THE PATH AHEAD
Is Mold Toxicity Really a Problem for Our
Patients? Part 2—Nonrespiratory Conditions
Joseph Pizzorno, ND, Editor in Chief; Ann Shippy, MD
Abstract
In my last editorial, I addressed the respiratory effects of
mold exposure. The surprising research shows that as
many as 50% of residential and work environments have
water damage1 and that mold toxicity should be
considered in all patients with any chronic respiratory
condition. This is especially true in adult-onset asthma,
two-thirds of which appears to be caused by toxins
released from water-damaged buildings. The carcinogenic
effects of food-borne mold contamination are also well
documented. Less clear is the role of indoor mold
exposure in water-damaged buildings and its relationship
to nonrespiratory conditions. As we look at the research
on mold toxicity and toxins in general, we propose that
the medical community (by all its names) has focused too
much on the “yellow canaries” and missed the big picture
National and International Organizations on Mold
and Nonrespiratory Conditions
According to the World Health Organization (WHO),
“Although mycotoxins can induce a wide range of adverse
health effects in both animals and human beings, the
evidence that they play a role in health problems related to
indoor air is extremely weak.”1 The US Centers for Disease
Control and Prevention (CDC) issued a report in 2004
that asserts there is no conclusive evidence of
nonrespiratory conditions being caused by mold or damp
buildings. Review of the current recommendations
according to its Web site shows no apparent change in its
position.2 These statements appear highly conclusive but
are in fact based on a very limited body of published
research and are probably outdated. Research in this area
has been limited, because it has not been possible to build
cohorts of individuals exposed to mycotoxins and their
controls and study them. This is due primarily to the
serious limitations of the testing technology used to detect
the presence of hidden indoor mold.
There are many different testing approaches all with
unique limitations and all with many false negatives. In
8 Integrative Medicine • Vol. 15, No. 3 • June 2016
that toxins have now become a primary driver of disease
in the general population, not only among those most
susceptible. The mold toxicity conundrum illustrates this
issue quite well. As summarized in this editorial, there
clearly is a portion of the population, the size of which is
currently unknown, who experience neurological and/or
immunological damage from mold toxicity. In addition,
a substantial portion of the population experiences
chronic respiratory problems from mold exposure. This
does not mean we should stop paying attention to our
more affected patients. Rather, we need to realize that
almost everyone is being affected by toxins to some
degree: molds, metals, solvents, persistent organic
pollutants, etc.
addition, human testing for mold toxin load via sampling
tissue and body fluids is very limited. At the time of this
publication, we can test for only 4 mycotoxin groups with
15 individual toxins. There are likely hundreds of
mycotoxins, possibly even an order of magnitude more.
Another challenge with standard research is that statistical
results in population groups inherently obfuscate
individual susceptibility. This, of course, is where our
medicine is so important for suffering patients who are
outside those statistical norms. Clearly, we know that
toxins affect individuals in different ways depending on
their genetics, synergistic toxins present, and nutritional
status. Studies that evaluate the most important variables
of genetics, toxin exposure, and nutritional status and
their complex effect on health need to be conducted.
Toxins Produced in Water-damaged Buildings
The research is unequivocal that water-damaged
buildings expose their occupants to a diverse range of toxins
with many physiologically damaging effects. They are
produced by chemical, microbial, and physical processes
that break down building materials. Tables 1 and 2 list the
Pizzorno and Shippy—The Path Ahead
 Table 1. Toxic Metabolites Produced by Bacteria Isolated From Water-damaged Materials and Indoor Air3

Metabolite Organisms Physiological Effects Disease

Valinomycin Streptomyces griseus
Leptomycin B Streptomyces species
Toxic peptide Bacillus amyloliquefaciens
Mitochondrial toxin Bacillus pumilus
Mitochondrial toxin Nocardiopsis species
Cytostatic compounds Coculture of Stachybotrys
chartarum and
Stachybotrys californicus
Mitochondrial poison Unknown
Inhibition of inducible nitric oxide synthetase Unknown
Depolarized transmembrane; decreased ATP Unknown
and NADH cell death
Disruption of mitochondrial membrane Unknown
Disruption of mitochondrial membrane Unknown
Cytotoxic compounds that are just as toxic as Unknown
doxorubicin and AMD

Abbreviations: ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide + hydrogen;

AMD, actinomycin D.

