Fungal Spores: Hazardous to Health?

W.G. Sorenson

Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, West Virginia USA

Fungi have long been known to affect human well being in various ways, including disease of
essential crop plants, decay of stored foods with possible concomitant production of mycotoxins,
superficial and systemic infection of human tissues, and disease associated with immune
stimulation such as hypersensitivity pneumonitis and toxic pneumonitis. The spores of a large
number of important fungi are less than 5 pm aerodynamic diameter, and therefore are able to
enter the lungs. They also may contain significant amounts of mycotoxins. Diseases associated
with inhalation of fungal spores include toxic pneumonitis, hypersensitivity pneumonitis, tremors,
chronic fatigue syndrome, kidney failure, and cancer. Key words: mold, fungi, mycotoxin, lung
disease, toxic pneumonitis. - Environ Health Perspect 1 07(suppl 3):469-472 (1999).
http.//ehpnet1.niehs.nih.gov/docs/1999/suppl-3/469-472sorenson/abstract.html

Background

Fungi are heterotrophic, filamentous
organisms that by virtue of their depen-
dence on external sources of organic car-
bon and their rigid cell walls are confined
to a saprobic and/or parasitic lifestyle in
which they absorb soluble nutrients
through the cell membrane. The fungi,
together with the bacteria, are responsible
for decay of organic matter and the fungi
have been estimated to comprise approxi-
mately 25 % of the biomass of the earth
(1). As such, they are among the principal
microorganisms involved in biodeteriora-
tion and are found universally in human
habitations and occupational settings. The
possible role of airborne microorganisms
in indoor air health problems as a result of
energy-saving measures was accentuated
by Tobin et al. (2) and a number of
studies have noted a strong relationship
between mold growth in homes and respi-
ratory symptoms (3-5). When one con-
siders that urban residents typically spend
more than 90% of their time indoors (6),
it is readily recognized that very large
numbers of people, both adults and chil-
dren, are potentially exposed to indoor air
contaminants. Although spore concentra-
tions are usually much lower in homes
than in agricultural workplaces, concentra-
tions as high as 450,000 colony-forming
units/m3 have been reported (7). In some
of these homes, the toxigenic Stachybotrys
chartarum (= Stachybotrys atra) was promi-
nent on the walls and in the air. This arti-
cle focuses on health effects due to
mycotoxins, but fungi in general also cause
other diseases such as infections, allergy,
and inflammation.

Mycotoxins and

Mycotoxigenic Fungi

Excluding mushroom toxins, approximately
350 to 400 fungal metabolites are consid-
ered to be toxic. Most of these are relatively
small molecules of greater than 200 and the
majority are less than 500 mass units (8).
Perhaps the most important mycotoxins in
agriculture are the aflatoxins, the 12,13-
epoxytrichothecenes, the fumonisins, and
ochratoxin. Species belonging to the genera
Aspergillus, Penicillium, and Fusarium are
common contaminants of agricultural com-
modities, and some of the mycotoxins pro-
duced by these species are produced by
fungi common in house dust (2). In addi-
tion, some toxigenic fungi produce many
different mycotoxins. For example, the
Penicillium verrucosum complex (P. verruco-
sum, P. aurantiogriseum, P. viridicatum, P.
crustosum, and P. solitum) produce nearly
20 different mycotoxins (9) and S. char-
tarum produces several trichothecenes
including the highly potent macrocyclic tri-
chothecenes as well as a variety of other
mycotoxins (10). Other toxigenic fungi
include species of Alternaria, Paecilomyces,
Rhizopus, Trichoderma, and Trichothecium.
All of these fungi occur commonly in soil,
agricultural products, grain dust, and house
dust (2).

