Re: Mold/FINALLY PROOF OF NON-ALLERGIC EFFECTS

[Guest guest]

toy know what else this means? for people with allergy testing

positive to many toxigenuc molds that it is proof of exposure and to

more than just allergies. " fungal " aka toxic mold exposure.

>

>

>

> Excess dampness and mold growth in homes:

> An evidence-based review of the aeroirritant effect

> and its potential causes

> P. Hope, M.D.,*# and A. Simon, M.D.*

> ABSTRACT

>

> Exposure to fungi produces respiratory disease in humans through

> both allergic and nonallergic mechanisms. Occupants of

> homes with excess dampness and mold growth often present to

> allergists with complaints of aeroirritant symptoms. This review

> describes the major epidemiological and biological studies

> evaluating the association of indoor dampness and mold growth with

> upper respiratory tract symptoms. The preponderance of

> epidemiological data supports a link between exposure to dampness

> and excess mold growth and the development of aeroirritant

symptoms.

> In addition, biological and clinical studies evaluating

> potential causal substances for the aeroirritant effect, notably

> volatile organic compounds (VOCs), are examined in detail. These

> studies support the role of VOCs in contributing to the

aeroirritant

> symptoms of occupants of damp and mold-contaminated

> homes.

>

> (Allergy Asthma Proc 28:262–270, 2007; doi:

10.2500/aap.2007.28.3004)

> Key words: Adverse health effect, aeroirritant, allergy, evidence

> based, fungi, mold, nonallergic rhinitis, respiratory

> symptoms, toxicity, volatile organic compounds

> Fungi produce a broad array of effects on human

> health. Exposures to outdoor and indoor fungi

> have been associated with allergic respiratory disease,

> systemic toxic syndromes, and infections.1 Epidemiological

> studies have linked exposure to a damp indoor

> environment with adverse health effects.2 Excess mold

> growth commonly associates with a damp indoor environment,

> and exposure to indoor mold itself has

> been cited in large studies as a predictor of adverse

> health outcomes.2 Well-established routes of exposure

> to mold components as a cause of adverse health effects,

> such as allergic respiratory disease, account for

> some of the adverse symptoms experienced by patients.

> In addition, there appear to be many people who

> develop a transient aeroirritant effect from exposure to

> indoor dampness and molds, separate from the development

> or worsening of allergic disease.3,4 The aim of

> this study was to review the scientific evidence evaluating

> the aeroirritant effects of dampness and mold

> growth and to consider the most likely biological explanations

> for these effects, focusing on the potential

> role of volatile organic compounds (VOCs).

>

> METHODS

> A narrative review was prepared based on available

> literature. A search using the Pubmed database was

> performed to identify studies evaluating the link between

> a damp and/or mold-contaminated indoor environment

> and upper airway irritant symptoms.

> Search terms included " dampness, " " mold, " " fungus, "

> " irritant, " " upper airway symptoms, " " rhinitis, " and

> " eye irritation. " Studies were included if upper airway

> symptoms, such as rhinitis, eye irritation, or throat

> symptoms, were included as an end point. Studies

> evaluating only lower airway symptoms or other putative

> mold-related symptoms (i.e., neurological) were

> excluded. Pediatric and adult studies were analyzed

> separately. Hierarchy of evidence was subjectively

> graded using standard criteria for evaluating clinical

> studies.5,6

>

> For evaluation of the effects of volatile organic compounds

> on human subjects, both basic science and

> clinical studies were identified via Pubmed with search

> terms including " volatile organic compounds, " " microbial

> VOCs, " (MVOCs) " VOC, " " irritant, " " fungus, "

> and " mold. " Higher level evidence was used where

> available, but out of necessity, small-scale and laboratory

> studies were included also because of a lack of

> high-quality evidence in some subject areas.

>

> Mold-Related Health Effects

> Molds can cause diverse health effects, related to the

> type of exposure and unique characteristics of an individual's

> physiological response. It is important to dif-

> From the *Division of Allergy, Asthma and Immunology, Scripps

> Clinic, La Jolla,

> California, and #La Jolla Institute for Allergy and Immunology, La

> Jolla, California

> Funding source: Self-funded

> Conflict of interest and financial disclosure: P. Hope,

M.D.,

> had no conflicts

> of interest or financial disclosure; A. Simon, M.D., has

> served as both defense

> and plaintiff medical expert in mold cases and received

compensation

> for his expertise

> Address correspondence and reprint requests to Hope, M.D.,

> Scripps Clinic,

> 10666 N. Torrey Pines Rd., La Jolla, CA 92037

> E-mail address: aph11@...

> Copyright © 2007, OceanSide Publications, Inc., U.S.A.

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> OceanSide Publications

> IP: 71.183.183.18

> ferentiate the better known effects of molds on human

> health from the common, but less well-described, aeroirritant

> effects.

>

> Allergic and Other Immunologic Respiratory Disease.

> Allergic sensitivity to fungi is common, with 3.6% of

> the general population7 and 22–38% of asthmatic patients8–

> 10 possessing specific IgE for indoor and outdoor

> fungal allergens. For outdoor fungi, most notably

> Alternaria, epidemiological studies have linked daily

> outdoor spore counts with asthma outcomes including

> frequency of symptoms11,12 and exacerbations.13–15 In

> some studies, indoor fungus exposure as measured by

> spore counts is associated also with allergic sensitization

> and rhinoconjunctivitis symptoms,16as well as

> asthma symptoms in sensitized patients.17,18 However,

> not all patients exposed to indoor or outdoor mold

> develop allergic sensitization. In addition, not all patients

> who develop respiratory symptoms after exposure

> to indoor mold possess specific IgE to fungal

> allergens. Aside from allergic rhinitis and asthma associated

> with fungal allergen exposure, immunologic

> reactivity to fungi also plays a pathological role in the

> well-characterized but relatively rare diseases of hypersensitivity

> pneumonitis, classic allergic fungal sinusitis,

> and allergic bronchopulmonary aspergillosis.

>

> Mycotoxicosis. Exposure to large doses of toxins produced

> by fungi can result in overwhelming acute systemic

> illness.19 Contamination of cereal by ergot alkaloids

> produced by the fungus Claviceps purpurea led to

> ergotism with gangrene during the Middle Ages.20

> More recently, Aspergillus-derived aflatoxins in contaminated

> nut and cereal products have led to mass

> poisonings in India and Kenya in the last 45 years.19

> The media popularized the term " toxic mold " after a

> cluster of 10 cases of acute idiopathic pulmonary hemorrhage

> occurred in Cleveland in 1993. An initial review

> suggested that the cases were associated with

> common exposure to Stachybotrys chartarum, but subsequent

> analysis showed this was not the cause.21

> Nonetheless, the terms " toxic mold " or " black mold "

> often are associated in the public mind with indoor

> mold exposure.

