CLINICAL MICROBIOLOGY REVIEWS, Jan. 2003, p. 144–172 0893-8512/03/$08.00 0 DOI: 10.1128/CMR.16.1.144–172.

2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Vol. 16, No. 1

Indoor Mold, Toxigenic Fungi, and Stachybotrys chartarum: Infectious Disease Perspective
D. M. Kuhn1,2,3 and M. A. Ghannoum2,3*
Division of Infectious Diseases, Department of Medicine,1 and Center for Medical Mycology, Department of Dermatology,2 University Hospitals of Cleveland, and Case Western Reserve University,3 Cleveland, Ohio 44106 INTRODUCTION .......................................................................................................................................................144 INDOOR AIR AND BUILDING-RELATED ILLNESS.........................................................................................145 FUNGI IN THE INDOOR ENVIRONMENT .........................................................................................................145 Fungal Organisms in Damp Buildings ...............................................................................................................145 Technical Problems in Determining Fungal Exposure ....................................................................................146 Difficulties in measuring fungal organisms ....................................................................................................146 Difficulties in measuring mycotoxins ...............................................................................................................147 Problems with Clinical Studies ...........................................................................................................................147 ASSOCIATION OF STACHYBOTRYS SPECIES WITH “SICK BUILDINGS”.................................................149 FUNGI AND FUNGAL TOXINS..............................................................................................................................150 Mycotoxins ..............................................................................................................................................................150 Stachybotrys Species as Pathogens .......................................................................................................................151 Associations with Human Disease ......................................................................................................................152 Mycotoxins from Stachybotrys ..............................................................................................................................152 SPECIFIC TOXICITIES............................................................................................................................................155 Pulmonary ..............................................................................................................................................................155 Rationale for concerns regarding Stachybotrys ...............................................................................................155 Organic toxic dust syndrome, hypersensitivity pneumonitis, and allergic lung disease ..........................155 Cleveland infant idiopathic pulmonary hemorrhage outbreak ....................................................................156 Potential mechanisms of Stachybotrys-induced lung injury...........................................................................158 Neurologic ...............................................................................................................................................................159 Hematologic and Immunologic ............................................................................................................................160 General concerns ................................................................................................................................................160 Aflatoxin ...............................................................................................................................................................160 Trichothecenes.....................................................................................................................................................160 Malignancy .............................................................................................................................................................161 General concerns ................................................................................................................................................161 Aflatoxin ...............................................................................................................................................................162 Other mycotoxins ................................................................................................................................................162 Hepatic ....................................................................................................................................................................163 Endocrine ................................................................................................................................................................163 Renal .......................................................................................................................................................................163 Pregnancy ...............................................................................................................................................................163 Other Toxicities .....................................................................................................................................................164 CONCLUSIONS .........................................................................................................................................................164 ACKNOWLEDGMENTS ...........................................................................................................................................164 REFERENCES ............................................................................................................................................................164 INTRODUCTION Damp buildings often have a moldy smell or obvious mold growth, and some molds are known human pathogens. This has caused concern regarding potential health effects of moldy indoor environments. As a result, there have been many studies of moisture- and mold-damaged buildings. More recently, there have been a growing number of articles in the media and of lawsuits claiming severe illness as a result of indoor mold exposure, particularly to Stachybotrys chartarum. However,
* Corresponding author. Mailing address: Center for Medical Mycology, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106. Phone: (216) 844-8580. Fax: (216) 844-1076. E-mail: mag3@po.cwru.edu. 144

while many authors report a clear relationship between fungal contaminated indoor environments and illness, close examination of the literature reveals a much more confusing picture. In this review, we discuss indoor environmental mold exposure and mycotoxicosis, with an emphasis on S. chartarum and its toxins (due to the breadth of the topic, we will not discuss better understood areas such as invasive disease caused by Aspergillus). We also discuss specific organ effects, focusing on illnesses purportedly caused by indoor mold. These illnesses include pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage (IPH) reports in some detail, since they provided much of the fuel for current concerns about Stachybotrys exposure. As we will see, while there is cause for concern about

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the potential effects of indoor mold exposure, particularly to Stachybotrys species, there is no well-substantiated evidence linking the presence of this fungus to health concerns elaborated in the scientific and lay press. As patients and society at large become increasingly concerned that illnesses may be due to the home or work environment, an understanding of mycotoxins by microbiologists and clinicians (especially infectious-disease subspecialists) is of growing importance. Such knowledge is critical to the diagnosis of potential fungus-related disease and is necessary to assuage fears instilled by extensive media coverage (34; J. MacFarlane, 1997, Beware the mold Stachybotrys, http://www.cnn.com /HEALTH/9711/05/deadly.mold; J. McKenzie, 2001, Hidden menace: insurers worry about toxic mold claims, http://more .abcnews.go.com/sections/wnt/dailynews?toxicmold_010626 .html; E. Moriarty, 2000, Invisible killers, OBS News, New York, N.Y.; N. Morris, 2001, Moldy Schools: are your kids getting sick at school? http://more.abcnews.go.com/sections /wnt/WorldNewsTonight/wnt010418_moldyschools_feature .html). Finally, such knowledge may be important in the wake of recent terrorist events in the United States. Some toxins, particularly aflatoxins and trichothecenes, have the potential to be used as weapons. There is evidence that several countries are currently involved in mycotoxin weapon research (30, 239, 465). The latter point is beyond the scope of this article. INDOOR AIR AND BUILDING-RELATED ILLNESS It has long been postulated that exposure to damp, moldy home and workplace environments has detrimental health effects. At the beginning of the 18th century, Ramazzini, considered “the father of occupational medicine,” described an illness of workers inhaling ‘foul and mischievous powder’ from handling crops (116, 302). More recently, Platt et al. (333), found that occupants of wet, moldy buildings had an increase in subjective complaints. Brunekreef et al. (47) found a similar pattern in 6,000 children in six states in the United States and reported home dampness was a strong predictor of respiratory and other illness in this age group. The list of putative symptoms generally consists of upper respiratory complaints, including headache, eye irritation, epistaxis, nasal and sinus congestion, cough, “cold and flu” symptoms, as well as generalized gastrointestinal complaints (240). Taskinen et al. (409, 410) reported an increased prevalence of asthma in moisture-affected schools, although there were no objective measurements of respiratory disease. A number of studies have reported a relationship between similar symptoms and damp housing or workplace environments, although the proposed etiologies have varied (117, 118, 164, 416, 419, 444). The causal relationship between damp housing and illness is unclear. Establishing such a relationship is complicated since there are a variety of pollutants in the indoor environment (143) including volatile organic compounds such as toluene, benzene, alkenes, aromatic hydrocarbons, esters, alcohols, aldehydes, and ketones (208, 267, 277, 310, 332, 357, 450); radon (256); combustion gases, sulfur dioxide, nitrogen dioxide, carbon dioxide, ozone (16, 20, 357); and the essentially ubiquitous formaldehyde (205, 357). Other items (copy paper) and activities (photocopying and video terminal exposure) have been linked to symptoms (178). Other studies have suggested that shade, organic debris, landscaping quality, central electrostatic

systems, ventilation rates, temperature, noise levels, dust control compliance, and patient gender may be important (23, 42, 77, 215, 264, 298, 308, 344, 437, 440), as well as the presence of tobacco smoke (81, 123, 276). Psychosocial issues may be playing a role in building-related complaints. Several studies have reported that the quality of the work environment, stress, and somaticization may all be significant (31, 42, 89, 232, 276, 307, 308, 413). The indoor environment also contains a wide range of microorganisms including bacteria (e.g., Legionella and other gram-negative species) (85), mycobacteria (9, 415), and molds (161), as well as their products, including endotoxins and mycotoxins. There may often be a much higher bacterial load than fungal load (161, 416). Most fungi are metabolically active over a broad temperature range (203); however, high moisture and relative humidity are required for optimal growth (69). The lowest relative humidity supporting mold growth is approximately 75%, although the requirements of Stachybotrys are much higher, around 93% at 25°C (142). Increasing temperature and nutritional status of the substrate can lead to lower moisture requirements. Surfaces that are soiled or have susceptible paint or paper do not need to be as damp for mold to develop. While promoting mold growth, moisture itself may be critical in “sick-building syndrome” (SBS) illnesses, since humidity affects mite and ozone levels, as well as off-gassing, salt, and acid formation (26). The links between moisture damage, any of these related cofactors, and building-related illnesses are not clear (24, 27, 50, 83, 260). For example, dust mites are notorious allergic agents and produce many of the upper airway symptoms ascribed to mold exposure or SBS; moreover, they are almost always found in association with mold species (90, 262, 359), confounding moisture- and mold-related findings. Gram-negative bacteria, endotoxin, and mycobacteria are found in water-damaged buildings in association with mold (9, 85). To our knowledge, only one paper has actually reported a lack of association between symptom prevalence and endotoxin, dust mites, or other nonfungal agents (85). In moldy office buildings there is an association between microbial contamination and repeated flooding or stagnant pools of water (280). Some geographic locales are obviously more likely to be affected than others. For example, 12% of English building stock suffer serious dampness; extrapolation suggested that there were 2.5 million affected dwellings in the United Kingdom but that 60% of these were from condensation rather than overt flooding (362; Anonymous, Bldg. Res. Estab. Semin. Proc., 1981). Readers interested in an in-depth review of these issues are referred to the recent comprehensive report by the Institute of Medicine (175). FUNGI IN THE INDOOR ENVIRONMENT Fungal Organisms in Damp Buildings A host of mold species have been isolated from damp buildings: the most frequently isolated in one study were Penicillium (96%), Cladosporium (89%), Ulocladium (62%), Geomyces pannorum (57%), and Sistronema brinkmannii (51%) (142, 168). There were 66 species of filamentous fungi, and yeasts were found in 94% of dwellings and 13% of CFU on Anderson sampler plates. In contrast to the aforementioned species,

Stachybotrys was less common. gypsum. The predilection for cellulose. While a detailed description of such techniques is beyond the scope of this article.) Conant Yeasts Aspergillus versicolor (Vuill. little can be deduced from single air samples. Although available studies provide information regarding which organisms are present in the indoor environment. moisture. since aggressive measures (e. 215.) ex Gray Ulocladium botrytis Preuss Penicillium fellutinum Biourge Penicillium decumbens Thom Cladosporium herbarum (Pers. However.. 142. where it is a tertiary wall colonizer that comes after primary (Penicillium and A. Periconia spp. The nutritional and growth requirements of the organism may also explain the lack of recovery from cultures and perhaps underreporting of Stachybotrys incidence.. Stachybotrys can sometimes be isolated from other substrates including pipe insulation. there can be huge variations (up to 1. and Aspergillus species (144. 267). Other factors affecting apparent airborne fungal spore load are carpeting type (162). with positive cultures in up to 30% of water-damaged homes (121). Similar issues may exist when trying to identify mycotoxin-producing Fusarium strains (420). This fact is critical. there are significant concerns associated with sampling methods. . Thus. Hunter et al. several points are worth mentioning. The fungus proliferates more slowly than other species. 416). 379. Torula herbarum (Pers. and aluminum foil (144). found in one house only. and recent work suggests that volatiles from S. Penicillium.146 KUHN AND GHANNOUM TABLE 1. vacuuming) will probably overestimate actual exposure levels (238. 416). 171). Aspergillus fumigatus Fresen. cellulose based) are used. dust control measures (215). Fungi found in dust and air samplesrepresentative findingsa % of houses where species was found in: Dust samples Air samples CLIN. An increase of 3. 405). sampling needs to be done under normal room activity. 267. 358. Aureobasidium pullulans (deBary) Arnaud Monilia sitophila Sacc. (168) found that while large numbers of spores in the internal air were associated with surface mold growth and construction work. 416). Furthermore. Stachybotrys is rarely found in isolation. Most traditional sampling methods (e. Other studies have reported similar organism frequencies (Table 1) (72. 267. In most studies. Paecilomyces spp. and humidification (394). Penicillium janthinellum Biourge Penicillium lividum West Penicillium purpurogenum Stoll Penicillium rugulosum Thom Penicillium simplicissimum (Oud. which necessitates the use of devices such as Anderson samplers (135. 420). REV. Curvularia inaequalis (Shear) Boedijn Geotrichum candidum Link Penicillium aurantiogriseum Dierckx Penicillium brevi-compactum Dierckx Penicillium chrysogenum Thom Penicillium digitatum Sacc. 347). Difficulties in measuring fungal organisms. Even using such quantitative devices. discussed below. Such culture difficulties may eventually be circumvented using new techniques such as PCR (80. MICROBIOL. 202). Phialophora melinii (Nannf. 80 73 67 57 55 53 39 31 25 22 20 18 16 10 10 8 6 6 6 6 6 4 4 4 4 82 X X X X X X X X X X X X X X X X X X 47 8 Xb 6 6 X 6 4 14 10 Stachybotrys has a fondness for cellulose (350)..) Link ex Gray Verticladiella sp. 168. Cladosporium cladosporioides (Fresen) de Vries Alternaria alternata (fr. Species Penicillium spp.) Tiraboschi Basidiomycetes (clamp connections) Cladosporium sp. being present in less than 3% of samples (214. 144. the rapid settling of the large spores of Ulocladium species probably accounts for their being underrepresented in the airborne spore load (144.8% of dwellings and 4.) Link Paecilomyces variotii Bainier Phoma spp. These last two points are critical to examination of the Cleveland IPH reports. and protocols involving multiple samples from suspect houses versus single samples from control houses will probably disproportionately find fungus in case houses due to attrition (142). disturbance of surface growth and vacuum cleaning of carpets (techniques often involved in surveys) caused large temporary increases in the atmospheric spore count.g. by wiping with a hand).000-fold) between essentially identical specimens (168).g. since many of the other species are capable of producing mycotoxins (70. and nutrient-poor settings explains the appearance of Stachybotrys in affected buildings.) Thom Stachybotrys atra Corda Thamnidium elegans Link. the same is true for Cladosporium. 185.300% in the number of four categories of mold was observed after disturbing mural mold growth (e. fiberglass wallpaper.g. versicolor) and secondary (Cladosporium) fungal colonizers (327). leading to overgrowth by other molds unless appropriate culture substrates (e. b X. 359. chartarum may represent a small fraction of the total amount present in problem buildings where other fungi exist (139). Aspergillus candidus Link Aspergillus ochraceus Wilhelm Aspergillus spp. Studies using cellulose-based agar techniques have reported a relatively high prevalence of Stachybotrys. While cellulose (especially water damaged) may promote Stachybotrys growth. Rhizopus spp. Stachybotrys has had a low prevalence. some recent work has suggested that it may be more common than was initially thought (144. being found in 12.) Keissler Sterile isolates Aspergillus niger van Tieghem Penicillium viridicatum Westling Mucor spp. particle size may play a key role when attempting to quantitate some species.. exposed agar plates) are incapable of adequately measuring either airborne or sedentary organisms. nearly always occurring in the presence of other fungi (164.5% of samples. Trichoderma viride (Pers. for example. Arthrinium spp.g. pets (394). Finally. Regardless. 419). Technical Problems in Determining Fungal Exposure X 8 6 X X X 6 X X 8 X X a Adapted from reference (267) (a survey of Canadian homes) with permission of the publisher.

