Damp Indoor Spaces and Health (2004) / Chapter Skim
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4 Toxic Effects of Fungi and Bacteria
4 Toxic Effects of Fungi and Bacteria
Pages 125-182
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From page 125... ...
It first discusses the bioavailability of the toxic components of fungi and bacteria and the routes of exposure to them and then summarizes the results of research on various toxic effects -- respiratory, immunotoxic, neurotoxic, sensory, dermal, and carcinogenic -- seen in studies of microbial contaminants found indoors. It does not address possible toxic effects of nonmicrobial chemicals released under damp conditions by building components, furniture, and other items in buildings; chemical releases from such materials are discussed in Chapter 2.
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From page 126... ...
Animal studies are also useful for generating hypotheses that can be tested through studies of human health outcomes in controlled exposures, clinical studies, or epidemiologic investigations, and they are useful for risk assessment that informs regulatory and policy decisions. BIOAVAILABILITY AND ROUTE OF EXPOSURE Issues That Affect Bioavailability Some molds found in damp indoor spaces can produce mycotoxins.
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From page 127... ...
Macrocyclic trichothecenes (having carbon Stachybotrys, Myrothecium, others Sorensen, 1993; Jarvis, 1991 chain between C-4 and 15 in ester or ether linkage, for example, satratoxins G, H; verrucarins B, J; trichoverrins A, B) Substituted furans, for example, citreoviridin Penicillium citreoviride Nishie et al., 1988 Epipolythiodioxopiperazines, for example, At least six species of Aspergillus, Waring and Beaver, 1996 gliotoxin Penicillium Lactones, lactams, for example, patulin, Penicillium, Stachybotrys Jarvis et al., 1995, 1998 stachybotrylactones, stachybotrylactams Estrogenic compounds, for example, Many species of Fusarium Betina, 1989; Kuiper 127 zearalenone Goodman et al., 1987
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From page 128... ...
Some molds (such as Stachybotrys chartarum and Memnoniella echinata) that do not spread their spores through aerosol dispersion are wet
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From page 129... ...
0.5 40 0.4 30 0.3 20 0.2 0.1 10 0 0 Arthirinium Aspergillus Penicillium Cladosporium Fusarium Paecilomyces Aureobasidium Curvularia Memnoniella Botrytis Stachybotrys Ulocladium Pithomyces Alternaria Bipolaris Dreschlera Epicoccum Oidium Peronospora Stemphyllium Genus FIGURE 4-1 Spore-deposition coefficients of mold genera in indoor environments. SOURCE: Miller et al., 2001.
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From page 130... ...
. Such bacteria as Streptomyces californicus isolated from damp indoor spaces are about 1 µm in diameter and can reach the lower airways and alveoli when inhaled (Jussila et al., 2001)
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From page 131... ...
(1986) , using head-only exposures, compared the acute inhalation toxicity of T-2 toxin in guinea pigs, which tend to be sensitive to respiratory irritants, with effects of subcutaneous administration.
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From page 132... ...
Deposition dose was measured by extraction of toxin from sacrificed animals, and LD50 of 0.05 and 0.4 mg/kg, respectively, were estimated. In that study, inhalation exposure to T-2 was about 20 times as toxic in rats and twice as toxic in guinea pigs as in studies of intraperitoneally administered T-2 toxin (LD50, 1 mg/kg in the rat; and 1–2 mg/kg in the guinea pig.
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From page 133... ...
TOXIC EFFECTS OF INDOOR MOLDS AND BACTERIA Exposure to various mold products -- including volatile and semivolatile organic compounds and mycotoxins -- and components of and substances produced by bacteria that grow in damp environments has been implicated in a variety of biologic and health effects. This section discusses irritation and inflammation of mucous membranes, respiratory effects, immunotoxicity, neurotoxicity, sensory irritation (irritation of nerve endings of the common chemical sense)
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From page 134... ...
. A number of in vitro, animal, and human studies that have investigated the irritation and inflammation responses to exposure to microorganisms and molds commonly found in damp indoor spaces are discussed below.
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From page 135... ...
(2002) tested the effects of three molds (Stachybotrys chartarum, Aspergillus versicolor, and Penicillium spinulosum)
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From page 136... ...
(2001) compared the mouse inflammatory response to a single intratracheal instillation of one of three doses of Streptomyces californicus spore isolates from the indoor air of moldy buildings with the response to 50 µg of lipopolysaccharide (LPS)
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From page 137... ...
TABLE 4-2 Summary of Inflammatory and Toxic Responses to Two Bacteria and Two Fungi in Mice TNFα IL-6 Response Response (Lowest Dose (Lowest Dose Increased Albumin/ to Cause to Cause iNOS-NO Inflammatory LDH Microorganism Increase) Increase)
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From page 138... ...