>

> It has been difficult to correlate levels of detectable

> Stachybotrys chartarum conidia and its associated mycotoxins

> in the air of mold-contaminated homes with

> symptoms, which has led to the general idea that there

> may be little contribution by mycotoxins to irritant

> respiratory disease.22 However, recent studies have

> demonstrated S. chartarum mycotoxins on respirable

> mold fragments,23 suggesting an underestimate of the

> burden of airborne mycotoxins in previous epidemiological

> studies.

> Infection. Common infections due to fungi include

> dermatophyte skin infections and yeast-related vaginosis.

> The causative agents for these conditions usually

> are not found in significant quantities in air or surface

> sampling of the home environment. Only in severely

> immunocompromised patients, e.g., recipients of organ

> transplants or those with HIV/AIDS, can a range of

> opportunistic infections commonly occur because of

> fungi.

>

> Aeroirritation. Common symptoms of patients exposed

> to a damp environment include upper and

> lower respiratory complaints. An Institute of Medicine

> expert panel performed a comprehensive review of the

> relevant literature and found an association between

> exposure to a damp indoor environment and cough,

> wheeze, and nasal and throat symptoms.2 In addition,

> the same expert panel found that epidemiological studies

> associate the presence of mold in a damp indoor

> environment with cough, wheeze, and nasal and throat

> symptoms. In the setting of an allergy clinic, patients

> commonly present with upper airway symptoms resembling

> these complaints. The question often arises

> whether a damp and/or moldy indoor environment

> may be contributing to symptoms despite the absence

> of documented IgE-mediated allergic sensitivity. A review

> of the evidence evaluating the validity of such an

> assertion will help the allergist make informed decisions

> regarding treatment of symptoms, whether mold

> remediation may be necessary, and how to allay the

> anxiety of concerned patients.

>

> Several large epidemiological studies have found an

> association between exposure to a damp indoor environment

> and/or the presence of mold in the indoor

> environment with irritant upper airway symptoms.

> These symptoms include irritated eyes, rhinorrhea, nasal

> congestion, and throat irritation. These epidemiological

> studies often assessed for other conditions as

> well, and this review of the literature will focus on

> upper airway symptoms suggesting aeroirritation,

> both in adults and children.

>

> Population Studies in Adults. Several cross-sectional

> studies have found a significant correlation between

> exposure to a damp indoor environment and the presence

> of eye, nose, and/or throat irritation symptoms.

> These studies have been performed in a variety of

> countries and in both new and old building environments.

> Multiple studies also have found a dose–response

> relationship between the number of indicators

> of dampness present and aeroirritant symptoms.

> Engvall et al.24 surveyed 3241 adults in 261 buildings

> in Sweden and determined rates of high humidity

> indicators, such as moldy odor and history of water

> leakage, in the past 5 years. They found an odds ratio

> (OR) of 1.92 (CI, 1.78 –2.07) for presence of nasal symp-

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> toms, and an OR of 4.42 (CI, 4.09–4.77) for throat

> irritation in association with these dampness indicators.

> There was a finding analogous to a dose response

> in that an increase in the number of signs of dampness

> incrementally increased the OR of having respiratory

> symptoms.

>

> Wan and Li25 performed a questionnaire study on

> office workers in buildings in Taiwan. Twelve hundred

> thirty-seven subjects were surveyed, and they found an

> OR of 1.34 for eye irritation when stuffy odor or mold

> was present. The OR increased to 3.14 if water damage,

> stuffy odor, and mold were present, and was 5.03 if

> four measures of dampness were present. All of these

> findings were statistically significant. This again indicated

> a dose–response-type relationship, this time between

> eye irritation and dampness in the building.

> Statistically significant relationships were not found

> for nasal congestion and runny nose.

>

> A study by Wieslander et al.26 evaluated 95 hospital

> workers, both by recording reported symptoms and by

> performing a medical examination and measurement

> of nasal lavage, acoustic rhinometry, and tear film

> stability. Working in a damp building (as indicated by

> presence of dampness in the concrete floor) was found

> to be associated with an OR of 1.10 (CI, 1.15–1.45) for

> nasal symptoms and 1.29 (CI, 1.02–1.18) for eye irritation

> symptoms. Mold contamination and MVOCs (discussed

> later) in the various buildings were of relatively

> low levels, with total MVOCs measured at 1 g/m3.

> Koskinen et al.27 studied occupants of 310 random

> homes in Finland. Moisture in the home was assessed

> by site visit with specially trained personnel, as well as

> by occupant-assessed current or past mold presence in

> the home. Six hundred ninety-nine adults were surveyed

> for respiratory and other symptoms; rhinitis

> (OR, 1.89; CI, 1.15–3.11) and sore throat (OR, 2.40; CI,

> 1.56 –3.69) were significantly associated with presence

> of mold. Sore throat (OR, 1.46; CI, 1.03–2.08) and sinusitis,

> but not rhinitis (OR, 1.06; CI, 0.71–1.59), were

> significantly associated with surveyor-assessed moisture.

> However, in the parallel study evaluating the

> children in these homes,28 rhinitis was strongly associated

> with surveyor-assessed moisture (OR, 4.31; CI,

> 1.80 –10.34), as was sore throat (OR, 2.34; CI, 1.13– 4.86).

> Given the possibility that reporting bias may affect

> the description of symptoms for subjects also reporting

> mold in their homes, Pirhonen et al.29 performed a

> survey-based study and then controlled for markers of

> a " complainer " predisposition. Their initial findings

> were that several symptoms were positively associated

> with the presence of mold in the home in their random

> sampling of 1460 Finnish adults. Among these were

> rhinitis, with an OR of 1.69 (CI, 1.31–2.18), and eye

> irritation (OR, 1.52; CI, 1.18 –1.96). However, lumbar

> backache and recurrent stomach ache, two conditions

> that should be pathophysiologically unrelated to mold

> exposure, also were found to be associated. Removing

> the subjects with reported stress and/or depression,

> who might be expected to be affected by reporting bias,

> did not affect the significance of the findings. The

> investigators adjusted their data by removing the

> " complainers " from the analysis and still found eye

> irritation (OR, 1.69; p 0.05) to be significantly associated

> with presence of mold, whereas rhinitis became

> a nonsignificant trend (OR, 1.21; p NS).