Health Effects Linked with
Inhalation of Mycotoxins

Although extensive literature has been
developed since the discovery of the aflatox-
ins, few studies have been conducted to doc-
ument the occurrence of these substances in
airborne grain or other organic dust or to
estimate the inhalation hazard to workers

and others exposed to contaminated
airborne dust. Several studies have pro-
vided evidence for the association of cancer
in humans with inhalation of aflatoxin-
contaminated dust, e.g., lung cancer
(11-13) or colon cancer (14). Olsen et al.
(13) noted elevated risks for liver cancer
and cancers of biliary tract among animal
feed workers that increased by 2- to 3-fold
significance after a 10-year latency. Their
daily pulmonary exposure was estimated to
be approximately 170 ng. Autrup et al.
(15) used measurements of aflatoxin
bound to serum albumin as an index of
exposure and showed that 7 of 45 workers
exposed to feed contaminated with low lev-
els of aflatoxin B, (AFBI; 0-26 pg/kg) had
detectable levels of AFB, bound to serum
albumin, confirming systemic exposure.
Zarba et al. (16) demonstrated that aerosol
inhalation is an effective route of exposure
to AFB, in rats. In their experiments,
approximately 2% of the administered
dose became bound to liver DNA and the
amounts of DNA adducts were statistically
different among the treated groups. These
workers (17) also demonstrated that nose-
only aerosol in exposure of rats at an esti-
mated dose of 16.8 pg/kg body weight
suppressed alveolar macrophage (AM)
phagocytosis, with the effect persisting for
approximately 2 weeks. These findings
indicate that inhalation exposure to AFB,
is an occupational hazard where exposure
to AFBI-laden dust is common.

Inhalation exposure to spores of S.
chartarum has also been associated with
episodes of human illness. Andrassy et al.
(18) reported an outbreak of illness in
which workers exposed to hay heavily cont-
aminated with S. chartarum unanimously
complained of dyspnea, airway obstruction,
sore throat, bloody nose or nasal secretions,
conjunctivitis, and inflammation of the

This article is based on a presentation at the
International Conference on Indoor Mold and Children
held 21 to 24 April 1998 in Alexandria, Virginia.

Address correspondence to W.G. Sorenson,
Immunology Section, NIOSH, 1095 Willowdale Road,
MS 215, Morgantown, WVA 26505. Telephone: (304)
285-5797. Fax: (304) 285-5861. E-mail: wgsl @cdc.gov

Received 3 September 1998; accepted 8 January
1999.

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999

469

W.G. SORENSON

skin on the face and body. Croft et al. (19)
reported long-term illness, apparently caused
by heavy infestation of a water-damaged
home in Chicago, Illinois. Between 1993
and 1998, there were 34 cases, induding 10
deaths, of idiopathic pulmonary hemosidero-
sis among infants in Cleveland, Ohio.
Incidence of this disease is generally quite
low (20,21). The vast majority of cases
occurred within a very small geographic area
of the city. Case homes tended to have a
higher prevalence of water damage (22) and
higher quantities of toxigenic S. chartarum
(23). Strains of S. chartarum isolated from
both case and control homes were shown to
be toxigenic, but there was no correlation
between toxigenicity of the isolate and
source, i.e., case versus control. The disease
seemed to correlate with frequency of occur-
rence and quantity of the organism rather
than with strain (24). Memnoniella echinata;
a close relative of S. chartarum with similar
biochemical and physiologic characteristics
and habitat preferences, was also found in
samples from a case home. M. echinata
produces some of the same toxins as S. char-
tarum (24,25) but has smaller spores,
although the conidia of both species are
small enough to reach the alveoli (25).
Aqueous rinses of the spores of both species
were nearly as toxic as methanolic extracts of
the spores themselves (25), indicating that
these highly potent toxins would be readily
released into the microenvironment of the
developing lung cells in vivo.