the authors tried to confirm the findings by objective measures (87). To examine the validity of self-reported symptoms. can be produced (291). 410). becoming airborne only when dry and disturbed or when attached to other particles such as dust (161). and nocturnal cough recordings. They found that more mold was present if odor or water damage were reported and that twice as much Aspergillus and Penicillium was found when mold was mentioned.g. Some studies which claim that moisture and mold were associated with respiratory infections. and wheezing (again with no objective measures) also fail to show differences in asthma prevalence between case and control schools (409. Other authors report that despite claims of symptoms being more prevalent in case groups (reporting exposure to fungi. While many species can produce toxins (Table 2). The same group tested the validity of questions commonly used to indicate presence of indoor molds. Such findings may explain the confusing results of earlier studies. including a protein translation (luciferase) assay for trichothecene toxicity in airborne particulates (457). pets.. some authors have claimed links between childhood asthma and damp. inaccuracy was high and there was evidence of systemic bias. mold odor. and odors were associated with elevated levels of indoor fungi. There are obviously potential problems with such an approach. Toxins purportedly produced by a particular organism may suffer from misidentification of that organism (237). Similar negative findings have been found when examining subjective neurologic complaints in the setting of SBS (310). and temperature (161. dust. However. 153). The results showed there was extremely low agreement between the two measures. 396. Remarkably few studies have included physical examinations or diagnostic testing. 267. while reported mold. 294). many unknown secondary metabolites. and when study validity was examined. the degree of bronchospasm was not different between groups. actual asthma prevalence was no different (177). 388). Using the same group as in their previous work (n 403 homes).g.VOL. toxin-bearing spores are produced in a slimy mass with high moisture content (Fig. are appropriate. present (267. the presence of potentially toxigenic fungi does not imply the presence of mycotoxins. In another study of associations between residential mold growth and symptoms. There are also extreme variations in toxin production between strains (11. allergy patients were more likely to report visible fungus despite low levels of viable fungus in dust. causing the authors to conclude that objective measures. 295). cough. Serologic testing of potentially exposed individuals is not useful. mycobacteria. since the compounds are not volatile. and man-made organic chemicals. compared to established objective measures of mold (e. For example. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 147 A final problem in measuring fungal organisms in the indoor environment relates to selective sampling. as well as bacteria. moisture. It is worth noting the authors of this work are in fact proponents of a mold-illness link. with overnight cough recording (88). while smokers were less likely to report visible mold). airborne ergosterol) (86). Many purported fungal volatiles are in fact common and are not unequivocally fungal in origin (267). and chest cold symptoms in children from affected houses. there was no supporting objective evidence. most studies cited below have used methods that preferentially select for Stachybotrys species and mycotoxins. yet to be detected or identified. parental smokers underreported their children’s coughing. In addition. one group compared parental reports of children’s coughing. 283). As discussed in detail below. or was. Problems with Clinical Studies Most studies describing the health effects of indoor dampness and mold have relied on subjective and retrospective questionnaires. despite the claim that there was a causal association between moldy houses and wheezing. 420. Of more immediate scientific and medicolegal concern. this has usually been in the context of heavy industrial contamination (240. moldy housing (401). neither symptoms nor recorded cough were related to objective measures of mold. nutrient levels. Toxin production is dependent on substrates. making their conclusions that subjective complaints are inadequate measures of pathology perhaps even stronger. water damage. Therefore. since specific immunoglobulin levels do not correlate with exposure (419). similar problems exist regarding the detection and significance of indoor environmental mycotoxins.g. nor does the finding of mycotoxins prove that a particular species is.6 if their reports were relied on instead. the presence of reported mold or water damage was unrelated to objective measures. the ability to produce toxin varies under particular conditions. However. While some true mycotoxins have been detected in indoor air. arthropods. some notable conclusions were reached. making culture insufficient as an indicator for the presence of mycotoxins. they are usually isolated from inert dust or building materials (9. specific tests for individual mycotoxins or biological assays (e. pH. viable fungus counts.1 (based on recording) down to 0. They are often present in settings which select for a host of other fungal species and their potential mycotoxins. . Although it is occasionally possible to collect mycotoxins by using air filters followed by extraction (318. which biased the actual odds ratio (OR) of 3. and dampness).. newer analytic methods are being developed. Additionally. Difficulties in measuring mycotoxins. 451). cough. not questionnaires. In the case of Stachybotrys. and there was evidence of substantial reporting bias (e. While retrospective questionnaires reported more wheezing. 420). Overall. and often “known” toxin producers will not make the compounds (291). As noted above. Most importantly. Stachybotrys species rarely exist in isolation. 1). This may misrepresent exposure.. This technique offers a greatly increased sensitivity compared with prior systems and may provide a novel way to measure environmental mycotoxins. Thus. they compared reported respiratory symptoms with objective measures including airborne ergosterol. In this regard. It is reasonable to conclude that retrospective subjective questionnaires are at best suspect. skin irritation) need to be performed as tools for mycotoxin screening (317. Despite a 25 to 50% relative increase in symptom prevalence when mold was reported. and new compounds are constantly being identified (166). 16. Fungal species identification is not a simple process but often requires the expertise of specialized medical mycologists. 79. 111. many studies of purportedly affected housing are surveying only for Stachybotrys species while ignoring other organisms (our unpublished experience).

initially obtained from contaminated wallboard (40 objective). . http:// www. 1. Slime has been removed by scanning electron microscope processing. chartarum. (B) Pure culture of S.apsnet. REV. Morphology of S.148 KUHN AND GHANNOUM CLIN. Note the areas of black discoloration.org/online/feature /stachybotrys/ with permission. (E) Scanning electron micrograph of mature conidia. chartarum. FIG. (D) Scanning electron micrograph of conidia at the tip of a conidiaphore. (A) Representative section of damaged wallboard. (C) Higher-power view of the same culture as in panel B (100 oil objective). MICROBIOL. Panels D and E are reprinted from Nelson.

...Aflatoxins Aspergillus fumigatus . citrinin. Stachybotrys was found. Other authors have reported anecdotal cases of illness in which S. fumigillin.. laboratory parameters) to support the claim. 150.. 16.... although a number of other species were seen....... nor were there objective measures of illness. The authors implied these mycotoxins were the cause of respiratory and immune problems..Gliotoxin Penicillium cyclopium ..... (267) examined 50 Canadian homes in which the occupants had complaints of respiratory or allergic symptoms for which there was no explanation.. Miller et al. The authors identified mycotoxins including satratoxins G and H (see below) in moldy ceiling tiles. 184... gliotoxin Aspergillus versicolor ... verrucarol Trichoderma viride .. in this study. House dust usually contained “appreciable” amounts of filamentous fungi and yeast. Tuomi et al. as we discuss below..g. versicolor. 79.. (164) reported building-related illness in Florida.. reporting that “exposed” children had a higher prevalence of respiratory symptoms and infection.Fumiclavines. P. viomellein. In fact schools may have lower mean viable mold spore counts than the students’ homes (105). they found S. there was no evidence that Stachybotrys was a causative agent... penicillic acid. but only on surface swabs and not air specimens. decumbens... trichodermol.” sometimes resulting in building closures (367. cyclopiazonic acid Penicillium brevicompactum.. Hodgeson et al... there was in fact no clear evidence (e..Gliotoxin. and got better post renovation (367).. and clearly not the same as the serious illnesses of equine stachybotryotoxicosis and alimentary toxic aleukia described below..... Even when large amounts of fungus are detected.. and presented no physical diagnosis or objective measures... averufin... While authors claim the health effects are similar to past cases of stachybotryotoxicosis.. The researchers did not look for other etiologies. doctor visits. xanthomegnin Stachybotrys chartarum ... 91. Many authors have reported ill effects in relation to Stachybotrys... occupants of only 6 houses had “building-related illnesses... depending on the activity in the room. PR-toxin. chartarum in only one house. ...VOL. Johanning et al. Toxigenic species of mold isolated from indoor air of housesa Species Toxins produced TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 149 Aspergillus flavus ..” the study was neither controlled nor blinded. satratoxin H.Citreoviridin. ABC News online article). viridiol a Adapted from reference 130 with permission of the publisher. and analyzing air and dust for fungus and fungal products in 37 of the homes... Taskinen et al.Patulin. trichoverrins. Alternaria.. versicolorin. citrinin Penicillium spinulosum . 423..... fumigatoxin. fumitrems.. chartarum in only 1 of 19 cellulose agar cultures from building materials. T-2 toxin.Penicillic acid Penicillium expansum. penicillic acid.Kojic acid. 188... (420) examined Finnish buildings with water damage and identified a host of fungal organisms and mycotoxins (satratoxins G and H.... Toxigenic fungi included P...... although the significance of these findings is unclear. chartarum and A... and so it was expected that spores could be found in air.. and A. 157. roquefortin C Penicillium citrinum .. Sudakin (404) examined water-damaged buildings in the Pacific Northwest. In one 22-month study of 48 schools in which there were concerns regarding indoor air quality and health (rhinitis and congestion which improved when the students were away from school). ASSOCIATION OF STACHYBOTRYS SPECIES WITH “SICK BUILDINGS” Because of concerns of mold-induced building-related illness and the particular characteristics of Stachybotrys species. 241.. headache. chartarum and mycotoxins have been isolated from building materials. there has been a great concern regarding exposure of school children in “contaminated schools.increased the indoor air problems of the schools and affected the respiratory health of the children... 424). including surprisingly low incidences of positive skin prick tests. mycophenolic acid.. 318. and antibiotic use. sporidesmin G.. and Aureobasidium) (391). fatigue. 197.. However despite claiming “[exposure]. although........ although at the time of the study.... moisture levels... the claims are questionable. viridicatum...... Norris... 409... mycophenolic acid Penicillium chrysogenum. there has been growing concern about the health of occupants of Stachybotrys-“damaged” buildings (9. Recently.. .... Other evidence suggests that Stachybotrys exposure is not responsible for these building-related episodes.. and the aflatoxin precursor sterigmonisin) in bulk samples. (197) isolated satratoxin H and spirocyclic lactones from water damaged material. However. this was described as symptoms consisting of mucosal irritation... 414.. One of the best studies of building-related illness showed minimal relation to Stachybotrys.” Looking at air exchange rate. as explored below. citrinin. .. such effects are often vague. 410) also reported an increase in asthma in moisture.Spinulosin Penicillium viridicatum ..... citrinin Penicillium fellutanum .. Trichoderma viride.. During parts of the year when windows are open... Examining buildings with building-related illness complaints.. due to occupants’ neurobehavioral and upper respiratory health complaints (there were no objective pulmonary data) and found S. fewer than 50% of affected schools had fungal CFUs higher than outdoor air (72).Sterigmatocystin.. trichodermin... While they concluded the symptom outbreak was likely a result of inhalation of fungal toxins.. 133.. indoor fungi are comparable to outdoor species (Cladosporium... outdoor air spores were negligible and Penicillium and other soil fungi were most important.. the fungus was not detected in any of the above samples.. Other authors have presented similar findings.... The symptoms were purportedly caused by S..... but again there are few objective measurements of illness or clear etiologic links to the fungus (79)... 2003 TABLE 2.. aspercolorin......... poorly described.Brevianamide A... In 11 schools where complaint areas had samples with the same organisms as outdoors..Roridin E. although the relationship between the organisms and toxins was unclear...and mold-affected schools but presented no objective measurements of asthma and very limited immune data. although it is critical to note these reports are often associations rather than proof of causation.. While employees felt better after being relocated. analysis of the 6 “sick” houses did not indicate fungus-related disease.... versicolor.. T-2 toxin.....Citrinin..Brevianamide A. citreoviridin Penicillium corylophilum. and chest tightness that occurred within weeks of moving into the affected building. (409.

