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 , zearalenone 69 , and secalonic acid D This is because purified mycotoxins are not volatile , due to their high molecular weights Therefore, inhalation exposure probably occurs through inhalation of airborne particulates containing mycotoxins, such as dust and fungal components , ; H.
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. Mold spore size depends on the organism; e. This point will become important below, when discussing models of stachybotryotoxicosis. It is only recently that the idea that Stachybotrys can cause significant disease has risen to national prominence , 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 well as anecdotal reports 11 , , 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 , , Possible links between mold and respiratory disease have been recognized for more than a century; literature describing connections between 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 , Early Soviet literature described a toxicosis associated with inhalation of dust heavily contaminated with spores of a variety of fungi e. 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 , However, occupational lung disease occurs in many industries, generally in the absence of an infectious agent 73 , so that it is often unclear if fungi are the responsible agents or epiphenomenona.
With the dissemination of the concept of toxigenic indoor mold, scientific reports see below and legal claims 13 , 14 , 17 ; C.
Mold Illness and Mold Remediation Made Simple, by James Schaller
Kingdollar, , Pollution litigation review—August , http: For example, Johanning et al. However, it must be noted that many different conditions can produce essentially the same respiratory symptoms 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. It is also critical to distinguish conditions which are readily reversible from those which produce permanent damage: McConnell, , Awareness of mold problem increasing among homeowners, hvac industry, http: 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 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 , Exposure 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 , , All describe an acute organic dust toxic syndrome or silo unloaders syndrome also called atypical 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 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. In addition to fungal organisms, histopathologic testing showed acute and organizing diffuse alveolar damage or bronchopneumonia Serologic studies for antigens capable of causing hypersensitivity pneumonitis were negative 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 , there was nothing to suggest that these 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 coincident conjunctivitis to asthma, allergic pulmonary aspergillosis the latter usually affecting patients with intrinsic lung disease and bronchiectasis , and HP 73 , , , 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. There is substantial evidence that the last two illnesses are caused by endotoxin exposure 58 , , 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 , , Summer-type HP in Japan is probably caused by T.
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 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.
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 effects 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 salmonicolor inhalation provocation tests 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 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 ; H. Ammann, , Is indoor mold contamination a threat to human health?
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Objective studies have found nasal mucosal hyperreactivity , and alterations in tear film stability Jaakkola and Jaakkola 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 , even though allergic asthma is IgE mediated 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 , 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 After the outbreak, patients were found to have elevated IgE levels, and Penicillium and Mucor species were identified on the sugarcane Other studies failed to show associations between IgE and disease 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 Furthermore, potential fungal antigens are many, and not well identified.
In the wake of an outbreak of infant pulmonary hemorrhage 60 , 65 , Montana et al. Affected infants were found to have significant differences from controls in red blood cell indices, hemolysis, and serum cholinesterase levels.
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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 differences existed 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 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 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 levels of serum cholinesterase compared to controls, though still within the normal range. The same group examined whether fungal exposure was a risk factor for IPH 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 implicate stachybotryotoxicosis since Stachybotrys toxins may produce hemorrhagic disease and hemolysis in animals , , 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 was 9. While Aspergillus, Cladosporium, and Penicillium species were abundant 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.
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 , since release of spores is variable and dependent on environmental factors including temperature, relative humidity, light, and air movement Moreover, isolation of organisms may not reflect toxin levels in homes, since toxin production is also variable and depends on many factors, as noted above In , the same group published an overview of the Cleveland investigations, with 37 case infants including 12 fatalities reported from to ; they also mentioned cases in the United States during the preceding 5 years 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 of Memnoniella echinata since reclassified as Stachybotrys echinata 21 , which made trichodermol, trichodermin, and griseofulvins , , as well as Cladosporium species Details regarding over cases reported nationally are not available 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. The OR of 9. Additionally, exclusion of a house with an imputed mold value also brought down the OR from 5. Some of the CDC's concerns e. 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 These patients had a very similar presentation, but no mold-related disease was identified. In fact, a strong negative disease association was noted with Stachybotrys, 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 , 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.
