The Role of Mycotoxins in Building-related Illness
The Role of Mycotoxins in Building-related Illness
The Role of Mycotoxins in Building-related Illness
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<strong>The</strong> <strong>Role</strong> <strong>of</strong> <strong>Mycotox<strong>in</strong>s</strong> <strong>in</strong>Build<strong>in</strong>g-<strong>related</strong> <strong>Illness</strong>Elena Page, MD, MPHDouglas Trout, MD, MHS
National Institute forOccupational Safety and Health! Four missions" Research" Develop and recommend criteria forOSHA/MSHA standards" Respond to requests for <strong>in</strong>vestigation <strong>of</strong>workplace hazards – health hazardevaluations (HHE)" Tra<strong>in</strong><strong>in</strong>g
Introduction! Increased attentionregard<strong>in</strong>g role <strong>of</strong>mycotox<strong>in</strong>s, primarilyfrom Stachybotrys, ascauses <strong>of</strong> illness <strong>in</strong> the<strong>in</strong>door environment! Recommendations forbuild<strong>in</strong>g remediationbased on reportedhealth effects believeddue to mycotox<strong>in</strong>s
Sick Build<strong>in</strong>g Syndrome! Common, nonspecific symptoms" headache, fatigue, irritability, difficultyconcentrat<strong>in</strong>g, mucous membrane irritation,chest tightness, and sk<strong>in</strong> irritation! Occur while <strong>in</strong> the build<strong>in</strong>g, but resolveshortly after leav<strong>in</strong>g it! Typically no objective f<strong>in</strong>d<strong>in</strong>gs! Dist<strong>in</strong>ct from SBS are build<strong>in</strong>g-<strong>related</strong>illnesses
Build<strong>in</strong>g-<strong>related</strong> <strong>Illness</strong>! Variety <strong>of</strong> recognized disease entities" Allergic rh<strong>in</strong>itis, asthma, hypersensitivitypneumonitis, Legionnaires’ Disease, andhumidifier fever! Characterized by objective cl<strong>in</strong>ical f<strong>in</strong>d<strong>in</strong>gs<strong>related</strong> to specific exposures <strong>in</strong> the <strong>in</strong>doorenvironment! Can be caused by microorganisms,<strong>in</strong>clud<strong>in</strong>g many species <strong>of</strong> bacteria andfungi
Fungi! Fungus is a term used to encompassdifferent plants <strong>of</strong> the K<strong>in</strong>gdom Fungi! Characterized by the absence <strong>of</strong> chlorophyll" Mushrooms, toadstools, yeasts, molds, mildews,smuts, and rusts! Fungi comprise 25% <strong>of</strong> the biomass <strong>of</strong> earth" Human exposure to fungi is ubiquitous! Thousands <strong>of</strong> fungal species; < 100 speciescause human and animal disease
Fungi! Saprophytic varieties (those utiliz<strong>in</strong>g nonliv<strong>in</strong>gorganic matter as a food source)<strong>in</strong>habit soil, vegetation, water, or anyreservoir that can provide an ample supply<strong>of</strong> a nutrient substrate! Generally, the <strong>in</strong>door levels expected to bebelow outdoor levels with consistentlysimilar rank<strong>in</strong>g among the microbial species
Health Effects <strong>of</strong> Fungi! Allergy! Infection (i.e., mycosis)! Toxic reactions" Organic dust toxic syndrome" Mycotoxicosis specifically refers to a reactionto tox<strong>in</strong>s produced by the fungus! In addition, more than 500 VOCs identifiedfrom a variety <strong>of</strong> fungi" Most common is ethanol
Fungal Allergy! Based on a geneticpredisposition! Examples" Allergic rh<strong>in</strong>itis,asthma, allergicbronchopulmonaryaspergillosis (ABPA),and extr<strong>in</strong>sic allergicalveolitis(hypersensitivitypneumonitis)
Mycoses! Systemic" Histoplasmosis and coccidioidomycosis! Local" R<strong>in</strong>gworm, thrush, and monilial vag<strong>in</strong>itis.! Indoor fungi do not usually cause <strong>in</strong>fection" Bird dropp<strong>in</strong>gs near air <strong>in</strong>takes can be a source<strong>of</strong> Histoplasma capsulatum and Cryptococcusne<strong>of</strong>ormans if disturbed" Aspergillus fumigatus is a well known hazard tothe immunocompromised
<strong>Mycotox<strong>in</strong>s</strong>! Non-volatile fungal metabolites! Produced by many molds! More than 300 known mycotox<strong>in</strong>s! Mycotox<strong>in</strong> production is poorly understood,thought to be affected by conditions such asfungal stra<strong>in</strong>, genetic susceptibility <strong>of</strong> thehost plant or commodity, moisture content,temperature, aeration, microbial population,and stress factors