> Recently, an analysis of 50 patients referred for evaluation

> of mold-related illness has been published.3

> Thirty-three patients were found to have plausible

> nonmold-related causes of their complaints or nonphysiological

> bases for their symptoms, and 17 patients

> (34%) were found to have symptoms thought related to

> aeroirritant effects of indoor mold.

>

> Although more studies of dampness and indoor

> health have focused on older dwellings, Saijo et al.30

> surveyed 317 occupants of newly built houses in Japan.

> Occupants related whether they had symptoms including

> eye, nose, and throat/respiratory complaints. The

> investigators found that condensation on windowpanes

> and visible mold growth were associated with

> eye, nose, and throat/respiratory symptoms in a statistically

> significant manner. There also was a dose–

> response effect, in that when both dampness factors

> were present, the ORs increased compared with the

> presence of either condensation or mold growth alone.

> If both factors were present, for eye symptoms the OR

> was 4.36 (CI, 1.60 –11.9), for nose symptoms the OR

> was 3.70 (CI, 1.42–9.60), and for throat/respiratory

> symptoms the OR was 3.45 (CI, 1.23–9.66). Their conclusion,

> as was the conclusion of the authors in several

> other studies reviewed here, was that the presence of

> dampness and/or visible mold growth in the indoor

> environment was significantly associated with irritant

> eye and/or nose symptoms in adults.

>

> Population Studies in Children. Several epidemiological

> studies have addressed the question of whether a damp

> indoor environment correlates with adverse respiratory

> health effects in children. In addition to cross-sectional

> studies, longitudinal studies and nested case-control

> studies in children provide higher-level evidence supporting

> a causative role for indoor dampness and mold

> growth in producing aeroirritant symptoms.

> Zacharasiewicz et al.31 surveyed parents about their

> 6- to 9-year-old children to determine the rates of nasal

> symptoms relating to exposures in the indoor environment.

> Two thousand and eight hundred forty-nine

> children were analyzed, and the investigators found an

> increased OR of 1.51 (CI, 1.31–1.74) of having nasal

> symptoms if there was dampness/mold present at

> home. A study in Canada by Dales and 32 correlated

> itchy eyes and nose irritation with reported mold

> growth in the homes of 403 elementary school children,

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> with an OR of 1.81 (CI, 1.02–3.24) for risk of these

> symptoms. In addition, controlling for level of dust

> mites and endotoxin did not eliminate the association.

> Bornehag et al.33 performed a cross-sectional survey of

> 10,851 1- to 6-year-old children to assess the prevalence

> of rhinitis symptoms in relation to environmental

> dampness. Rhinitis symptoms significantly correlated

> with visible dampness, condensation, floor moisture,

> and history of water damage. Another cross-sectional

> study of 20,016 children in Italy found that rhinoconjunctivitis

> was associated with early exposure to visible

> mold or dampness, with an OR of 1.46 (CI, 1.13–1.89)

> after adjusting for confounding variables.34

> A nested case control study within a prospective

> longitudinal cohort also found that home dampness

> correlated with respiratory complaints in children

> aged 7–8 years old.35 Within the cohort, 781 children

> with respiratory complaints were identified and

> matched with controls. It was found that, among other

> risk factors, long-term exposure to dampness significantly

> correlated with respiratory symptoms (OR, 2.98;

> CI, 1.10–8.28).

>

> A study by Jaakkola et al.36 highlighted the importance

> of mold odor in assessing fungal contamination.

> Surveys were sent to parents of 1- to 6-year-old children,

> and 2568 children were included. Along with

> several other respiratory symptoms, nasal congestion

> (OR, 1.94; CI, 1.15– 4.98) was associated with all of the

> determinants of dampness/mold, which included history

> of water damage, presence of moisture and visible

> mold, and perceived mold odor at home. However,

> perception of mold odor had a stronger association

> with nasal congestion (OR, 2.39; CI, 1.15– 4.98) and

> nasal excretion (OR, 2.38; CI, 1.13– 4.99). In addition,

> water damage over 1 year before the survey had a

> strong correlation with nasal congestion (OR, 4.60; CI,

> 2.57– 8.22) and nasal excretion (OR, 3.19; CI, 1.64–6.19).

> A study published as part of the Danish Mold in

> Buildings Program found a significant correlation between

> levels of mold colony-forming units in settled

> dust and eye and throat irritation in 13, to 17-year-old

> adolescents.37 Nasal irritation was not significantly associated.

> One thousand fifty-three children were surveyed

> in the cross-sectional study, which found the

> significant correlation even after adjusting for numerous

> confounding variables such as presence of asthma,

> hay fever, recent airway infection, and psychosocial

> factors.

>

> Finally, a recent longitudinal study38 has added

> stronger evidence that moisture damage and its related

> higher fungal contamination levels have a causal effect

> on upper airway symptoms in children. Children aged

> 6–17 years old were assessed for upper airway symptoms

> in moisture-damaged schools before and after

> either complete or partial remediation efforts. Trained

> engineers assessed the level of water damage before

> and after remediation, and airborne fungal concentrations

> were recorded. In the study, authors found that

> there were statistically significant decreases in stuffy

> nose, rhinitis, sore throat, cough, and eye symptoms

> after mold and water damage remediation had been

> performed. In addition, airborne fungal contamination

> and building moisture were lower after remediation in

> parallel with the decrease in symptoms. As a control,

> another group of children was assessed at a school that

> underwent partial remediation, which caused no significant

> improvement in moisture or fungal contamination.

> In these children, there was no improvement in

> upper airway symptoms. This study suggested not

> only that a damp environment is associated with upper

> airway symptoms, but also that remediation efforts

> may be effective in reversing those symptoms. In addition,

> it endorses the notion that aeroirritant symptoms

> are transient if the source of the aeroirritants is

> removed. Other reports also suggest that mold remediation

> efforts may be successful in reducing mold

> spore levels39 and mold-related respiratory symptoms.

