Is Stachybotrys mold exaggerated as a health risk?
Note from mold expert Phillip Fry: This attack on
Stachybotrys being a health threat may have been biased because funding for
this study was provided by an unrestricted grant from the CNA Insurance
Clinical Microbiology Reviews, January 2003, p. 144-172, Vol. 16, No. 1
0893-8512/03/$08.00+0 DOI: 10.1128/CMR.16.1.144-172.2003
Copyright © 2003, American
Society for Microbiology.
All Rights Reserved.
Indoor Mold, Toxigenic Fungi, and Stachybotrys
Infectious Disease Perspective
D. M. Kuhn1,2,3 and
M. A. Ghannoum2,3*
Division of Infectious Diseases, Department of Medicine,1 Center
for Medical Mycology, Department of Dermatology,2 University
Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio
Damp buildings often have a moldy smell or obvious mold growth; some
molds are human pathogens. This has caused concern regarding health
effects of moldy indoor environments and has resulted in
many studies of moisture- and mold-damaged buildings. Recently, there
have been reports of severe illness as a result of indoor mold
exposure, particularly due to Stachybotrys chartarum. While many
authors describe a direct relationship between fungal contamination and
illness, close examination of the literature reveals a confusing picture.
Here, we review the evidence regarding indoor mold exposure
and mycotoxicosis, with an emphasis on S. chartarum. We
also examine possible end-organ effects, including pulmonary, immunologic,
neurologic, and oncologic disorders. We discuss the
Cleveland infant idiopathic pulmonary hemorrhage reports in
detail, since they provided important impetus for concerns about
Stachybotrys. Some valid concerns exist regarding the relationship
between indoor mold exposure and human disease.Review of the literature
reveals certain fungus-disease associations in
humans, including ergotism (Claviceps species), alimentary toxic
aleukia (Fusarium), and liver disease (Aspergillys). While many
papers suggest a similar relationship between Stachybotrys and
human disease, the studies nearly uniformly suffer from significant
methodological flaws, making their findings inconclusive. As
a result, we have not found well-substantiated supportive evidence
of serious illness due to Stachybotrys exposure in the
contemporary environment. To address issues of indoor mold-related illness,
there is an urgent need for studies using objective markers
of illness, relevant animal models, proper epidemiologic techniques,
and examination of confounding factors.
Damp buildings often have a moldy smell or obvious mold growth, and
some molds are known human pathogens. This has caused concern regarding
potential health effects of moldy indoor environments. As
a result, there have been many studies of moisture- and mold-damaged buildings.
More recently, there have been a growing number of articles
in the media and of lawsuits claiming severe illness as
a result of indoor mold exposure, particularly to Stachybotrys chartarum. However,
while many authors report a clear relationship between
fungal contaminated indoor environments and illness, close
examination of the literature reveals a much more confusing picture.
In this review, we discuss indoor environmental mold exposure and
mycotoxicosis, with an emphasis on S.
(due to the breadth of the topic, we will not discuss better
understood areas such as invasive disease caused by Aspergillus). We
also discuss specific organ effects, focusing on illnesses purportedly
caused by indoor mold. These illnesses include pulmonary, immunologic,
neurologic, and oncologic disorders. We discuss the
Cleveland infant idiopathic pulmonary hemorrhage (IPH) reports in
some detail, since they provided much of the fuel for current concerns
about Stachybotrys exposure.
As we will see, while there
is cause for concern about the potential effects of indoor mold
exposure, particularly to Stachybotrys species,
there is no
well-substantiated evidence linking the presence of this fungus
to health concerns elaborated in the scientific and lay press.
As patients and society at large become increasingly concerned that
illnesses may be due to the home or work environment, anunderstanding of
mycotoxins by microbiologists and clinicians (especially
infectious-disease subspecialists) is of growing importance.
Such knowledge is critical to the diagnosis of potential fungus-related
disease and is necessary to assuage fears instilled by
extensive media coverage (34; J. MacFarlane, 1997, Beware the
mold Stachybotrys, http://www.cnn.com/HEALTH/9711/05/deadly.mold; J.
McKenzie, 2001, Hidden menace: insurers worry about toxic mold
claims, http://more.abcnews.go.com/sections/wnt/dailynews?toxicmold_010626.html; E.
Moriarty, 2000, Invisible killers, OBS News, New York, N.Y.; N.
Morris, 2001, Moldy Schools: are your kids getting sick at school?http://more.abcnews.go.com/sections/wnt/WorldNewsTonight/wnt010418_moldyschools_feature.html). Finally,
such knowledge may be important in the wake of recent terrorist
events in the United States. Some toxins, particularly aflatoxins
and trichothecenes, have the potential to be used as
weapons. There is evidence that several countries are currently involved
in mycotoxin weapon research (30, 239, 465).
The latter point
is beyond the scope of this article.
INDOOR AIR AND BUILDING-RELATED ILLNESS
It has long been postulated that exposure to damp, moldy home and
workplace environments has detrimental health effects. At the
beginning of the 18th century, Ramazzini, considered "the father
of occupational medicine," described an illness of workers inhaling
‘foul and mischievous powder' from handling crops (116, 302).
More recently, Platt et al. (333),
found that occupants of
wet, moldy buildings had an increase in subjective complaints. Brunekreef
et al. (47)
found a similar pattern in >6,000 children
in six states in the United States and reported home dampness
was a strong predictor of respiratory and other illness in
this age group. The list of putative symptoms generally consists of
upper respiratory complaints, including headache, eye irritation,epistaxis,
nasal and sinus congestion, cough, "cold and flu" symptoms,
as well as generalized gastrointestinal complaints (240).
Taskinen et al. (409, 410)
reported an increased prevalence of
asthma in moisture-affected schools, although there were no
objective measurements of respiratory disease. A number of studies
have reported a relationship between similar symptoms and
damp housing or workplace environments, although the proposed etiologies
have varied (117, 118, 164, 416, 419, 444).
The causal relationship between damp housing and illness is unclear.
Establishing such a relationship is complicated since there
are a variety of pollutants in the indoor environment (143)
including volatile organic compounds such as toluene, benzene,
alkenes, aromatic hydrocarbons, esters, alcohols, aldehydes, and
ketones (208, 267, 277, 310, 332, 357, 450);
radon (256); combustion
gases, sulfur dioxide, nitrogen dioxide, carbon dioxide, ozone
(16, 20, 357);
and the essentially ubiquitous formaldehyde (205, 357).
Other items (copy paper) and activities (photocopying and
video terminal exposure) have been linked to symptoms (178). Other
studies have suggested that shade, organic debris, landscaping quality,
central electrostatic systems, ventilation rates, temperature, noise
levels, dust control compliance, and patient gender may be
important (23, 42, 77, 215, 264, 298, 308, 344, 437, 440), as
well as the presence of tobacco smoke (81, 123, 276).
may be playing a role in building-related complaints. Several
studies have reported that the quality of the work environment, stress,
and somaticization may all be significant (31, 42, 89, 232, 276, 307, 308, 413).
The indoor environment also contains a wide range of microorganisms including
bacteria (e.g., Legionella and
other gram-negativespecies) (85),
mycobacteria (9, 415),
and molds (161),
as well as
their products, including endotoxins and mycotoxins. There may
often be a much higher bacterial load than fungal load (161, 416).
Most fungi are metabolically active over a broad temperature range
however, high moisture and relative humidity are required
for optimal growth (69).
The lowest relative humidity supporting
mold growth is approximately 75%, although the requirements ofStachybotrys are
much higher, around 93% at 25°C (142). Increasing
temperature and nutritional status of the substrate can
lead to lower moisture requirements. Surfaces that are soiled or
have susceptible paint or paper do not need to be as damp for
mold to develop. While promoting mold growth, moisture itself may
be critical in "sick-building syndrome" (SBS) illnesses, since
humidity affects mite and ozone levels, as well as off-gassing, salt,
and acid formation (26).
The links between moisture damage, any
of these related cofactors, and building-related illnesses are
not clear (24, 27, 50, 83, 260).
For example, dust mites are
notorious allergic agents and produce many of the upper airway
symptoms ascribed to mold exposure or SBS; moreover, they
are almost always found in association with mold species (90, 262, 359),
confounding moisture- and mold-related findings. Gram-negative
bacteria, endotoxin, and mycobacteria are found in
water-damaged buildings in association with mold (9, 85). To
our knowledge, only one paper has actually reported a lack of
association between symptom prevalence and endotoxin, dust mites,
or other nonfungal agents (85).
In moldy office buildings there
is an association between microbial contamination and repeated
flooding or stagnant pools of water (280).
Some geographic locales
are obviously more likely to be affected than others. For
example, 12% of English building stock suffer serious dampness; extrapolation
suggested that there were 2.5 million affected dwellings
in the United Kingdom but that 60% of these were from condensation
rather than overt flooding (362;
Anonymous, Bldg. Res.
Estab. Semin. Proc., 1981). Readers interested in an in-depth review
of these issues are referred to the recent comprehensive report
by the Institute of Medicine (175).
FUNGI IN THE INDOOR ENVIRONMENT
Fungal Organisms in Damp Buildings
A host of mold species have been isolated from damp buildings: the
most frequently isolated in one study were Penicillium(96%), Cladosporium (89%), Ulocladium (62%), Geomyces
pannorum (57%), and Sistronema
There were 66 species of
filamentous fungi, and yeasts were found in 94% of dwellings and
13% of CFU on Anderson sampler plates. In contrast to the aforementioned
species, Stachybotrys was
less common, being found
in 12.8% of dwellings and 4.5% of samples. Other studies have
reported similar organism frequencies (Table 1)
(72, 144, 215, 267, 420).
In most studies, Stachybotrys has
had a low prevalence,
being present in less than 3% of samples (214, 267). However,
some recent work has suggested that it may be more common
than was initially thought (144, 405).
Regardless, Stachybotrys is
rarely found in isolation, nearly always occurring in the presence
of other fungi (164, 419).
This fact is critical, since many
of the other species are capable of producing mycotoxins (70, 379, 416),
and recent work suggests that volatiles from S.
represent a small fraction of the total amount present
in problem buildings where other fungi exist (139).
a fondness for cellulose (350).
While cellulose (especially
water damaged) may promote Stachybotrys growth, the
same is true for Cladosporium,
Penicillium, and Aspergillus species
(144, 185, 202).
The predilection for cellulose, moisture, and
nutrient-poor settings explains the appearance of Stachybotrys in
affected buildings, where it is a tertiary wall colonizer that
comes after primary (Penicillium and A.
(Cladosporium) fungal colonizers (327). Stachybotrys can
sometimes be isolated from other substrates including pipe insulation,
gypsum, fiberglass wallpaper, and aluminum foil (144).
The nutritional and growth requirements of the organism may
also explain the lack of recovery from cultures and perhaps underreporting
of Stachybotrys incidence.
The fungus proliferates more
slowly than other species, leading to overgrowth by other molds
unless appropriate culture substrates (e.g., cellulosebased) are used.
Studies using cellulose-based agar techniques have
reported a relatively high prevalence of Stachybotrys, with
positive cultures in up to 30% of water-damaged homes (121). Similar
issues may exist when trying to identify mycotoxin-producing Fusariumstrains
Technical Problems in Determining Fungal Exposure
Difficulties in measuring fungal organisms. Although
available studies provide information regarding which organisms
are present in the indoor environment, there are significant concerns
associated with sampling methods. While a detailed description
of such techniques is beyond the scope of this article, several
points are worth mentioning. Most traditional sampling methods
(e.g., exposed agar plates) are incapable of adequately measuring
either airborne or sedentary organisms, which necessitates the
use of devices such as Anderson samplers (135, 142, 168, 267, 358, 416).
Even using such quantitative devices, there can
be huge variations (up to 1,000-fold) between essentially identical
Thus, little can be deduced from single
air samples, and protocols involving multiple samples from
suspect houses versus single samples from control houses will
probably disproportionately find fungus in case houses due
to attrition (142).
Furthermore, sampling needs to be done under
normal room activity, since aggressive measures (e.g., vacuuming)
will probably overestimate actual exposure levels (238, 359, 416).