Table 2. Mycotoxins Produced by Toxic Molds3

Metabolite Organisms Physiological Effects Disease

Gliotoxin Aspergillus fumigatus, Immune toxicity, immune Invasive
terreus, flavus, niger; suppression, neurotoxicity aspergillosis
Trichoderma virens;
Penicillium spp;
Candida albicans
Aflatoxin B1, kojic acid, Aspergillus flavus Liver pathology and cancer, immune Carcinogenesis
aspergillic acid, toxicity, neurotoxicity
nitropropionic acid
Fumigaclavines, Aspergillus fumigatus Lung disease, neurotoxicity, tremors, Aspergillosis
fumitoxins, immune toxicity
fumitremorgins,
verruculogen, gliotoxin
Ochratoxin A Immunosuppression BEN
Urinary tract tumors Aspergillus niger BEN
Aspergillosis Penicillium Lung disease
verrucosum
Ochratoxin A Aspergillus ochraceus Nephropathology Urinary tract
damage
Penicillic acid, Tumors
xanthomegnin, viomellein,
vioxanthin
Sterigmatocystin, Aspergillus versicolor Liver pathology and cancer Carcinogenesis
5-methoxysterigmato
cystin
Chaetomiums Chaetomium globosum Cytotoxicity Unknown
Chaetoglobosum A and C Cell division Unknown
Griseofulvin Memnoniella echinata Carcinogenesis? Unknown
Dechlorogriseofulvins Reproductive toxin

Pizzorno and Shippy—The Path Ahead Integrative Medicine • Vol. 15, No. 3 • June 2016 9
 Table 2. (continued)

Metabolite Organisms Physiological Effects Disease

Trichodermin Hypersensitivity?
Trichodermo Protein synthesis inhibition
Mycophenolic acid Penicillium Cytotoxic, mutagen Unknown
brevicompactum
Botryodiploidin Penicillium expansum Immune toxicity, cytotoxic Unknown
Patulin, citrinin, Tremors
chaetoglobosin,
roquefortine C
Verrucosidins Penicillium plonicium Cytotoxicity Tremors
Penicillic acid, nephrotoxic Nephropathology
glycopeptides
Trichothecenes Trichoderma species Trichothecene toxicity Unknown
Trichodermol, trichodermin, Immunotoxicity Immune
gliotoxin, viridin impairment
Fumonisins Fusarium verticillioides Neural tube defects in animals and CNS birth defects
(AKA Fusarium humans
moniliforme)
Spirocyclic Stachybotrys Respiratory bleeding Pulmonary bleeding
chartarum
Drimanes, roridin Protein synthesis inhibition
Satratoxins (F, G, H) Neurotoxicity
Hydroxyroridin E Cytotoxicity
Verrucarin J; trichodermin; Immune toxicity
dolabellanes; altrones B, C;
stachybotrylactams

Abbreviations: BEN, Balkan endemic nephropathy; CNS, central nervous system.