>

> 40

> Potential Offending Substances

> The finding that exposure to a damp indoor environment

> and/or indoor mold is associated with adverse

> respiratory symptoms prompts an evaluation of the

> types of mold-associated compounds that potentially

> could be responsible for the effect. Any candidate compound

> must be able to interact with the respiratory

> tract to produce symptoms. As such, one requirement

> for potential offending substances is that they have the

> ability to become airborne in sufficient quantities to

> cause health effects via inhalation. Several types of

> mold-related compounds may become airborne. Most

> commonly considered in the practice of allergy/immunology

> are mold spores, which contain allergenic mold

> proteins and cause respiratory symptoms in patients

> with mold-related IgE hypersensitivity. However,

> most patients presenting with upper airway symptoms

> in relation to indoor mold exposure do not have IgEmediated

> hypersensitivity to molds. This prompts a

> consideration of nonallergenic but potentially irritating

> substances produced by molds.

>

> The -d-glucans have been proposed as one possible

> agent causing aeroirritant symptoms, but, currently,

> there are limited epidemiological data available to

> evaluate their contribution to respiratory disease.41

> Mycotoxins, mentioned previously, may associate with

> respirable fungal fragments,23 which could theoretically

> produce aeroirritant symptoms. Additional epidemiological

> studies are needed to evaluate this possibility.

> Another group of compounds are VOCs, called

> MVOCs when produced by fungi or bacteria. VOCs

> have the quality of becoming easily airborne and are

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> known to produce irritant nose and eye symptoms, as

> discussed later. Because of these features, VOCs are an

> attractive candidate as an agent producing aeroirritant

> symptoms in the damp indoor environment where

> mold is present.

>

> Aside from the contributions of mold-related compounds

> to aeroirritant symptoms, other factors in the

> damp indoor environment, such as bacterial mVOCs

> and decaying debris (i.e., human skin scale, food products,

> insects, water-damaged building materials, carpeting,

> furniture, and other porous personal possessions)

> could theoretically contribute to the symptoms

> of subjects in these studies.

> -(133)-d-Glucans. These compounds are structural

> components of the cell walls of fungi. Glucans are

> polyglucose moieties that persist after death of the

> fungus. Concentrations of -(133)-d-glucans are elevated

> in concordance with the amount of mold present

> in a given location.41 Studies have been performed

> with both animals and humans to assess the effect of

> -(133)-d-glucan exposure on airway inflammatory

> markers. Young et al.42 instilled increasing doses of

> -d-glucans into the tracheas of rats and found dosedependent

> increases in neutrophil influx and nitric

> oxide production. Wan et al.43 showed that -d-glucans

> can potentiate ovalbumin-induced production of IgE

> antibodies in mice.

>

> In humans, exposure of 26 subjects to aerosolized

> curdlan, a glucan, produced nasal and throat irritation

> but no changes in forced expiratory volume at 1 second

> or airway hyperreactivity.44 However, nasal instillation

> of glucans in another experiment failed to produce

> symptoms or eosinophil influx.45

>

> Limited epidemiological studies have evaluated the

> correlation between exposure to glucans and upper

> airway symptoms.41 The results have been inconsistent,

> with some studies showing a positive correlation

> between glucan exposure and nose or eye symptoms46

> and others showing no association.47–49 In general,

> although the data are limited, the preponderance of

> epidemiological studies have been unable to show consistently

> that exposure to -d-glucans correlates with

> irritant upper airway and/or eye symptoms.

> A recent study has been suggested that endorses the

> lack of effect of mold particles, such as those that

> contain glucans, on irritant symptoms.22 Roponen et

> al.50 studied 11 healthy male sawmill workers and the

> relation of their occupational exposures to production

> of proinflammatory cytokines. In these subjects with

> no history of irritant or other respiratory symptoms,

> they found no difference in the reports of symptoms

> while at work or on vacation and no difference in

> proinflammatory cytokine levels in nasal lavage, including

> nitrites, TNF-, IL-4, IL-5, and IL-6. The small

> size of the study (n 11) limited its power to find a

> difference, and the confidence intervals of the results

> were several times larger than the measured values.

> Interestingly, the only statistically significant correlate

> was between the concentration of TNF- in nasal lavage

> fluid and the concentration of total terpenes as

> well as individual terpenes in the work environment.

> Terpenes are VOCs (discussed later), and it is interesting

> that among measured exposures such as fungal

> spores, inhalable dust, endotoxin, and terpene VOCs,

> the only association with increased TNF- production

> was the VOC concentration. Similar studies performed

> in a large number of symptomatic individuals while in

> damp home environments would be highly illustrative

> albeit difficult to accomplish.

>

> VOCs and MVOCs. MVOCs are small molecules produced

> as a byproduct of metabolism by numerous

> microbial organisms. In composition and physicochemical

> properties, they resemble nonmicrobially derived

> VOCs, differing primarily in their production

> source. VOCs derive from such sources as paint, solvents,

> and petroleum products. The strong odor and

> often accompanying irritant sensation associated with

> being in a freshly painted room is likely caused by the

> effects of VOCs.51 A longitudinal study of professional

> painters suggested that exposure to VOCs in paints is

> associated with development of airway symptoms.52

> Molds produce a number of organic compounds,

> including alcohols, aldehydes, and sulfur-containing

> chemicals, many of which are volatile. MVOC production

> results in the musty and pungent odors associated

> with indoor mold growth.53,54 Examples of MVOCs

> include 3-methyl-1-butanol, 1-hexanol, 1-octen-3-ol,

> 2heptanone, and 3-octanone. Although other organisms,

> such as bacteria, produce MVOCs, the discussion

> here will be limited to general characteristics of VOCs

> as well as studies of mold-associated MVOCs.

>

> Aeroirritant Effects of VOCs: Characteristics and Threshold

> Dose. VOCs act as odorants and irritants. Olfactory

> stimulation results from interaction between VOC molecules

> and receptors in the olfactory groove. The irritant

> effect has afferent and efferent paths. Sensory

> nerve fibers in the nasal mucosa carry irritative signals

> via the pathways for common chemical sense, through

> the trigeminal, glossopharyngeal, and vagus nerves.53

> This stimulation results in the sensation of irritation as

> well as mucous hypersecretion. Some of the symptoms

> (nasal and throat irritation and cough) that have been

> associated with exposure to mold in a damp indoor

> environment resemble the irritant effects caused by

> VOCs in controlled laboratory circumstances.53,55

> The dose–response curve of the irritant effects of

> VOCs has been studied in animal and human models.