Further support for the proposed
mycotoxin etiology of infant pulmonary
hemosiderosis comes from animal studies
in which mice were treated intranasally
with both nontoxic and toxic spores of S.
chartarum (26). Severe inflammatory
changes, including hemorrhage, were
observed in mice receiving toxic spores of
this species. Two recent studies report
occupational illness associated with
chronic, low-level exposure to S. chartarum
in water-damaged office buildings (27,28).
Dill et al. (29) noted massive development
of S. chartarum on decomposable flower
pots made of recycled paper, which led to
the development of very painful inflammed
efflorescences at the fingertips followed by
scaling of the skin. The symptoms disap-
peared when gloves were worn to handle
the pots and were ascribed to trichothecene
mycotoxins. Although respiratory symp-
toms were not noted in the report, viable
spore counts of S. chartarum up to 7,500
spores/m3 were determined when the pots
were handled (30-100 spores/m3 when the
pots were not handled).

Two other recent reports of human
disease thought to be due to inhalation of
mycotoxins are noteworthy. Di Paolo et al.
(30) reported acute renal failure in a
female agricultural worker exposed to grain
dust in an enclosed granary, believed to be
due to inhalation of ochratoxin in the
spores of Aspergillus ochraceous. Ochratoxin
was not demonstrated in airborne dust in
the granary, but the authors were able to
isolate A. ochraceous from a sample of
wheat from the granary. Ochratoxin A was
observed in extracts of ground moldy
grains, and Di Paolo and colleagues were
able to demonstrate acute kidney failure in
experimental animals (rabbits and guinea
pigs) exposed for 8 hr to aerosols generated
by their natural movement on moldy
wheat in their cages.

Gordon et al. (31) reported tremorgenic
encephalopathy in a young man exposed to
high concentrations of grain dust contami-
nated with several species of fungi known to
be capable of producing tremorgenic myco-
toxins. Because of the circumstances of
exposure, the similarity of his syndrome to
that of an animal model, and the lack of an
alternative explanation, the authors pro-
posed that his illness may have resulted from
inhalation of tremorgenic mycotoxin(s).

Mycotoxins in Spores

Species of fungi in which mycotoxins have
been reported in the spores include
Alternaria alternata (32), Aspergillus
fumigatus (33-35), Aspergillus flavus and
Aspergillus parasiticus (36), Fusarium
graminearum (1), Fusarium sporotrichioides
(1), and S. chartarum (37). Several differ-
ent mycotoxins were demonstrated in these
investigations induding deoxynivalenol (1),
fumitremorgen and verruculogen (35),
fumigaclavine C (34), T-2 toxin (1),
tryptacidin (33), alternariol and alternariol
monomethylether (32), and the macro-
cyclic trichothecenes satratoxins G and H
(37). Gliotoxin has been demonstrated in
tissues infected by A. fumigatus (38) and
Candida albicans (39) but was not detected
in spores of A. fumigatus (40). It is likely
that mycotoxins occur in spores of toxi-
genic species much more commonly than is
currently appreciated, as they have been
found in spores in a high proportion of
species in which attempts were made to
find them. In a study in Scotland, extracts
from spores of 47% of a group of 83 iso-
lates collected from damp public sector
housing in Scotland were cytotoxic to the
human embryonic hybrid fibroblast lung
cell line MRC-5 (41).

These findings seem to support earlier
findings of health hazards in epidemiologic
studies of the inhabitants of damp, moldy
houses (42). Spores of P. aurantiogriseum
containing the benzodiazepine metabolite
auranthine cause nephrotoxicity and
pathology typical of Balkan endemic
nephropathy when mixed with feed and
fed to rats (43). These findings confirm the
presence of auranthine in the spores and
suggest that workers and others who han-
dle infected grain may be at risk of expo-
sure by inhalation. The vast majority of
mycotoxins are nonvolatile and therefore
mycotoxin exposure by inhalation is most
likely to occur via inhalation of spores.
Effects of Mycotoxins on

Alveolar Macrophages and
Immune Function

T-2 toxin, patulin, and penicillic acid were
shown to be acutely toxic to rat AM in
vitro, causing membrane damage, inhibi-
tion of protein and RNA synthesis, inhibi-
tion of phagocytosis, and inhibition of the
ability of AM to respond to lymphokines
(44-47). Ayral et al. (48) showed that the
trichothecenes diacetoxyscirpenol and
deoxynivalenol reduce phagocytosis, sup-
press microbicidal activity, and inhibit
superoxide anion production and phago-
some-lysosome fusion of peritoneal
macrophages at concentrations that did not
affect cell viability. Similarly, Vidal and
Mavet (49) demonstrated inhibition of
phagocytosis of Pseudomonas aeruginosa by
murine peritoneal macrophages in the
presence of 0.001 pM T-2 toxin.