These last two points are critical to examination of
the Cleveland IPH reports, discussed below. Hunter et al. (168)
found that while large numbers of spores in the internal air
were associated with surface mold growth and construction work,
disturbance of surface growth and vacuum cleaning of carpets (techniques
often involved in surveys) caused large temporary increases
in the atmospheric spore count. An increase of 3,300% in
the number of four categories of mold was observed after disturbing
mural mold growth (e.g., by wiping with a hand). Other
factors affecting apparent airborne fungal spore load are
carpeting type (162),
dust control measures (215),
and humidification (394).
Finally, particle size may play
a key role when attempting to quantitate some species; for
example, the rapid settling of the large spores of Ulocladium species
probably accounts for their being underrepresented in the
airborne spore load (144, 171).
Such culture difficulties may
eventually be circumvented using new techniques such as PCR
A final problem in measuring fungal organisms in the indoor environment
relates to selective sampling. As noted above, Stachybotrysspecies
rarely exist in isolation. They are often present in settings
which select for a host of other fungal species and their
potential mycotoxins, as well as bacteria, mycobacteria, arthropods,
and man-made organic chemicals. However, most studies cited
below have used methods that preferentially select for Stachybotrys species
and mycotoxins. Of more immediate scientific and
medicolegal concern, many studies of purportedly affected housing
are surveying only for Stachybotrys species
while ignoring other
organisms (our unpublished experience).
Difficulties in measuring mycotoxins. As
discussed in detail below, similar problems exist regarding the
detection and significance of indoor environmental mycotoxins. Many
purported fungal volatiles are in fact common and are not unequivocally
fungal in origin (267).
While some true mycotoxins have
been detected in indoor air, this has usually been in the context
of heavy industrial contamination (240,295).
is occasionally possible to collect mycotoxins by using air filters
followed by extraction (318, 388),
they are usuallyisolated from inert dust or building materials (9, 79, 111, 267, 294).
This may misrepresent exposure, since the compounds are
not volatile. In the case of Stachybotrys, toxin-bearing spores
are produced in a slimy mass with high moisture content (Fig. 1),
becoming airborne only when dry and disturbed or when attached
to other particles such as dust (161).
Serologic testing of
potentially exposed individuals is not useful, since specific immunoglobulin
levels do not correlate with exposure (419).
Most importantly, the presence of potentially toxigenic fungi does
not imply the presence of mycotoxins, nor does the finding of
mycotoxins prove that a particular species is, or was, present (267, 396, 420).
Toxin production is dependent on substrates, nutrient
levels, moisture, pH, and temperature (161, 283).
species can produce toxins (Table 2),
the ability to produce toxin
varies under particular conditions, and often "known" toxin
producers will not make the compounds (291).
There are also
extreme variations in toxin production between strains (11, 153),
making culture insufficient as an indicator for the presence
of mycotoxins. In addition, many unknown secondary metabolites,
yet to be detected or identified, can be produced (291),
and new compounds are constantly being identified (166). Fungal
species identification is not a simple process but often requires
the expertise of specialized medical mycologists. Toxins purportedly
produced by a particular organism may suffer from misidentification
of that organism (237).
Therefore, specific tests
for individual mycotoxins or biological assays (e.g., skin
irritation) need to be performed as tools for mycotoxin screening
In this regard, newer analytic methods are
being developed, including a protein translation (luciferase) assay
for trichothecene toxicity in airborne particulates (457). This
technique offers a greatly increased sensitivity compared with
prior systems and may provide a novel way to measure environmental mycotoxins.
Problems with Clinical Studies
Most studies describing the health effects of indoor dampness and
mold have relied on subjective and retrospective questionnaires.Remarkably
few studies have included physical examinations or diagnostic
testing. There are obviously potential problems with such
an approach, and when study validity was examined, some notable
conclusions were reached. To examine the validity of self-reported
symptoms, one group compared parental reports of
children's coughing, with overnight cough recording (88). The
results showed there was extremely low agreement between the
two measures. Additionally, parental smokers underreported their
children's coughing, which biased the actual odds ratio (OR)
of 3.1 (based on recording) down to 0.6 if their reports were
relied on instead. The same group tested the validity of questions
commonly used to indicate presence of indoor molds, compared
to established objective measures of mold (e.g., airborne ergosterol)
They found that more mold was present if odor or
water damage were reported and that twice as muchAspergillus and Penicillium was
found when mold was mentioned. However, the
presence of reported mold or water damage was unrelatedto objective
measures, and there was evidence of substantial reporting
bias (e.g., allergy patients were more likely to report visible
fungus despite low levels of viable fungus in dust, while
smokers were less likely to report visible mold). Overall, while
reported mold, water damage, and odors were associated with
elevated levels of indoor fungi, inaccuracy was high and there
was evidence of systemic bias, causing the authors to conclude
that objective measures, not questionnaires, are appropriate. In
another study of associations between residential mold growth and
symptoms, the authors tried to confirm the findings by objective measures
Using the same group as in their previous work (n =
403 homes), they compared reported respiratory symptoms with
objective measures including airborne ergosterol, dust, viable
fungus counts, and nocturnal cough recordings. Despite a
25 to 50% relative increase in symptom prevalence when mold was
reported, neither symptoms nor recorded cough were related to
objective measures of mold. It is reasonable to concludethat retrospective
subjective questionnaires are at best suspect. It
is worth noting the authors of this work are in fact proponents of
a mold-illness link, making their conclusions that subjective complaints
are inadequate measures of pathology perhaps even stronger.
Similar negative findings have been found when examining subjective
neurologic complaints in the setting of SBS (310).
Such findings may explain the confusing results of earlier studies. For
example, some authors have claimed links between childhoodasthma and damp,
moldy housing (401).
While retrospective questionnaires reported
more wheezing, cough, and chest cold symptoms in children from
affected houses, the degree of bronchospasm was not different between
groups. Thus, despite the claim that there was a causal association
between moldy houses and wheezing, there was no supporting
objective evidence. Some studies which claim thatmoisture and mold were
associated with respiratory infections, cough,
and wheezing (again with no objective measures) also fail
to show differences in asthma prevalence between case and control
schools (409, 410).
Other authors report that despite claims
of symptoms being more prevalent in case groups (reporting exposure
to fungi, pets, mold odor, and dampness), actual asthma prevalence
was no different (177).
ASSOCIATION OF STACHYBOTRYS SPECIES
WITH "SICK BUILDINGS"
Because of concerns of mold-induced building-related illness and
the particular characteristics of Stachybotrys species,there
has been growing concern about the health of occupants of Stachybotrys-"damaged"
buildings (9, 79, 91, 133,150, 157, 184, 188, 197, 241, 318, 423, 424).
Many authors have reported ill
effects in relation to Stachybotrys,although
it is critical to
note these reports are often associations rather than proof of
causation. Hodgeson et al. (164)
reported building-related illness
in Florida; this was described as symptoms consisting of
mucosal irritation, fatigue, headache, and chest tightness that
occurred within weeks of moving into the affected building. The
symptoms were purportedly caused by S.
chartarum and A. versicolor,although
a number of other species were seen. The authors
identified mycotoxins including satratoxins G and H (see
below) in moldy ceiling tiles, although the significance of
these findings is unclear. While they concluded the symptom outbreak
was likely a result of inhalation of fungal toxins, there
was in fact no clear evidence (e.g., laboratory parameters) to
support the claim. Tuomi et al. (420)
examined Finnish buildings with
water damage and identified a host of fungal organisms and
mycotoxins (satratoxins G and H, T-2 toxin, and the aflatoxin precursor
sterigmonisin) in bulk samples, although the relationship between
the organisms and toxins was unclear, as explored below. Examining
buildings with building-related illness complaints, Johanning
et al. (197)
isolated satratoxin H and spirocycliclactones from water damaged material.
The authors implied these mycotoxins
were the cause of respiratory and immune problems,although, as we discuss
below, the claims are questionable. Other
authors have reported anecdotal cases of illness in which S.
mycotoxins have been isolated from building materials,
but again there are few objective measurements of illness
or clear etiologic links to the fungus (79).
While authors claim
the health effects are similar to past cases of stachybotryotoxicosis, such
effects are often vague, poorly described, and clearly not
the same as the serious illnesses of equine stachybotryotoxicosis and
alimentary toxic aleukia described below.
One of the best studies of building-related illness showed minimal relation
to Stachybotrys. Miller
et al. (267)
examined 50 Canadianhomes in which the occupants had complaints of
respiratory or allergic
symptoms for which there was no explanation, although at
the time of the study, occupants of only 6 houses had "building-related illnesses."
Looking at air exchange rate, moisture levels, and analyzing
air and dust for fungus and fungal products in 37 of
the homes, they found S.
only one house; analysis of
the 6 "sick" houses did not indicate fungus-related disease. During
parts of the year when windows are open, indoor fungi are
comparable to outdoor species (Cladosporium, Alternaria, and Aureobasidium)
However, in this study, outdoor air spores
were negligible and Penicilliumand
other soil fungi were
most important. Toxigenic fungi included P.
viride, P. decumbens, and A.
contained "appreciable" amounts of filamentous fungi and
yeast, and so it was expected that spores could be found in
air, depending on the activity in the room.
Recently, there has been a great concern regarding exposure of
school children in "contaminated schools," sometimes resulting in
building closures (367, 409, 414;
Norris, ABC News online article).
In fact schools may have lower mean viable mold spore counts
than the students' homes (105).
In one 22-month study of
48 schools in which there were concerns regarding indoor air
quality and health (rhinitis and congestion which improved when
the students were away from school), fewer than 50% of affected
schools had fungal CFUs higher than outdoor air (72). In
11 schools where complaint areas had samples with the same organisms
as outdoors, Stachybotrys was
found, but only on surface swabs
and not air specimens. The researchers did not look for other
etiologies, nor were there objective measures of illness. Taskinen
et al. (409, 410)
also reported an increase in asthma in
moisture- and mold-affected schools but presented no objectivemeasurements
of asthma and very limited immune data, including surprisingly
low incidences of positive skin prick tests. Other authors
have presented similar findings, reporting that "exposed" children
had a higher prevalence of respiratory symptoms and infection,
doctor visits, and antibiotic use, and got better post
However despite claiming "[exposure]...increased the
indoor air problems of the schools and affected the respiratory health
of the children," the study was neither controlled nor blinded,
and presented no physical diagnosis or objective measures.
Other evidence suggests that Stachybotrys exposure
is not responsible for
these building-related episodes. Sudakin (404)
examinedwater-damaged buildings in the Pacific Northwest, due to occupants' neurobehavioral
and upper respiratory health complaints (there were
no objective pulmonary data) and found S.
chartarum in only
1 of 19 cellulose agar cultures from building materials; the
fungus was not detected in any of the above samples. While employees
felt better after being relocated, there was no evidence that Stachybotrys was
a causative agent. Even when large amounts of
fungus are detected, analysis often fails to show direct links
between symptomatic residents and fungal growth (41). In
studies reporting that exposure to home dampness and mold may
be a risk factor for respiratory disease, other factors such
as smoking may be more contributory (84).
In buildings with
moisture problems where mycotoxins have been identified, a
variety of species are identified, and links between a particular organism
and toxin often cannot be established (420).
Despite these problems and an almost complete lack of objective evidence
to support guidelines, broad recommendations have been made
concerning indoor mold exposure, acceptable air contamination limits,
and remediation goals. The sources range from individual authors
to the American Academy of Pediatrics (7a) to
government agencies (15).
Nikodemusz et al. (292)
microbial monitoring of air is important even though the organisms
the author found were not pathogens. While Miller et
admit that their "data seriously call into question any
attempt to set arbitrary standards for fungal CFU values," they
proposed that some fungi should be considered unacceptable, e.g.,
pathogens and certain toxigenic species such as S.
though complete elimination would be untenable. The same authors
stated that it is reasonable to assume there is a problem if
a single species predominates with >50 CFU m-3;
that <150 CFU
acceptable if there is a mix of benign species; and that
there is no problem when up to 300 CFU ofCladosporium or
other common phylloplane fungi m-3 is
isolated. Notably there is
no source material to support these assertions. The American Association
of Pediatrics produced guidelines in the wake of the
Cleveland IPH story (7a),
again without substantial evidence.More moderate recommendations (while
recognizing that the presence of
fungi does not necessarily imply illness) would appear reasonable(240).