Clinical toxicological syndromes caused by ingestion of large amounts of mycotoxins have been well characterized in animals and range from acute mortality to slow growth and reduced reproductive efficiency. the conditions necessary for mycotoxin production are usually very different from those required for growth. 335. a variety of species are identified. A variety of factors affect toxin occurrence (157). In buildings with moisture problems where mycotoxins have been identified. patulin production relates to limiting nitrogen.corn toxicosis.” they proposed that some fungi should be considered unacceptable. while others kill other fungi and microorganisms and thus may represent spillover effects when causing disease in animals (322). but it is important to note that individuals get better with remediation efforts (6. Moriarty. zinc. ergot production relates to phosphate limitation (48). e. These could include maintaining heating. mycotoxicosis has usually been associated with oral consumption of moldy grain (157). CO2. The most notorious and best described of the mycotoxins are the aflatoxins. Despite these problems and an almost complete lack of objective evidence to support guidelines. 157). The disease is rare today due to food hygiene and the lability of the alkaloid toxins. 420). that 150 CFU m 3 is acceptable if there is a mix of benign species. chartarum (34. regularly cleaning the home environment with dust removal. Indeed. are generally effective in controlling contamination and result in “clean” air samples (430). 390. 53. CNN online article. again without substantial evidence. parasiticus toxin production relates to temperature (35). including removing damaged material and spraying affected areas with bleach. It is unlikely that such extreme measures are warranted. controlling humidity. MICROBIOL. These considerations are critical. an outbreak of turkey X . 133). produced under suboptimal growth conditions (48) or in the presence of limited nutrients (161). Aspergillus. FUNGI AND FUNGAL TOXINS Mycotoxins Perhaps the earliest recorded cases of mycotoxicosis date to the Middle Ages with the description of “St. ventilation. In some cases. There are two types of toxicity: C. 329). while C. and A. and poultry hemorrhagic syndrome (76. and remediation goals. other factors such as smoking may be more contributory (84). pathogens and certain toxigenic species such as S. 321. REV. and ergot alkaloids from fungi were identified as toxins in the 18th century (53. Ochratoxin production relates to air exhaustion (69). since the recovery of toxigenic species from any environment does not substantiate the presence of a mycotoxin (mycotoxin production is not a necessary result of fungal growth) (48). 292) to the American Academy of Pediatrics (7a) to government agencies (15). 382). There are at least 21 different mycotoxin classes (71). While Miller et al. and air conditioning (HVAC) systems. for example. moisture. as well as physical location (A.g. even though complete elimination would be untenable. see references 46 and 406. A number of these are plant disease virulence factors. fusiformis causes convulsive ergotism (discussed below). As discussed below. Aflatoxin production by Aspergillus is dependent on concentrations of O2. That ergotism was produced by oral consumption is important. Mycotoxins are probably responsible for a range of acute and chronic effects that cannot be attributed to fungal growth within the host (301) or allergic reactions to foreign proteins (370). Mycotoxins are diverse secondary metabolites produced by fungi growing on a variety of foodstuffs consumed by both animals and humans (Table 2) (76). temperature and humidity control may be adequate (142). broad recommendations have been made concerning indoor mold exposure. and copper. McFarlane. 79. By the 17th century. inspecting and repairing water damage and other sources of contamination. while upright silos favor Fusarium species) (402). including sweet clover poisoning. The same authors stated that it is reasonable to assume there is a problem if a single species predominates with 50 CFU m 3.. 69. 72. fumigatus and A. cornstalk disease. bovine hyperkeratosis. Fusarium tricintum produces a significant amount of T-2 toxin at 15°C but little at higher temperatures (69). The American Association of Pediatrics produced guidelines in the wake of the Cleveland IPH story (7a). and formulating guidelines to standardize the levels of fungal and bacterial contamination. and that there is no problem when up to 300 CFU of Cladosporium or other common phylloplane fungi m 3 is isolated. Anthony’s Fire” or ignis sacer (sacred fire) due to ergotism from Claviceps purpurea (which can also be produced by some species of Penicillium. analysis often fails to show direct links between symptomatic residents and fungal growth (41). 191. Outbreaks of various types of animal mycotoxicosis have occurred worldwide in livestock. flavus grow in trench silos. although perhaps not always (164). Simple methods.) Temperature. it was recognized that moldy rye produced the disease. cleaning carpets. 334. CBS News program). The effects on humans are much less well characterized (Table 3) (76. 367). Nikodemusz et al. moldy. In studies reporting that exposure to home dampness and mold may be a risk factor for respiratory disease. Notably there is no source material to support these assertions. relative humidity. More moderate recommendations (while recognizing that the presence of fungi does not necessarily imply illness) would appear reasonable (240).150 KUHN AND GHANNOUM CLIN. with over 400 individual toxins produced by at least 350 fungi (38. Methods are discussed further below. chartarum. acceptable air contamination limits. They are all complex organic compounds of 200 to 800 kD and are not volatile at ambient temperatures. There have been a number of media reports on the abandonment or destruction of buildings contaminated with S. (For reviews of toxin synthesis. other routes of instillation result in significantly different types and degrees of toxicity. removing visible mold growth. and growth rate all affect fungal mass as well as toxin synthesis. Many toxins are secondary metabolites. reflecting the fact that historically. purpura produces gangrenous ergotism. (292) declared that microbial monitoring of air is important even though the organisms the author found were not pathogens. and links between a particular organism and toxin often cannot be established (420). 192. The sources range from individual authors (267. and Rhizopus) (322. In the early 1960s. The source of ergot affects both the type of alkaloid produced and the clinical syndrome. (267) admit that their “data seriously call into question any attempt to set arbitrary standards for fungal CFU values.

VOL. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR TABLE 3. Myrothecium. and 334. hyperesthesia (hypersensitivity to pain). a unique disease of horses was recognized that was characterized by lip edema. Aflatoxins were subsequently identified as the toxic agent. Fusarium spp. Aspergillus spp. where they show the most potent effects. at least 29 mycotoxins have been identified in commercially available foods or feeds (57). While aflatoxin contaminates many imported goods (from almonds to melon seeds). and route dependent. milk. urine. Most have been classified as type 1 carcinogens (172). these toxins are also produced by Penicillium and Fusarium species (406). Cephalosporium spp. The case of aflatoxin also illustrates the problems of elucidating clinically relevant levels of mycotoxins. rhinitis. and eggs. equine leukomalacia Pediatric neurotoxicity Kodua poisoning Tremors Renal damagec Hepatoxicityc Teratogenicc Tumorsc AIDS AIDS Cervical cancer Cardiac beriberi Pellagra Reye’s syndrome. 16. See Table 4. including humans (102). which was primarily neurological and highly fatal. Data validity is suspect when looking at small quantities. The symptoms often progressed through well-defined stages to pancytopenia. mutogenic. DAS)b Zearalenone Vomitoxin. oral necrosis. gait disturbance. The aflatoxins are toxic. hepatitis. flavus makes aflatoxin B (AFB). A. it becomes a matter of how hard one looks. urinary tract tumors Cancerc Fescuec Mushroom poisoning Immunosuppressionc Akakabi-byo disease Onyalai disease Kashin-Beck disease Esophageal cancer. For many mycotoxins. Stachybotrys Species as Pathogens In the Ukraine in the early 1930s. kwashiorkor Adapted from references 180. Fusarium spp. not humans. and in rare cases of high feed contamination they have been found in meat. Species variability may relate to the ability to form epoxide derivatives in liver microsomes and endoplasmic reticulum. liver injury. and their main target is the liver. causing acute. Fusarium spp. and carcinogenic. and conjunctivitis.000 fowl died. Penicillium Penicillium citrinin Penicillium rubrum Penicillium oxalicum Penicillium expansum Various species Aspergillus. there is a large variation in toxin distribution. superinfections. AFM1 and AFM2 are oxidative metabolic products made after ingestion and appear in milk. stomatitis. others?b Premature thelarchec Anorexiac BEN. teratogenic. while A. Aspergillus parasiticus Fusarium. Aspergillus parasiticus Fusarium spp. neurologic compromise (irritability. with areflexia (loss of sensorimotor reflexes). and feces. in which over 100. F.000 ng/g. stachybotryotoxicosis. Trichoderma spp. and as more sensitive methods are developed. Penicillium viridicatum Aspergillus versicolar Acremonium coenophialum Toxic mushrooms Aspergillus flavus. blindness. Determining actual exposure levels is exceedingly difficult. AFB1 is probably the most potent liver carcinogen for a variety of species. deoxynivalenol Ochratoxin Sterigmatocystin Ergovaline Amatoxins Possible agents Aflatoxin Fusarium metabolites Fusarium metabolites Fusarium metabolites Fumonisins 3-Nitropropionic acid Cyclopiazonic acid Penitrem Citrinin Rubratoxin Secalonic acid D Patulin Unlikely or wrong agents Cyclosporins Gliotoxins Zearalenone Citreoviridin T-2 toxin Aflatoxin a b c Cladosporium purpurea Aspergillus flavus. often fatal. The compounds have been best studied in veterinary practice. disease in England. immunosuppressive. There was also a rare “atypical” or “shocking” form. graminearum Aspergillus ochraceus. hyperirritability. Toxicity is species. more toxins are found. and finally death (133). and blindness). Aspergillus. age. While made primarily by Aspergillus species. Ergotism (gangrenous and convulsive) Aflatoxicosis. Penicillium spp. childhood cirrhosis ATA. Aflatoxin-related disease can occur in outbreaks. Fusarium equiseti Fusarium moniliforme Arthrinium spp. farm animals ingest large quantities in feed (402). Fusarium spp. since aflatoxin is normally found in only very limited portions of a food lot and levels in such samples can range from 0 to 400. 213. parasiticus produces both AFB and AFG. Penicillium Aspergillus. even in known contaminated foodstuffs (334). coagulopathy and hemorrhage. Supportive evidence in animals. was later traced to contaminated peanuts from Brazil (454). for example. Trichoderma. Mycotoxin-related illnesses postulated to affect animals and humansa Toxin Principal fungus Primary disease 151 Probable or definite agents Ergot alkaloids Aflatoxins Trichothecenes (T-2 toxin. liver cancer. Currently. and .