The trichothecene mycotoxins are
immunotoxic in rats and mice, causing
acute inhibition of antibody and delay of
skin graft rejection (50,51). Gliotoxin has
antiphagocytic and immunomodulating
activity, it is produced by A. fimigatus (52),
and it has been demonstrated in tissues
infected by A. Jfumigatus (38). Gliotoxin also
contributes to the pathogenesis of vaginal
candidiasis (39). Jakab et al. (17) confirmed
earlier reports that dietary exposure to AFB1
impairs innate and acquired host defenses.
Subsequent work by these authors also
showed that AM phagocytosis was sup-
pressed for approximately 2 weeks following
nose-only inhalation exposure to an esti-
mated dose of 16.8 pg/kg. Exposure using
intracheal instillation (IT) of AFB1 also sup-
pressed AM phagocytosis in a dose-depen-
dent manner, but approximately 10-fold
higher doses were required for IT than for
inhalation. Animals exposed by IT adminis-
tration also had impaired release of tumor

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999

470

FUNGAL SPORES: HAZARDOUS TO HEALTH?

necrosis factor-ax, primary splenic antibody
response, and peritoneal macrophage
phagocytosis. These studies show that
experimental respiratory tract exposure can
suppress pulmonary and systemic host
defenses and that inhalation exposure to
AFB1 could lead to increased susceptibility
to infection. Richard et al. (53) used killed
spores of A. fimigatus as carrier vehicles for
AFB1 in studies of the effect of long-term
exposure to aflatoxin. Lung lesions were not
observed in unexposed animals, but lesions
of varying severity were observed in the
lungs of rats exposed to aflatoxin. The
authors reported that the general response
of the exposed animals appeared to be that
of a compromised host.

Although the effects of mycotoxins as a
result of dietary exposure is beyond the
scope of the present discussion, a number
of mycotoxins, especially aflatoxin, the
trichothecenes, ochrataoxin A, patulin,
citrinin, and zearalenone, experimentally
alter immunity, causing inhibition of nat-
ural killer cell activity, impaired resistance
to pathogenic microorganisms, suppres-
sion of antibody response, lymphoid
depletion of the thymus associated with
delayed hypersensitivity, and functional
alteration of bone marrow cells. This
subject has been extensively reviewed by
Richard et al. (54), Thurston et al. (55),
and Pestka and Bondy (56,57).

In studies of the acute inhalation
toxicity of T-2 toxin in mice, Creasia et al.
(58) demonstrated that T-2 toxin, when
given by inhalation, was at least 10 times
more toxic than systemic administration
and at least 20 times more toxic than
dermal administration.

Because of technical limitations, it is
difficult to accurately assess the role of
mycotoxins in human health effects associ-
ated with damp environments. For example,
demonstration of mycotoxin production in
the laboratory does not prove their presence
in the environment; we are generally unable
to measure mycotoxins in the field at the
site of exposure and, with the exception of
aflatoxin, there is a general lack of biomark-
ers of either exposure or effect. In addition,
it appears that isolates of many toxigenic
species vary in their ability to produce
mycotoxins, but it is uncertain to what
extent this is due to actual genotypic differ-
ences between the isolates or to the effect of
the stress of isolation in artificial culture. It
is prudent to take the possibility of myco-
toxin exposure into consideration whenever
known toxigenic species are demonstrated
in these environments.

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