toxins released, organisms involved, physiological
dysfunctions induced, and disease associations. Although
we are focusing on molds in water-damaged buildings,
Table 1 shows that bacterial growth also releases toxins.
As can be seen from the above, a wide diversity of
physiological dysfunction can be caused by these toxins
released in water-damaged buildings and many have
associated diseases. In addition, food-borne mycotoxins
have been shown to cause cancer, impaired child growth,
neural tube defects, immunotoxicity, gastroenteritis, and
renal disease.4
Add to this biochemical individuality, and most any
chronic clinical condition could be caused by these toxins.
The challenge is that statistical, generic research makes
documenting such effects in specific patients very difficult
to prove.
Mycotoxins
A tremendous amount of research has been published
on the clinical effects mycotoxins: more than 40 000 hits in
PubMed and still a huge 10 000 with limit humans. Although
this is the area apparently of most interest in the integrative
medicine community, outside respiratory effects of
mycotoxins the research is disappointingly limited.
Andrew Campbell, MD, editor in chief of our sister
publication Alternative Therapies in Health and Medicine,
has written several excellent articles on mold toxicity. In a
comprehensive review published in 2004, Campbell in
collaboration with functional medicine laboratory expert
Aristo Vojdani, PhD, and colleagues5 evaluated the research
on the physiological effects of mold toxins. The research
they reported included the symptoms of people living or
working in water-damaged buildings. Particularly
important is that they compared their symptoms with an
“unexposed” control population. (I believe this is critical,
as too often ignoring false positives overstates the
significance of symptoms.) This is a conservative view, as
the “controls” may have included individuals being
exposed to hidden active mold, which is estimated to be as
high as 50%. In Table 3, I reworked their data a bit to show

10 Integrative Medicine • Vol. 15, No. 3 • June 2016 Pizzorno and Shippy—The Path Ahead
 Table 3. Symptoms Caused by Mold Toxicity/Water-damaged Buildings5

Symptom % in Exposed Population % in Controls P Value

Memory problems 5.1 3.3 .0002
Spaciness 4.8 3.2 .0007
Excessive fatigue 5.8 4.3 .0001
Coughing 4.6 3.2 .001
Slurred speech 4.5 3.1 .002
Weak voice 4.1 2.8 .003
Watery eyes 4.6 3.4 .004
Lightheadedness 4.4 3.2 .006
Dizziness 4.3 3.1 .005
Weakness 4.2 3.0 .008
Headache 5.2 4.1 .005
Throat discomfort 4.5 3.4 .008
Sinus discomfort 4.7 3.6 .01
Coordination 4.0 2.9 .01
problems
Nasal symptoms 5.1 4.1 .02
Bloating 4.2 3.2 .02
Visual changes 3.9 2.9 .02
Rash 3.9 2.9 .02

which symptoms have the best predictive value for
suspicion of mold exposure. As can be seen, neurological
symptoms are predominant.
Although damage from mold/damp buildings can
affect all systems of the body, the two nonrespiratory
systems with the strongest research are neurological and
immunological. Authors comparing mycotoxins with
pesticides have concluded that mycotoxins are more toxic
than pesticides.6 In addition, fungal metabolites have
synergistic genotoxic and other harmful effects.7
Microbial Volatile Organic Compounds
In addition to mycotoxins, active mold produces
microbial volatile organic compounds (mVOCs). This is
currently a very active area of research. mVOCs are low
molecular weight compounds that include numerous
alcohols, esters, ethers, ketones, aldehydes, terpenoids,
thiols, and their derivatives. Because these compounds are
small and volatile, they can diffuse into the air and enter the
body through the lungs and skin. Some researchers have
suggested that mVOCs be thought of as mycotoxins and
have proposed the term volatoxin.8 Research is showing that
mVOCs are even more toxic than the chemicals traditionally
thought of as being industrial toxins. For example,
1-Octen-3-ol has been shown to be more toxic to human
embryonic stem cells than is toluene.9 Another study
reported that fungal VOCs had a greater toxic effect than do
formaldehyde, xylene, benzene, and toluene.10
mVOCs increase inflammation biomarkers such as
myeloperoxidase, lysozyme, and eosinophil cationic
protein, and they cause headache, nausea, and mucosal
irritation.11 A recent study reported:
The impact of fungal VOCs, 2-octenal and oct-1-en-3-ol on
bone marrow stromal cells that are vital for the appropriate
development and activation of the immune system showed
increased membrane fluidity.12
The same study also stated that “these vast changes in
membrane are known to contribute to the breakdown of
normal cellular function and possibly lead to death.” mVOCs
induce neurotoxicity in the Drosophila model even at very
low concentrations inducing locomotor defects and changes
in antigen-labeled dopaminergic neurons.13 Another
Drosophila study showed that the mVOC 1-Octen-3-ol
induces nitric oxide-mediated inflammatory response.14
Neurotoxicity
Neurotoxicity is clearly associated with mycotoxins
and other chemicals produced by mold. An interesting
study looked at neurobehavioral and pulmonary
impairment in 105 adults with indoor exposure to molds
and 100 exposed to chemicals, comparing them with