Response Cells in BALF Response Reference (28 days) Aspergillus Rapid; peaked Massive at NA Dose-dependent Slower Jussila et al., versicolor after 24 h at 7- 1 × 10 8 spores increase starting response; 2002b fold increase (1 × 106 at 1 × 106 spores acute (1 × 10 6 spores)
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From page 139... ...
atra had much milder inflammatory responses, and no necrotic changes were seen. It is interesting that in this study, in which exposure was to the spores 1Toxicity was characterized as a function of the amount of crude methanol-extracted solid needed to cause 50% inhibition of growth of feline fetal lung cells.
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From page 140... ...
(1998) examined the effect of Stachybotrys chartarum conidia and isosatratoxin-F, compared to the negative control fungus Cladosporium cladosporioides, on surfactant production in cultures of undifferentiated fetal type II alveolar cells from rabbit lung, and their effects following intratracheal instillation in mice.
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From page 141... ...
They observed severe inflammatory changes and interstitial inflammation with hemorrhagic exudate. Exposed animals lost 10% of their body weight within 24 h.
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From page 142... ...
chartarum spores -- 4–8 × 105 spores/g of body weight -- led to macroscopically detected hemorrhage that was frequently fatal; 73% and 83% of animals treated with 4 × 105 and 8 × 105 spores/g, respectively, died; the LD50 was 2.7 × 105 spores/g. Conidia were present in the alveoli and distal airways of a sample of 75 treated rat pups; the number of spores was greatest 4 days after treatment, at which time they were localized in the macrophages.
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From page 143... ...
chartarum spores/mL saline toxin at ≥ 35 ng/kg of body weight, mice treated with 50 mL of 1.4 × 106 Cladosporium cladosporioides spores/mL saline, and mice that received 50 mL of saline solution. Treatment with fungal spores of either species resulted in granuloma formation at the sites of spore impaction, but some lung tissue treated with S
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From page 144... ...
The toxin was observed predominantly in alveolar macrophages, but it was also found in alveolar type II cells; this finding supported other studies that demonstrated that these cells are sensitive to S chartarum spores, isosatratoxin, and satratoxin G exposure, all of which affect surfactant production and composition in BALF (Mason et al., 1998, 2001; Sumarah et al., 1999)
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From page 145... ...
chartarum strains (30 spores/g of body weight) still precipitated responses that were significantly higher than those associated with C
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Jarvis and colleagues (1998) examined samples of Stachybotrys chartarum (16 isolates)
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From page 147... ...
chartarum isolated from eight case and eight control homes from the Cleveland outbreak and 12 strains from diverse geographic locations other than Cleveland. The goal of their study was to determine whether the effects of strains from the Cleveland case homes were different from those of strains from control homes and strains isolated elsewhere.
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From page 148... ...
chartarum showed some toxicity, as measured by inhibition of protein synthesis. Five of the Cleveland strains and two of the non-Cleveland strains were highly toxic, with effects seen above 90 µg of T-2 toxin equivalents per gram wet weight of conidia; one Cleveland strain and three non-Cleveland strains had intermediate toxicity; and the 17 other strains were consistently less toxic than 20 µg of T-2 toxin equivalents per gram wet weight of conidia.
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From page 149... ...
were isolated. Clear variations in cytotoxicity were observed when two additional human cell lines were used: Chang liver cells and Detroit 98 normal human sternal bone marrow cells.
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Interpretation of data regarding immunologic end points is extremely difficult, but many mycotoxins have been found to affect alveolar macrophages in in vitro studies. Some of those studies are summarized here.
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From page 151... ...
In a second experiment, alveolar macrophage phagocytosis was measured 2, 4, 7, and 13 days after exposure; a single dose of AFB1 aerosol suppressed alveolar macrophage phagocytosis for nearly 2 weeks. In a third experiment, 250-µL suspensions of 50 and 150 µg of crystalline AFB1 were instilled, and alveolar macrophage phagocytosis was assessed 1, 3, and 7 days after exposure by measuring the capacity of alveolar macrophages to produce TNFα elsewhere after LPS stimulation.
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From page 152... ...
depletion, inhibits protein synthesis
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From page 153... ...
decrease IgA impairs MP activity Trichothecenes Stachybotrys T-2 toxin: 0.1 µg/kg Inhibits protein synthesis, Immunosuppression, chartarum; oral in monkeys: severe inhibits peptidyl immune modulating, Trichoderma immunosuppression synthesis, causes decrease in host viride lymphoid necrosis, causes resistance to infection Stachybotrytoxin: LD50 dysregulation of IgA 0.1 mg/kg ip in mice production Cyclosporin A Stachybotrys IC50 = 26.8 ng/mL Inhibits lymphocyte Immunosuppression (CsA) chartarum, proliferation, IL-2 and Streptomyces interferon production, sutubaensis protein folding Zearalenone Fusarium spp.