> Korpi et al.56 exposed mice to increasing concentrations

> of individual and a mixture of VOCs, while measuring

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> the concentration required to reduce the respiratory

> rate. Respiratory depression is representative of the

> irritant effect as manifested in rodents and correlates

> with the threshold concentration for nasal irritation in

> humans.57 The study found that all of the VOCs were

> able to elicit a respiratory response, and a mixture of

> five VOCs together elicited a response at a lower overall

> concentration than any of the compounds individually.

>

> In humans, a comparison of subjects with normal

> olfaction to anosmics found odor and irritant thresholds,

> respectively, for numerous VOCs.53 Odor thresholds

> ranged from the 1 part per million (ppm) range

> (i.e., 4-heptanol with an odor threshold of 8.2 ppm) to

> hundreds of ppm (i.e., 2-propanol, 503 ppm). Pungency

> or irritant thresholds in anosmics averaged approximately

> one to two orders of magnitude higher values;

> e.g., 4-heptanol had a pungency threshold of 335 ppm

> and 2-propanol had a pungency threshold of 18,135

> ppm. Measurements were made instantaneously after

> exposure, and it was not possible to extrapolate what

> effect longer-term exposure at lower levels may have

> had. Another study found that nasal pungency and

> ocular irritation (which can be assessed using longer

> duration exposure) occurred at a relatively similar concentration

> of VOCs.58 Specific individual VOCs and

> mixtures of VOCs had different thresholds for odor

> and irritation. In general, longer carbon chain lengths

> of VOCs corresponded with a lower nasal detection

> threshold.58

>

> The authors of the studies mentioned previously

> suggest that longer duration exposure to VOCs may

> produce symptoms at a lower concentration than the

> instantaneous experiments indicate. In a damp indoor

> environment, the duration of exposure is likely to be

> longer than in the laboratory setting, and longer duration

> experiments would be more representative. Although

> odor sensation produces tachyphylaxis over

> time, irritation does not. In a controlled exposure to the

> VOC 2-ethylhexanol, olfactory symptoms decreased,

> nasal irritation remained unchanged, and eye irritation

> increased in subjects over a 4-hour exposure.59

> Hempel-nsen et al.60 studied the effect of exposure

> to single and mixed VOCs on eye symptoms.

>

> Healthy volunteers were exposed to increasing concentrations

> of VOCs, starting at a concentration of either

> 312.5 or 423.0 ppm and increasing to a highest value of

> either 3125 or 2311 ppm. Sensory irritation intensity

> was recorded. For all VOC mixtures, a dose–response

> curve was seen for eye irritation. The concentration

> required to produce eye irritation varied depending on

> the VOC mixture, but for two of the three mixtures, a

> mean 50% irritation intensity level was seen at 1000–

> 1500 ppm concentrations. In a damp indoor environment,

> the specific composition of MVOC production

> and, importantly, the concentration, would affect the

> intensity of ocular exposure and irritant symptoms.

> Long-term exposure has not been studied in a similarly

> controlled way.

> In summary, VOCs produce olfactory stimulation at

> low concentrations, but at higher concentrations, eye

> and nose irritation develop. Dose-dependent irritant

> effects have been found in both animal and human

> studies. Most experiments have evaluated mostly

> short-term effects of relatively high concentrations of

> VOCs. The limited data available suggest that longterm

> exposure may produce irritation at a lower overall

> VOC concentration than that required for shortterm

> effects.

>

> Concentration of VOCs in the Ambient Environment.

> The studies described previously support the potential

> for VOCs to cause irritant symptoms of the nose and

> eyes. MVOCs, because they are chemically identical in

> many cases, should have similar effects. However, to

> be responsible for symptoms, VOCs and/or MVOCs

> must be present in a sufficient concentration in the

> damp indoor environment. Recently, the level of current

> knowledge about VOCs in the ambient environment

> has been highlighted,22 with some studies postulating

> that the levels of MVOCs in the damp indoor

> environment are too low to cause irritant symptoms.

> One cited study, by Pasanen et al.,61 performed a

> theoretical computation to estimate the probability that

> ambient VOCs might cause irritant symptoms. Lacking

> information regarding actual irritation thresholds in

> humans for several of the VOCs that were modeled,

> theoretical irritation potency was determined based on

> a mathematical calculation derived from VOC exposure

> studies in mice. They estimated that ambient VOC

> concentrations in the range of hundreds of micrograms

> per cubic meter to a few milligrams per cubic meter

> would be required to cause irritant symptoms. They

> compared measurements of VOC concentrations in

> damp and mold problem buildings performed in previous

> studies to these mathematically derived recommended

> indoor air levels. The authors found that in

> most calculations, levels of VOCs in the problem buildings

> would be unlikely by prediction of this model to

> cause irritant symptoms. Theoretical calculations of

> predicted effects, without actually measuring irritation

> potency of VOCs, will provide low-grade evidence for

> or against VOCs as potential irritants. The relevance of

> a calculated VOC irritation potency to human health is

> unknown.

>

> Mathematical modeling does not usually provide

> information adequate to guide patient care but may

> guide estimates useful in generating hypotheses and

> designing studies. Several epidemiological studies

> have begun to address the question of ambient VOC

> levels by measuring them in indoor environments.

> et al.62 sampled 52 Canadian homes in which the

> occupants had reported " respiratory health problems

> Allergy and Asthma Proceedings 267

> Property of

> OceanSide Publications

> IP: 71.183.183.18

> and/or allergic reactions to indoor air for which no

> satisfactory cause could be determined. " Air samples

> were analyzed for VOCs, airborne particle content, and

> fungal colony-forming units. On average, homes contained

> 12–13 types of VOCs. VOC estimates ranged

> from 0.08 to 1.89 mg/m3, with a mean concentration of

> 0.68 mg/m3. Four houses had a VOC concentration of

> 2 mg/m3. In general, concentrations of VOCs did not

> correlate well with other measurements of levels of

> fungal burden. The study avoided sampling rooms

> that had obvious nonfungus-related VOC sources,

> such as perfume bottles, glue, or fresh paint, but,

> clearly, there are nonfungal sources of VOCs in any

> sampling of indoor air. The range of VOC concentrations

> was consistent with levels needed to cause irritant

> symptoms in laboratory experiments.