There was no evidence that the fungus itself was a pathogen. pancytopenia. it was soon realized the disease was not limited to horses. Despite the association of Stachybotrys with animal and human disease. Primary disease manifestations appeared on the skin. with dermatitis on the scrotum. and younger animals fared better than older ones (134). 455). the isolates produced the same local and systemic responses (104).” By the late 1940s. MICROBIOL. developed a dermatologic and respiratory syndrome (103. spores stay viable for years to decades. Interested readers should refer to the article by Jong and Davis (200) as well as the recent on-line review by Nelson (B. especially fodder-handlers and others who had close contact with musty straw. the organism is found in soil and strata rich in cellulose (hay.) (133). G. The affected animals had fever. listlessness. these findings were perhaps the first indication that the entity had a toxigenic origin rather than being due to direct tissue infection. Nelson. When applied to the skin of volunteers. In these latter cases. These factors. There are 148 natural trichothecenes alone (147). At most. 1990). 322). Mycotoxins from Stachybotrys The mycotoxins responsible for many of the described effects of Stachybotrys were isolated in the 1940s during the aforementioned Russian equine outbreak and were found to have an empiric formula of C25H34O6 or C26H38O6. and derivatives of others) (68). did not become ill. APSnet. While disinfectants kill conidia and mycelia. 360. 434). with involvement of the entire alimentary tract. It has also appeared in cigarette tobacco (1. 429). 2001. Pathologic examination of tissue from affected animals revealed diffuse hemorrhage and necrosis. less frequently. since there was no zone of demarcation around necrotic foci and since the tissue appeared to be in a “nonreactive state.org/online/feature /stachybotrys). hemp.152 KUHN AND GHANNOUM CLIN. Stachybotrys chartarum: the toxic indoor mold. Subsequently. verrucarin J. and a significant mortality rate. Lesion location suggested that rather than direct contact. fabrics. including dust (satratoxins. 212. chest tightness. jateli (133. The organism can survive a wide temperature range. as well as among nonequine species (134. alternans and S. and conidia retain viability despite passage through the gastrointestinal tract (but are killed in composting and degradation of manure). Close family members without such exposures. roriden E. and fusarenon-X (Fig. While in 1938 this animal disease was associated with Stachybotrys species. Stored Product Prot. 2). and scientists could not transmit infection or disease by injection of tissue from affected animals (104). throat pain. it was nearly a decade before the etiologic organism was identified in contaminated grain as S. oral lesions. straw. etc. In South Africa. stupor. injection of the fungus caused a local response but no systemic invasion (429). verrucarol. producing areal fructifications. At the same time. only dying at temperatures of 60°C. verrucarins. individuals who used straw for fuel or bedding became ill (133). More recently. and. Subsequently. The most potent of these are T-2 toxin. produced mainly by Fusarium species (71). 5th Int.htm). Pulmonary changes consisted of lung congestion and edema (429). grain. animal disease has been seen from Europe to South Africa (150. plant fiber-processing plants. axilla.apsnet. the lesions were due to aerosolization of the offending substances. Associations with Human Disease The possible association of Stachybotrys species with human disease became apparent coincident with the equine epidemics. both in symptoms (dermatologic versus systemic illness) and in the route of exposure (ingested versus aerosolized contact) (7. Drobotko coined the term “stachybotryotoxicosis. In 1837. alternans isolates that were toxic in a rabbit dermal toxicity test. diacetoxyscirpenol (DAS or anguidine). Members of the Stachybotrys genus exist worldwide. Respiratory symptoms were described. which developed the characteristic equine illness. 225. The toxins have been isolated from a variety of substrates. from a strain growing on domestic wallpaper in Prague (75). chartarum (www . with primary effects in dermal areas with abundant moisture and skin-toskin contact. In the wake of the equine outbreak. there were no blood dyscrasias. 115).doctorfungus. cell walls are quite stable. Le Bars. 434. atra are obsolete species names. In areas of enzootic equine disease. there were marked species and age effects on susceptibility: cattle were less affected than horses.org/imageban/synonyms/stachybotrys. alternans var. 104. opportunistic infections. 373. 133). The fungus can survive over winter. and trichoverrols A and B. deoxynivalenol (vomitoxin). bloody rhinitis. Occasionally. 104. consistent with the trichothecene class of compounds (103. similar outbreaks of livestock disease had been reported in the rest of the USSR and Eastern Europe.. and the organism has been renamed S. At least 40 of these are mycotoxins. D. 224. 229. chartarum is dematiaceous and is a member of the Fungi Imperfecti. with subsequent resolution (429). REV. wood pulp. a case of sheep disease was seen in the 1990s after animals consumed heavily contaminated grain cubes (374). and occasional fever. including catarrhal angina.” In retrospect. straw yielded S. from Finland to the South Pacific Islands (133. Some patients suffered erosions on the oral and gingival mucosa (7. and were identified in the United States in the 1940s (442). Lesions progressed from hyperemia to crusting exudates to necrosis. 387. they are all tricyclic sesquiterpenes with a 12. A striking aspect of these observations is their significant difference from animal disease. Working Conf. Pathologic changes in tissue appeared unique. dead roots. P. S. early researchers were unable to fulfill Koch’s postulates with the fungus. 196. 434). However. trichoverrols. While trichothecenes are chemically diverse. cotton. Le Bars and J. 229). combined with their geographic range. S. scientists recognized that the disease was toxin mediated and that exposure to isolated toxin could produce symptoms (133). some of the best described of which are satratoxins F. It was only with the identification and application of Stachybotrys toxins that the nature of the disease process was understood. medial thighs. the hands and other areas. Corda first defined the Stachybotrys genus. nivalenol. book bindery glue. 104) reported finding the fungus on straw and fed it to horses. cough. plant debris. (103. http://www. and H. trichoverrins) and grain (T-2 toxin.13-epoxy-trichothec-9-ene ring (187. humans. Proc. hemorrhage. In the 1940s Drobotko et al. In general. and even workers protected by clothing. 361). Some patients experienced transient leukocytopenia. 429. Sites of action include initiation of . paper. suggest that Stachybotrys species are essentially ubiquitous.

2. DAS. masking the underlying toxicosis (322. and T-2 toxin) and elongation or termination (trichodermin. trichothecolone. protein synthesis (scirpentriol. As a result. and endothelin receptor antagonists (287). many diagnoses were entertained before alimentary toxic aleukia (see below) was correctly linked to fusarial toxins (Table 4) (194). Because of their potency in affecting protein synthesis. phenylspirodrimanes which inhibit complement activation (275). Structures of some representative mycotoxins. cytotoxic. trichodermol. 258). Trichothecenes resist sun- . and cytostatic properties (186) and recently described stachyflin compounds with potent antiviral activity (269). trichothecin. and verrucarol) (187. crotocol. 337). Stachybotrys species can produce spirolactams and spirolactones related to anticomplement components (188). There is also a beneficial trichothecene complex of antibiotics exerting phytotoxic.VOL. 16. verucarin A. cyclosporins (354). 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 153 FIG. 15-acetoxyscirpendiol. they may cause a predilection to other diseases.

429). diarrhea. 234). and poaefusariogenin). and M. sporotrichioides or F. or red mold disease. The illness had a substantial mortality rate. and T-2 toxin produces an ATA-like illness in cats (233. or ammonium hydroxide or gaseous ammonia (28. most potential products are uncharacterized (e.154 KUHN AND GHANNOUM TABLE 4. 188). REV. 183. pig. dermal necrosis. 453). which allows for detoxification with sodium. sterols (sporofusarin. fowl Vomiting. poae: trichothecenes (T-2. cow Human. MICROBIOL. diarrhea. 69. there was pancytopenia accompanied by fatigue. abortion Shock. and diacetoxyscirpenol. despite much work. systemic effects of . and fatty acids (29. Several important points are worth mentioning. and even experienced investigators can obtain different toxin results from identical strains (e. using differing culture media or pH). It occurred in Russia in the early 20th century. poae (194). and Cylindrocarpon (186). 274). First. due to irreversible column gel binding) (188). cyclic movement Skin inflammation Vomiting. 408. 252. Second. M. although it should be noted that other main producers of trichothecenes are Fusarium. and so there have been no recent episodes to study by modern analytical techniques. potassium. and little research has been performed to examine combined toxicity. angina Convulsions. nor does the appearance of a toxin in environmental samples mean that Stachybotrys (or another relevant fungus) is present. heat (up to 120°C). 195. calcium. As noted above the presence of potentially toxigenic strains does not imply the production of toxin (either in the environment from which the organism was isolated. Cephalosporium.) The reasons for the disappearance of ATA are probably multifactorial. and acids. Fungus Alimentary toxic aleukia (ATA) Bean hull toxicosis Dendrodochiotoxicosis Moldy corn toxicosis Red-mold toxicosis Stachybotryotoxicosis “Taumelgetreide” toxicosis a USSR Japan Europe USA Japan Europe USSR (Siberia) Human. horse. S. ATA has not been seen since the last Soviet reports in the late 1940s. Third. horse. 382. at least in part due to opportunistic bacterial infections developing in the later stages of the disease (53. Trichothecene mycotoxicosesa Toxicosis Geographical location Affected species Symptoms CLIN. Initially. and was characterized by several stages. Saito and Tatsuno [353] described four human cases of Akakabi-byo. This has important ramifications for building remediation. UV light. The illness was initially dubbed “septic sore throat” and subsequently called alimentary toxic aleukia (ATA) (7. 452. pig. Koch’s postulates could not be fulfilled during research into the disease’s etiology. however. leukopenia Headaches. which can produce similar symptoms. HT-2. the population affected by ATA also suffered severe nutritional deficiency (252. One-third of family members who ate contaminated grain became ill. morbidity and mortality were much lower (7. stomatitis.. leukopenia. 193–195. which had some similarity to ATA. Where nutrition was good. Toxicity can also vary widely during culture (134). while the clinical picture of ATA is similar to that of equine stachybotryotoxicosis. 253. As in the case of the equine stachybotryotoxicosis. A number of mycotoxins were obtained from laboratory cultures of F. the levels at which these toxins are produced in laboratory cultures have never appeared sufficient to cause such profound toxic effects as have been observed in animals (188). poaefusarin. 336). X-rays. The illness was subsequently attributed to trichothecene mycotoxins in overwintered grain infected with F. the former disease is almost certainly caused by Fusarium rather than Stachybotrys species. The grain had been left in the fields due to the severe conditions prior to and during the war. and neosolaniol). most notably prior to and during World War II. light. nausea. roridum. pig Horse Horse Pig. Trichoderma. Experimentally. 150–152. horse. including improved grain handling and nutrition. While S.. hemorrhage. verrucaria. the exact toxicologic mechanism has not been determined. many of the other compounds also produced toxic effects in cats (195). Subsequently. sporotrichioides and F. sporofusariogenin. skin inflammation. The precise toxic cause of the illness was never fully identified. this was responsible for thousands of deaths. 380. and one-third of those died. chartarum produces several very toxic macrocyclic trichothecenes (32. Verticimonosporum. chills. 274. While the effects of large amounts of orally ingested mycotoxins on animals have been well described. The relevance of these mycotoxins to the observed human illness is still not clear. fusarenone-X. T-2 toxin was commonly produced and may be responsible (69). refusal of feed Vomiting. Analysis of fungus-contaminated grain revealed F. Other fungi capable of synthesizing these compounds include Trichothecium.g.g. there was oral mucosal ulceration and gastroenteritis. two-thirds of Stachybotrys isolates produce stachybotryotoxins. and hypotension. vertigo. nor the laboratory). 369. (In 1970. 273. 253). Levels are also low in environmental samples. vomiting Fusarium sporotrichioides Fusarium solani Dendrochium toxicum Fusarium tricinctum Fusarium graminearum Stachybotrys chartarum Giberella saubinetti Adapted from references 68 and 424. graminanum and mycotoxins including nivalenol. chartarum is the species most closely associated with trichothecene mycotoxicosis. 370). cow Horse Human. Chemical analysis of such samples is difficult due to intrinsic compound properties and secondary metabolite production. Matters are further complicated by the fact that more than one compound is often involved in field outbreaks. The most famous purported case of mass human trichothecene toxicity was in fact due to Fusarium. They are readily destroyed by alkali.