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 pulmonary hemorrhage related to fungal exposure, the infant was formula fed and exposed to tobacco smoke 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 no Stachybotrys. The finding of other species is an important confounder, since Trichoderma can make trichothecenes , ; this genus has been linked to pulmonary disease STHP , and Penicillium and Alternaria have been associated with animal pulmonary hemorrhage possibly via rubratoxin Finally, there has been one report of Stachybotrys being isolated from the lungs of a sick child 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 Some concerns raised by the CDC are of limited validity. While there was no evidence documenting actual exposure i. 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 Concerns that the clinical syndrome described was not consistent with historic accounts of human and animal illness is of limited relevance: While animal models are open to question, some do include pulmonary hemorrhage.
Pathogenic mechanisms responsible for Stachybotrys -induced lung injury, if it exists, are unclear. The contention by Dearborn et al. 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 , , 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 , , , , ; W.
Fungi Bacteria Indoor Air Environ. 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 used transtracheal 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.
Recently, a new hemolysin, stachylysin, was characterized from S. Hemolysins and siderophores have been isolated from a number of strains, although levels vary markedly across isolates , and toxicity does not correlate well with source location or illness Other animal studies of Stachybotrys pulmonary toxicity suffer similar limitations. Subsequent work 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 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. 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. In indoor air settings, spore counts as high as those modeled in the above studies are rarely detected, since Stachybotrys produces spores in a slimy mass that become airborne only when dried 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 However, this is based on work involving extensively processed spores, which are of questionable relevance to actual exposure conditions In more appropriate models, even if spores are liberated, it is unlikely they reach the lower airways due to their size While intranasal instillation of spores causes them to be flushed into the lungs , , it does not reflect human exposure conditions 61 - 64 , 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 , and probably only the latter is physiologically relevant. In one of the only studies using a relevant model, Wilkins et al. The authors concluded that while there may have been a weak effect of exposure to S. 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.
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 78 , , , acute inhalation of AFB 1 causes tracheobronchial cell destruction in hamsters and guinea pigs Fumonisin may produce pulmonary disease in pigs; animals fed this mycotoxin developed hydrothorax and pulmonary edema , These lesions 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. Complicating this has been obvious difficulty in detecting subtle neurological changes, even with sophisticated neuropsychological testing, as well as separating out psychiatric and factitious causes.
There is precedent for concern regarding neurotoxicity, both for mycotoxins in general and for stachybotryotoxins in particular. At the same time, coincident nonfungal compounds e. VOCs may exert neurologic effects , , Neurologic or convulsive ergotism is characterized by symptoms including muscle spasms, seizures, and hallucinations 4 , often from compounds produced during the baking of bread using contaminated grain Nonfatal cases may exhibit tabes dorsalis-like features 4. There may be a link to malnutrition. The last major epidemic of ergotism was one of convulsive ergotism in India in 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 96 , Affected children suffer dystonia, convulsions, carpopedal spasm, and coma , and there may be basal ganglia lesions Fumonisins, of which the most naturally abundant is fumonisin B 1 , cause equine leukoencephalomalacia , 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 Cyclopiazonic acid produced by Penicillium and Aspergillus may be responsible for Kodua poisoning from Kodo millet , characterized by somnolence, tremors, and giddiness ; in chicks it causes convulsions and rigidity Unfortunately, studies of many of these toxins were conducted using intraperitoneal injections 45 , , Because the route of administration matters greatly and since intraperitoneal injection has no physiologic correlate, the results are of questionable clinical relevance.
Postulated disease associations that have not been borne out include the neurologic changes of Reye's syndrome aflatoxin [ 97 ] and pellagra Affected animals developed neurologic problems including areflexia, hyperesthesia, hyperirritability, blindness, and stupor; almost all affected animals died However, experimental stachybotryotoxicosis in animals as well as well-documented human cases do not support the existence of significant neurological sequelae. Animal experiments produced pulmonary , gastrointestinal , and topical toxicity with some systemic toxicity but no specific neurologic signs.
Even in cases of heavy exposure, effects described are dermatologic , , respiratory , , 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 , , , or do so only in vague terms, unsupported by objective neurological findings 47 , 79 , , , , Notably, in recent cases where S.
Finally, some studies have shown a neuroprotective role for certain mycotoxins: In summary, despite many reported subjective complaints, there is no objective evidence for neurological compromise caused by indoor mold exposure, in particular from S. 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.