These could include maintaining heating, ventilation, and
air conditioning (HVAC) systems, controlling humidity, inspecting and
repairing water damage and other sources of contamination, regularly
cleaning the home environment with dust removal, cleaning carpets,
removing visible mold growth, and formulating guidelines to
standardize the levels of fungal and bacterial contamination.
There have been a number of media reports on the abandonment or
destruction of buildings contaminated with S.
CNN online article; Moriarty, CBS News program). It
is unlikely that such extreme measures are warranted. Methods are
discussed further below, but it is important to note that individuals
get better with remediation efforts (6, 72, 79, 191, 321, 367),
although perhaps not always (164).
Simple methods, including
removing damaged material and spraying affected areas with
bleach, are generally effective in controlling contamination and
result in "clean" air samples (430).
In some cases, temperature and
humidity control may be adequate (142).
FUNGI AND FUNGAL TOXINS
Perhaps the earliest recorded cases of mycotoxicosis date to the
Middle Ages with the description of "St. Anthony's Fire"or ignis sacer
(sacred fire) due to ergotism from Claviceps purpurea (which
can also be produced by some species of Penicillium,Aspergillus, and Rhizopus)
By the 17th century, it
was recognized that moldy rye produced the disease, and ergot alkaloids
from fungi were identified as toxins in the 18th century (53, 69, 157).
The source of ergot affects both the type of alkaloid
produced and the clinical syndrome. There are two types of
gangrenous ergotism, while C.
convulsive ergotism (discussed below). The
disease is rare today due to food hygiene and the lability of
the alkaloid toxins. That ergotism was produced by oral consumption is
important, reflecting the fact that historically, mycotoxicosis has
usually been associated with oral consumption of moldy grain (157).
As discussed below, other routes of instillation result in
significantly different types and degrees of toxicity.
Mycotoxins are diverse secondary metabolites produced by fungi growing
on a variety of foodstuffs consumed by both animals and
humans (Table 2)
Clinical toxicological syndromes caused
by ingestion of large amounts of mycotoxins have been well
characterized in animals and range from acute mortality to
slow growth and reduced reproductive efficiency. The effects on
humans are much less well characterized (Table 3)
(76, 329). Outbreaks
of various types of animal mycotoxicosis have occurred worldwide
in livestock, including sweet clover poisoning, moldy- corn
toxicosis, cornstalk disease, bovine hyperkeratosis, and poultry
hemorrhagic syndrome (76, 133).
Mycotoxins are probably responsible for a range of acute and chronic
effects that cannot be attributed to fungal growth within the
or allergic reactions to foreign proteins (370). There
are at least 21 different mycotoxin classes (71),
400 individual toxins produced by at least 350 fungi (38, 53, 192, 334, 335, 390, 420).
They are all complex organic compounds of
200 to 800 kD and are not volatile at ambient temperatures. A
number of these are plant disease virulence factors, while others
kill other fungi and microorganisms and thus may represent spillover
effects when causing disease in animals (322).
A variety of factors affect toxin occurrence (157).
Many toxins are
secondary metabolites, produced under suboptimal growth conditions
or in the presence of limited nutrients (161). (For
reviews of toxin synthesis, see references 46 and 406.) Temperature,
relative humidity, moisture, and growth rate all affect
fungal mass as well as toxin synthesis. Aflatoxin production by Aspergillus is
dependent on concentrations of O2,
copper, as well as physical location (A. fumigatus and A. flavus grow
in trench silos, while upright silos favor Fusarium species)
Ochratoxin production relates to air exhaustion (69),
patulin production relates to limiting nitrogen, ergot production
relates to phosphate limitation (48),
production relates to temperature (35).
These considerations are
critical, since the recovery of toxigenic species from any environment
does not substantiate the presence of a mycotoxin (mycotoxin
production is not a necessary result of fungal growth) (48).
Indeed, the conditions necessary for mycotoxin production are
usually very different from those required for growth; for example, Fusarium
a significant amount of T-2
toxin at 15°C but little at higher temperatures (69).
The most notorious and best described of the mycotoxins are the
aflatoxins. In the early 1960s, an outbreak of turkey X disease
in England, in which over 100,000 fowl died, was later traced
to contaminated peanuts from Brazil (454).
subsequently identified as the toxic agent. While made primarily
by Aspergillus species,
these toxins are also produced by Penicillium and Fusariumspecies
(AFB), while A.
both AFB and AFG. AFM1 and
oxidative metabolic products made after ingestion and
appear in milk, urine, and feces. The aflatoxins are toxic, immunosuppressive,
mutogenic, teratogenic, and carcinogenic, and
their main target is the liver. Most have been classified as
type 1 carcinogens (172).
probably the most potent liver
carcinogen for a variety of species, including humans (102).
Aflatoxin-related disease can occur in outbreaks, causing acute,
often fatal, liver injury. The compounds have been best studied
in veterinary practice, where they show the most potent effects.
Toxicity is species, age, and route dependent; for example,
farm animals ingest large quantities in feed (402). Species
variability may relate to the ability to form epoxide derivatives
in liver microsomes and endoplasmic reticulum.
The case of aflatoxin also illustrates the problems of elucidating clinically
relevant levels of mycotoxins. Determining actual exposure
levels is exceedingly difficult, even in known contaminated foodstuffs
While aflatoxin contaminates many imported goods
(from almonds to melon seeds), there is a large variation in
toxin distribution. Data validity is suspect when looking at
small quantities, since aflatoxin is normally found in only very
limited portions of a food lot and levels in such samples can
range from 0 to >400,000 ng/g. For many mycotoxins, it becomes
a matter of how hard one looks, and as more sensitive methods
are developed, more toxins are found. Currently, at least
29 mycotoxins have been identified in commercially available foods
or feeds (57),
and in rare cases of high feed contaminationthey have been found in meat,
milk, and eggs.
In the Ukraine in the early 1930s, a unique disease of horses was
recognized that was characterized by lip edema, stomatitis, oral
necrosis, rhinitis, and conjunctivitis. The symptoms often progressed
through well-defined stages to pancytopenia, coagulopathy and
hemorrhage, neurologic compromise (irritability, gait disturbance, and
blindness), superinfections, and finally death (133).
also a rare "atypical" or "shocking" form, which was primarily neurological
and highly fatal, with areflexia (loss of sensorimotor reflexes),
hyperesthesia (hypersensitivity to pain), hyperirritability, blindness,
and stupor. In these latter cases, there were no blood
dyscrasias. Pathologic examination of tissue from affected animals
revealed diffuse hemorrhage and necrosis, with involvement of
the entire alimentary tract. Pulmonary changes consisted of
lung congestion and edema (429).
Pathologic changes in tissue appeared
unique, since there was no zone of demarcation around necrotic
foci and since the tissue appeared to be in a "nonreactive state."
In retrospect, these findings were perhaps the first indication
that the entity had a toxigenic origin rather than being
due to direct tissue infection. In the wake of the equine outbreak,
it was soon realized the disease was not limited to horses.
However, there were marked species and age effects on susceptibility:
cattle were less affected than horses, and younger animals
fared better than older ones (134).
While in 1938 this animal disease was associated with Stachybotrys species,
it was nearly a decade before the etiologic organism was
identified in contaminated grain as S.
alternans var. jateli (133, 429).
In 1837, Corda first defined the Stachybotrys genus, from
a strain growing on domestic wallpaper in Prague (75). S.
alternans and S.
obsolete species names, and the organism
has been renamedS. chartarum (www.doctorfungus.org/imageban/synonyms/stachybotrys.htm). S.
dematiaceous and is a member of the Fungi Imperfecti. Interested
readers should refer to the article by Jong and Davis (200)
as well as the recent on-line review by Nelson (B. D. Nelson,
toxic indoor mold, APSnet,http://www.apsnet.org/online/feature/stachybotrys).
In the 1940s Drobotko et al. (103, 104)
reported finding the fungus
on straw and fed it to horses, which developed the characteristicequine
illness. At the same time, scientists recognized that the
disease was toxin mediated and that exposure to isolated toxin
could produce symptoms (133).
Subsequently, Drobotko coined the
term "stachybotryotoxicosis." By the late 1940s, similar outbreaks
of livestock disease had been reported in the rest of
the USSR and Eastern Europe, as well as among nonequine species (134, 387, 434,455).
More recently, animal disease has been seen
from Europe to South Africa (150, 212, 224, 225, 373;
Bars and J. Le Bars, Proc. 5th Int. Working Conf. Stored Product
Prot., 1990). In South Africa, a case of sheep disease was
seen in the 1990s after animals consumed heavily contaminated grain
The affected animals had fever, listlessness, oral
lesions, pancytopenia, hemorrhage, opportunistic infections, and
a significant mortality rate.
Members of the Stachybotrys genus
exist worldwide, from Finland to
the South Pacific Islands (133, 434),
and were identified in
the United States in the 1940s (442).
In general, the organism is
found in soil and strata rich in cellulose (hay, straw, grain, hemp,
plant debris, dead roots, wood pulp, cotton, fabrics, paper,
book bindery glue, plant fiber-processing plants, etc.) (133).
It has also appeared in cigarette tobacco (1, 115).
can survive a wide temperature range, only dying at temperatures
of >60°C. The fungus can survive over winter, spores
stay viable for years to decades, and conidia retain viability
despite passage through the gastrointestinal tract (but
are killed in composting and degradation of manure). These factors,
combined with their geographic range, suggest thatStachybotrys species
are essentially ubiquitous. While disinfectants kill
conidia and mycelia, cell walls are quite stable.
Associations with Human Disease
The possible association of Stachybotrys species
with human disease
became apparent coincident with the equine epidemics. In
areas of enzootic equine disease, humans, especially fodder-handlers and
others who had close contact with musty straw, developed a
dermatologic and respiratory syndrome (103, 104, 196, 229, 429, 434).
Occasionally, individuals who used straw for fuel or
bedding became ill (133).
Close family members without such exposures,
and even workers protected by clothing, did not become ill.
Primary disease manifestations appeared on the skin, with dermatitis
on the scrotum, medial thighs, axilla, and, less frequently,
the hands and other areas. Lesions progressed from hyperemia
to crusting exudates to necrosis, with subsequent resolution
Lesion location suggested that rather than direct
contact, the lesions were due to aerosolization of the offending
substances, with primary effects in dermal areas with abundant
moisture and skin-to-skin contact. Some patients suffered erosions
on the oral and gingival mucosa (7, 229).
were described, including catarrhal angina, bloody rhinitis,
cough, throat pain, chest tightness, and occasionalfever. Some patients
experienced transient leukocytopenia. Subsequently, straw
that were toxic in a rabbitdermal toxicity test, producing areal
fructifications. When applied
to the skin of volunteers, the isolates produced the same
local and systemic responses (104).
A striking aspect of these
observations is their significant difference from animal disease,
both in symptoms (dermatologic versus systemic illness) and
in the route of exposure (ingested versus aerosolized contact) (7, 360, 361).
Despite the association of Stachybotrys with
animal and human disease,
early researchers were unable to fulfill Koch's postulates with
the fungus. There was no evidence that the fungus itself was
a pathogen, and scientists could not transmit infection or
disease by injection of tissue from affected animals (104). At
most, injection of the fungus caused a local response but no
systemic invasion (429).
It was only with the identification and
application of Stachybotrys toxins
that the nature of the disease
process was understood.
Mycotoxins from Stachybotrys
The mycotoxins responsible for many of the described effects of Stachybotrys were
isolated in the 1940s during the aforementionedRussian equine outbreak and
were found to have an empiric formula of
consistent with the trichothecene class of
compounds (103, 104, 133).
There are 148 natural trichothecenes alone
At least 40 of these are mycotoxins, produced mainly byFusarium species
While trichothecenes are chemically diverse,
they are all tricyclic sesquiterpenes with a 12,13-epoxy-trichothec-9-ene ring
some of the best described of which are satratoxins F,
G, and H, roriden E, verrucarin J, and trichoverrols A and B.