Pizzorno and Shippy—The Path Ahead Integrative Medicine • Vol. 15, No. 3 • June 2016 11
 202 “unexposed” community referents.15 A big challenge,
of course, is, as noted in past IMCJ editorials, we conclude
finding a control group without toxin exposure is
essentially impossible. Looking at several respiratory
measures, they found 6.1% abnormalities in mold exposed
and 7.1% in chemical exposed compared with 1.2%
abnormalities in controls. This is consistent with the
clearly demonstrable respiratory effects reported in the
last editorial. Neurologically, they found statistically
significant problems in both exposed groups: decreased
balance, longer reaction times, increased blink reflex
latency, increased color discrimination errors, decreased
visual field, and reduced grip strength. They also found
several measures of cognitive and memory performance
measures abnormal, again in both exposed groups. We
find interesting that they found little difference in virtually
all measures between the mold and chemical exposed
populations.
A study of 100 individuals exposed to mold in their
home found multiple neurological deficits in 70% and
abnormalities in T and B cells in more than 80% of the
patients.16 A study of 95 employees working in a well-
documented water-damaged school building compared
with 110 “unexposed” controls found statistically
significant loss of visual contrast sensitivity  (VCS), an
apparently sensitive measure of neurodysfunction, as well
as the usual respiratory problems.17
An important study suggests that individuals
exposed to satratoxin (SH), a trichothecene, and
microbial organisms results in a chronic immune
response (inflammation and oxidative stress) leading to
neural damage.18 Their results demonstrate that
“regardless of whether the neurons were exposed to SH
alone or under additive effects, the sensitivity of the
neurons to these compounds is high and neurological
system cell damage can occur from SH exposure.” In
addition, these data demonstrate that constant activation
of inflammatory and apoptotic pathways at low levels
amplifies the devastation and leads to neurological cell
damage from indirect events triggered by the presence of
a trichothecene mycotoxin. And they concluded, “From
this study and others, we show that neurological system
cell damage from exposure to mycotoxins is a potential
public health threat for occupants of water-damaged
buildings.”
Immunotoxicity
A number of animal studies have clearly shown mold-
induced immunotoxicity. The research in humans is quite
clear that chronic mold/damp building exposure increases
production of multiple inflammatory measures and alters
immune function mediators. These effects are not small,
with the immune systems of those working in damp
buildings reacting to exposure with 2- to 1000-fold
increased production of a wide variety of these
inflammatory/immune mediators.19
12 Integrative Medicine • Vol. 15, No. 3 • June 2016
While digging our way through the mold toxicity
research, we came across a fascinating article that proposed
multiple sclerosis is primarily a mold toxin disease.20 Their
basic thesis is that gliotoxin, a heat-stable secondary
metabolite produced by various species of Aspergillus and
Candida, suppresses immune function, increases blood-
brain-barrier permeability, and is highly neurotoxic. As is
well known, the incidence of multiple sclerosis (MS)
increases with distance from the equator, which also
correlates with mold exposure and decreased vitamin D—a
critical nutrient for immune system modulation. Could MS
be primarily due to the combination of mold exposure and
vitamin D deficiency?
Another study of chronic fatigue syndrome (CFS)
patients showed a high correlation in the presence of
mycotoxins in the patient’s urine and having a diagnosis of
CFS. Of the 102 CFS patients studied, 93% had
1 mycotoxin present. Almost 30% had 2 or more
mycotoxins present.21 Further research is warranted to
better understand this association.
Conclusion
The research cited in this and the last editorial supports
the conclusion that indoor mold metabolites have a harmful
effect on human health. The nonrespiratory mold evidence,
although limited, is quite compelling. We need further
data/research. It is somewhat shocking that more research is
not being done based on what is known about these
environmental toxins and their potential effect, especially
given the common occurrence of water damage in buildings.
As can be seen in Tables 1 and 2, the bacterial, mold,
and building material breakdown products have definitively
been documented in cell culture, animal models, and very
limited human studies to cause diverse physiological