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 It is important to keep in mind that while some mycotoxins have been recognized to affect the immune system, many earlier putative associations e. Immune effects of mycotoxins have been studied extensively in animals but not in humans beyond observational studies for an excellent review, see reference 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 In theory, 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 Aflatoxin effects on immune organs in animals include thymus and bursa atrophy in fowl , , Cyclopiazonic acid causes bursal lymphoid necrosis , as well as similar changes in the spleen and lymph nodes of dogs Trichothecenes, particularly T2 toxin, induce necrosis and lymphoid depletion in the thymus, spleen, and lymph nodes of various laboratory animals, livestock, and fowl Aflatoxin exerts a variety of cellular and humoral effects.
There is suppression of mitogen-induced T- and B-cell blastogenesis in humans and bovines 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 , High-dose aflatoxin exposure 0.
There may be clinical veterinary correlates with increased frequency of swine salmonellosis , vaccination failure, and fowl cholera, salmonellosis, and coccidiosis A. Ochratoxin A OA has similar effects, but these vary with dose only higher doses induce lymphopenia and species higher effects in mice, less in cows Critically, OA effects on immunoglobulin production and the antibody responses vary with the route of administration: 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 , ; G.
Mycotoxins Anim Production, 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 vitamins B 12 , K, and methionine are also protective. Trichothecenes 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 , Other potent trichothecenes include DAS, deoxyivalenol vomitoxin , and fusarenon-X.
These compounds are among the most potent small-molecule inhibitors of protein synthesis , , By blocking RNA and DNA synthesis via inhibition of peptidyltransferase, they can produce characteristic radiomimetic lesions in rapidly dividing tissues , , This may account for organ and cellular effects noted above and the decreased immunoglobulin synthesis, antibody responses, and complement activity in animal models , as well as cell proliferative and activity responses 36 , Trichothecenes may affect cytokine production 43 , , 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 Trichothecenes have been associated with decreased resistance to infectious organisms, including Salmonella, Mycobacterium tuberculosis, Listeria, herpes simplex virus, Candida, and Cryptococcus One report of an outbreak of stachybotryotoxicosis in sheep reported frequent isolation of a normally commensal organism, Pasteurella haemolytica, from 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 , 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 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 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. Immunological studies of stachybotryotoxin effects in humans are limited to observational studies 82 , , In contrast to early reports of severe leukopenia and radiomimetic effects in ATA-like syndromes after trichothecene ingestion in Eastern Europe , , , , these observational studies have not found the same hematopoietic effects In addition, environments were not checked for endotoxins or volatile organic compounds, nor was diet examined.
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 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. A subsequent study by the same author of children and adults seen in an environmental health specialty clinic failed to show significant differences in immune parameters 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 Pestka 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 While there are over toxigenic fungi and more than mycotoxins , , only two aflatoxin and sterigmatocystin have been shown to cause tumors in primate experiments Studies with other animals have implicated the following as mutogenic: Most are directly genotoxic e.
Results of animal studies, often cited as proof of carcinogenicity, must be interpreted with extreme caution in regard to humans. From to , many model carcinogens were found to be tumorogenic in rodents; however, only one urethane was found to cause cancer in primates 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 extends to mycotoxins. For instance, whereas AFB 1 appears to be the most hepatocarcinogenic compound known for the rat, the adult mouse is essentially totally resistant to its hepatocarcinogenicity. Aflatoxin is the best characterized of the potential human mycotoxin carcinogens , , While it is acutely lethal in large amounts, chronic low-level exposure produces cancer, particularly hepatocellular carcinoma HCC in many animal species 52 , 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 , AFB 1 is produced by Aspergillus flavus and A.
The primary mode of human exposure is the consumption of contaminated foodstuffs, e. Aflatoxin can be detected in the blood of pregnant women, cord blood where levels can be very high , and breast milk; AFM 1 and AFM 2 oxidative 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 AFB 1 - N 7 -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 , , , This mutation may be situationally specific, since AFB 1 -induced monkey tumors are associated with a different mutation 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 development 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 Similarly, bioactivation of aflatoxin into carcinogenic metabolites shows significant species differences 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 , , ; the relative risk for HCC is as high as 59 if both urinary aflatoxins and positive HBsAg status are present , , There may be modulation of damage by nutrients, antioxidants, herbs, drugs, and malnutrition , , Other mycotoxins such as sterigmatocystin may play a role Because of theoretical protective effects of dietary supplements, there have been trials of chemoprotectants like ethoxyquin and oltipraz , There is limited evidence regarding carcinogenicity of inhaled aflatoxins.