The toxins have been isolated from a variety of substrates, including
dust (satratoxins, trichoverrols, verrucarol, verrucarins,trichoverrins) and
grain (T-2 toxin, nivalenol, and derivatives of
The most potent of these are T-2 toxin, diacetoxyscirpenol(DAS or anguidine),
deoxynivalenol (vomitoxin), and fusarenon-X (Fig. 2).
Sites of action include initiation of protein synthesis(scirpentriol,
15-acetoxyscirpendiol, DAS, verucarin A, and T-2
toxin) and elongation or termination (trichodermin, trichodermol, crotocol,
trichothecolone, trichothecin, and verrucarol) (187, 258).
Because of their potency in affecting protein synthesis, they
may cause a predilection to other diseases, masking the underlying
toxicosis (322, 337).
As a result, many diagnoses were
entertained before alimentary toxic aleukia (see below) was
correctly linked to fusarial toxins (Table 4)
(194). Stachybotrys species
can produce spirolactams and spirolactones related to anticomplement
phenylspirodrimanes which inhibit complement
and endothelin receptor
There is also a beneficial trichothecene complex
of antibiotics exerting phytotoxic, cytotoxic, and cytostatic properties
and recently described stachyflin compounds with
potent antiviral activity (269).
Trichothecenes resist sunlight,
UV light, X-rays, heat (up to 120°C), and acids. They
are readily destroyed by alkali, which allows for detoxification with
sodium, potassium, calcium, or ammonium hydroxide or gaseous ammonia
This has important ramifications for building remediation.
Experimentally, two-thirds of Stachybotrys isolates
produce stachybotryotoxins. S.
the species most closely associated
with trichothecene mycotoxicosis, although it should be
noted that other main producers of trichothecenes are Fusarium, M.
roridum. Other fungi capable of synthesizing these
compounds include Trichothecium,
Trichoderma, Cephalosporium,Verticimonosporum, and Cylindrocarpon (186).
As noted above the
presence of potentially toxigenic strains does not imply the
production of toxin (either in the environment from which the
organism was isolated, nor the laboratory), nor does the appearance
of a toxin in environmental samples mean that Stachybotrys (or
another relevant fungus) is present. While S.
several very toxic macrocyclic trichothecenes (32, 150-152, 183, 188),
the levels at which these toxins are produced in
laboratory cultures have never appeared sufficient to cause such
profound toxic effects as have been observed in animals (188).
Levels are also low in environmental samples. Chemical analysis
of such samples is difficult due to intrinsic compound properties
and secondary metabolite production; despite much work,
most potential products are uncharacterized (e.g., due to
irreversible column gel binding) (188),
and even experienced investigators
can obtain different toxin results from identical strains
(e.g., using differing culture media or pH). Toxicitycan also vary widely
during culture (134).
Matters are further complicated
by the fact that more than one compound is often involved
in field outbreaks, and little research has been performed to
examine combined toxicity.
The most famous purported case of mass human trichothecene toxicity was
in fact due to Fusarium. The
illness was initially dubbed"septic sore throat" and subsequently called
alimentary toxic aleukia
(ATA) (7, 193-195, 252, 253, 274, 369, 380, 408, 429). It
occurred in Russia in the early 20th century, most notably prior
to and during World War II, and was characterized by several stages.
Initially, there was oral mucosal ulceration and gastroenteritis. Subsequently,
there was pancytopenia accompanied by fatigue, vertigo,
and hypotension. The illness had a substantial mortality rate,
at least in part due to opportunistic bacterial infections developing
in the later stages of the disease (53, 69, 370). One-third
of family members who ate contaminated grain became ill,
and one-third of those died; this was responsible for thousands of
deaths. Where nutrition was good, morbidity and mortality were
much lower (7, 274).
As in the case of the equine stachybotryotoxicosis, Koch's
postulates could not be fulfilled during research into the
disease's etiology. The illness was subsequently attributed to
trichothecene mycotoxins in overwintered grain infected with F.
sporotrichioides or F.
The grain had been left in
the fields due to the severe conditions prior to and during the
The precise toxic cause of the illness was never fully identified. A
number of mycotoxins were obtained from laboratory cultures of F.
sporotrichioides and F.
(T-2, HT-2, and
neosolaniol), sterols (sporofusarin, sporofusariogenin, poaefusarin,
and poaefusariogenin), and fatty acids (29, 195, 273, 382, 452, 453).
The relevance of these mycotoxins to the observed
human illness is still not clear. T-2 toxin was commonly produced
and may be responsible (69),
and T-2 toxin produces an
ATA-like illness in cats (233,234);
however, many of the other
compounds also produced toxic effects in cats (195).
not been seen since the last Soviet reports in the late 1940s,
and so there have been no recent episodes to study by modern
analytical techniques. (In 1970, Saito and Tatsuno  described
four human cases of Akakabi-byo, or red mold disease, which
had some similarity to ATA. Analysis of fungus-contaminated grain
mycotoxins including nivalenol, fusarenone-X,
and diacetoxyscirpenol.) The reasons for the disappearance of
ATA are probably multifactorial, including improved grain handling
and nutrition. Several important points are worth mentioning. First,
while the clinical picture of ATA is similar to that of
equine stachybotryotoxicosis, the former disease is almost certainly
caused by Fusarium rather
than Stachybotrys species. Second,
the exact toxicologic mechanism has not been determined. Third,
the population affected by ATA also suffered severe nutritional deficiency
which can produce similar symptoms.
While the effects of large amounts of orally ingested mycotoxins on
animals have been well described, systemic effects of exposure to
inhaled mycotoxins have been much less characterized. As noted
above, workers exposed to aerosolized mold or mycotoxins during
the equine stachybotryotoxicosis outbreak had a very different
constellation of symptoms from animals ingesting affected grain.
Only a few mycotoxins have been conclusively shown in aerosols,
including aflatoxin, some trichothecenes (157),
and secalonic acid D (112).
This is because purified mycotoxins are
not volatile (370),
due to their high molecular weights (71).
Therefore, inhalation exposure probably occurs through inhalation
of airborne particulates containing mycotoxins, such as
dust and fungal components (314,443;
H. B. Schiefer, Proc. 5th
Int. Conf. Indoor Air Qual. Climate, 1990). Moreover, since mycotoxins
have been postulated to normally be confined in spores, it
is doubtful that they frequently reach the lower airways due
to size limitations. The depth of particle penetration isinversely
proportional to size; the upper airways trap particles of
10 to 60 µm, while particles 2 to 4 µm in diameter can
reach the alveoli (141).
Mold spore size depends on the organism;
e.g., Alternaria spores
are more than 7 µm in diameter,
while thermophillic actinomycetes are less than 1 µm
This point will become important below, when discussing
models of stachybotryotoxicosis.
Rationale for concerns regarding Stachybotrys. It
is only recently that the idea that Stachybotrys can
causesignificant disease has risen to national prominence (137), although
the documented pulmonary effects of exposure to some fungal
species date to the 18th century. The transient acute upper
respiratory symptoms in workers exposed to contaminated materials
during the equine Stachybotrys outbreak
as anecdotal reports (11, 423),
suggested that this fungus could
exert at least minor pulmonary effects. Concerns in the United
States regarding Stachybotrys developed
primarily due to
reports linking an unusual cluster of pediatric IPH and mold exposure
in the Cleveland area (65, 123, 278).
in some cases its mycotoxins, was isolated in
building materials and air samples in buildings associated with
moisture problems and complaints of SBS-like illnesses (41,79, 164, 168, 267;
E. Johanning, P. Morey, and M. Goldberg, Proc.
Sixth Int. Conf. Indoor Air Qual. Climate, 1993).
Possible links between mold and respiratory disease have been recognized
for more than a century; literature describing connectionsbetween indoor air
and pulmonary disease is cited above. Initial study
of the problem came about due to work-related problems in
several areas, including farming and industry (73, 376). Early
Soviet literature described a toxicosis associated with inhalation
of dust heavily contaminated with spores of a variety of
fungi (e.g., A.
fumigatus, A. niger, Dendrodochium toxicum, and Stachybotrys),
which was subsequently dubbed respiratory mycotoxicosis
or pneumomycotoxicosis (360, 361).
This illness was
considered an occupational disease in many professions, including
those involving work in binder twine factories, cottonseed oil
processing plants, grain elevators, and mills (133, 360). However,
occupational lung disease occurs in many industries, generally
in the absence of an infectious agent (73),
so thatit is often unclear if fungi are the responsible agents or
With the dissemination of the concept of toxigenic indoor mold, scientific
reports (see below) and legal claims (13, 14, 17; C.
Kingdollar, 2001, Pollution litigation review—August 2001, http://www.facworld.com/FACworld.nsf/doc/pollitrev0801) of
mold-induced respiratory complaints have become commonplace. For
example, Johanning et al. (197)
reported that exposure to toxigenic S.
other atypical fungi was associated with
disorders of the respiratory system, although pulmonary disease
was never documented beyond subjective complaints. However, it
must be noted that many different conditions can produce essentially
the same respiratory symptoms (129).
These range from
the benign, such as congestion and cough from rhinitis, to
reactive airways disease to more serious syndromes including alveolitis,
bronchiectasis, and pulmonary fibrosis. Within the rubric
of subjective complaints subsequently described as "asthma," there
may be a variety of actual syndromes ranging from asthma to
allergic bronchopulmonary aspergillosis, hypersensitivitypneumonitis,
emphysema, pulmonary fibrosis, and pulmonary hemosiderosis (73, 128).
It is also critical to distinguish conditions which are
readily reversible from those which produce permanent damage: most
mold-related respiratory diseases in fact appear reversible (72).
This is especially important given legal claims of permanent lung
injury and "lung scarring" (Anonymous, 2000, New details from
mold investigation: news comes too late for former employee, ChannelCincinnati,http://www.channelcincinnati.com/cin/news/investigations/stories/investigations-20000126-221100.html; Kingdollar,
Pollution litigation review—August 2001 online article;
M. McConnell, 2001, Awareness of mold problem increasing among
homeowners, hvac industry, http://www.snipsmag.com/CDA/ArticleInformation/features/BNP_Features_Item/0,3374,20041,00.html).Although
these conditions can be diagnosed by methods ranging from
radiology to pulmonary function tests (PFTs) to biopsy, most
studies have not done so, relying only on subjective reports instead.
A number of papers have made claims regarding asthma and
interstitial and emphysematous lung disease with no data beyond
subjective questionnaires, which cannot diagnose many of
these conditions (164).
As noted above, objective studies often
reveal poor correlation between complaints (on retrospective questionnaires)
and actual pathology. Thus, a main concern lies in
determining if there is actually disease beyond mild upper airway
inflammatory responses and in whether these symptoms are
due to fungus as opposed to other contaminants (73, 319).
Organic toxic dust syndrome, hypersensitivity pneumonitis, and allergic lung
to massive amounts of fungus can cause a significant, but
transitory, acute lung injury. Anecdotal reports have documented disease,
generally in farmers, who inhaled large quantities of
organisms (116, 286, 324).
All describe an acute organic dust
toxic syndrome or silo unloaders syndrome (also calledatypical farmer's lung
or pulmonary mycotoxicosis). This illness differs
from hypersensitivity pneumonitis (HP) in that it is transient,
occurs in naive patients, needs intense exposure, neutrophils
and not lymphocytes are found on brochoalveolar lavage
(BAL), and fungal precipitin testing is negative (377). The
episodes described occurred shortly after inhalation of unusually
massive amounts of fungus and resulted in cough, respiratory distress
(sometimes requiring ventilatory support), fever, fatigue, alveolar
and interstitial infiltrates on chest X-ray, and leukocytosis. These
cases are relatively unusual since lung biopsy alveolar specimens
showed fungus, including A.
niger (286),Fusarium, Penicillium (324),
and in one case five different organisms (116).
In addition to fungal organisms, histopathologic testingshowed acute and
organizing diffuse alveolar damage or bronchopneumonia (324).
Serologic studies for antigens capable of causing hypersensitivity pneumonitis
were negative (286).
Most importantly, all patients recovered,
with no residual chest X-ray abnormalities or residual deficits
While one author claimed that these cases were due
to fungal toxins (116),
there was nothing to suggest thatthese responses were more than an acute
pneumonitis or near-drowning-type response.