dysfunctions. The challenge when applying this data to
humans is obvious, ranging from differences between
human and animal physiology, to dramatically varying
dosages, sensitization, genetic polymorphisms, etc. Even so,
the animal, Drosophila, and human cellular studies support
similar conclusions to the very limited human findings thus
far. Note that the Disease columns in Tables 1 and 2 are full
of unknowns as the research simply has not been done or is
inconclusive when considering population groups. And, as
we all well know, real patients are very different from
generic populations used for statistical analyses of
significance. As can be seen in these tables, disrupting
mitochondrial function, misbalancing nitric oxide synthesis,
inflammatory mediators, neurotoxicity, cytotoxicity,
immune suppression, carcinogenesis, and mutagenesis—
the list is long and can show up in virtually any clinical
manifestation in our patients depending on their specific
exposure and unique biochemistry.
Because as many as 50% of buildings in North America
show water damage, here are our recommendations for
when to consider investigating the presence of mold toxins
or hidden water damage in homes and/or workplaces:
Pizzorno and Shippy—The Path Ahead
 1. Every patient with a chronic respiratory disease,
especially asthma.
2. Every patient with a chronic disease, especially
neurological or immunological, and chronic
respiratory symptoms.
3. Any patient with a chronic disease, again especially
neurological or immunological, who is not
responding as expected and all other causes have
been ruled out.
Let us be clear: We do not believe that every patient in one
of the 3 categories above is affected by mold. We do believe
that potential mold exposure should be considered. With
the solid advances in technology for both medical and
environmental testing during the last 10 years, we can
now, as practitioners, actively begin to link medical symp-
toms with indoor mold exposure. For individual patients
we can now use enzyme-linked immunosorbent assay
(ELISA) testing to detect 15 mycotoxins both in the
patient and in their environment and assess the relation-
ship between the two. In addition, we can now detect and
quantify the presence of 36 molds by qualitative poly-
merase chain reaction (QPCR) in human tissue and the
environment.
Genetic testing can help us to identify those most
susceptible to mold toxins and other environmental toxins.
Genetic single nucleotide polymorphisms (SNPs),
proteomics, and other markers of cellular function of the
immune, detoxification, mitochondrial, and methylation
systems may help identify those most susceptible and
those most affected, as well as potential treatment options.
In addition, assessing potential nutritional deficiencies
and levels of other environmental toxins that may help
identify those with increased individual susceptibility. As
additional research is completed, it will be imperative to
improve and expand these technologies. Given the
complex nature of the interaction between the human
genome and environmental toxins, this seems a likely
problem to be solved, at least in part, with applying the
science of bioinformatics. Such an approach will help us
understand more fully the relationship (ie, severity and
magnitude) of indoor mold exposure to human health.
In This Issue
Thank you Ann Shippy, MD, for coauthoring the
second part of this mold editorial with me. I was really
struggling with the topic and she brought clarity. As a
former IBM engineer, Dr Shippy left over a decade in
engineering to adapt her skill-set to the world of medicine
after recovering from an illness that allopathic medicine
alone did not have solutions for. She attended the University
of Texas Medical School and has a thriving functional
medicine practice in Austin, Texas. She is board certified in
internal medicine and functional medicine.
As part of our efforts to continually improve IMCJ, we
are now also putting commentaries through our standard
Pizzorno and Shippy—The Path Ahead
peer-review process. I would to express my sincere
appreciation to our contributing editors for being willing
to subject themselves to this added rigor. As widely
acknowledged and leading experts in their field, having
others critique their work might be felt as disrespectful. I
believe their receptivity is a powerful validation of their
commitment to excellence and egoless advancement of
this medicine that is so critical to restoring and improving
health.
Associate Editor Jeffrey Bland, PhD, leads off this issue
with an intriguing discussion of the intersection of