occupational lung disease occurs in many industries. This is especially important given legal claims of permanent lung injury and “lung scarring” (Anonymous. Coincidentally. chartarum. most studies have not done so. so that it is often unclear if fungi are the responsible agents or epiphenomenona. 79. needs intense exposure. E. such as dust and fungal components (314. Conf. As noted above. bronchiectasis. 14. 267.. Conf. Morey. http://www. This illness differs from hypersensitivity pneumonitis (HP) in that it is transient. B. The transient acute upper respiratory symptoms in workers exposed to contaminated materials during the equine Stachybotrys outbreak (312). and mills (133. literature describing connections between indoor air and pulmonary disease is cited above. (197) reported that exposure to toxigenic S.channelcin cinnati. This illness was considered an occupational disease in many professions. and in some cases its mycotoxins. although the documented pulmonary effects of exposure to some fungal species date to the 18th century. Climate. Indoor Air Qual. the upper airways trap particles of 10 to 60 m.00. Although these conditions can be diagnosed by methods ranging from radiology to pulmonary function tests (PFTs) to biopsy. 278). fumigatus. occurs in naive patients. A number of papers have made claims regarding asthma and interstitial and emphysematous lung disease with no data beyond subjective questionnaires. grain elevators. 5th Int. cottonseed oil processing plants. With the dissemination of the concept of toxigenic indoor mold. zearalenone (69). it must be noted that many different conditions can produce essentially the same respiratory symptoms (129). inhalation exposure probably occurs through inhalation of airborne particulates containing mycotoxins. Therefore. and Stachybotrys). Early Soviet literature described a toxicosis associated with inhalation of dust heavily contaminated with spores of a variety of fungi (e. emphysema. A. However. Initial study of the problem came about due to workrelated problems in several areas. Climate.html. Johanning. as well as anecdotal reports (11.VOL.. neutrophils and not lymphocytes are found on brochoalveolar lavage (BAL). Indoor Air Qual. SPECIFIC TOXICITIES Pulmonary Rationale for concerns regarding Stachybotrys. scientific reports (see below) and legal claims (13.com/CDA/ArticleInforma tion/features/BNP_Features_Item/0. 123. New details from mold investigation: news comes too late for former employee. which cannot diagnose many of these conditions (164). 376). Exposure to massive amounts of fungus can cause a significant. Dendrodochium toxicum. Goldberg. although pulmonary disease was never documented beyond subjective complaints. and M. This point will become important below. Thus. However. which was subsequently dubbed respiratory mycotoxicosis or pneumomycotoxicosis (360. Alternaria spores are more than 7 m in diameter. Sixth Int. Possible links between mold and respiratory disease have been recognized for more than a century. 17. objective studies often reveal poor correlation between complaints (on retrospective questionnaires) and actual pathology. As noted above.g. it is doubtful that they frequently reach the lower airways due to size limitations. P. http://www. suggested that this fungus could exert at least minor pulmonary effects. a main concern lies in determining if there is actually disease beyond mild upper airway inflammatory responses and in whether these symptoms are due to fungus as opposed to other contaminants (73. 319). generally in the absence of an infectious agent (73). 2001. For example.20041.snipsmag. 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. 164. 2001. All describe an acute organic dust toxic syndrome or silo unloaders syndrome (also called atypical farmer’s lung or pulmonary mycotoxicosis). and fungal precipitin testing is negative (377). and pulmonary hemosiderosis (73. generally in farmers. Organic toxic dust syndrome. was isolated in building materials and air samples in buildings associated with moisture problems and complaints of SBS-like illnesses (41. Mold spore size depends on the organism. M. chartarum and other atypical fungi was associated with disorders of the respiratory system. Johanning et al. 168. Schiefer. Proc. due to their high molecular weights (71). niger. hypersensitivity pneumonitis. McConnell. 128). relying only on subjective reports instead. Pollution litigation review—August 2001. Proc. when discussing models of stachybotryotoxicosis. and secalonic acid D (112). pulmonary fibrosis. http://www. workers exposed to aerosolized mold or mycotoxins during the equine stachybotryotoxicosis outbreak had a very different constellation of symptoms from animals ingesting affected grain. but transitory. to reactive airways disease to more serious syndromes including alveolitis. S. while particles 2 to 4 m in diameter can reach the alveoli (141).facworld. The episodes described occurred shortly after inhalation of unusually massive amounts . including farming and industry (73. acute lung injury. It is only recently that the idea that Stachybotrys can cause significant disease has risen to national prominence (137). A. including those involving work in binder twine factories. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 155 exposure to inhaled mycotoxins have been much less characterized. The depth of particle penetration is inversely proportional to size. C. hvac industry.html). 1993). 361). 2000. Pollution litigation review—August 2001 online article. including aflatoxin. e. hypersensitivity pneumonitis.3374. and pulmonary fibrosis. 16. who inhaled large quantities of organisms (116. while thermophillic actinomycetes are less than 1 m (141). Awareness of mold problem increasing among homeowners.g. These range from the benign. 423). Within the rubric of subjective complaints subsequently described as “asthma. 443. ChannelCincinnati. and allergic lung disease. H.nsf/doc/pollitrev0801) of mold-induced respiratory complaints have become commonplace. 360). Moreover. 324).com/cin/news/investigations/stories/investigations -20000126-221100. Kingdollar.com/FACworld. some trichothecenes (157). This is because purified mycotoxins are not volatile (370). Anecdotal reports have documented disease. Only a few mycotoxins have been conclusively shown in aerosols. since mycotoxins have been postulated to normally be confined in spores. Kingdollar.” there may be a variety of actual syndromes ranging from asthma to allergic bronchopulmonary aspergillosis. 286. 1990). It is also critical to distinguish conditions which are readily reversible from those which produce permanent damage: most mold-related respiratory diseases in fact appear reversible (72). such as congestion and cough from rhinitis.

allergic pulmonary aspergillosis (the latter usually affecting patients with intrinsic lung disease and bronchiectasis). the study did not document which fungus was responsible or if the results were controlled for confounding factors.g. respiratory distress (sometimes requiring ventilatory support). some findings are worth mentioning. After the outbreak.doh. all patients recovered. 345. ranging from bird proteins to thermophilic actinomycetes (376). although the etiology is unclear and is probably varied (176.156 KUHN AND GHANNOUM CLIN. the differential diagnosis of the condition includes organic dust toxic syndrome. Surprisingly. Other work found increased concentrations of eosinophils. Higher mold IgE levels have been found in individuals exposed to water damaged structures (242. 156. 351. 301. while evidence suggests a larger amount of allergic markers in individuals exposed to water-damaged structures. 37.-D-glucan is widely quoted to cause airways inflammation. While one author claimed that these cases were due to fungal toxins (116). even though allergic asthma is IgE mediated (345). there was nothing to suggest that these responses were more than an acute pneumonitis or near-drowning-type response. These authors apparently did not check for IgE to nonmold allergens. potential fungal antigens are many. HP has been documented after exposure to indoor mold (usually Penicillium species). inhaled toxins. ranging from upper airway inflammation (rhinitis with coincident conjunctivitis) to asthma. Despite claims that building contamination increases asthma symptoms. e. Other authors have failed to show links between atopy and symptoms. While some forms of HP appear to be due to fungi. histopathologic testing showed acute and organizing diffuse alveolar damage or bronchopneumonia (324). including industrial bronchitis. In some cases it appears there is a correlation between SBS and upper airway allergic symptoms. secondary (from chemotherapy. in concentrations high enough that they can later be seen in lung tissue. alveolar and interstitial infiltrates on chest X-ray. 458). 2001. H. Other studies failed to show associations between IgE and disease (164). Occupational lung disease alone consists of a number of subtypes. and Penicillium and Mucor species were identified on the sugarcane (155). since as discussed below. REV. To our knowledge.g. 385. Cleveland infant idiopathic pulmonary hemorrhage out- . Ammann. Another paper reported decreased diffusion capacity in individuals with respiratory symptoms who worked a problem building.. While airborne 1-3. 126. as well as evidence of volatiles from degraded polyvinyl chloride floor coatings. although in some cases prolonged (years) exposure may lead to pulmonary fibrosis and pulmonary hypertension. fatigue. 368). there is limited evidence to support the assertion (132. 42% developed allergic alveolitis. occupational asthma (in which a very small amount of offending agent can cause bronchospasm after airways sensitization. 235).. and pneumoconiosis) and idiopathic pulmonary fibrosis. While an in-depth discussion of this topic is beyond the scope of this review. and HP (73. A small Finnish study reported new cases of asthma in occupants of a water-damaged building. 412). Objective studies have found nasal mucosal hyperreactivity (305). Fusarium. patients were found to have elevated IgE levels.536 strains of fungi [459]). Furthermore. Allergic pulmonary effects of mold have been well described. However. and congestive heart failure (376). and alterations in tear film stability (285). byssinosis (Monday morning fever). and nitric oxide levels in relation to periods of documented exposure (163). niger (286). Is indoor mold contamination a threat to human health? http: //www. although it occurred in a minority of patients. humidifier fever. and leukocytosis. Summertype HP in Japan is probably caused by T. Finally. Nasal lavage of individuals from contaminated buildings show increased tumor necrosis factor alpha. although supporting studies are limited by lack of objective data as well as cocontamination (11 case homes had 3. and in one case five different organisms (116). 436). 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). most animal models of Stachybotrys pulmonary toxicity rely on direct inoculation of organisms into the airway. Jaakkola and Jaakkola (178) found that symptoms were associated with the use of photocopy paper.wa. there is a profound lack of objective data. MICROBIOL. In addition to fungal organisms. Several groups have reported links between Alternaria allergen sensitivity (measured by specific IgE). in animal handlers and crab processors). M. These cases are relatively unusual since lung biopsy alveolar specimens showed fungus. Polyvinyl chloride degradation products have been linked to symptoms by using objective physical measures (444). Of a group of Chinese schoolteachers exposed to moldy sugarcane. fever. with no residual chest X-ray abnormalities or residual deficits (324). In several cases. and myeloperoxidase in the nasal lavage fluid of office workers in damp buildings compared to controls (435. Thus. with one exception noted below. HP is reversible if the patient is removed from exposure to the offending agent. but this is of unclear significance. including A. the etiology of these changes is far from certain (242). and not well identified. Damp buildings had larger amounts of molds and bacteria. radiotherapy.html). of fungus and resulted in cough. 376). Notably. sarcoid).gov/ehp/oehas/mold. Serologic studies for antigens capable of causing hypersensitivity pneumonitis were negative (286). there was not an association with self-reported hay fever or asthma (222). eosinophil cationic protein. Penicillium (324). one of the few studies to employ objective measures of lung function (PFTs with methacholine challenge) failed to show lower respiratory effects (284). granulomatous disease (e. 356). confirmed by Sporobolomyces salmonicolor inhalation provocation tests (381) but simultaneously claimed the illnesses were not immunoglobulin E (IgE) mediated. given there were no changes in other PFTs and it was not certain if the symptoms were related to the building or preexisting conditions (164). There is substantial evidence that the last two illnesses are caused by endotoxin exposure (58. Additionally. cutaneum (10. interleukin-6 (IL-6). and grain dust-induced bronchitis (73). an experiment which allowed workers to have individual control of their ventilation systems actually led to higher concentrations of airborne dust and fungi while producing fewer symptoms (263). This is an important point. 393. but the relationship was not as strong as that between routine indoor allergens and asthma (325). the disease can be caused by dozens of agents. generally in the setting of faulty ventilation systems (2. Researchers have sometimes found an association between building-related symptoms and mold-specific IgE. Most importantly. 355.