>

> Saijo et al.30 assessed symptoms in occupants of

> newly constructed homes in Japan. Aside from the

> association with dampness and mold growth discussed

> previously, in this study authors found that concentrations

> of each of seven VOCs individually measured, as

> well as total VOC levels in the home, significantly

> correlated with symptoms after adjusting for age, gender,

> smoking, pets, time in the dwelling, size of household,

> and allergy or asthma history. Total VOC levels

> were associated with an increased OR of 9.79 (CI, 1.67–

> 57.5) for eye symptoms. The range of VOC mean concentration

> was 2.3–325.5 g/m3 for each individual

> compound, and the overall mean total VOC level was

> 482 g/m3 for houses when toluene was measured and

> 221.9 g/m3 when it was not measured. These levels

> are considerably lower than some estimates (as mentioned

> previously) felt to be theoretically required to

> cause irritant symptoms. Also important to note is the

> enhanced concentration of VOCs released from building

> materials. It is interesting to hypothesize that

> dampness may synergize with new building materials

> to enhance VOC levels in the air.

>

> An epidemiological study in West Virginia63 studied

> the question of whether proximity to chemical manufacturing

> plants and the associated higher levels of

> VOCs in the air correlated with an increased frequency

> of respiratory symptoms. Children from 74 schools

> answered surveys regarding the presence of lower respiratory

> symptoms as well as acute irritant symptoms.

> Concentrations of 15 VOCs were measured at the

> schools. The study did not attempt to quantify MVOCs

> specifically. They found statistically significant correlations

> indicating that schools located closer to the

> manufacturing facilities had children with more physician-

> diagnosed asthma and wheeze-related symptoms.

> Acute eye symptoms, but not nose or throat

> symptoms, correlated with closer proximity to factories.

> Lower respiratory symptoms had a dose-dependent

> correlation with increased concentration of VOCs

> (p 0.05). Acute eye symptoms had a similar trend

> that was not statistically significant. For petroleumrelated

> VOCs, a dose effect was seen for each increase

> of 10 g/m3 and for process-related VOCs, the dose

> associated with a change was 2 g/m3. In this study

> authors concluded that proximity to VOC-emitting factories

> was associated with increased respiratory symptoms

> in a dose-dependent manner.63

>

> There are difficulties in measuring VOCs in indoor

> air, and aside from their presence as free airborne

> molecules, association with larger particles such as

> dust could enhance their delivery to the respiratory

> tract. For example, a recent study64 showed that

> MVOCs produced in a laboratory setting adsorb to

> dust particles. As dust particles are respirable, the authors

> suggest that a portion of MVOCs reaching the

> respiratory tract could be adsorbed into these larger

> particles and thereby penetrate the airways more efficiently.

> Additional studies are necessary to determine

> whether this may lead to underestimates of VOC burden

> in indoor air and whether this mechanism may

> contribute to human health effects.

>

> The summary of these studies suggests that it is

> difficult to estimate a priori the level of an individual

> VOC that may be sufficient to cause irritant symptoms.

> The data so far available suggest that, in the presence

> of newly constructed homes with or without dampness,

> other damp homes, and locations in proximity to

> VOC-emitting factories, the total ambient air VOC concentration

> has been shown to correlate with eye, nose,

> and other respiratory symptoms. In addition, the possibility

> of VOCs adhering to larger respirable particles

> could increase the overall VOC burden in the typical

> damp indoor environment.

>

> CONCLUSIONS

> The presence of indoor mold is a common, if not

> ubiquitous, phenomenon. At least partially because of

> reports in the media, patients may have the perception

> that indoor fungus commonly produces dangerous adverse

> health effects. Although some patients may have

> anxiety-based symptoms related to mold exposure out

> of proportion to the actual risk to health, there remains

> a large population of patients who do suffer medical

> problems related to damp indoor home environments.

> Some of the complaints are those that allergists commonly

> see in practice, such as cough, wheeze, and

> upper airway symptoms such as nasal and eye irritations.

> The allergist's position as the main specialist

> performing testing (in our case, for IgE-mediated allergy)

> for possible sensitivity to mold puts us in the

> unique position of requiring knowledge of a broad

> spectrum of health effects potentially caused by indoor

> fungus.

> The data reviewed here represent initial steps toward

> defining the pathophysiological mechanisms for

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> OceanSide Publications

> IP: 71.183.183.18

> the aeroirritant effects of damp homes and associated

> excess mold growth. The delineation of a biological

> mechanism would allow allergists to approach patients

> with a rational explanation for their symptoms and at

> the same time provide reassurance of the transient

> nature of the effect. Ideally, identifying the true nature

> of the agents causing the symptoms may alleviate anxiety

> and help direct appropriate medical treatment and

> mold remediation efforts.

>

> MVOCs are produced by indoor mold, and VOCs

> have been linked in controlled experiments with irritant

> symptoms of the eyes and nose. Additional studies

> are needed to determine levels of MVOCs in a variety

> of damp homes and to try to identify the proportion of

> VOC production that indoor molds contribute. In addition,

> larger epidemiological studies could address

> questions of aeroirritation with a directed effort at

> examining MVOC levels and symptoms. Most of the

> dose–response studies in humans have identified

> threshold levels for brief exposures. The typical occupant

> of a damp home with a heavy indoor mold burden

> has a much longer exposure and to many more

> elements in the indoor environment than subjects in

> experimental settings. The duration of exposure could

> affect the threshold dose needed to cause symptoms,57

> and this also should be evaluated in controlled studies,

> if possible.

>

> In summary, epidemiological studies support the

> link between a damp indoor environment and mold

> growth with upper airway irritant symptoms. MVOCs

> are produced by indoor fungus, and, based on available

> data, are the most likely candidate compounds as

> the cause of this aeroirritant effect. Studies have shown

> that MVOCs produce nose and eye irritant symptoms

> with a consistent dose–response effect. In addition, the

> limited epidemiological studies performed to date suggest

> that VOCs are likely to be present in damp indoor

> homes at a level sufficient to produce irritant symptoms.

>

> REFERENCES

> 1. Hardin BD, Kelman BJ, and Saxon A. Adverse human health

> effects associated with molds in the indoor environment. J

> Occup Environ Med 45:470–478, 2003.

> 2. Institute of Medicine Committee on Damp Indoor Spaces and

> Health. Damp indoor spaces and health. NM, Ammann

> HM, Brunekreef B, et al (Eds). Washington: National Academy

> of Sciences, 183–269, 2004.

> 3. Khalili B, Montanaro MT, and Bardana EJ Jr. Inhalational mold

> toxicity: Fact or fiction? A clinical review of 50 cases. Ann

> Allergy Asthma Immunol 95:239 –246, 2005.