Aflatoxin can be aerosolized and has been detected in air near farm sources 49 , , Inhaled aflatoxin causes tracheobronchial cell destruction in hamsters and guinea pigs ; rats receiving intratracheal doses develop cancer of the liver, intestines, and kidneys 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. Anecdotal studies reported premature cancer in three exposed laboratory workers ; G. The findings may indicate that aflatoxins are secondary findings in chronic lung disease, since lung cancer and pulmonary fibrosis are unrelated illnesses.
Other mycotoxins have been implicated as carcinogens. Ochratoxins are structurally related metabolites from A. OA is the only one of major carcinogenic significance , , 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 OA can form DNA adducts, and the kidney may be the worst affected organ While OA has been listed as a mammalian carcinogen , , 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 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. Significant concerns have been raised as a result of its estrogenic activity and thus its potential for stimulating estrogen-sensitive tumors 25 , 93 , , It causes increased cancer rates in mice but not rats ; in fact, in the latter species it may exert protective effects It was once postulated to cause cervical cancer , but the assertion has not been borne out due to the clear association of this malignancy with human papillomavirus There may be a link between mycotoxins and esophageal carcinoma 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 B 1 from F. Selected fumonisins are hepatocarcinogenic in rats and have been designated group 2b carcinogens, i. However, some studies have found many cocontaminants 67 or present only equivocal data Such data must be interpreted with caution, since Fusarium 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 Some mycotoxins are antineoplastic agents.
Ergosterol peroxide and acetoxyscirpenediol from Paecilomyces tenuipes, a silkworm larva parasite, and Chinese entomopathogenic fungi are more potent than cisplatin against human gastric tumor, hepatoma, colorectal cell lines, and murine sarcoma T-2 toxin inhibits the proliferation of neoplastic cell lines, including mouse melanoma B16 cells, human myeloid leukemia K cells, and human cervical carcinoma HeLa cells New fungal compounds with similar anti-neoplastic traits are constantly being found As shown above, some trichothecenes are potentially carcinogenic.
To date, there are only conflicting reports in animal studies 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 In addition to HCC, aflatoxin in significant doses can cause acute liver injury.
Acute aflatoxicosis generally occurs in outbreaks due to contaminated foodstuffs. While there have been claims that aflatoxin causes other diseases such as Reye's syndrome 97 and neonatal jaundice , they have not been validated. In the field, rubratoxins are often mixed with aflatoxin due to cogrowth of A. Hepatobiliary effects have not been reported for Stachybotrys toxins. Endocrine toxicity has been seen primarily with zearalenone F-2 toxin The compound is produced by several Fusarium species under very particular growth conditions and has estrogenic effects in animals.
Such effects are well characterized in swine the most sensitive animals and include primary effects e. Similar effects have not been demonstrated in humans, even though zearalenone has been found in the blood of children exposed to contaminated food There have been no reports of Stachybotrys -related endocrine toxicity. 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 well 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 Ochratoxin A is the most common and most toxic chemical of its class: 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 isolated from air samples in areas where BEN occurs, but study of the isolates was limited to animal feeding experiments There has been one case of apparent inhalational nephrotoxicity, and an OA-producing strain of A.
Citrinin is produced by several Penicillium species and is sometimes isolated from contaminated rice 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 , It is unclear if these findings are part of a mycotoxin syndrome, were secondary to severe illness e.
To date, there has been no evidence linking Stachybotrys toxins to renal disease. A number of mycotoxins affect pregnancy in experimental animals; however, none of the observations extend to humans. Ergotoxins may prevent embryo implantation in mice , There are conflicting reports of their ability to induce abortions, and they may cause stillbirths and agalactia , , Secalonic acid D has been found in dust and aerosols.
