Is Mold Toxicity Really a Problem for Our Patients? Part 2—Nonrespiratory Conditions

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982651/

Comment; Excellent review article of the non-respiratory, more serious effects of mold-related illness with recognition that mold is simply a surrogate marker for water-damaged buildings; bacteria, actinomyctes, mycobacteria–numerous other microbes & biotoxins are involved.

Joseph Pizzorno, ND, Editor in Chief and Ann Shippy, MD

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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 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.

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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 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.

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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 ​and22 list the 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.

Table 1

Toxic Metabolites Produced by Bacteria Isolated From Water-damaged Materials and Indoor Air3

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

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, terreus, flavus, niger; Trichoderma virens; Penicillium spp; Candida albicans	Immune toxicity, immune suppression, neurotoxicity	Invasive aspergillosis
Aflatoxin B1, kojic acid, aspergillic acid, nitropropionic acid	Aspergillus flavus	Liver pathology and cancer, immune toxicity, neurotoxicity	Carcinogenesis
Fumigaclavines, fumitoxins, fumitremorgins, verruculogen, gliotoxin	Aspergillus fumigatus	Lung disease, neurotoxicity, tremors, immune toxicity	Aspergillosis
Ochratoxin A		Immunosuppression	BEN
Urinary tract tumors	Aspergillus niger		BEN
Aspergillosis	Penicillium verrucosum	Lung disease
Ochratoxin A	Aspergillus ochraceus	Nephropathology	Urinary tract damage
Penicillic acid, xanthomegnin, viomellein, vioxanthin			Tumors
Sterigmatocystin, 5-methoxysterigmato cystin	Aspergillus versicolor	Liver pathology and cancer	Carcinogenesis
Chaetomiums	Chaetomium globosum	Cytotoxicity	Unknown
Chaetoglobosum A and C		Cell division	Unknown
Griseofulvin	Memnoniella echinata	Carcinogenesis?	Unknown
Dechlorogriseofulvins			Reproductive toxin
Trichodermin			Hypersensitivity?
Trichodermo		Protein synthesis inhibition
Mycophenolic acid	Penicillium brevicompactum	Cytotoxic, mutagen	Unknown
Botryodiploidin	Penicillium expansum	Immune toxicity, cytotoxic	Unknown
Patulin, citrinin, chaetoglobosin, roquefortine C			Tremors
Verrucosidins	Penicillium plonicium	Cytotoxicity	Tremors
Penicillic acid, nephrotoxic glycopeptides			Nephropathology
Trichothecenes	Trichoderma species	Trichothecene toxicity	Unknown
Trichodermol, trichodermin, gliotoxin, viridin		Immunotoxicity	Immune impairment
Fumonisins	Fusarium verticillioides (AKA Fusarium moniliforme)	Neural tube defects in animals and humans	CNS birth defects
Spirocyclic	Stachybotrys chartarum	Respiratory bleeding	Pulmonary bleeding
Drimanes, roridin		Protein synthesis inhibition
Satratoxins (F, G, H)		Neurotoxicity
Hydroxyroridin E		Cytotoxicity
Verrucarin J; trichodermin; dolabellanes; altrones B, C; stachybotrylactams		Immune toxicity

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

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.

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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 which symptoms have the best predictive value for suspicion of mold exposure. As can be seen, neurological symptoms are predominant.

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 problems	4.0	2.9	.01
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

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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

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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 Drosophilamodel 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

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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 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.”

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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

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.

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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 ​and2,2, 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 ​and22are 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:

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 symptoms 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 relationship between the two. In addition, we can now detect and quantify the presence of 36 molds by qualitative polymerase 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.

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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 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 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

moc.mhnoisivonni@onrozziprd

Tweets by drpizzorno

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References

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