and other organisms were identified in three of eight cases (Serratia. there was no evidence of increased illness in other family members. trace amounts of household pesticides were present in case and control homes. and air movement (228). including two strains of Memnoniella echinata (since reclassified as Stachybotrys echinata) (21). (278) described a cluster of 10 infants from the Cleveland area who were diagnosed with IPH after presenting with severe respiratory disturbances requiring intensive care treatment. In the wake of an outbreak of infant pulmonary hemorrhage (60.5 to 1. No other family members in the Cleveland cluster were ill. personal care products. since release of spores is variable and dependent on environmental factors including temperature. which was 9. and Penicillium species were abundant in case infant homes. There were several problems with the study. 4 cases were associated with upper airway obstruction and 1 was associated with probable asphyxiation. Retrospective questionnaires and home surveys appeared to rule out pesticides. inappropriate age matching. if true. race.83 for IPH (risk of disease given a 10-fold increase in fungi). matched analysis failed to demonstrate differences between case and control homes. The latter finding does not reflect previous reports of this disease. Subsequently. First. Finally. birth weight. Details regarding over 100 cases reported nationally are not available (405). 16. or maternal cocaine use as etiologies. including satratoxins G and H. which is inconsistent with the prior Stachybotrys literature. Other fungi capable of producing mycotoxins may have confounded the picture. The same group examined whether fungal exposure was a risk factor for IPH (123). 22% had seizures. The authors concluded that infants with IPH were more likely than controls to live in homes with toxigenic S. gram-negative bacteria and endotoxin levels were not examined. hemolysis. although these events occurred anywhere from days to many months afterward. Other important CDC concerns were that case home sampling was biased. In fact.. because of insufficient evidence. the same group published an overview of the Cleveland investigations. 373. Most importantly. since toxin production is also variable and depends on many factors. which made trichodermol.” Primary criticisms focused on the calculation of the OR for Stachybotrys exposure. water damage was not well defined (making the high OR suspect). 11% had developmental delay or failure to thrive. [it is] not solely because of the purported Stachybotrys/Acute IPH association.g. due to apparent shortcomings of the aforementioned studies. and because hemolysis on case infants’ blood smears might implicate stachybotryotoxicosis (since Stachybotrys toxins may produce hemorrhagic disease and hemolysis in animals) (133. The definition of close relatives with pulmonary hemorrhage (PH) was erroneous. a strong negative disease association was noted with Stachybotrys.16). although toxigenicity was not in fact demonstrated. 65). While mold isolates produced mycotoxins. hypernatremia. and the home of the one child who died had the largest amount of airborne solvents and pesticide residues. exclusion of a house with an imputed mold value also brought down the OR from 5. and respiratory syncytial virus). The CDC stated that. 19% had another infection (including Pneumocystis carinii pneumonia). and griseofulvins (189. trichodermin.8 dropped to 1. birth weight (normal birth weight OR 0. Montana et al. nonsignificant differences existed for gestational and maternal age. Some of the CDC’s concerns (e. chartarum and infant IPH was not proven. Cladosporium. Moreover. Affected infants were found to have significant differences from controls in red blood cell indices. Concerns were strengthened by analysis of another cluster of IPH cases in Chicago.VOL. Moreover. Importantly. The OR of 9. While the Cleveland study did not find an effect of pesticides. 190). The hypothesis arose from previous work on the issue of pulmonary disease from wet building and fungal exposure. and febrile seizure). As later noted by the Centers for Disease Control and Prevention CDC (61–64). Staphylococcus aureus. the CDC published a retraction of its support of the papers’ conclusions (61–64). especially in smokers (129). case houses had more fungi. In 1999. 407). They also reported that “while [it is] advisable to remediate homes of mold for a variety of reasons. The clinical profile of the larger group of cases was heterogeneous.12). In general. Of the affected infants. including 4 with stresses “that do not normally produce respiratory failure” (anesthesia. relative humidity. Additionally. which could in fact affect potential exposure) may be overstated. and 39% of infants needed additional therapy for reactive airway disease. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 157 break. smoking. but no mold-related disease was identified. 50% had symptom recurrence after returning home. Other factors appeared to include “any relative who coughed blood” (OR 33). Epidemiologic investigation using retrospective questionnaires and home examinations concluded that home water damage prior to the clinical event was the main risk factor (OR 16). The case children in Cleveland had significantly decreased levels of serum cholinesterase compared to controls.9). and home smoking (OR 7. but the OR was near 1 for all species but Stachybotrys. water intoxication. chartarum and other fungi. These patients had a very similar presentation. and sampling was performed weeks to months after exposure. All 22 patients available for follow-up bronchoscopy had ongoing hemosiderosis (most 6 months). and serum cholinesterase levels. this could invalidate the studies. in part due to inclusion of one extreme outlier in the case group. there was no difference between case and control-homes in this ability (189). with 37 case infants (including 12 fatalities) reported from 1993 to 1997. as well as Cladosporium species (279). an association between S.9. possibly caused by pesticides in grain stored near children’s sleeping areas (56). light. and there were cases of hemolysis with hemoglobinuria. Close examination of the data also revealed that Stachybotrys was present in a similar number of water-damaged case and control homes. since there are many causes of hemoptysis in adults other than true PH. isolation of organisms may not reflect toxin levels in homes. a prior paper had described a cluster of Greek infants with IPH. the last two factors became nonsignificant after stratification in a model which included home water damage. breastfeeding. the reviewers felt that the diagnoses of . While Aspergillus. as noted above (157). despite seemingly common exposure to fungi. though still within the normal range. and the presence of electric fans. breastfeeding (OR 0. occurring in parallel to the Cleveland cases (59).5 on the CDC reanalysis. case and control infants were significantly different with regard to sex. they also mentioned 138 cases in the United States during the preceding 5 years (122). surface samples of mold cannot reliably predict airborne contamination or individual exposure (323).

The child was older than the other patients (7 years). (131) describe a child with pulmonary hemorrhage (as defined by hemosiderin-laden macrophages) and shock. stachylysin. Knapp et al... only the former animals developed specific IgG. There was no consistent definition of lung disease. the infant was formula fed and exposed to tobacco smoke (302).” However in addition to the model limitations. 120. G. but no Stachybotrys. It is not clear what causal link between the lung disease and fungus existed or whether this was more than a variant of atypical farmer’s lung or an epiphenomenona (350). thymus. which is in fact rarely seen in actual illness. REV. using intranasal installation into the trachea of a high volume of spores of toxin-producing (spirolactones. it is unclear if a single etiology could be responsible. 346). These findings are similar to those of other researchers (342). Subsequent work has shown that alveolar type II cells. and red blood cell microcytosis.. and Penicillium and Alternaria have been associated with animal pulmonary hemorrhage (possibly via rubratoxin) (417).g. Conf. Periconia. Finally. hepatic. Ascospores. In another case of pulmonary hemorrhage related to fungal exposure. cases were inadequate and the source of cases was inconsistent (61. 160. and many “new” diseases have been described in the last 20 years that have probably occurred for considerably longer (e. there were many laboratory abnormalities including endocrine. Sorenson. As noted below. 255. it is questionable if these were of physiologic relevance. illness is presumably toxin mediated. As above.. and satratoxin H) in contaminated wallboard. Pathogenic mechanisms responsible for Stachybotrys-induced lung injury. chartarum (433) from the Cleveland cluster. the presence of spores in pulmonary parenchyma raises concerns about the relevance of the model to actual human and animal disease. but detailed laboratory data and home conditions were not reported. particularly renal. tobacco smoke) results in stress hemorrhage. which caused intra-alveolar. The contention by Dearborn et al. Recently. Subsequent anecdotal cases demonstrate similar problems. is not supported by experimental evidence. bronchiolar. (418) described an infant with laryngospasm and pulmonary hemorrhage during general anesthesia. It is unclear from most studies whether statistical differences observed are physiologically meaningful. since Trichoderma can make trichothecenes (157. including Cladosporium and Stachybotrys species (181. spirolactams. are unclear. Since it is unknown if the illness was a single disease entity.. and toxicity does not correlate well with source location or illness (432). severe inflammation. or intestines. this genus has been linked to pulmonary disease (STHP). nor is there a yeast form. Finally. While the authors found Stachybotrys in areas near where the child slept.e. there was no hemolysis on blood smears. Other toxic mechanisms could be responsible. purified trichothecenes and S. Early studies showed that surfactant production is up-regulated in type II alveolar cells exposed to pollutants (98.g. macrophages. Other animal studies of Stachybotrys pulmonary toxicity suffer similar limitations. Chaetomium. as well as Alternaria. Int. the study lacked proper controls and statistical power. While there were hematological differences between animals exposed to toxic and nontoxic spores.e. 64). a new hemolysin. they did not assay for other compounds. human immunodefi- ciency virus infection). The finding of other species is an important confounder. and myxomycetes. MICROBIOL. While there was no evidence documenting actual exposure (i. roridin E. if it exists. they in fact found more (both by frequency and amount) Aspergillus. Subsequent work (297) using the same model showed intratracheal instillation of toxigenic spores produced interstitial inflammation with hemorrhagic exudate in the alveolar lumen. not via direct infection) (92). Proc. although levels vary markedly across isolates (431). 196. there were a host of laboratory abnormalities. while there were hemosiderin-laden macrophages on BAL. 311). positive serologic tests or organisms on BAL). and surfactant production and composition are affected by exposure to fungal spores and their mycotoxins. The authors attributed these effects to “toxins. Concerns that the clinical syndrome described was not consistent with historic accounts of human and animal illness is of limited relevance: prior descriptions of the disease occurred before modern analytic techniques. Hemolysins and siderophores have been isolated from a number of strains. 1994). and interstitial inflammation with hemorrhagic exudates in the alveolar and bronchial lumen. Penicillium. As discussed below. Home inspection conducted 4 months after the events revealed water damage and fungal growth. and bronchial obliteration with leukocytes associated with Stachybotrys spores. 250. the child was bottle-fed and the parent was a smoker. In addition to anemia. Looking at a variety of in-home sources. W. which upon exposure to stressors (e. 422). which has questionable physiologic relevance. Again. serologic testing is an ineffective marker for exposure even in heavily exposed animals (92) or humans (164. gram-negative rods and Rhodotorula were also present. spleen. a problem typical of the indoor-mold literature. (296) described experimental murine lung mycotoxicosis. was characterized from S. Nikulin et al. (209) and Flappan et al. While they found mycotoxins (including riordin L-2. Furthermore. since toxins and not organisms are the disease-producing agents. Work with animal models has shown effects on surfactant production. For example. most studies used transtracheal instillation of a high volume of spores or toxins. Fungi Bacteria Indoor Air Environ. there has been one report of Stachybotrys being isolated from the lungs of a sick child (114). the authors found many species of fungi including Penicillium and Trichoderma. 249. no histopathological changes were noted in the other normal target organs of trichothecenes. i.158 KUHN AND GHANNOUM CLIN. and Cladosporium. 197. Other fungal species (including Aspergillis and Penicillium) were recovered from the home. While animal models are open to question. Serious problems with these models exist in regard to routes . chartarum extracts can cause hemolysis (95. Potential mechanisms of Stachybotrys-induced lung injury. there were marked differences in immune response between animals exposed via the intraperitoneal and the inhalational route. Tripi et al. who was subsequently found to have prior exposure to Stachybotrys. 419). some do include pulmonary hemorrhage. (92) that inhibition of type IV collagen synthesis in rapidly growing young lungs produces capillary fragility. and renal. 378. Finding organisms on BAL is not a relevant test (Stachybotrys does not germinate in the lungs. moreover it has not been determined whether observed changes are toxic effects or compensatory mechanisms. satratoxins G and H) strains. Some concerns raised by the CDC are of limited validity.

this is based on work involving extensively processed spores. 310). Even if there is a sufficient organism burden. 206).g. The authors concluded that while there may have been a weak effect of exposure to S. VOCs) may exert neurologic effects (208. while statistically significant. convulsions. 16. there were no major immediate pulmonary effects. While intranasal instillation of spores causes them to be flushed into the lungs (296. Unfortunately. which. 297). These lesions were consistent with outbreaks of porcine pulmonary edema. of which the most naturally abundant is fumonisin B1. “atypical” equine Stachybotrys disease. the source of the ergot affects the type of alkaloid produced as well as the symptoms. in chicks it causes convulsions and rigidity (338). 4. even with sophisticated neuropsychological testing. cause equine leukoencephalomalacia (348. This suggests similar changes in physiological parameters reported in some studies discussed in this review may be no more than statistical variation. While some researchers have thought that the spore burden in models parallels cases of human exposure (92).to 5. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 159 and levels of exposure. to date there is no sound evidence linking mycotoxin exposure to serious or permanent lung injury. since Stachybotrys produces spores in a slimy mass that become airborne only when dried (296). In indoor air settings. The estimated exposure level was nearly three times estimated human levels (the satratoxin H level was 100 g/dish). characterized by somnolence. Affected children suffer dystonia. In summary. control mice had changes of tidal volume of 5%. the response to toxigenic spores is different from the response to toxins alone (296). as well as separating out psychiatric and factitious causes. Stachybotrys spores are single-celled ellipsoid structures 5 to 7 by 8 to 12 m in size (144). Spores or fragments probably need to be 1 m in diameter to reach the lower respiratory tract by airborne exposure. Verruculogens and penitrem A may be “tremorgenic mycotoxins. ataxia. it does not reflect human exposure conditions (61–64. There is precedent for concern regarding neurotoxicity. 164. In one of the only studies using a relevant model.VOL. However. and in particular IPH. In more appropriate models. 315). Because the route of administration matters greatly and since intraperitoneal injection has no physiologic correlate. This may explain why effects seen in murine experimental models have not been seen in humans. chartarum has been reported to cause human neurotoxicity.” Thus. tremors. studies of many of these toxins were conducted using intraperitoneal injections (45.” responsible for tremors. and convulsions in animals (392). as evidenced by an earlier outbreak in Ethiopia which produced primarily gangrenous rather than neurologic disease (96. 3-Nitropropionic acid is a secondary metabolite of Arthrinium species. 174. Postulated disease associations that have not been borne out include the neuro- . 312. 406). both for mycotoxins in general and for stachybotryotoxins in particular. Much of this is based on ergotism. Complicating this has been obvious difficulty in detecting subtle neurological changes. Furthermore. the authors point out these findings parallel building studies “in which air contained a low number of colony forming units although the ventilation and air conditioning system were extensively colonized by different types of mold (5). there is clear evidence that exposure to indoor mold may have adverse pulmonary effects. limiting spore release.m-median-diameter particles deposited (90%) in the nose and then went on to the gastrointestinal tract. and Stachybotrys spores are much larger than this. which are of questionable relevance to actual exposure conditions (397). The last major epidemic of ergotism was one of convulsive ergotism in India in 1975 due to C. weakness. Neurologic Exposure to S. spore size in relation to respiratory tract physics must be considered. fusiformis (39). and probably only the latter is physiologically relevant. As noted above. Cyclopiazonic acid produced by Penicillium and Aspergillus may be responsible for Kodua poisoning (from Kodo millet). it is worth noting that in this study. 277. Fumonisin may produce pulmonary disease in pigs. They did not examine long-term effects. which results in the blocking of complex sphingolipid biosynthesis and the accumulation of sphingosine (282). as well as the ability of organisms in “field settings” to actually reach the alveoli. Nonfatal cases may exhibit tabes dorsalis-like features (4). 445). 79. Fumonisins. (445) grew Stachybotrys in an open dish in a closed chamber (to mimic human exposure) and examined acute murine pulmonary toxicity by a bioassay of respiratory parameters. an- imals fed this mycotoxin developed hydrothorax and pulmonary edema (124. In response to the low density of spore formation. 267. has not been proven. even if spores are liberated. and giddiness (221). often from compounds produced during the baking of bread using contaminated grain (322). 404. it is difficult to correlate the number of organisms per cubic meter of room air with concentrations in the nasal passages. 333. coincident nonfungal compounds (e. While aflatoxin is primarily suspected of systemic inhalational toxicity (78. There is also no evidence to support more than mild upper airway allergic effects of SBS and mold exposure. it is unlikely they reach the lower airways due to their size (445). 423). and coma (231). Neurologic or convulsive ergotism is characterized by symptoms including muscle spasms. a link to pulmonary disease beyond transient irritative symptoms. Finally. The substrate was wet. it is more reflective of normal conditions. Other mycotoxins have been implicated in inhalational toxicity. the results are of questionable clinical relevance. seizures. acute inhalation of AFB1 causes tracheobronchial cell destruction in hamsters and guinea pigs (157). the degree of liberation of spores and mycelial particles must be considered if model systems are to be useful. However. which can cause an acute food poisoning known as “mouldy sugarcane poisoning” (230). While there are reasonable concerns regarding Stachybotrys exposure. 301. and there may be basal ganglia lesions (270). 316). While this could have been a major limitation of the study. spore counts as high as those modeled in the above studies are rarely detected. 197. It has been claimed that Stachybotrys spores can reach the distal airways (92). although proof is lacking (11. 266). There may be a link to malnutrition. especially by inducing allergic reactions. In mice studied with monodisperse spheres. 47. At the same time. Wilkins et al. and the effects of cyclopeptides and muscarine from toxic mushrooms (4). chartarum. pulmonary deposition was 1% (340). carpopedal spasm. were neither clinically significant nor due to fungus. This may occur due to their action as competitive inhibitors of sphingosine N-acetyltransferase. and hallucinations (4).