Zearalenone has been found in dust and aerosols and may cause infertility and fetal malformations in domestic animals through estrogenic effects discussed above 69 , , OA may cause fetal death, as well as uterohemorrhagic effects, in rats , T-2 toxins and DAS have been reported to cause limb and tail abnormalities While T-2 and DAS in feed do not cause abortion, preconception exposure may cause infertility and reduced litter size , Aflatoxin is of special concern, since it is teratogenic in nearly all animals Various investigators have found uteroplacental hemorrhage and fetal death in rats and mice given intraperitoneal aflatoxin 99 , , while others have noted only fetal retardation in rats given oral aflatoxin Aflatoxin has been detected in the blood of pregnant women, cord blood, and breast milk 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 that Stachybotrys can affect fetuses even though no maternal effects may be evident , 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 , , , and cardiac 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 is supported by several other recent reports 64 , , , , 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.
Isham for technical advice, M. Smith for secretarial assistance. National Center for Biotechnology Information , U. Journal List Clin Microbiol Rev v. Kuhn 1, 2, 3 and M. This article has been cited by other articles in PMC. Abstract Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. Fungi found in dust and air samples- representative findings a. Dust samples Air samples Penicillium spp. Link 16 Paecilomyces variotii Bainier 10 Phoma spp.
Conant 4 Yeasts 82 6 Aspergillus versicolor Vuill. X Torula herbarum Pers. Link ex Gray X Verticladiella sp. Open in a separate window. Difficulties in measuring mycotoxins. Toxigenic species of mold isolated from indoor air of houses a.
Species Toxins produced Aspergillus flavus Aflatoxins Aspergillus fumigatus Fumiclavines, fumigatoxin, fumigillin, fumitrems, gliotoxin Aspergillus versicolor Sterigmatocystin, versicolorin, aspercolorin, averufin, cyclopiazonic acid Penicillium brevicompactum Brevianamide A, mycophenolic acid Penicillium chrysogenum Citrinin, penicillic acid, PR-toxin, roquefortin C Penicillium citrinum Kojic acid, citrinin, citreoviridin Penicillium corylophilum Gliotoxin Penicillium cyclopium Penicillic acid Penicillium expansum Patulin, citrinin Penicillium fellutanum Citreoviridin, citrinin Penicillium spinulosum Spinulosin Penicillium viridicatum Brevianamide A, citrinin, mycophenolic acid, penicillic acid, viomellein, xanthomegnin Stachybotrys chartarum Roridin E, satratoxin H, sporidesmin G, trichoverrins, verrucarol Trichoderma viride Gliotoxin, T-2 toxin, trichodermin, trichodermol, viridiol.
Problems with Clinical Studies Most studies describing the health effects of indoor dampness and mold have relied on subjective and retrospective questionnaires. Stachybotrys Species as Pathogens In the Ukraine in the early s, a unique disease of horses was recognized that was characterized by lip edema, stomatitis, oral necrosis, rhinitis, and conjunctivitis. Associations with Human Disease The possible association of Stachybotrys species with human disease became apparent coincident with the equine epidemics.
Mycotoxins from Stachybotrys The mycotoxins responsible for many of the described effects of Stachybotrys were isolated in the s during the aforementioned Russian equine outbreak and were found to have an empiric formula of C 25 H 34 O 6 or C 26 H 38 O 6 , consistent with the trichothecene class of compounds , , Organic toxic dust syndrome, hypersensitivity pneumonitis, and allergic lung disease.
Cleveland infant idiopathic pulmonary hemorrhage outbreak. Potential mechanisms of Stachybotrys -induced lung injury. Neurologic Exposure to S.
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Hematologic and Immunologic General concerns. Hepatic In addition to HCC, aflatoxin in significant doses can cause acute liver injury. Endocrine Endocrine toxicity has been seen primarily with zearalenone F-2 toxin Renal 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. Pregnancy A number of mycotoxins affect pregnancy in experimental animals; however, none of the observations extend to humans. Other Toxicities A host of other mycotoxin effects in animals and to a lesser extent in humans, have been described.
Acknowledgments We thank N. Mycoflora and trichothecene toxins of paddy grains from Egypt. Acute hypersensitvity pneumonitis related to forced air systems—a review of selected literature and a commentary on recognition and prevention. Fungal colonization of fiberglass insulation in the air distribution system of a multi-story office building: VOC production and possible relationship to a sick building syndrome.