> 4. Portnoy JM, Kwak K, Dowling P, et al. Health effects of indoor

> fungi. Ann Allergy Asthma Immunol 94:313–319, 2005.

> 5. B, Ball C, Sackett D, et al. Levels of Evidence and

> Grades of Recommendation. Oxford, UK: Oxford Centre for

> Evidence-Based Medicine, 2001. Available online at www.

> cebm.net. Last accessed Jan. 10, 2007.

> 6. Hayward R (Electronic Ed). Users' Guides Interactive. Chicago,

> IL: JAMA Publishing Group, 2002. Available online at www.

> usersguides.org. Last accessed Jan. 10, 2007.

> 7. Gergen PJ, and Turkeltaub PC. The association of individual

> allergen reactivity with respiratory disease in a national sample:

> Data from the second National Health and Nutrition Examination

> Survey, 1976–80 (NHANES II). J Allergy Clin Immunol

> 90:579 –588, 1992.

> 8. Huss K, Adkinson NF Jr, Eggleston PA, et al. House dust mite

> and cockroach exposure are strong risk factors for positive

> allergy skin test responses in the Childhood Asthma Management

> Program. J Allergy Clin Immunol 107:48 –54, 2001.

> 9. Kattan M, H, Eggleston P, et al. Characteristics of

> inner-city children with asthma: The National ative Inner-

> City Asthma Study. Pediatr Pulmonol 24:253–262, 1997.

> 10. Lehrer SB, JM, Altman LC, et al. Prevalence of

> basidiomycete

> allergy in the USA and Europe and its relationship to

> allergic respiratory symptoms. Allergy 49:460–465, 1994.

> 11. Bruce CA, Norman PS, Rosenthal RR, et al. The role of ragweed

> pollen in autumnal asthma. J Allergy Clin Immunol 59:449–459,

> 1977.

> 12. Delfino RJ, Coate BD, Zeiger RS, et al. Daily asthma severity in

> relation to personal ozone exposure and outdoor fungal spores.

> Am J Respir Crit Care Med 154:633– 641, 1996.

> 13. O'Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an

> aeroallergen as a possible precipitating factor in respiratory

> arrest in young patients with asthma. N Engl J Med 324:359–

> 363, 1991.

> 14. Atkinson RW, Strachan DP, R, et al. Temporal

> associations

> between daily counts of fungal spores and asthma

> exacerbations. Occup Environ Med 63:580 –590, 2006 (Epub

> Mar. 21, 2006).

> 15. Newson R, Strachan D, Corden J, et al. Fungal and other spore

> counts as predictors of admissions for asthma in the Trent

> region. Occup Environ Med 57:786 –792, 2000.

> 16. B, Ritz B, Gehring U, et al. Indoor exposure to molds and

> allergic sensitization. Environ Health Perspect 110:647– 653,

> 2002.

> 17. Garrett MH, Rayment PR, Hooper MA, et al. Indoor airborne

> fungal spores, house dampness and associations with environmental

> factors and respiratory health in children. Clin Exp

> Allergy 28:459–467, 1998.

> 18. Lin RY, and KD. Hypersensitivity to molds in New

> York City in adults who have asthma. Allergy Asthma Proc

> 24:13–18, 2003.

> 19. Peraica M, Radic B, Lucic A, et al. Toxic effects of mycotoxins

> in

> humans. Bull World Health Organ 77:754 –766, 1999.

> 20. Eadie MJ. Convulsive ergotism: Epidemics of the serotonin

> syndrome? Lancet Neurol 2:429–434, 2003.

> 21. Centers for Disease Control and Prevention (CDC). Update:

> Pulmonary hemorrhage/hemosiderosis among infants—Cleveland,

> Ohio, 1993–1996. MMWR Morb Mortal Wkly Rep 49(9):

> 180–184, 2000.

> 22. Bush RK, Portnoy JM, Saxon A, et al. The medical effects of

> mold exposure. J Allergy Clin Immunol 117:326 –333, 2006.

> 23. Brasel TL, DR, SC, et al. Detection of airborne

> Stachybotrys chartarum macrocyclic trichothecene mycotoxins

> on particulates smaller than conidia. Appl Environ Microbiol

> 71:114 –122, 2005.

> 24. Engvall K, Norrby C, and Norback D. Ocular, airway, and

> dermal symptoms related to building dampness and odors in

> dwellings. Arch Environ Health 57:304 –310, 2002.

> 25. Wan GH, and Li CS. Dampness and airway inflammation and

> systemic symptoms in office building workers. Arch Environ

> Health 54:58–63, 1999.

> 26. Wieslander G, Norback D, Nordstrom K, et al. Nasal and ocular

> symptoms, tear film stability and biomarkers in nasal lavage, in

> Allergy and Asthma Proceedings 269

> Property of

> OceanSide Publications

> IP: 71.183.183.18

> relation to building-dampness and building design in hospitals.

> Int Arch Occup Environ Health 72:451– 461, 1999 Oct.

> 27. Koskinen OM, Husman TM, Meklin TM, and Nevalainen AI.

> The relationship between moisture or mould observations in

> houses and the state of health of their occupants. Eur Respir J

> 14:1363–1367, 1999.

> 28. Koskinen OM, Husman TM, Meklin TM, et al. Adverse health

> effects in children associated with moisture and mold observations

> in houses. Intl J Environ Health Res 9:143–156, 1999.

> 29. Pirhonen I, Nevalainen A, Husman T, et al. Home dampness,

> moulds and their influence on respiratory infections and symptoms

> in adults in Finland. Eur Respir J 9:2618 –2622, 1996.

> 30. Saijo Y, Kishi R, Sata F, et al. Symptoms in relation to

> chemicals

> and dampness in newly built dwellings. Int Arch Occup Environ

> Health 77:461– 470, 2004.

> 31. Zacharasiewicz A, Zidek T, Haidinger G, et al. Symptoms

> suggestive

> of atopic rhinitis in children aged 6–9 years and the

> indoor environment. Allergy 55:945–950, 2000.

> 32. Dales RE, and D. Residential fungal contamination and

> health: Microbial cohabitants as covariates. Environ Health Perspect

> 107(suppl 3):481– 483, 1999.

> 33. Bornehag CG, Sundell J, Hagerhed-Engman L, et al. " Dampness "

> at home and its association with airway, nose, and skin

> symptoms among 10,851 preschool children in Sweden: A

> cross-sectional study. Indoor Air 15(suppl 10):48 –55, 2005.