Aflatoxin is transformed in vivo into active components that bind DNA and RNA and impair DNAdependent RNA polymerase. many earlier putative associations (e. Notably. . this would impair the proliferation and differentiation of immune cells and perhaps the synthesis of immunomodulating compounds. but oral administration did not. Immune effects of mycotoxins have been studied extensively in animals but not in humans beyond observational studies (for an excellent review. Gastrointestinal disorders and blood dyscrasias of the “typical form” were not seen. Animal experiments produced pulmonary (361). Proc. This may account for organ and cellular effects noted above and the decreased immunoglobulin synthesis. Other studies reporting neurologic problems after exposure to Stachybotrys or trichothecenes often do not describe significant specific neurologic symptoms (11. C. Richard. no neurologic effects were reported (122. zearalenone have similar effects in some animal models. By blocking RNA and DNA synthesis via inhibition of peptidyltransferase. Effects of aflatoxin are probably directly related to impaired protein synthesis (76). Finally. T-cell delayed-type hypersensitivity responses and graft-versus-host responses are suppressed in chickens (140). salmonellosis. to a lesser extent. thus inhibiting RNA and protein synthesis (138. Trichothecenes. Affected animals developed neurologic problems including areflexia. due to its toxic and immunosuppressive effects and its potential as a biologic weapon (76. deoxyivalenol (vomitoxin). However. There is suppression of mitogen-induced T. and Stachybotrys species can produce a cyclosporin-like immunosuppressive agent capable of increasing skin graft survival in rats (354). Critically. Aflatoxin exerts a variety of cellular and humoral effects. It is important to keep in mind that while some mycotoxins have been recognized to affect the immune system. These compounds are among the most potent small-molecule inhibitors of protein synthesis (243. and intracellular killing by heterophils and monocytes in chickens after ingestion (66. and fowl (76). chartarum. Cyclopiazonic acid and. antibody responses. 1978 Symp. In summary. Finally. in recent cases where S. In theory. 258. 402. Patulin has similar effects (398). experimental stachybotryotoxicosis in animals as well as well-documented human cases do not support the existence of significant neurological sequelae. Hematologic and Immunologic General concerns. chartarum (210). 449). Interact. particularly T2 toxin. 278). see reference 76). In theory. Mycotoxins Anim Production. 421). Thurston. Even in cases of heavy exposure. 1979). including chemokines and immunoglobulins. Akikabi-byo disease (460). 1978 Symp. and J. 265). 423) or do so only in vague terms. Mycotoxins Anim. there could be a common end point of opportunistic infection. K. 312. There may be clinical veterinary correlates with increased frequency of swine salmonellosis (402). and coccidiosis (A. unsupported by objective neurological findings (47. 429). High-dose aflatoxin exposure (0. and complement activity in animal models (240).160 KUHN AND GHANNOUM CLIN. 411). livestock. 267. and stupor. and methionine) are also protective. Increased dietary protein and vitamins (B12. similar to some animal models where aflatoxin has been associated with increased disease susceptibility (329). some studies have shown a neuroprotective role for certain mycotoxins: stachybotrin C and parvosporin from S. despite many reported subjective complaints. Ochratoxin A (OA) has similar effects. almost all affected animals died (133). hyperirritability. although immunosuppression is not among its known significant human toxicities. Aflatoxin. Trichothecenes. vaccination failure. blindness. 1979). hyperesthesia. animal experiments showing pancytopenia after ingestion of S. Pier. and lymph nodes of various laboratory animals. MICROBIOL. 164. especially T-2 toxin. Trichothecenes produced by Stachybotrys and Fusarium species have been extensively studied. Interact. 309). they can produce characteristic radiomimetic lesions in rapidly dividing tissues (220. 197. gliotoxin from Aspergillus as a cause of AIDS [113]) have proven quite erroneous. and perhaps most importantly. 328. 79. chartarum has been implicated in pediatric disease. Proc. Aflatoxin has been the most extensively studied. 227. and possibly gastrointestinal. Other potent trichothecenes include DAS. there is no objective evidence for neurological compromise caused by indoor mold exposure. without neurologic toxicity. effects described are dermatologic (104. respiratory (104. G. but these vary with dose (only higher doses induce lymphopenia) and species (higher effects in mice.g. ATA from Fusarium species. J. R. 404). 259). and fowl cholera. and fusarenon-X. and topical (134) toxicity with some systemic toxicity but no specific neurologic signs. Fungi are the source of immunosuppressive drugs such as cyclosporin. 353.and B-cell blastogenesis in humans (366) and bovines (320). 361). gastrointestinal (210). phagocytosis. induce necrosis and lymphoid depletion in the thymus. T. Such findings have become of increasing concern due to reports of “immune suppression” and increased infections in Stachybotrys-exposed individuals (197). the degree of immune suppression and clinical signs is contingent on the nutritional status and general health of the exposed animal (109. logic changes of Reye’s syndrome (aflatoxin [97]) and pellagra (365). and the African idiopathic thrombocytopenic purpura (ITP)-like syndrome Onyalai disease (341).6 to 10 ppm) suppresses IgG or IgA levels in chickens (140). REV. 261). and there is impaired chemotaxis. as well as cell proliferative and activity responses (36. as well as similar changes in the spleen and lymph nodes of dogs (304). in particular from S. 333. 149. Cyclopiazonic acid causes bursal lymphoid necrosis (101). OA effects on immunoglobulin production and the antibody responses vary with the route of administration: intraperitoneal injection suppressed antibody responses. and good rations reduce residual tissue levels and improve organ function. as shown for trichothecenes in equine stachybotryotoxicosis. Production. as well as antibody responses to Salmonella (44) and sheep red blood cells (411). The presence of diseases and other toxins may affect responses to aflatoxin.. Trichothecenes may affect cytokine production (43. less in cows) (402). Aflatoxin effects on immune organs in animals include thymus and bursa atrophy in fowl (140. L. 372). parvispore stimulate neurite outgrowth (303). Edds. spleen. An atypical or “shocking” form of stachybotryotoxicosis was first recognized in the 1930s and 1940s in the USSR during the equine stachybotryotoxicosis outbreak. Some mycotoxins have the potential to affect hematopoetic cells.

and often in animals with different disease susceptibilities from humans (74. and NK cells were reportedly affected. Pasteurella haemolytica.” (213). whereas AFB1 appears to be the most hepatocarcinogenic compound known for the rat.. except for fumonisin. luteoskyrin. however. and CD4-toCD8 ratios were of borderline significance (P 0. chartarum.. 16. was shown to not be a primate carcinogen. One study (82) claimed that residential fungal contamination affected peripheral lymphocyte counts in children. saccharine.g. only white blood cells. 197. delayed-type hypersensitivity reactions. as well as levels to mite antigens. Almost all studies have been with animals. cat epithelium. The rodent carcinogenicity of saccharine may be due to the high renal concentrating ability of rodents. Despite measurement of multiple immune parameters. As part of these studies. on average be 2 years older. as well as superinducing IL-1 and IL-2.5/1. since most studies have been conducted via various noninhalational routes. intraperitoneal). and Cryptococcus (309). 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 161 Trichothecenes have been associated with decreased resistance to infectious organisms. Most are directly genotoxic (e. the adult mouse is essentially totally resistant to its hepatocarcinogenicity. 219). splenocyte IgA production. have a bedroom humidifier. at most only an association exists. fumonisin. The claims of persistent immunological changes over time are not supported statistically. including volatiles and endotoxins. 364). often cited as proof of carcinogenicity. which had been shown to be a mouse urological carcinogen and was subsequently banned as a food additive. “a problem in extrapolating animal data to humans is the extremely wide range of species susceptibility to AFB1.g. 383). sterigmatocystin. In summary. Candida. zearalenone.3 to 0. For example. indoor fungus) there are no data to support this assertion. close examination of the data leads to questions about these conclusions: in addition to exposure to water damage and apparent mold. due to the probable carcinogenic effects of aflatoxin. including citrinin. The studies are further weakened by the fact that they did not test the levels or effects of other likely contaminants.VOL. and examination of the CD4-to-CD8 ratios for case versus control subjects revealed no significant differences (1. and dog dander. must be interpreted with extreme caution in regard to humans. Listeria.” although multiple other species were isolated).9 versus 1. even these data are questionable. Fiftythree workers were reportedly exposed to fungal bioaerosols (“particularly S. nor was diet examined. little is known about the effects of airborne exposure (43). from organs. to date there is no good evidence of significant immunological compromise from inhaled fungal toxins. As Corrier (76) points out. A subsequent study by the same author of 147 children and adults seen in an environmental health specialty clinic failed to show significant differences in immune parameters (198). and even T-2 toxin (119. environments were not checked for endotoxins or volatile organic compounds. 198).5 for all numbers). The latter can increase the number of antibody-producing cells in the spleen. On closer examination. pets. Malignancy General concerns.566 versus 7.0. which disrupts signal transduction (438). these observational studies have not found the same hematopoietic effects (197). Immunological studies of stachybotryotoxin effects in humans are limited to observational studies (82. and penicillic acid). CD3 cells. While medical complaints were higher in ex- posed individuals than in controls. This wide species variation in susceptibility to mutogenic effects (158) extends to mycotoxins. many model carcinogens were found to be tumorogenic in rodents. and low-risk patients had values more different from controls than did high-risk patients. and blastogenesis of B and T cells. affected children were more likely to be in the presence of household smoking. it is unknown if this was a result of immunosuppression or breakdown of mucosal barriers (150). since the statistically significant variations of these numbers (e. which is much lower in primates. While there are over 100 toxigenic fungi and more than 300 mycotoxins (268. Often immune stimulation or suppression is related to the amount of toxin. physical examinations. In contrast to early reports of severe leukopenia and radiomimetic effects in ATA-like syndromes after trichothecene ingestion in Eastern Europe (182. Differences of CD45RO.05). however. As in the case of neurologic complaints. or routine laboratory tests. CD29 (B cell). One report of an outbreak of stachybotryotoxicosis in sheep reported frequent isolation of a normally commensal organism. 312. For instance. and there was no documentation of actual infection beyond a retrospective questionnaire.6/0. including Salmonella.04 to 0.365 cells/ml) lack clinical significance. and some Penicillium toxins (citrinin. suggesting that nonmycotoxin sources may have had a significant impact on the findings. Some mycotoxins can enhance immune function. often using single high-dose purified toxins.. Interested readers are referred to the recent review by Bondy and Pestka (43). . herpes simplex virus. Despite claims in the latter paper that pediatric cases with preexisting immunodeficiency are at increased risk from “unnecessary” fungal exposure (i. with standard deviations of 0. From 1961 to 1997.e. reporting that contaminated homes were associated with more CD45RO (antigen experienced T-cells) and a reduced CD4/CD8 ratio and thus “that residential fungal contamination leads to chronic stimulation of children’s’ lymphocytes.g. 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. only one (urethane) was found to cause cancer in primates (375). and less likely to have a current cold reported by the parent. The study most widely cited as proving immune effects of Stachybotrys exposure in fact does not prove this (197). be male. In addition. 363. 145.290 and CD3 counts of 7. Results of animal studies. ochratoxin. The potential of mycotoxins to act as carcinogens is of concern. 343). white blood cell counts of 6. Mycobacterium tuberculosis. by nonnatural routes of administration (e. Children from contaminated homes had higher total IgE levels. only two (aflatoxin and sterigmatocystin) have been shown to cause tumors in primate experiments (375).. there were no objective measurements of physical complaints.” However. and higher dust mite antigen concentrations. patulin. AFB-DNA adducts). patulin. Studies with other animals have implicated the following as mutogenic: aflatoxin.060 versus 6. as well as recent legal claims that patients exposed to mycotoxins may need long-term cancer monitoring (331).

