases, the outcomes have been anecdotally related to the environments; in others, effects have been noted in high-level (often ingestion) exposure scenarios in humans or animals. Generally, rela- tively little attention has been paid to evaluating or controlling for other potential explanations of the reported problem. The association between fungal exposures and opportunistic fungal infections of the skin of severely immunocompromised persons is well es- tablished. For all the other listed outcomes, the committee concludes that there is inadequate or insufficient information to determine whether an association exists between them and exposure to a damp indoor environ- ment or the presence of mold or other agents associated with damp indoor environments. A small number of case studies have associated those adverse health outcomes with damp or moldy environments but only in persons with highly compromised immune systems or when the circumstances, such as ingestion of contaminated foodstuffs, are not relevant to this report.

HUMAN HEALTH EFFECTS 253 FINDINGS, RECOMMENDATIONS, AND RESEARCH NEEDS Research on health outcomes that may be associated with damp indoor environments is challenging: formidable study-design issues and prohibitive costs are associated with comprehensive investigations. Chapter 3 delin- eates the committee’s finding that the limitations of knowledge regarding indoor microbial agents and related health problems are due primarily to a lack of valid quantitative methods for assessing exposure. It also offers research recommendations to address that problem. On the basis of its review of the papers, reports, and other information presented in this chapter, the committee has reached the following findings and recommendations and has identified the following research needs re- garding the human health effects of damp indoor environments. Findings Tables 5-12 and 5-13 summarize the committee’s findings on the state of the scientific evidence regarding the association between various health outcomes and exposure to damp indoor environments or the presence of TABLE 5-12 Summary of Findings Regarding the Association Between Health Outcomes and Exposure to Damp Indoor Environmentsa Sufficient Evidence of a Causal Relationship (no outcomes met this definition) Sufficient Evidence of an Association Upper respiratory (nasal and throat) tract symptoms Wheeze Cough Asthma symptoms in sensitized asthmatic persons Limited or Suggestive Evidence of an Association Dyspnea (shortness of breath) Asthma development Lower respiratory illness in otherwise-healthy children Inadequate or Insufficient Evidence to Determine Whether an Association Exists Airflow obstruction (in otherwise-healthy persons) Skin symptoms Mucous membrane irritation syndrome Gastrointestinal tract problems Chronic obstructive pulmonary disease Fatigue Inhalation fevers (nonoccupational exposures) Neuropsychiatric symptoms Lower respiratory illness in otherwise-healthy adults Cancer Acute idiopathic pulmonary hemorrhage in infants Reproductive effects Rheumatologic and other immune diseases aThese conclusions are not applicable to immunocompromised persons, who are at increased risk for fungal colonization or opportunistic infections.

254 DAMP INDOOR SPACES AND HEALTH TABLE 5-13 Summary of Findings Regarding the Association Between Health Outcomes and the Presence of Mold or Other Agents in Damp Indoor Environmentsa Sufficient Evidence of a Causal Relationship (no outcomes met this definition) Sufficient Evidence of an Association Upper respiratory (nasal and throat) tract symptoms Wheeze Asthma symptoms in sensitized asthmatic persons Cough Hypersensitivity pneumonitis in susceptible personsb Limited or Suggestive Evidence of an Association Lower respiratory illness in otherwise-healthy children Inadequate or Insufficient Evidence to Determine Whether an Association Exists Dyspnea (shortness of breath) Skin symptoms Airflow obstruction (in otherwise-healthy persons) Asthma development Mucous membrane irritation syndrome Gastrointestinal tract problems Chronic obstructive pulmonary disease Fatigue Inhalation fevers (nonoccupational exposures) Neuropsychiatric symptoms Lower respiratory illness in otherwise-healthy adults Cancer Rheumatologic and other immune diseases Reproductive effects Acute idiopathic pulmonary hemorrhage in infants aThese conclusions are not applicable to immunocompromised persons, who are at increased risk for fungal colonization or opportunistic infections. bFor mold or bacteria in damp indoor environments. mold or other agents in damp indoor environments. As already noted, fungi and bacteria are omnipresent in the environment, and the committee re- stricted its evaluation to circumstances that could be reasonably associated with damp indoor environments. Studies regarding homes, schools, and office buildings were considered; such other indoor environments as barns, silos, and factories—which may subject people to high occupational expo- sures to organic dusts and other microbial contaminants—were not. The tables’ conclusions are not applicable to persons with compromised im- mune systems, who are at risk for fungal colonization and opportunistic infections. The committee considered whether any of the health outcomes addressed in this chapter met the definitions for the categories “sufficient evidence of a causal relationship” and “limited or suggestive evidence of no association” defined in Chapter 1, and concluded that none did. Recommendations and Research Needs • Indoor environments subject occupants to multiple exposures that may interact physically or chemically with one another and with the other

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Almost all homes, apartments, and commercial buildings will experience leaks, flooding, or other forms of excessive indoor dampness at some point. Not only is excessive dampness a health problem by itself, it also contributes to several other potentially problematic types of situations. Molds and other microbial agents favor damp indoor environments, and excess moisture may initiate the release of chemical emissions from damaged building materials and furnishings. This new book from the Institute of Medicine examines the health impact of exposures resulting from damp indoor environments and offers recommendations for public health interventions.

Damp Indoor Spaces and Health covers a broad range of topics. The book not only examines the relationship between damp or moldy indoor environments and adverse health outcomes but also discusses how and where buildings get wet, how dampness influences microbial growth and chemical emissions, ways to prevent and remediate dampness, and elements of a public health response to the issues. A comprehensive literature review finds sufficient evidence of an association between damp indoor environments and some upper respiratory tract symptoms, coughing, wheezing, and asthma symptoms in sensitized persons. This important book will be of interest to a wide-ranging audience of science, health, engineering, and building professionals, government officials, and members of the public.

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