> 34. Simoni M, Lombardi E, Berti G, et al. Mould/dampness exposure

> at home is associated with respiratory disorders in Italian

> children and adolescents: The SIDRIA-2 Study. Occup Environ

> Med 62:616–622, 2005.

> 35. Mommers M, Jongmans-Liedekerken AW, Derkx R, et al. Indoor

> environment and respiratory symptoms in children living

> in the Dutch–German borderland. Int J Hyg Environ Health

> 208:373–381, 2005.

> 36. Jaakkola JJ, Jaakkola N, and Ruotsalainen R. Home dampness

> and molds as determinants of respiratory symptoms and

> asthma in pre-school children. J Expo Anal Environ Epidemiol

> 3(suppl 1):129 –142, 1993.

> 37. Meyer HW, Wurtz H, Suadicani P, et al. Molds in floor dust and

> building-related symptoms in adolescent school children. Indoor

> Air 14:65–72, 2004.

> 38. Meklin T, Potus T, Pekkanen J, et al. Effects of moisture-damage

> repairs on microbial exposure and symptoms in schoolchildren.

> Indoor Air 15(suppl 10):40–47, 2005.

> 39. Rockwell W. Prompt remediation of water intrusion corrects

> the resultant mold contamination in a home. Allergy Asthma

> Proc 26:316 –318, 2005.

> 40. Kercsmar CM, Dearborn DG, Schluchter M, et al. Reduction in

> asthma morbidity in children as a result of home remediation

> aimed at moisture sources. Environ Health Perspect 114:1574–

> 1580, 2006.

> 41. Douwes J. (1-33)-Beta-d-glucans and respiratory health: A review

> of the scientific evidence. Indoor Air 15:160 –169, 2005.

> 42. Young SH, VA, Barger M, et al. Acute inflammation

> and recovery in rats after intratracheal instillation of a 1-33-

> beta-glucan (zymosan A). J Toxicol Environ Health A 64:311–

> 325, 2001.

> 43. Wan GH, Li CS, Guo SP, et al. An airbone mold-derived product,

> beta-1,3-Dglucan, potentiates airway allergic responses. Eur

> J Immunol 29:2491–2497, 1999.

> 44. Rylander R. Airway responsiveness and chest symptoms after

> inhalation of endotoxin or (1 fi 3)--d-Glucan. Indoor Built Environ

> 5:106 –111, 1996.

> 45. Beijer L, and Rylander R. (1-33)-beta-d-glucan does not induce

> acute inflammation after nasal deposition. Mediators Inflamm

> 2005:50 –52, 2005.

> 46. Rylander R, Thorn J, and Attefors R. Airways inflammation

> among workers in a paper industry. Eur Respir J 13:1151–1157,

> 1999.

> 47. Eduard W, Douwes J, Mehl R, et al. Short term exposure to

> airborne microbial agents during farm work: Exposure-response

> relations with eye and respiratory symptoms. Occup

> Environ Med 58:113–118, 2001.

> 48. Wan GH, and Li CS. Indoor endotoxin and glucan in association

> with airway inflammation and systemic symptoms. Arch Environ

> Health 54:172–179, 1999.

> 49. Rylander R, Persson K, Goto H, et al. Airborne beta-1,3-glucan

> may be related to symptoms in sick buildings. Indoor Environ

> 1:263–267, 1992.

> 50. Roponen M, Seuri M, Nevalainen A, et al. Fungal spores as such

> do not cause nasal inflammation in mold exposure. Inhal Toxicol

> 14:541–549, 2002.

> 51. U.S. Environmental Protection Agency, American Lung Association,

> The Consumer Product Safety Commission, and The

> American Medical Association. Indoor Air Pollution: An Introduction

> for Health Professionals. EPA 402-R-94-007, 1994.

> 52. Wieslander G, Norback D, and Edling C. Airway symptoms

> among house painters in relation to exposure to volatile organic

> compounds (VOCS)—A longitudinal study. Ann Occup Hyg

> 41:155–166, 1997.

> 53. Cometto-Muniz JE, and Cain WS. Efficacy of volatile organic

> compounds in evoking nasal pungency and odor. Arch Environ

> Health 48:309 –314, 1993.

> 54. Molhave L, Jensen JG, and Larsen S. Subjective reactions to

> volatile organic compounds as air pollutants. Atmos Environ

> 25A:1283–1293, 1991.

> 55. Alarie Y. Sensory irritation by airborne chemicals. CRC Crit Rev

> Toxicol 2:299 –363, 1973.

> 56. Korpi A, Kasanen JP, Alarie Y, et al. Sensory irritating potency

> of some microbial volatile organic compounds (MVOCs) and a

> mixture of five MVOCs. Arch Environ Health 54:347–352, 1999.

> 57. Cain WS, and Cometto-Muniz JE. Irritation and odor as indicators

> of indoor pollution. Occup Med 10:133–145, 1995.

> 58. Cometto-Muniz JE, and Cain WS. Relative sensitivity of the

> ocular trigeminal, nasal trigeminal and olfactory systems to

> airborne chemicals. Chem Senses 20:191–198, 1995.

> 59. van Thriel C, Kiesswetter E, Schaper M, et al. From neurotoxic

> to chemosensory effects: New insights on acute solvent neurotoxicity

> exemplified by acute effects of 2-ethylhexanol. Neurotoxicology

> 2006 (Epub ahead of print).

> 60. Hempel-nsen A, Kjaergaard SK, Molhave L, et al. Sensory

> eye irritation in humans exposed to mixtures of volatile organic

> compounds. Arch Environ Health 54:416–424, 1999.

> 61. Pasanen AL, Korpi A, Kasanen JP, et al. Critical aspects on the

> significance of microbial volatile metabolites as indoor air

> pollutants.

> Environ Int 24:703–712, 1998.

> 62. JD, LaFlamme AM, Sobol Y, et al. Fungi and fungal

> products in some Canadian homes. Int Biodeterior 24:103–120,

> 1988.

> 63. Ware JH, Spengler JD, Neas LM, et al. Respiratory and irritant

> health effects of ambient volatile organic compounds. The Kanawha

> County Health Study. Am J Epidemiol 137:1287–1301,

> 1993.

> 64. Wady L, and Larsson L. Determination of microbial volatile

> organic compounds adsorbed on house dust particles and gypsum

> board using SPME/GC-MS. Indoor Air 15(suppl 9):27–32,

> 2005. e

> 270 May–June 2007, Vol. 28, No. 3

>