Improved health after intervention in a school with moisture problems. Epidemiological features of the mycotoxicoses. Toxic effects of indoor molds. Bacteria, molds, and toxins in water-damaged building materials. Specific bronchoalveolar lavage IgA antibody in patients with summer-type hypersensitivity pneumonitis induced by Trichosporon cutaneum. Mass incidence of mycotoxicoses in Hajdu-Bihar County. Aflatoxins from foodborne pathogenic microorganisms and natural toxins handbook. Colorado couple files suit alleging defects caused mold.
Guidelines on assessment and remediation of fungi in indoor environments. Indoor air quality environmental information task force: Department of Energy, Washington, D. Maine employees sue building owner over fungus exposure. SF6 tracer gas field sampling procedures. Associations between indoor CO2 concentrations and sick building syndrome symptoms in U.
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Epidemiology of the sick building syndrome. Xenoestrogens significantly enhance risk for breast cancer during growth and adolescence. Indirect health effects of relative humidity in indoor environments. Clinical experience with patients suffering from a chronic fatigue-like syndrome and repeated upper respiratory infections in relation to airborne molds.
Toxins from moldy cereals. Foreign suppliers to Iraq's biological weapons program obtain microbial seed stock for standard or novel agent. Macrocyclic trichothecene toxins produced by Stachybotrys atra strains isolated in Middle Europe. Ochratoxin A in the food chain. Influence of whitelight on production of aflatoxins and anthraquinones in Aspergillus parasiticus.
Effects of mycotoxins on human immune functions in vitro. Exposure to respirable, airborn Penicillium from a contaminated ventilation system: Elsevier, New York, N. Foodborne diseases in India. A foodborne disease outbreak due to the consumption of moldy sorghum and maize containing fumonisin mycotoxins.
Fungi associated with urea-formaldehyde foam insulation in Canada. Symptoms related to the sick building syndrome in a general population sample: Immunomodulation by fungal toxins. Interaction of aflatoxin and paratyphoid infections in broiler chickens. Brain neurotoxicity of Penitrem A: Genetic and molecular analysis of aflatoxin biosynthesis. Home dampness and respiratory morbidity in children. Mycotoxins as secondary metabolites, p. Measurement of airborne aflatoxins during the handling of contaminated corn.
Moisture, organisms, and health effects, p. A disease of swine and cattle caused by eating moldy corn. Experimental production with true cultures of molds. American Chemical Society, Washington, D. Edward Arnold, London, United Kingdom. The effects of aflatoxin B 1 on the pregnant rat. Food and Drug Administration, Washington, D. Epidemiologic observations in idiopathic pulmonary hemosiderosis.
Task Force report Inhaled endotoxin and decreased spirometric values. An exposure-response relation for cotton dust. Centers for Disease Control and Prevention. Acute pulmonary hemorrhage among infants—Chicago, April November From the Centers for Disease Control and Prevention. Impaired phagocytosis by heterophils from chickens during aflatoxicosis.
Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People's Republic of China in regions with high incidences of esophageal cancer. Microbial food and feed toxicants: Visible mold in and around your house is far less dangerous than the mold you cannot see. Indoor mold toxicity, in addition to causing its own unique set of health problems and symptoms, also greatly contributes to the severity of most chronic illnesses.
In this book, a top physician and experienced contractor team up to help you quickly recover from indoor mold exposure. This book is easy to read with many color photographs and illustrations. Schaller is a practicing physician in Florida who has written more than 15 books. He is one of the few physicians in the United States successfully treating mold toxin illness in children and adults. He has written several books and is an expert in the mold remediation of homes. Rosen and his family are sensitive to mold toxins so he writes not only from professional experience, but also from personal experience.
Together, the two authors have certification in mold testing, mold remediation, and indoor environmental health. This book is one of the most complete on the subject, and includes discussion of the following topics: The book is written in a friendly, casual tone that allows easy comprehension and information retention.
Many people are affected by mold toxins. If you can find a smarter or clearer book on this subject, buy it! He is often surprised at the limited time you can get from sincere doctors. Many sincere physicians are too worn out for problem solving creativity. Schaller does not claim to be "smarter" or "more sincere" than any of your doctors. Nevertheless, he is very creative, likes tough questions and also educating patients. He also researches and treats with very diverse options.
Schaller is the author of 15 books covering many diverse areas of medicine.