personalization of health care, technology, and innovation.
I thought particularly compelling his quote from NEJM of
how this will impact health care professionals and
professions and the choices they can make. To paraphrase:
ignore, regulate, or compete. We know the choices made
by the conventional medicine political entities in the past.
Let’s not make the same mistakes.
Congratulations to John Weeks, the new editor in chief
of Journal of Alternative and Complementary Medicine.
Good luck in your new endeavor my friend. In his review of
the new federal strategies on opioid addiction, he chastises
the Obama administration for total lack of consideration of
nonpharmacological approaches and the non-MD healing
arts experts. One of the first chapters written for the
Textbook of Natural Medicine in 1985 was
“Non-Pharmacological Control of Pain” by Richard Kitaeff,
MA, ND, LAc. Come on people, the research has been there
for more than 30 years and practiced for centuries!
Loren Israelsen and Frank Lampe take on the very
challenging issue of the politics, regulatory environment, and
marketplace dynamic that powerfully affect the quality of the
natural health products we prescribe our patients. Long-time
readers will remember that we have published more than
50 editorials and articles on the extremely important issue of
product quality and safety. We practitioners must take a lead
in recognizing and supporting the companies investing the
resources to create truly great product and warn our patients
about the unscrupulous who don’t.
Christopher Hobbs, PhD, LAc, through his interview by
Managing Editor Craig Gustafson provides us useful
guidance in the use of mushrooms for wellness and health
promotion. He is a keynote lecture at the 14th Annual
International Conference of the Association for the
Advancement of Restorative Medicine. I will also be
lecturing at this conference on how toxicity has become
one of the primary causes of chronic disease.
Original research on postmarketing safety of Rheum
rhaponticum is provided by Jyh-Lurn Chang, PhD; Michael
B. Montalto, PhD; Peter W. Heger; Eva Thiemann; Reinhard
Rettenberger, PhD; and Jürgen Wacker, MD, PhD. Assessing
the efficacy AND safety of natural medicines is critical for
the advancement of our medicine.
Ferdi Yavuz, MD; Bayram Kelle, MD; and Birol
Balaban, MD, from Turkey provide us an informative case
report of the use of neural therapy in patients with Bell’s
Integrative Medicine • Vol. 15, No. 3 • June 2016 13
 palsy. I thought especially interesting the efficacy on a
nonpharmacological approach after conventional
treatments had failed. Great to see growing international
interest in IMCJ.
Mikhail Kogan, MD; Carlos Cuellar Castillo, MS; and
Melissa S. Barber, MS, provide us a case report on a woman
with comorbidities of chronic rhinosinusitis and irritable
bowel syndrome. An excellent example of how the
symptom-treatment model fails so many patients who
then experience real cure by treating the actual causes of
their illness. Great that innovative laboratories are
providing us an ever growing range of tests to help us
understand our unique patients.
When I first heard Datis Kharrazian, DHSc, DC, MS,
MNeuroSci, CNS, lecture, my immediate thought was, “This
fells like a Jeff Bland firehose lecture!” Such a treat. Another
great interview by Craig. Full disclosure, I think his work so
important I have accepted Datis’s invitation to join the
board of his International Association of Functional
Neurology and Rehabilitation. If you’ve not heard him
lecture, you are in for quite a treat that will change how you
think about patients with neurological disease.
Finally, Bill Benda, MD in BackTalk makes a very, very
valid point: While easy to critique conventional medicine
for being the third leading cause of death in the United
States, this is totally unfair as dramatically more deaths
were prevented by conventional medicine. The problem is
not the conventional medicine model—where
appropriately applied. The problem is use of symptom
suppression instead of curative understanding of why
patients are sick and how to restore health. Such a
monolithic system is only possible when other perspectives
have been actively suppressed. See my comment about
Jeff ’s commentary above.
An optimal health care system collaboratively
combines public health, life-saving conventional medicine,
and the curative health restoration we advocate.
Joseph Pizzorno, ND, Editor in Chief
drpizzorno@innovisionhm.com
http://twitter.com/drpizzorno
14 Integrative Medicine • Vol. 15, No. 3 • June 2016
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Pizzorno and Shippy—The Path Ahead