and high levels of OA are found in human blood (428). chronic low-level exposure produces cancer. E. P. China and areas of southern Africa have the highest rates of esophageal cancer. Similarly. 322. and kidneys (301). while potentially tumorogenic. and breast milk. has been established to date” for human HCC. 1976). Olsen et al. since lung cancer and pulmonary fibrosis are unrelated illnesses. While patulin frequently contaminates apple juice (P. MICROBIOL. 462).. including one German study where the toxin was reported in 56% of randomly collected blood samples (33). since serum hepatitis B surface antigen (HBsAg) is a key risk marker (439. Other mycotoxins have been implicated as carcinogens. possibly carcinogenic (172). 446). Patulin. There may be modulation of damage by nutrients. Hayes et al.. The findings may indicate that aflatoxins are secondary findings in chronic lung disease. and epidemiological investigations have shown increased aflatoxin ingestion correlates with increased risk (179. Levels of these adducts may reflect risk for disease development (438). Other data indicate that urine DNA adducts and serum albumen adducts reflect the amount of hepatic genotoxic damage. and mycotoxins (especially fumonisin B1 from F. and a p53 G3T mutation may serve as marker of aflatoxin exposure (165. but the assertion has not been borne out due to the clear association of this malignancy with human papillomavirus (125). 293. produced mainly by Fusarium graminearum. viridicatum. Zearalenone. there are high foodstuff contamination rates. which may explain its absence from processed foods. There may be a link between mycotoxins and esophageal carcinoma (334). 172. rats are very sensitive while mice are resistant. This mutation may be situationally specific. Other mycotoxins such as sterigmatocystin may play a role (438). Ki-ras. There is limited evidence regarding carcinogenicity of inhaled aflatoxins. Mechanisms of aflatoxin carcinogenesis are unclear but probably involve tumor promotion or progression. REV. OA can form DNA adducts. the chemical is unstable in the presence of sulfhydryl groups. They do not cause murine tumors when administered orally. (306) showed a two. Because of theoretical protective effects of dietary supplements. AFB1 is produced by Aspergillus flavus and A. 448). It causes increased cancer rates in mice but not rats (173). cord blood (where levels can be very high). 167. However. While it is acutely lethal in large amounts. Penicillium species produce patulin and penicillic acid. 247. moniliforme) are major contaminants found in corn consumed by patients with esophageal cancer (67. 406). particularly hepatocellular carcinoma (HCC) in many animal species (52. 463). 451). 399). 438). In these areas. antioxidants. As noted. peanuts.g. G. Aflatoxin can be detected in the blood of pregnant women. in the latter species it may exert protective effects (159). as well as mutations at the p53 suppressor gene target (169. in fact.to threefold increase in the risk of HCC and biliary cancer. and the kidney may be the worst affected organ (438). 384). The link to human disease is much more tenuous. drugs. most of these studies were seriously flawed. HCC is one of the leading causes of cancer mortality in Asia and Africa. and N-ras) by aflatoxin. i. 223. 93. although such a high prevalence appears suspect. but aflatoxin was detected not only in the two patients with lung cancer but also in three with pulmonary fibrosis (107).e. the relative risk for HCC is as high as 59 if both urinary aflatoxins and positive HBsAg status are present (339. Significant concerns have been raised as a result of its estrogenic activity and thus its potential for stimulating estrogen-sensitive tumors (25. catalyzed by glutathione S-transferase mYc (158). due to efficient conjugation of aflatoxin with glutathione. illustrates the importance of the route of administration and coincident environmental factors (334). Deger. c-Ha-ras. Other mycotoxins. 282). Selected fumonisins are hepatocarcinogenic in rats (246) and have been designated group 2b carcinogens. corn is a main staple. 326. 179. There have been increasing reports of OA in human tissue samples. (154) found an increased rate of overall cancer and pulmonary cancer mortality in exposed peanut workers but failed to include smoking as a factor and did not find HCC. although Pohland (334) has cautioned that “one must still conclude that only a debatable association. Ann. bioactivation of aflatoxin into carcinogenic metabolites shows significant species differences (251). and there is no direct proof in humans. and feces. 85:204–205. Inhaled aflatoxin causes tracheobronchial cell destruction in hamsters and guinea pigs (157). Among rodents. It is thought to be the most potent liver carcinogen for a variety of species including humans (102. there have been trials of chemoprotectants like ethoxyquin and oltipraz (204. which can cause tumors when subcutaneously injected into mice. Med. and other Penicillium species (216). While OA has been listed as a mammalian carcinogen (426. 334). AFM1 and AFM2 (oxidative metabolic products) appear in milk. Coinfection with hepatitis B virus is important. intestines. parasiticus (12). Aflatoxin. Ochratoxins are structurally related metabolites from A. herbs. 322). Letter. e. Intern. which has not been postulated to be caused by this compound. the data come from a small number of rodent strains. OA is the only one of major carcinogenic significance (216. is among the most widely distributed of the fusarial mycotoxins (217) and is found in 6 to 28% of corn samples destined for human consumption (334). expansum is a main cause of apple rot). but the aflatoxin concentrations were historical and were not measured. there is great species variability in susceptibility to aflatoxin. Nonetheless. and malnutrition (108. 395. Aflatoxin and p53 mutations have been tightly epidemiologically linked in China and Southern Africa. since AFB1-induced monkey tumors are associated with a different mutation (136). There is evidence of activation of proto-oncogenes (c-myc. 170. urine. Anecdotal studies reported premature cancer in three exposed laboratory workers (106. 389.162 KUHN AND GHANNOUM CLIN. It was once postulated to cause cervical cancer (248). There is strong evidence suggesting cofactors affect carcinogenisis. Aflatoxin can be aerosolized and has been detected in air near farm sources (49. In regions where Balkan endemic nephropathy (BEN) is endemic. 349. That these chemicals are systemically absorbed is supported by data showing a high correlation between exposure and urinary excretion of AFB1N7-Gua (146. 438). and not a direct causal relationship. 464). The primary mode of human exposure is the consumption of contaminated foodstuffs. 456. rats receiving intratracheal doses develop cancer of the liver. some studies have found many cocontami- . While epidemiological and anecdotal studies have reported associations between in- haled mycotoxin and cancer. Aflatoxin is the best characterized of the potential human mycotoxin carcinogens (127. ochraceus and related species. 438). 438).

while others have noted only fetal retardation in rats given oral aflatoxin (54). as well as uterohemorrhagic effects. there are only conflicting reports in animal studies (402). although effects of the latter have been reported more frequently. Ergosterol peroxide and acetoxyscirpenediol from Paecilomyces tenuipes. ochraceus was subsequently isolated from wheat to which the individual had been exposed (100). but study of the isolates was limited to animal feeding experiments (280). not direct proof. New fungal compounds with similar anti-neoplastic traits are constantly being found (166). As shown above. 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 (148). and mild smooth muscle contraction (290). There are conflicting reports of their ability to induce abortions. decreased litter size. rubrum can cause liver disease and disseminated hemorrhage in animals (51. a silkworm larva parasite. T-2 toxin inhibits the proliferation of neoplastic cell lines. coffee. immunosuppressive.” (402). even though zearalenone has been found in the blood of children exposed to contaminated food (352). and there may be synergistic hepatotoxic effects (447). they have not been validated.. it is part of the secalonic acid family and is teratogenic in mice (112). and fetal malformations (69). electrolyte disturbances. there has been no evidence linking Stachybotrys toxins to renal disease. some trichothecenes are potentially carcinogenic.g. In the field. oxalicum. but it was found along with other Fusarium mycotoxins. Hepatobiliary effects have not been reported for Stachybotrys toxins. Produced by P. 2003 TOXIGENIC EFFECTS OF STACHYBOTRYS IN INDOOR AIR 163 nants (67) or present only equivocal data (461). “many reports in the literature of ill effects are very questionable due to possible involvement of other mycotoxins. vomiting. Ochratoxin A is the most common and most toxic chemical of its class: it is nephrotoxic.VOL. and they may cause stillbirths and agalactia (299. To date. The toxin can cause glomerulonephrosis and may cause cholinergic responses such as bronchial constriction. none of the observations extend to humans. The resultant liver injury can be severe. Ochratoxin belongs to a group of secondary metabolites of Aspergillus and Penicillium. Citrinin is produced by several Penicillium species and is sometimes isolated from contaminated rice (402). While T-2 and DAS in feed do not cause abortion. flavus. however. as well as urinary tract malignancies noted above. Ergotoxins may prevent embryo implantation in mice (244. 334. 422). human myeloid leukemia K562 cells. There is currently no sound evidence linking Stachybotrys-produced mycotoxins to human malignancy or evidence to support claims that individuals exposed to Stachybotrys are at long-term risk of cancer or require cancer surveillance (438). 447).. 441). While there have been claims that aflatoxin causes other diseases such as Reye’s syndrome (97) and neonatal jaundice (322). . preconception exposure may cause infertility and reduced litter size (271. hepatoma. found on cereals. Secalonic acid D has been found in dust and aerosols. Citrinin may exert more renal toxicity than OA. including non-anion gap acidosis. and an OAproducing strain of A. although on close inspection the data provide only disease association. Aflatoxin is of special concern. including mouse melanoma B16 cells. carcinogenic. Due to abundant circumstantial evidence. rubratoxins are often mixed with aflatoxin due to cogrowth of A. Citrinin and OA may have a synergistic interaction (55). 386). in rats (211. and aminoaciduria (209. shock). were secondary to severe illness (e. and teratogenic in all animals tested (451). It is unclear if these findings are part of a mycotoxin syndrome. 218). Zearalenone has also been implicated in livestock “scabby grain toxicosis. Hepatic In addition to HCC. Various investigators have found uteroplacental hemorrhage and fetal death in rats and mice given intraperitoneal aflatoxin (99. aflatoxin in significant doses can cause acute liver injury. Endocrine Endocrine toxicity has been seen primarily with zearalenone (F-2 toxin) (322). 245). OA from Aspergillus and Penicillium has been implicated in porcine nephropathy and BEN (68). A nephrotoxic strain of Penicillium was isolated from air samples in areas where BEN occurs. Renal Diverse renal and urological toxicities have been reported in humans due to OA. and drowsiness (40. 400). or represent an underlying disease process. . T-2 toxins and DAS have been reported to cause limb and tail abnormalities (271). Zearalenone has been found in dust and aerosols and may cause infertility and fetal malformations in domestic animals through estrogenic effects discussed above (69. Finally. Acute aflatoxicosis generally occurs in outbreaks due to contaminated foodstuffs. Such effects are well characterized in swine (the most sensitive animals) and include primary effects (e. with a 10 to 60% case fatality rate (322). There has been one case of apparent inhalational nephrotoxicity. 302). colorectal cell lines. since it is teratogenic in nearly all animals (451). Such data must be interpreted with caution. 211. There have been no reports of Stachybotrys-related endocrine toxicity. 16.” characterized by nausea. vasodilation. Pregnancy A number of mycotoxins affect pregnancy in experimental animals. OA may cause fetal death. The compound is produced by several Fusarium species under very particular growth conditions (402) and has estrogenic effects in animals.g. Aflatoxin has been detected in the blood of pregnant women. Similar effects have not been demonstrated in humans. Some mycotoxins are antineoplastic agents. and human cervical carcinoma (HeLa) cells (201). As pointed out by Stuart and Bedel. several of the papers postulating a link between infant IPH and Stachybotrys have reported mild renal abnormalities. vulval hyperemia) as well as infertility. Rubratoxins from T. and foods of animal origin (322). and Chinese entomopathogenic fungi are more potent than cisplatin against human gastric tumor. bread. To date. and murine sarcoma (288). 272). .

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