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From page 154... ...
Neither histologic nor inflammatory alterations occurred as a result of inhalation or intratracheal instillation of AFB1. Those experiments indicate that suppression of alveolar macrophages could suppress the clearance of particles from the lung, the killing of bacteria, the suppression of tumor cells, and the modulation of inflammatory and immune processes, both through suppression of phagocytosis and through the inhibition of TNFα.
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From page 155... ...
After 1 month, alveolar macrophages increased in number and became foamy macrophages as they ingested and digested mold spores. The macrophages expressed IL-1, IgA antigens, and intercellular adhesion molecules intensely bound to lymphocytes.
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From page 156... ...
tested the effect of a mixture of aflatoxin (AFB1, AFB2, AFG1, and AFG2) exposures on phagocytosis of Aspergillus fumigatus spores by rabbit alveolar macrophages.
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From page 157... ...
Results were similar to those for patulin in the earlier study, except that patulin is slightly more toxic then penicillic acid. Neurotoxic Effects Occupants of damp and moldy buildings have sometimes reported central nervous system symptoms -- such as fatigue, headache, memory loss, depression, and mood swings -- that they attribute to the indoor environment.
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From page 158... ...
158 DAMP INDOOR SPACES AND HEALTH TABLE 4-4 Neurotoxic Mycotoxins and Effects Mycotoxin Producing Molds Potency Penitrem A Penicillium cyclopium, 250 µg/kg ip in mice: Penicillium tremors, LD 50 = 1.05 verruculosum, mg/kg; 24–25 µg/kg Penicillium crustosum orally in sheep: lethal; 2.2–4.4 µg/kg iv: tremors Penitrem E Penicillium crustosum 2.25 mg/kg ip in mice: tremors Aflatrem Aspergillus flavus 0.5 mg/kg ip in mice: tremors Roquefortine Penicillium commune, 0.1 potency of Penicillium palitans, penitrem A Penicillium crustosum Verruculogen Penicillium 3.0–4.0 µg/kg oral in verruculosum Peyronel sheep: tremors; 13.3 µg/kg oral: lethal; LD50 = 2.4 mg/kg ip Penicillium ED50 = 0.39 simplicissimum mg/kg ip in mice Penicillium crustosum Aspergillus caespitosus Verrucosidin Penicillium 4 mg/kg ip in mice verruculosum var. cyclopium Fumitrem B Aspergillus fumigatus 0.1 potency of Verrucologen Cyclopiazonic Penicillium cyclopium, 250 µg/kg ip in mice: acid Aspergillus flavus, tremors; 2.5 mg/kg: Penicillium crustosum clonic convulsions, death
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From page 159... ...
in interneurons of anterior horn of spinal cord Inhibits Hyper reactivity to Selala et al., 1989; neurotransmitter auditory and ºtactile Wilson et al., 1968 release (GABA) in stimuli, severe interneurons of whole-body tremors anterior horn of spinal cord Motor dysfunction in Norris et al., 1980; Peterson mice, convulsions and Penny, 1982; Selala et al., 1989 Tremors Fayos et al., 1974; Peterson et al., 1982 Paralysis Hodge et al., 1988 Peterson and Penny, 1982 Selala et al., 1989; Wilson et al., 1968 (continued on next page)
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From page 160... ...
Stachybotrys chartarum, Trichoderma viride NOTE: Abbreviations: DON, deoxynivalenol; ED50, effective dose50, amount required to produce specified effect in 50% of population; GABA, gamma-aminobutyric acid; IC50, inhibitory concentration50, concentration at which 50% of population shows immune change; Neurotoxic mycotoxins tend to fall into three general classes: tremorgenic toxins, paralytic toxins, and toxins that interfere with neurotransmitters or receptors either centrally or at the target organ. Many of the toxins are very potent and have immediate effects on animals exposed to a single dose by various routes.
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From page 161... ...
, Bruinick and Sidler, 1997; Phe, inhibits sensitive period day 10 of Miki et al., 1994 protein synthesis, gestation affects neural cell differentiation, neuritic Lesions of Chang et al., 1993; astrocytes Jarvis et al., 1995 Inhibits protein Central nervous system or Rotter et al., 1996 synthesis, gastrointestinal effects, increases probably mediated through serotonin vagal receptors because serotonin affects feeding behavior and emesis ip, intraperitoneal injection; iv, intravenous injection; LD50, lethal dose50, dose that kills 50% of population; Phe, phenylalanine; TDI, tolerable daily intake, amount that can be ingested daily without posing significant health risks. Tremor Tremorgenic toxins are produced predominantly by Aspergillus and Penicillium species (Ciegler et al., 1976; Land et al., 1994)
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From page 162... ...
