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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), Pieckov and Jesensk (1999), and Robbins et al. (2000). 183

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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 (Norbck 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; Seppnen 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

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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

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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,

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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-

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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; Wlinder 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 Blanger, 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

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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 Mgevand (2000) of risk factors for respiratory infections. The investigation, which examined 304 Swiss children 45 years old, reported associations between humidity in the home and colds (odds ratio [OR], 2.71; 95% confidence interval, 1.076.91), sore throats (3.02; 1.147.98), and ear infections (2.78; 1.136.80) after adjusting for mother's age and allergy status. The ORs for the association

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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 (1.782.07) multifamily buildings water leakage in preceding 5 for nasal symptoms; years 4.42 (4.094.77) for throat irritation Kilpelinen et al., 2001 10,667 students Self-reported visible mold 1.29 (1.011.66) (1825 years) for allergic rhinitis; 1.48 (1.171.88) for common cold 4 times per year Self-reported visible mold or 1.30 (1.121.51) damp stains or water damage for allergic rhinitis 1.28 (1.091.47) for common cold 4 times per year Rylander and 304 children Self-reported humidity 2.71 (1.076.91) Mgevand, 2000 (45 years old) for cold; 3.02 (1.147.98) for sore throat Self-reported mold at home 2.27 (.0826.33) for cold; 2.57 (0.867.71) for sore throat Zacharasiewicz et al., 2,849 children Self-reported dampness at home 1.51 (1.311.74) 2000 (69 years old) for nasal symptoms

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Dales and Miller, 1999 403 elementary school Self-reported mold or mildew 1.81(1.023.24) for children itchy eyes, rash or itch, nose irritation Wan and Li, 1999 1,113 workers in Self-reported mold 0.94 (0.501.77) for 19 office buildings nasal congestion or runny nose Self-reported flooding 1.55 (0.793.06) for nasal congestion or runny nose Wieslander et al., 1999 95 staff members in Measured dampness in concrete 1.10 (1.151.45) 4 hospitals floor for irritated, stuffy, or runny nose 1.29 (1.021.18) for itching, burning, or irritated eyes Koskinen et al., 1999a 699 adults (16+ years) Surveyor-assessed moisture 1.06 (0.711.59) in 310 households for rhinitis; 1.92 (1.113.30) for sinusitis; 1.46 (1.032.08) for sore throat Self-reported mold 1.89 (1.153.11) for rhinitis; 1.36 (0.782.39) for sinusitis; 2.40 (1.563.69) for sore throat (continued on next page) 191

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TABLE 5-1 continued 192 Reference Subjects Dampness or Mold Measure Risk Estimate Koskinen et al., 1999b 204 children (715 Surveyor-assessed moisture 4.31 (1.8010.34) years old) in 310 for rhinitis; households 0.75 (0.192.98) for sinusitis; 2.34 (1.134.86) for sore throat Thorn and Rylander, 129 adults Measured airborne glucan 1.23 (0.851.77) for 1998a (1883 years old) (> 24 ng/m3) irritation in nose Pirhonen et al., 1996 1,460 adults Selfreported damp or mold 1.68 (0.972.89) (2564 years old) problem for dry or sore throat Jaakkola et al., 1993 2,568 preschool Self-reported mold odor in 2.39 (1.154.98) for children preceding year nasal congestion; 2.38 (1.134.99) for nasal excretion Self-reported water damage 4.60 (2.578.22) for >1 year ago nasal congestion; 3.19 (1.646.19) for nasal excretion Brunekreef, 1992 2,685 adult parents of Self-reported damp stains or 1.03 (0.791.35) among children 612 years mold growth (last 2 years) women (for allergy); old 1.24 (0.951.73) among men (for allergy) Brunekreef et al., 1989 4,625 children Self-reported molds (ever) 1.57 (1.311.87) (711 years old) for hay fever Self-reported dampness (ever) 1.26(1.061.50) for hay fever

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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; 1.082.41), hoarseness (1.44; 0.992.10), sore throat (2.40; 1.563.68), rhinitis (1.89; 1.153.11), and eye irritation (1.43; 0.841.83) 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. Kilpelinen 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; 1.171.88) and "visible mold or damp stains or water damage" (1.28; 1.091.47). An association was also found with allergic rhinitis and visible mold (1.29; 1.011.66) and "visible mold or damp stains or water damage" (1.30; 1.121.51). 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; 1.151.45). 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

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