Mold_Excess_Dampness_and_Mold_Growth

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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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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

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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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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.

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