. The tremorgenic and nontremorgenic mycotoxins from Aspergillus and Penicillium work at a different functional level of the nervous system from mycotoxins that have more widespread targets for toxicity or work by inhibiting basic cellular functions, such as protein synthesis.
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From page 163... ...
. Neurotoxic effects might also be indirect through its effects on the immune system.
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From page 164... ...
Neurotoxic effects in laboratory animals include degeneration of nerve cells in the central nervous system, vomiting, central nervous systemmediated loss of weight and failure to thrive, anorexia, and thirst (Ueno, 1984a)
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From page 165... ...
. VOCs produced by building materials, paints, solvents, and combustion can irritate the mucous membranes of the eyes and respiratory tract and possibly the nerve endings of the common chemical sense either alone or in concert with other volatile and semivolatile compounds produced by microorganisms (Otto et al., 1990; Schiffman et al., 2000)
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From page 166... ...
A dose as low as 0.5 ng can cause skin reddening in guinea pigs (Ueno, 1984a)
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From page 167... ...
ochraceus, breaks, unscheduled urethra, bladder carcinomas 10 –5) = 0.18 ng/kg Penicillium DNA synthesis, DNA- in Balkans; IARC possible day verrucosum, adduct formation, human carcinogen Aspergillus damages chromosomes alutaceus, Penicillium viridicatum, Penicillium cyclopium (continued on next page)
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From page 168... ...
(1 × 10 –6) = 0.05 and liver µg/kg-day Citrinin Penicillium Nephrotoxic, mildly NA LD50 = 50 mg/kg in citrinum, hepatotoxic rats; 35–58 mg/kg Penicillium ip and 110 mg/kg verrucosum, orally in miceb 19 Penicillium mg/kg ip in rabbits vindicatum, Aspergillus terreus Patulin Penicillium NA US FDA: 50 µg/kg expansum, of body weight per Penicillium day patulum, Aspergillus terreus Penicillin Acid Aspergillus Affects heartc Hepatocarcinogen in some UK: 20–50 µg/kg of ochraceus animalsc food Luteoskyrin Penicillium Hepatotoxic, Carcinogend islandicum Nephrotoxicd NOTE: Abbreviations: LD50, lethal dose50, the dose that kills 50% of the population; VSD, virtually safe dose.
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From page 169... ...
Contamination with AFB1 is associated with high rates of hepatocarcinoma in some African countries and appears to potentiate the hepatocarcinogenic properties of hepatitis B virus through its immunotoxic effects (Autrup et al., 1987; Badria et al., 1999; Bechtel, 1989; Groopman et al., 1992)
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From page 170... ...
Therefore, the relevance of such exposures to those due to damp indoor spaces is unknown. FINDINGS, RECOMMENDATIONS, AND RESEARCH NEEDS On the basis of its review of the papers, reports, and other information presented in this chapter, the committee has reached several findings and recommendations and has identified several research needs regarding the nonallergic effects of molds and bacteria found in damp indoor environments.
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From page 171... ...
1997. The neurotoxic effects of Ochratoxin A are reduced by protein binding but are not affected by l-phenylalanine.
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From page 172... ...
1990. Acute inhalation toxicity of T-2 mycotoxin in the rat and guinea pig.
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From page 173... ...
2003. Immunocytochemical localization of stachylisin in Stachybotrys chartarum spores and spore-impacted mouse and rat lung tissues.
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From page 174... ...
2003. Production of proinflammatory mediators by indoor air bacteria and fungal spores in mouse and human cell lines.
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From page 175... ...
2001. Inflammatory responses in mice after intratracheal instillation of spores from Streptomyces californicus isolated from indoor air of a moldy building.
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From page 176... ...
1994. The presence of mycotoxin-associated fungal spores isolated from the indoor air of the damp domestic environment and cyto toxic to human cell lines.
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From page 177... ...
2001. Effects of Stachybotrys chartarum on surface convertase activity in juvenile mice.
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From page 178... ...
1999. Can microbial volatile metabolites cause irritation at indoor air concentrations?
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From page 179... ...
2002. Microanatomical changes in alveolar type II cells in juvenile mice intratracheally exposed to Stachybotrys chartarum spores and toxin.
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From page 180... ...
1999. Effects of Stachybotrys chartarum spores and toxin on mouse lung surfactant phospholipid com position.
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From page 181... ...
2000a. Quantification of siderophore and hemolysin from Stachybotrys chartarum strains, including a strain isolated from the lung of a child with pulmonary hemorrhage and hemosiderosis.
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2003. Germination, viability and clear ance of Stachybotrys chartarum in the lungs of infant rats.
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