To our knowledge, these cases are the only ones where fungi
have been demonstrated in lung tissue (aside from the quite
different diseases of frank pulmonary fungal infection with
organisms such as Aspergillus),
with one exception noted below.
This is an important point, since as discussed below, most
animal models of Stachybotrys pulmonary
toxicity rely on direct
inoculation of organisms into the airway, in concentrations high
enough that they can later be seen in lung tissue.
Allergic pulmonary effects of mold have been well described, ranging
from upper airway inflammation (rhinitis with coincidentconjunctivitis) to
asthma, allergic pulmonary aspergillosis (the
latter usually affecting patients with intrinsic lung disease and
bronchiectasis), and HP (73, 301, 345, 376).
While an in-depth discussion
of this topic is beyond the scope of this review, some
findings are worth mentioning. Occupational lung disease alone
consists of a number of subtypes, including industrial bronchitis,
occupational asthma (in which a very small amount of
offending agent can cause bronchospasm after airways sensitization, e.g.,
in animal handlers and crab processors), byssinosis (Monday morning
fever), and grain dust-induced bronchitis (73).
substantial evidence that the last two illnesses are caused by
endotoxin exposure (58, 156, 235).
In several cases, HP has been documented after exposure to indoor mold
(usually Penicillium species),
generally in the setting of
faulty ventilation systems (2, 37, 126, 356).
in Japan is probably caused by T.
cutaneum (10, 355, 385, 393, 458),
although supporting studies are limited by lack of objective
data as well as cocontamination (11 case homes had 3,536
strains of fungi ).
While some forms of HP appear to
be due to fungi, the disease can be caused by dozens of agents, ranging
from bird proteins to thermophilic actinomycetes (376). Additionally,
the differential diagnosis of the condition includes organic
dust toxic syndrome, humidifier fever, secondary (from chemotherapy,
radiotherapy, inhaled toxins, and pneumoconiosis) and
idiopathic pulmonary fibrosis, granulomatous disease (e.g., sarcoid),
and congestive heart failure (376).
HP is reversible if
the patient is removed from exposure to the offending agent, although
in some cases prolonged (years) exposure may lead to pulmonary
fibrosis and pulmonary hypertension.
Despite claims that building contamination increases asthma symptoms,
there is a profound lack of objective data. Notably, one
of the few studies to employ objective measures of lung function
(PFTs with methacholine challenge) failed to show lower respiratory
Another paper reported decreased diffusion
capacity in individuals with respiratory symptoms who
worked a problem building, but this is of unclear significance, given
there were no changes in other PFTs and it was not certain if
the symptoms were related to the building or preexisting conditions
A small Finnish study reported new cases of asthma
in occupants of a water-damaged building, confirmed by Sporobolomyces
provocation tests (381) but
simultaneously claimed the illnesses were not immunoglobulin E
(IgE) mediated. Finally, an experiment which allowed workers to
have individual control of their ventilation systems actually led
to higher concentrations of airborne dust and fungi while producing
fewer symptoms (263).
In some cases it appears there is a correlation between SBS and
upper airway allergic symptoms, although the etiology is unclear
and is probably varied (176;
H. M. Ammann, 2001, Is indoor
mold contamination a threat to human health?http://www.doh.wa.gov/ehp/oehas/mold.html). Objective
studies have found nasal mucosal hyperreactivity (305), and
alterations in tear film stability (285).
Jaakkola and Jaakkola (178)
found that symptoms were associated with the use of photocopy paper.
Researchers have sometimes found an association between building-related symptoms
and mold-specific IgE, although it occurred in a minority of
patients. Surprisingly, there was not an association with self-reported
hay fever or asthma (222),
even though allergic asthma
is IgE mediated (345).
These authors apparently did not check
for IgE to nonmold allergens. Other authors have failed to
show links between atopy and symptoms. Higher mold IgE levels have
been found in individuals exposed to water damaged structures (242, 368).
Several groups have reported links between Alternaria allergen
sensitivity (measured by specific IgE), but the relationship was
not as strong as that between routine indoor allergens and asthma
Of a group of Chinese schoolteachers exposed to moldy
sugarcane, 42% developed allergic alveolitis. After the outbreak,
patients were found to have elevated IgE levels, and Penicillium and Mucor species
were identified on the sugarcane (155).
Other studies failed to show associations between IgE and
Nasal lavage of individuals from contaminated buildings
show increased tumor necrosis factor alpha, interleukin-6 (IL-6),
and nitric oxide levels in relation to periods of documented exposure
However, the study did not document which fungus was
responsible or if the results were controlled for confounding factors.
Other work found increased concentrations of eosinophils, eosinophil
cationic protein, and myeloperoxidase in the nasal lavage
fluid of office workers in damp buildings compared to controls
Damp buildings had larger amounts of molds and
bacteria, as well as evidence of volatiles from degraded polyvinyl
chloride floor coatings. Polyvinyl chloride degradation products
have been linked to symptoms by using objective physical measures
Thus, while evidence suggests a larger amount of
allergic markers in individuals exposed to water-damaged structures,
the etiology of these changes is far from certain (242).
Furthermore, potential fungal antigens are many, and not
well identified. While airborne 1-3-ß-D-glucan is
widely quoted to cause airways inflammation, there is limited evidence
to support the assertion (132, 351, 412).
Cleveland infant idiopathic pulmonary hemorrhage outbreak. In
the wake of an outbreak of infant pulmonary hemorrhage (60, 65),
Montana et al. (278)
described a cluster of 10 infants from
the Cleveland area who were diagnosed with IPH after presenting with
severe respiratory disturbances requiring intensive care treatment.
Of the affected infants, 50% had symptom recurrence after
returning home, although these events occurred anywhere from
days to many months afterward. Epidemiologic investigation using
retrospective questionnaires and home examinations concluded that
home water damage prior to the clinical event was the main risk
factor (OR = 16). Other factors appeared to include "any relative
who coughed blood" (OR = 33), birth weight (normal birth
weight OR = 0.12), breastfeeding (OR = 0.16), and home smoking
(OR = 7.9); the last two factors became nonsignificant after
stratification in a model which included home water damage. Affected
infants were found to have significant differences from
controls in red blood cell indices, hemolysis, and serum cholinesterase
levels. There were several problems with the study.
First, case and control infants were significantly different with
regard to sex, race, birth weight, breastfeeding, smoking, and
the presence of electric fans; nonsignificant differencesexisted for
gestational and maternal age. The definition of close
relatives with pulmonary hemorrhage (PH) was erroneous, since
there are many causes of hemoptysis in adults other than true
PH, especially in smokers (129).
Moreover, there was no evidence
of increased illness in other family members, despite seemingly
common exposure to fungi. Finally, a prior paper had described
a cluster of Greek infants with IPH, possibly caused by
pesticides in grain stored near children's sleeping areas (56).
While the Cleveland study did not find an effect of pesticides, trace
amounts of household pesticides were present in case and control
homes, and the home of the one child who died had the largest
amount of airborne solvents and pesticide residues. The
case children in Cleveland had significantly decreased levelsof serum
cholinesterase compared to controls, though still within the
The same group examined whether fungal exposure was a risk factor for
The hypothesis arose from previous work on the issue
of pulmonary disease from wet building and fungal exposure, and
because hemolysis on case infants' blood smears might
implicatestachybotryotoxicosis (since Stachybotrys toxins
may produce hemorrhagic
disease and hemolysis in animals) (133, 373, 407).Retrospective
questionnaires and home surveys appeared to rule out
pesticides, personal care products, or maternal cocaine use
as etiologies. In general, case houses had more fungi, but the
OR was near 1 for all species but Stachybotrys, which
for IPH (risk of disease given a 10-fold increase in fungi). While Aspergillus,
Cladosporium, and Penicillium species
in case infant homes, matched analysis failed to demonstrate differences
between case and control homes. The authors concluded that
infants with IPH were more likely than controls to live in
homes with toxigenic S.
other fungi, although toxigenicity
was not in fact demonstrated. As later noted by the
Centers for Disease Control and Prevention CDC (61-64), surface
samples of mold cannot reliably predict airborne contamination or
individual exposure (323),
since release of spores is variable and
dependent on environmental factors including temperature, relative
humidity, light, and air movement (228).
of organisms may not reflect toxin levels in homes, since
toxin production is also variable and depends on many factors,
as noted above (157).
In 1999, the same group published an overview of the Cleveland investigations,
with 37 case infants (including 12 fatalities) reported
from 1993 to 1997; they also mentioned 138 cases in the
United States during the preceding 5 years (122).
The clinical profile
of the larger group of cases was heterogeneous, including 4
with stresses "that do not normally produce respiratory failure" (anesthesia,
hypernatremia, water intoxication, and febrile seizure);
4 cases were associated with upper airway obstruction and
1 was associated with probable asphyxiation; 11% had developmental delay
or failure to thrive; 22% had seizures; 19% had another infection
(includingPneumocystis carinii pneumonia); and there were
cases of hemolysis with hemoglobinuria. All 22 patients available
for follow-up bronchoscopy had ongoing hemosiderosis (most
>6 months), and 39% of infants needed additional therapy for
reactive airway disease. The latter finding does not reflect previous
reports of this disease. Importantly, gram-negative bacteria
and endotoxin levels were not examined. While mold isolates
produced mycotoxins, including satratoxins G and H, there
was no difference between case and control-homes in this ability
Other fungi capable of producing mycotoxins may have
confounded the picture, including two strains ofMemnoniella echinata (since
reclassified as Stachybotrys
made trichodermol, trichodermin, and griseofulvins (189,190),
as well as Cladosporium species
Details regarding over
100 cases reported nationally are not available (405).
Subsequently, the CDC published a retraction of its support of
the papers' conclusions (61-64),
due to apparent shortcomings of
the aforementioned studies. The CDC stated that, because of
insufficient evidence, an association between S.
infant IPH was not proven. They also reported that "while [it
is] advisable to remediate homes of mold for a variety of reasons,
[it is] not solely because of the purported Stachybotrys/Acute IPH
association." Primary criticisms focused on the calculation of
the OR for Stachybotrys exposure,
in part due to inclusion of
one extreme outlier in the case group. The OR of 9.8 dropped to
1.5 on the CDC reanalysis. Additionally, exclusion of a house with
an imputed mold value also brought down the OR from 5.5 to
1.9. Some of the CDC's concerns (e.g., inappropriate age matching,
which could in fact affect potential exposure) may be
Other important CDC concerns were that case home sampling was biased;
if true, this could invalidate the studies. Close examination of
the data also revealed that Stachybotrys was
present in a similar
number of water-damaged case and control homes; water damage
was not well defined (making the high OR suspect); and sampling
was performed weeks to months after exposure. Concerns were
strengthened by analysis of another cluster of IPH cases in
Chicago, occurring in parallel to the Cleveland cases (59). These
patients had a very similar presentation, but no mold-related disease
was identified. In fact, a strong negative disease association was
noted withStachybotrys, and other organisms were identified in
three of eight cases (Serratia, Staphylococcus aureus, and respiratory
syncytial virus). No other family members in the Cleveland
cluster were ill, which is inconsistent with the prior Stachybotrys literature.
Most importantly, the reviewers felt that the diagnoses of cases were
inadequate and the source of cases was inconsistent (61, 64).
There was no consistent definition of lung disease, a problem typical
of the indoor-mold literature. Since it is unknown if the
illness was a single disease entity, it is unclear if a single
etiology could be responsible. Subsequent anecdotal cases demonstrate
similar problems. Knapp et al. (209)
and Flappan et
describe a child with pulmonary hemorrhage (as defined
by hemosiderin-laden macrophages) and shock. As above, the
child was bottle-fed and the parent was a smoker. In addition to
anemia, there were many laboratory abnormalities including endocrine,
hepatic, and renal. While the authors found Stachybotrys in
areas near where the child slept, they in fact found more (both
by frequency and amount) Aspergillus,
Penicillium, and Cladosporium, as
well as Alternaria,
Ascospores, Periconia,Chaetomium, and
myxomycetes; gram-negative rods and Rhodotorula were
also present. While they found mycotoxins (including riordin L-2,
roridin E, and satratoxin H) in contaminated wallboard, they
did not assay for other compounds. In another case of pulmonaryhemorrhage
related to fungal exposure, the infant was formula fed
and exposed to tobacco smoke (302).
Again, there were a host
of laboratory abnormalities, particularly renal. Home inspection conducted
4 months after the events revealed water damage and fungal
growth. Looking at a variety of in-home sources, the authors
found many species of fungi including Penicillium and Trichoderma, but
noStachybotrys. The finding of other species is
an important confounder, since Trichoderma can
make trichothecenes (157, 422);
this genus has been linked to pulmonary disease (STHP),
and Penicillium and Alternaria have
been associated with
animal pulmonary hemorrhage (possibly via rubratoxin) (417). Tripi
et al. (418)
described an infant with laryngospasm and pulmonary
hemorrhage during general anesthesia, who was subsequently found
to have prior exposure to Stachybotrys, but
detailed laboratory data
and home conditions were not reported. Finally, there has been
one report of Stachybotrys being
isolated from the lungs of
a sick child (114).
The child was older than the other patients (7
years); while there were hemosiderin-laden macrophages on BAL,
and red blood cell microcytosis, there was no hemolysis on
blood smears. Other fungal species (including Aspergillis and Penicillium)
were recovered from the home. It is not clear what
causal link between the lung disease and fungus existed or
whether this was more than a variant of atypical farmer's lung
or an epiphenomenona (350).
Some concerns raised by the CDC are of limited validity. While there
was no evidence documenting actual exposure (i.e., positiveserologic tests
or organisms on BAL), serologic testing is an ineffective
marker for exposure even in heavily exposed animals (92)
or humans (164, 196, 197, 419),
since toxins and not organisms are
the disease-producing agents. Finding organisms on BAL is not
a relevant test (Stachybotrys does not germinate in the lungs,
nor is there a yeast form; illness is presumably toxin mediated,
not via direct infection) (92).
Concerns that the clinical
syndrome described was not consistent with historic accounts
of human and animal illness is of limited relevance: prior
descriptions of the disease occurred before modern analytic techniques,
and many "new" diseases have been described in the last
20 years that have probably occurred for considerably longer (e.g.,
human immunodeficiency virus infection). While animal models
are open to question, some do include pulmonary hemorrhage.
Potential mechanisms of Stachybotrys-induced lung injury. Pathogenic
mechanisms responsible for Stachybotrys-induced
if it exists, are unclear. The contention by Dearborn et
that inhibition of type IV collagen synthesis in rapidly
growing young lungs produces capillary fragility, which upon
exposure to stressors (e.g., tobacco smoke) results in stress
hemorrhage, is not supported by experimental evidence. Work
with animal models has shown effects on surfactant production. Early
studies showed that surfactant production is up-regulated in
type II alveolar cells exposed to pollutants (98, 120, 311). Subsequent
work has shown that alveolar type II cells, macrophages, and
surfactant production and composition are affected by exposure to
fungal spores and their mycotoxins, including Cladosporium and Stachybotrys species
(181, 249, 250, 255, 378;
W. G. Sorenson, Proc.
Int. Conf. Fungi Bacteria Indoor Air Environ., 1994). It
is unclear from most studies whether statistical differences observed
are physiologically meaningful; moreover it has not been
determined whether observed changes are toxic effects or compensatory
mechanisms. As discussed below, most studies usedtranstracheal instillation
of a high volume of spores or toxins, which
has questionable physiologic relevance. Other toxic mechanisms could
be responsible. For example, purified trichothecenes and S.
can cause hemolysis (95, 160, 346).
new hemolysin, stachylysin, was characterized from S.
from the Cleveland cluster. Hemolysins and siderophores have
been isolated from a number of strains, although levels vary
markedly across isolates (431),
and toxicity does not correlate well
with source location or illness (432).
Other animal studies of Stachybotrys pulmonary
toxicity suffer similar
limitations. Nikulin et al. (296)
described experimental murine
lung mycotoxicosis, using intranasal installation into the
trachea of a high volume of spores of toxin-producing (spirolactones, spirolactams,
satratoxins G and H) strains, which caused intra-alveolar, bronchiolar,
and interstitial inflammation with hemorrhagic exudates
in the alveolar and bronchial lumen. The authors attributed these
effects to "toxins." However in addition to the model limitations,
the study lacked proper controls and statistical power.
Subsequent work (297)
using the same model showed intratracheal instillation
of toxigenic spores produced interstitial inflammation with
hemorrhagic exudate in the alveolar lumen, severe inflammation, and
bronchial obliteration with leukocytes associated with Stachybotrys spores.
These findings are similar to those of other researchers (342).
As noted below, the presence of spores in pulmonary parenchyma raises
concerns about the relevance of the model to actual human and
animal disease. Furthermore, no histopathological changes were
noted in the other normal target organs of trichothecenes, i.e.,
thymus, spleen, or intestines. While there were hematological differences
between animals exposed to toxic and nontoxic spores, it
is questionable if these were of physiologic relevance. Finally, there
were marked differences in immune response between animals exposed
via the intraperitoneal and the inhalational route; only
the former animals developed specific IgG, which is in fact
rarely seen in actual illness.
Serious problems with these models exist in regard to routes and
levels of exposure, as well as the ability of organisms in
"field settings" to actually reach the alveoli. In indoor air
settings, spore counts as high as those modeled in the above studies
are rarely detected, sinceStachybotrys produces spores in
a slimy mass that become airborne only when dried (296). While
some researchers have thought that the spore burden in models
parallels cases of human exposure (92),
it is difficult to
correlate the number of organisms per cubic meter of room air
with concentrations in the nasal passages. Even if there is
a sufficient organism burden, spore size in relation to respiratory tract
physics must be considered. It has been claimed that Stachybotrys spores
can reach the distal airways (92).
However, this is based on
work involving extensively processed spores, which are of questionable
relevance to actual exposure conditions (397). In
more appropriate models, even if spores are liberated, it is
unlikely they reach the lower airways due to their size (445). Stachybotrys spores
are single-celled ellipsoid structures 5 to
7 by 8 to 12 µm in size (144).
In mice studied with monodisperse
spheres, 4- to 5-µm-median-diameter particles deposited
(90%) in the nose and then went on to the gastrointestinal tract;
pulmonary deposition was <1% (340).
Spores or fragments probably
need to be <1 µm in diameter to reach the lower
respiratory tract by airborne exposure, and Stachybotrysspores
are much larger than this. While intranasal instillation of
spores causes them to be flushed into the lungs (296, 297), it
does not reflect human exposure conditions (61-64, 445). This
may explain why effects seen in murine experimental models have
not been seen in humans. Furthermore, the response to toxigenic spores
is different from the response to toxins alone (296), and
probably only the latter is physiologically relevant.
In one of the only studies using a relevant model, Wilkins et al.
grew Stachybotrys in
an open dish in a closed chamber (to
mimic human exposure) and examined acute murine pulmonary toxicity
by a bioassay of respiratory parameters. The estimated exposure
level was nearly three times estimated human levels (the
satratoxin H level was 100
µg/dish). The authors concluded
that while there may have been a weak effect of exposure to S.
were no major immediate pulmonary effects. They
did not examine long-term effects. The substrate was wet, limiting
spore release. While this could have been a major limitation of
the study, it is more reflective of normal conditions. In response
to the low density of spore formation, the authors point
out these findings parallel building studies "in which air
contained a low number of colony forming units although the
ventilation and air conditioning system were extensively colonized
by different types of mold (5)."
Thus, the degree of
liberation of spores and mycelial particles must be considered if
model systems are to be useful. Finally, it is worth noting that
in this study, control mice had changes of tidal volume of
<5%, which, while statistically significant, were neither clinically
significant nor due to fungus. This suggests similar changes
in physiological parameters reported in some studies discussed
in this review may be no more than statistical variation.
Other mycotoxins have been implicated in inhalational toxicity. While
aflatoxin is primarily suspected of systemic inhalational toxicity
acute inhalation of AFB1 causes
destruction in hamsters and guinea pigs (157).
produce pulmonary disease in pigs; animals fed this mycotoxin developed
hydrothorax and pulmonary edema (124, 315).
were consistent with outbreaks of porcine pulmonary edema.
In summary, there is clear evidence that exposure to indoor mold
may have adverse pulmonary effects, especially by inducing allergic
reactions. However, to date there is no sound evidence linking
mycotoxin exposure to serious or permanent lung injury. There
is also no evidence to support more than mild upper airway allergic
effects of SBS and mold exposure. While there are reasonable concerns
regarding Stachybotrys exposure,
a link to pulmonary disease
beyond transient irritative symptoms, and in particular IPH,
has not been proven.
Exposure to S.
been reported to cause human neurotoxicity, although
proof is lacking (11, 47, 79, 164, 197, 267, 312,333, 404, 423).
Complicating this has been obvious difficulty in detecting
subtle neurological changes, even with sophisticatedneuropsychological
testing, as well as separating out psychiatric and
factitious causes. There is precedent for concern regardingneurotoxicity,
both for mycotoxins in general and for stachybotryotoxins in
particular. Much of this is based on ergotism, "atypical" equineStachybotrys disease,
and the effects of cyclopeptides and
muscarine from toxic mushrooms (4).
At the same time, coincident nonfungal
compounds (e.g. VOCs) may exert neurologic effects (208, 277, 310).
Neurologic or convulsive ergotism is characterized by symptoms including
muscle spasms, seizures, and hallucinations (4),
compounds produced during the baking of bread using contaminated grain
Nonfatal cases may exhibit tabes dorsalis-like features
There may be a link to malnutrition. The last major
epidemic of ergotism was one of convulsive ergotism in India
in 1975 due to C.
As noted above, the source
of the ergot affects the type of alkaloid produced as well
as the symptoms, as evidenced by an earlier outbreak in Ethiopia
which produced primarily gangrenous rather than neurologic disease
3-Nitropropionic acid is a secondary metabolite of Arthrinium species,
which can cause an acute food poisoning known as "mouldysugarcane poisoning"
Affected children suffer dystonia, convulsions,
carpopedal spasm, and coma (231),
and there may be
basal ganglia lesions (270).
Fumonisins, of which the most naturally
abundant is fumonisin B1,
cause equine leukoencephalomalacia (348, 406).
This may occur due to their action as competitive inhibitors
of sphingosine N-acetyltransferase,
which results in
the blocking of complex sphingolipid biosynthesis and the accumulation
of sphingosine (282).
Cyclopiazonic acid produced by Penicillium and Aspergillus may
be responsible for Kodua poisoning
(from Kodo millet), characterized by somnolence, tremors, and
in chicks it causes convulsions and rigidity (338).
Verruculogens and penitrem A may be "tremorgenic mycotoxins," responsible
for tremors, ataxia, weakness, and convulsions in animals
Unfortunately, studies of many of these toxins were
conducted using intraperitoneal injections (45,174, 266). Because
the route of administration matters greatly and since intraperitoneal
injection has no physiologic correlate, theresults are of questionable
clinical relevance. Postulated disease associations
that have not been borne out include the neurologicchanges of Reye's
syndrome (aflatoxin )
and pellagra (365).
An atypical or "shocking" form of stachybotryotoxicosis was first
recognized in the 1930s and 1940s in the USSR during the equine
stachybotryotoxicosis outbreak. Affected animals developed neurologic
problems including areflexia, hyperesthesia, hyperirritability,blindness,
and stupor; almost all affected animals died (133). Gastrointestinal
disorders and blood dyscrasias of the "typical form"
were not seen. However, experimental stachybotryotoxicosis in
animals as well as well-documented human cases do not support the
existence of significant neurological sequelae. Animal experiments produced
and topical (134)
toxicity with some systemic toxicity but no specific neurologic signs.
Even in cases of heavy exposure, effects described are dermatologic
respiratory (104, 361),
and possibly gastrointestinal,
without neurologic toxicity. Other studies reporting
neurologic problems after exposure to Stachybotrys or
trichothecenes often do not describe significant specific neurologic
symptoms (11, 267, 312, 423)
or do so only in vague terms,
unsupported by objective neurological findings (47, 79, 164, 197, 333, 404).
Notably, in recent cases where S.
been implicated in pediatric disease, no neurologic effects were
reported (122, 278).
Finally, some studies have shown aneuroprotective role for certain
mycotoxins: stachybotrin C and
parvosporin from S.
neurite outgrowth (303).
In summary, despite many reported subjective complaints, there is
no objective evidence for neurological compromise caused by
indoor mold exposure, in particular from S.
Hematologic and Immunologic
General concerns. Some
mycotoxins have the potential to affect hematopoetic cells, as
shown for trichothecenes in equine stachybotryotoxicosis, ATA
from Fusarium species,
animal experiments showing pancytopenia after
ingestion of S.
Akikabi-byo disease (460), and
the African idiopathic thrombocytopenic purpura (ITP)-like syndrome
Onyalai disease (341).
Fungi are the source of immunosuppressive drugs
such as cyclosporin, and Stachybotrys species
can produce a
cyclosporin-like immunosuppressive agent capable of increasing skin
graft survival in rats (354).
Such findings have become of
increasing concern due to reports of "immune suppression" and
increased infections in Stachybotrys-exposed
It is important to keep in mind that while some mycotoxins have
been recognized to affect the immune system, many earlier putative
associations (e.g., gliotoxin from Aspergillus as
acause of AIDS )
have proven quite erroneous.
effects of mycotoxins have been studied extensively in animals
but not in humans beyond observational studies (foran excellent review, see
Aflatoxin has been the most
extensively studied, although immunosuppression is not among
its known significant human toxicities. Effects of aflatoxin are
probably directly related to impaired protein synthesis (76).
Aflatoxin is transformed in vivo into active components that
bind DNA and RNA and impair DNA-dependent RNA polymerase, thus
inhibiting RNA and protein synthesis (138, 149, 261).
this would impair the proliferation and differentiation of
immune cells and perhaps the synthesis of immunomodulating compounds,
including chemokines and immunoglobulins. Patulin has
similar effects (398).
Aflatoxin effects on immune organs in animals include thymus and
bursa atrophy in fowl (140, 328, 411).
Cyclopiazonic acid causes
bursal lymphoid necrosis (101),
as well as similar changes in
the spleen and lymph nodes of dogs (304).
T2 toxin, induce necrosis and lymphoid depletion in
the thymus, spleen, and lymph nodes of various laboratory animals,
livestock, and fowl (76).
Aflatoxin exerts a variety of cellular and humoral effects. There
is suppression of mitogen-induced T- and B-cell blastogenesis in
and bovines (320).
T-cell delayed-type hypersensitivity responses
and graft-versus-host responses are suppressed in chickens
and there is impaired chemotaxis, phagocytosis, and
intracellular killing by heterophils and monocytes in chickens after
ingestion (66, 265).
High-dose aflatoxin exposure (0.6 to
10 ppm) suppresses IgG or IgA levels in chickens (140),
as antibody responses toSalmonella (44)
and sheep red blood
There may be clinical veterinary correlates with
increased frequency of swine salmonellosis (402),
and fowl cholera, salmonellosis, and coccidiosis (A. C.
Pier, J. L. Richard, and J. R. Thurston, Proc. 1978 Symp. Interact.
Mycotoxins Anim. Production, 1979). Ochratoxin A (OA) has
similar effects, but these vary with dose (only higher doses induce
lymphopenia) and species (higher effects in mice, less in
Critically, OA effects on immunoglobulin productionand the antibody
responses vary with the route of administration: intraperitoneal
injection suppressed antibody responses, but oral
administration did not. Cyclopiazonic acid and, to a lesser extent,
zearalenone have similar effects in some animal models. Finally,
and perhaps most importantly, the degree of immune suppression
and clinical signs is contingent on the nutritional status
and general health of the exposed animal (109, 402;
Edds, Proc. 1978 Symp. Interact. Mycotoxins Anim Production, 1979).
The presence of diseases and other toxins may affect responses
to aflatoxin, and good rations reduce residual tissue levels
and improve organ function. Increased dietary protein and
K, and methionine) are also protective.
produced by Stachybotrys and Fusarium species have
been extensively studied, especially T-2 toxin, due to its
toxic and immunosuppressive effects and its potential as a
biologic weapon (76, 309).
Other potent trichothecenes includeDAS, deoxyivalenol (vomitoxin), and
fusarenon-X. These compounds are
among the most potent small-molecule inhibitors of proteinsynthesis (243, 258, 372).
By blocking RNA and DNA synthesis via
inhibition of peptidyltransferase, they can produce
characteristicradiomimetic lesions in rapidly dividing tissues (220, 353, 421).
This may account for organ and cellular effects noted above
and the decreased immunoglobulin synthesis, antibody responses, and
complement activity in animal models (240),
as well as cell proliferative
and activity responses (36, 259).
affect cytokine production (43, 227, 449).
In theory, there could be a common end point of opportunistic infection,
similar to some animal models where aflatoxin has been
associated with increased disease susceptibility (329). Trichothecenes
have been associated with decreased resistance to
infectious organisms, including Salmonella,
simplex virus, Candida, and Cryptococcus (309).
One report of an outbreak of stachybotryotoxicosis in sheep
reported frequent isolation of a normally commensal organism, Pasteurella
organs; however, it is unknown if
this was a result of immunosuppression or breakdown of mucosal barriers
Some mycotoxins can enhance immune function, including
citrinin, patulin, and even T-2 toxin (119, 343). The
latter can increase the number of antibody-producing cells in
the spleen, splenocyte IgA production, delayed-type hypersensitivity reactions,
and blastogenesis of B and T cells, as well as superinducing IL-1
and IL-2. Often immune stimulation or suppression is related to
the amount of toxin; since most studies have been conducted via
various noninhalational routes, little is known about the effects
of airborne exposure (43).
As Corrier (76)
points out, in vivo studies of the immunomodulating effects
of mycotoxins may be influenced by contributing factors that
are not present or detected during in vitro studies. Almost all
studies have been with animals, often using single high-dose purified
toxins, by nonnatural routes of administration (e.g., intraperitoneal),
and often in animals with different disease susceptibilities
from humans (74,145, 219).
Immunological studies of
stachybotryotoxin effects in humans are limited to observational studies
(82, 197, 198).
In contrast to early reports of severe leukopenia
and radiomimetic effects in ATA-like syndromes after trichothecene
ingestion in Eastern Europe (182, 312, 363, 364), these
observational studies have not found the same hematopoietic effects
One study (82)
claimed that residential fungal contamination
affected peripheral lymphocyte counts in children, reporting
that contaminated homes were associated with more CD45RO
(antigen experienced T-cells) and a reduced CD4/CD8 ratio and
thus "that residential fungal contamination leads to chronic stimulation
of children's' lymphocytes." However, close examination of
the data leads to questions about these conclusions: in addition to
exposure to water damage and apparent mold, affected children were
more likely to be in the presence of household smoking,pets, and higher dust
mite antigen concentrations, have a bedroom humidifier,
be male, on average be 2 years older, and less likely to
have a current cold reported by the parent. In addition, environments
were not checked for endotoxins or volatile organic compounds,
nor was diet examined. Differences of CD45RO, CD29 (B
cell), and CD4-to-CD8 ratios were of borderline significance (P =
0.04 to 0.05), and examination of the CD4-to-CD8 ratios for
case versus control subjects revealed no significant differences (1.6/0.9
versus 1.5/1.0, with standard deviations of 0.3 to 0.5
for all numbers). The claims of persistent immunological changes
over time are not supported statistically. Children from
contaminated homes had higher total IgE levels, as well as
levels to mite antigens, cat epithelium, and dog dander, suggesting
that nonmycotoxin sources may have had a significant impact
on the findings.
The study most widely cited as proving immune effects of Stachybotrys exposure
in fact does not prove this (197).
Fifty-three workerswere reportedly exposed to fungal bioaerosols
although multiple other species were isolated). While
medical complaints were higher in exposed individuals than
in controls, there were no objective measurements of physical complaints,
physical examinations, or routine laboratory tests, and
there was no documentation of actual infection beyond a retrospective
questionnaire. Despite measurement of multiple immune
parameters, only white blood cells, CD3 cells, and NK cells
were reportedly affected. On closer examination, even these
data are questionable, since the statistically significant variations
of these numbers (e.g., white blood cell counts of 6,060
versus 6,290 and CD3 counts of 7,566 versus 7,365 cells/ml) lack
clinical significance, and low-risk patients had valuesmore different from
controls than did high-risk patients. A subsequent
study by the same author of 147 children and adults seen
in an environmental health specialty clinic failed to show significant
differences in immune parameters (198).
in the latter paper that pediatric cases with preexisting immunodeficiency
are at increased risk from "unnecessary" fungal exposure
(i.e., indoor fungus) there are no data to support this
assertion. The studies are further weakened by the fact that
they did not test the levels or effects of other likely contaminants,
including volatiles and endotoxins.
In summary, to date there is no good evidence of significant immunological
compromise from inhaled fungal toxins. As in the case
of neurologic complaints, at most only an association exists. Interested
readers are referred to the recent review by Bondy and
General concerns. The
potential of mycotoxins to act as carcinogens is of concern, due
to the probable carcinogenic effects of aflatoxin, as well as
recent legal claims that patients exposed to mycotoxins may need
long-term cancer monitoring (331).
While there are over 100
toxigenic fungi and more than 300 mycotoxins (268, 383), only
two (aflatoxin and sterigmatocystin) have been shown tocause tumors in
primate experiments (375).
Studies with other animals
have implicated the following as mutogenic: aflatoxin,sterigmatocystin,
ochratoxin, fumonisin, zearalenone, and some Penicillium toxins
(citrinin, luteoskyrin, patulin, and penicillic acid).
Most are directly genotoxic (e.g., AFB-DNA adducts), except
for fumonisin, which disrupts signal transduction (438). Results
of animal studies, often cited as proof of carcinogenicity, must
be interpreted with extreme caution in regard to humans. From
1961 to 1997, many model carcinogens were found to be tumorogenic in
rodents; however, only one (urethane) was found to cause cancer
in primates (375).
As part of these studies, saccharine, which
had been shown to be a mouse urological carcinogen and was
subsequently banned as a food additive, was shown to not be
a primate carcinogen. The rodent carcinogenicity of saccharine may
be due to the high renal concentrating ability of rodents, which
is much lower in primates. This wide species variation in
susceptibility to mutogenic effects (158)
extends to mycotoxins. For
example, "a problem in extrapolating animal data to humans is
the extremely wide range of species susceptibility to AFB1.For
instance, whereas AFB1 appears
to be the most hepatocarcinogenic compound
known for the rat, the adult mouse is essentially totally resistant
to its hepatocarcinogenicity." (213).
is the best characterized of the potential human mycotoxin carcinogens
(127, 179, 322).
While it is acutely lethal in large amounts,
chronic low-level exposure produces cancer, particularly hepatocellular
carcinoma (HCC) in many animal species (52,448). It
is thought to be the most potent liver carcinogen for a variety of
species including humans (102, 172, 406),
has cautioned that "one must still conclude that only a
debatable association, and not a direct causal relationship, has
been established to date" for human HCC. Nonetheless, HCC is
one of the leading causes of cancer mortality in Asia and Africa,
and epidemiological investigations have shown increased aflatoxin
ingestion correlates with increased risk (179, 463). AFB1 is
produced byAspergillus flavus and A.
parasiticus (12). The
primary mode of human exposure is the consumption of contaminated foodstuffs,
e.g., peanuts. Aflatoxin can be detected in the blood
of pregnant women, cord blood (where levels can be very high),
and breast milk; AFM1and
metabolic products) appear
in milk, urine, and feces. That these chemicals are systemically absorbed
is supported by data showing a high correlation between exposure
and urinary excretion of AFB1-N7-Gua
Mechanisms of aflatoxin carcinogenesis are unclear but probably involve
tumor promotion or progression. There is evidence of activation
of proto-oncogenes (c-myc, c-Ha-ras, Ki-ras, and N-ras)
by aflatoxin, as well as mutations at the p53 suppressor gene
target (169,170, 389, 438).
Aflatoxin and p53 mutations have
been tightly epidemiologically linked in China and Southern Africa,
and a p53 GT
mutation may serve as marker of aflatoxin exposure
(165, 223, 384).
This mutation may be situationally specific,
monkey tumors are associated with a
different mutation (136).
Other data indicate that urine DNA adducts
and serum albumen adducts reflect the amount of hepatic genotoxic
damage. Levels of these adducts may reflect risk for disease
As noted, there is great species variability in susceptibility to
aflatoxin. Among rodents, rats are very sensitive while mice are
resistant, due to efficient conjugation of aflatoxin with glutathione,
catalyzed by glutathione S-transferase
mYc (158). Similarly,
bioactivation of aflatoxin into carcinogenic metabolites shows
significant species differences (251).
There is strong evidence
suggesting cofactors affect carcinogenisis. Coinfection with
hepatitis B virus is important, since serum hepatitis B surface
antigen (HBsAg) is a key risk marker (439,456, 462); the
relative risk for HCC is as high as 59 if both urinary aflatoxins and
positive HBsAg status are present (339, 349, 438).
be modulation of damage by nutrients, antioxidants, herbs, drugs,
and malnutrition (108, 322, 438).
Other mycotoxins suchas sterigmatocystin may play a role (438).
Because of theoretical protective
effects of dietary supplements, there have been trials of
chemoprotectants like ethoxyquin and oltipraz (204, 464).
There is limited evidence regarding carcinogenicity of inhaled aflatoxins.
Aflatoxin can be aerosolized and has been detected in
air near farm sources (49, 395, 399).
Inhaled aflatoxin causes tracheobronchial
cell destruction in hamsters and guinea pigs (157);
rats receiving intratracheal doses develop cancer of the
liver, intestines, and kidneys (301).
The link to human disease
is much more tenuous. While epidemiological and anecdotal studies
have reported associations between inhaled mycotoxin and
cancer, most of these studies were seriously flawed. Hayes et
found an increased rate of overall cancer and pulmonary cancer
mortality in exposed peanut workers but failed to include smoking
as a factor and did not find HCC. Olsen et al. (306) showed
a two- to threefold increase in the risk of HCC and biliary cancer,
but the aflatoxin concentrations were historical and were
not measured. Anecdotal studies reported premature cancerin three exposed
laboratory workers (106;
G. E. Deger, Letter, Ann.
Intern. Med. 85:204-205,
1976), but aflatoxin was detected not
only in the two patients with lung cancer but also in three with
pulmonary fibrosis (107),
which has not been postulated to
be caused by this compound. The findings may indicate that aflatoxins
are secondary findings in chronic lung disease, since lung
cancer and pulmonary fibrosis are unrelated illnesses.
Other mycotoxins. Other
mycotoxins have been implicated as carcinogens. Ochratoxins are
structurally related metabolites from A.
related species, P.
other Penicillium species
is the only one of major carcinogenic significance (216, 326, 334).
In regions where Balkan endemic nephropathy (BEN) is
endemic, there are high foodstuff contamination rates, and high
levels of OA are found in human blood (428).
There have been
increasing reports of OA in human tissue samples, including one
German study where the toxin was reported in 56% of randomly collected
blood samples (33),
although such a high prevalence appears
suspect. OA can form DNA adducts, and the kidney may be
the worst affected organ (438).
While OA has been listed as
a mammalian carcinogen (426, 451),
the data come from a small number
of rodent strains, and there is no direct proof in humans.
Patulin, while potentially tumorogenic, illustrates the importance of
the route of administration and coincident environmental factors
(334). Penicillium species
produce patulin and penicillic acid,
which can cause tumors when subcutaneously injected into mice.
They do not cause murine tumors when administered orally. While
patulin frequently contaminates apple juice (P. expansum is
a main cause of apple rot), the chemical is unstable in the presence
of sulfhydryl groups, which may explain its absence from
Zearalenone, produced mainly by Fusarium
most widely distributed of the fusarial mycotoxins (217) and
is found in 6 to 28% of corn samples destined for human consumption
Significant concerns have been raised as a
result of its estrogenic activity and thus its potential for stimulating
estrogen-sensitive tumors (25, 93, 293, 446).
increased cancer rates in mice but not rats (173);
in the latter species it may exert protective effects (159).
It was once postulated to cause cervical cancer (248), but
the assertion has not been borne out due to the clear association of
this malignancy with human papillomavirus (125).
There may be a link between mycotoxins and esophageal carcinoma (334).
China and areas of southern Africa have the highest rates of
esophageal cancer. In these areas, corn is a main staple, and
mycotoxins (especially fumonisin B1 from F.
major contaminants found in corn consumed by patients with esophageal
cancer (67, 167, 247, 282).
Selected fumonisins arehepatocarcinogenic in rats (246)
and have been designated group 2b
carcinogens, i.e., possibly carcinogenic (172).
studies have found many cocontaminants (67)
or present only
equivocal data (461).
Such data must be interpreted with caution,
sinceFusarium mycotoxins in corn and corn products in
areas in China where people are at high risk for gastric cancer
do not appear to account for malignancy among those who consume
affected foods (148).
Some mycotoxins are antineoplastic agents. Ergosterol peroxide and
acetoxyscirpenediol from Paecilomyces
parasite, and Chinese entomopathogenic fungi are more potent
than cisplatin against human gastric tumor, hepatoma, colorectal
cell lines, and murine sarcoma (288).
T-2 toxin inhibits the
proliferation of neoplastic cell lines, including mouse melanoma
B16 cells, human myeloid leukemia K562 cells, and human cervical
carcinoma (HeLa) cells (201).
New fungal compounds with
similar anti-neoplastic traits are constantly being found (166).
As shown above, some trichothecenes are potentially carcinogenic. To
date, there are only conflicting reports in animal studies (402).
There is currently no sound evidence linking Stachybotrys-produced mycotoxins
to human malignancy or evidence to support claims that
individuals exposed to Stachybotrys are
at long-term risk of
cancer or require cancer surveillance (438).
In addition to HCC, aflatoxin in significant doses can cause acute
liver injury. Acute aflatoxicosis generally occurs in outbreaks
due to contaminated foodstuffs. The resultant liver injury
can be severe, with a 10 to 60% case fatality rate (322). While
there have been claims that aflatoxin causes other diseases such
as Reye's syndrome (97)
and neonatal jaundice (322),
not been validated. Rubratoxins from T.
disease and disseminated hemorrhage in animals (51, 447). In
the field, rubratoxins are often mixed with aflatoxin due to
cogrowth of A.
there may be synergistic hepatotoxic effects
Hepatobiliary effects have not been reported for Stachybotrys toxins.
Endocrine toxicity has been seen primarily with zearalenone (F-2
The compound is produced by several Fusarium species
under very particular growth conditions (402)
and has estrogenic
effects in animals. Such effects are well characterized in
swine (the most sensitive animals) and include primary effects (e.g.,
vulval hyperemia) as well as infertility, decreased litter size,
and fetal malformations (69).
Zearalenone has also been implicated
in livestock "scabby grain toxicosis," characterized by
nausea, vomiting, and drowsiness (40, 422),
but it was found along
with other Fusarium mycotoxins.
As pointed out by Stuart and
Bedel, "many reports in the literature of ill effects are very
questionable due to possible involvement of other mycotoxins..." (402).
Similar effects have not been demonstrated in humans, even
though zearalenone has been found in the blood of children exposed
to contaminated food (352).
There have been no reports of Stachybotrys-related
Diverse renal and urological toxicities have been reported in humans
due to OA, although on close inspection the data provide only
disease association, not direct proof. Due to abundant circumstantial
evidence, OA from Aspergillus and Penicillium has
been implicated in porcine nephropathy and BEN (68),
as urinary tract malignancies noted above. Ochratoxin belongs to
a group of secondary metabolites of Aspergillus and Penicillium, found
on cereals, coffee, bread, and foods of animal origin (322).
Ochratoxin A is the most common and most toxic chemical of
its class: it is nephrotoxic, immunosuppressive, carcinogenic, and
teratogenic in all animals tested (451).
The toxin can cause glomerulonephrosis
and may cause cholinergic responses such as
bronchial constriction, vasodilation, and mild smooth muscle contraction
A nephrotoxic strain of Penicillium was
air samples in areas where BEN occurs, but study of the isolates
was limited to animal feeding experiments (280).
been one case of apparent inhalational nephrotoxicity, and an
OA-producing strain of A.
subsequently isolated from
wheat to which the individual had been exposed (100).
Citrinin is produced by several Penicillium species
and is sometimes isolated
from contaminated rice (402).
Citrinin may exert more renal
toxicity than OA, although effects of the latter have been
reported more frequently. Citrinin and OA may have a synergistic interaction
Finally, several of the papers postulating a link between infant IPH
and Stachybotrys have
reported mild renal abnormalities, including
non-anion gap acidosis, electrolyte disturbances, and
aminoaciduria (209, 302).
It is unclear if these findings are
part of a mycotoxin syndrome, were secondary to severe illness (e.g.,
shock), or represent an underlying disease process. To date,
there has been no evidence linking Stachybotrys toxins to
A number of mycotoxins affect pregnancy in experimental animals; however,
none of the observations extend to humans. Ergotoxins may
prevent embryo implantation in mice (244, 245).
There are conflicting
reports of their ability to induce abortions, and they
may cause stillbirths and agalactia (299, 334, 386).
D has been found in dust and aerosols. Produced by P.
is part of the secalonic acid family and is teratogenic in mice
Zearalenone has been found in dust and aerosols and
may cause infertility and fetal malformations in domestic animals
through estrogenic effects discussed above (69, 211, 272).
OA may cause fetal death, as well as uterohemorrhagic effects,
in rats (211, 400).
T-2 toxins and DAS have been reported to
cause limb and tail abnormalities (271).
While T-2 and DAS in
feed do not cause abortion, preconception exposure may cause infertility
and reduced litter size (271, 441).
Aflatoxin is of special concern, since it is teratogenic in nearly
all animals (451).
Various investigators have found uteroplacentalhemorrhage and fetal death in
rats and mice given intraperitoneal aflatoxin
while others have noted only fetal retardation in
rats given oral aflatoxin (54).
Aflatoxin has been detected in
the blood of pregnant women, cord blood, and breast milk (322).
The clinical relevance of these findings is unknown.
Finally, there are some animal data suggesting similar effects from Stachybotrys toxins
Oral ingestion (of infected grain,
liquid growth medium, or partially purified toxin) caused a
decrease in the number of pregnant animals; an increased frequency in
dead, resorbed, or stunted fetuses; and decreased average litter
size. Histopathologic testing showed uteroplacental hemorrhages. There
have been some suggestive field data for mare and sow abortions
While this evidence has been cited as proof
affect fetuses even though no maternal effects
may be evident (211),
it must be noted that all of the above
data are related to oral exposure in animals, which may have
no relevance to human inhalational exposure.
A host of other mycotoxin effects in animals and to a lesser extent
in humans, have been described. These include dermatologic (as
described above), gastrointestinal (40, 230, 231),
and cardiac (425).
These effects are beyond the scope of this review.
Valid concerns exist regarding the relationship between indoor air,
mold exposure, mycotoxins, and human disease. Review of the
available literature reveals certain fungus-disease associations, including
ergotism, ATA from Fusarium, and
liver disease from Aspergillus species
However, while many studies suggest a
similar relationship between Stachybotrys and
human disease, these
studies nearly uniformly suffer from significant methodological flaws,
making their findings inconclusive. As a result, we have not
found supportive evidence for serious illness due to Stachybotrys exposure
in the contemporary environment. Our conclusion issupported by several other
recent reports (64, 138, 175, 313, 403).
To address issues of indoor mold-related illness, there is
an urgent need for studies using objective markers of illness, relevant
animal models, proper epidemiologic techniques, and careful
examination of confounding factors including bacteria, endotoxin,
man-made chemicals, and nutritional factors.
We thank N. Isham for technical advice, M. Petit and N. McLaughlin of
the University Hospitals Core Library for literature searches, and
K. Smith for secretarial assistance.
Funding was provided by an unrestricted grant from the CNA Insurance Corp.
* Corresponding author. Mailing address: Center for Medical Mycology,
University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106.
Phone: (216) 844-8580. Fax: (216) 844-1076. E-mail: email@example.com.
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