Important <strong>Mycotox<strong>in</strong>s</strong>Fungal SpeciesAspergillusAspergillus parasiticusAspergillus flavusAspergillus versicolorAspergillus terreusFusariumFusarium moniliformeFusarium spp.PenicilliumPenicillium viridicatumPenicillium spp.StachybotrysStachybotrys chartarum (atra)Tox<strong>in</strong>Aflatox<strong>in</strong>Sterigmatocyst<strong>in</strong>Patul<strong>in</strong>Citr<strong>in</strong><strong>in</strong>ZearalenoneTricothecenesOchratox<strong>in</strong>Citr<strong>in</strong><strong>in</strong>Patul<strong>in</strong>Tricothecenes
Tricothecenes! Commonly occurr<strong>in</strong>g, more than 150! Produced by variety <strong>of</strong> fungi" Fusarium, Trichoderma, Stachybotrys,Cephalosporium, and Tricothecium! Examples - rorid<strong>in</strong>, verrucar<strong>in</strong>, satratox<strong>in</strong>s! Primary mechanism <strong>of</strong> action is <strong>in</strong>hibition<strong>of</strong> prote<strong>in</strong> synthesis! Induce redness and irritation <strong>of</strong> the sk<strong>in</strong>
Stachybotrys! Found worldwide! Build<strong>in</strong>gs withStachybotrys growthproblems usually havechronic water damage! Stachybotrys chartarum(synonyms atra, alternans)is one <strong>of</strong> many fungicapable <strong>of</strong> produc<strong>in</strong>gtrichothecene mycotox<strong>in</strong>s
Alimentary Toxic Aleukia (ATA)! Human disease from tricothecenes that wasfirst reported <strong>in</strong> Russia from 1942-1947! Often fatal, characterized by vomit<strong>in</strong>g, sk<strong>in</strong><strong>in</strong>flammation, hemorrhag<strong>in</strong>g <strong>of</strong> the GI tract& mucous membranes, immunosuppression,& pancytopenia! Attributed to eat<strong>in</strong>g overw<strong>in</strong>tered gra<strong>in</strong>contam<strong>in</strong>ated by Fusarium species! T-2 tox<strong>in</strong> implicated as the causative agent
Other Mycotoxicoses! 1987 - GI illness from consumption <strong>of</strong>bread made from wheat contam<strong>in</strong>ated withAspergillus and Fusarium occurred <strong>in</strong> India" Deoxynivalenol, nivalenol,acetyldeoxynivalenol were isolated from wheatsamples! Similar illness reported after consumption<strong>of</strong> moldy rice <strong>in</strong> Ch<strong>in</strong>a" T-2 tox<strong>in</strong> implicated
Veter<strong>in</strong>ary Stachybotryotoxicosis! Reported <strong>in</strong> large and small animals! Stomatitis, hemorrhage and necrosis <strong>of</strong> thegastro<strong>in</strong>test<strong>in</strong>al tract, leukopenia,immunosuppression, and sk<strong>in</strong> ulcerations,hyperemia, edema, and tissue necrosis <strong>of</strong>vary<strong>in</strong>g severity! Atypical form - loss <strong>of</strong> reflexes,hyperirritability, loss <strong>of</strong> vision, and <strong>in</strong>abilityto move about
Human Stachybotryotoxicosis! Russians reported stachybotryotoxicosis <strong>in</strong>humans with contact with straw or hay <strong>in</strong>areas where stachybotryotoxicosis wasenzootic <strong>in</strong> horses! Severe dermatitis, chest pa<strong>in</strong>, sore throat,bloody rh<strong>in</strong>itis, cough, and leukopenia! Mold placed on the sk<strong>in</strong> reproduced thecl<strong>in</strong>ical syndrome described above
Human Stachybotryotoxicosis! 1977 - 23 workers load<strong>in</strong>g moldy haydeveloped dyspnea, sore throat, bloodynasal discharge, burn<strong>in</strong>g & water<strong>in</strong>g eyes,and hyperemic, swollen, crusted sk<strong>in</strong> on theface, & dermatitis <strong>in</strong> the gro<strong>in</strong> & buttocks! Symptoms manifested with<strong>in</strong> 24 hours <strong>of</strong>exposure! Recovery with<strong>in</strong> 1 week <strong>of</strong> cessation <strong>of</strong>exposure
Human Stachybotryotoxicosis! Sk<strong>in</strong> scrap<strong>in</strong>gs, nasal and throat swabs, andstraw grew Stachybotrys chartarum! Compared to <strong>in</strong>door, non-<strong>in</strong>dustrialenvironments, the environments describedabove <strong>in</strong>volved considerable differences <strong>in</strong>the extent <strong>of</strong> bioaerosol exposure or<strong>in</strong>gestion <strong>of</strong> significant quantities <strong>of</strong>mycotox<strong>in</strong>-contam<strong>in</strong>ated foodstuffs
<strong>Mycotox<strong>in</strong>s</strong> <strong>in</strong> IndoorEnvironments! Thirteen relevant articles! All <strong>of</strong> the articles except one <strong>in</strong>volveStachybotrys; six <strong>of</strong> the articles describe thesame <strong>in</strong>vestigation <strong>of</strong> pulmonaryhemorrhage <strong>in</strong> <strong>in</strong>fants
Cr<strong>of</strong>t, et al., 1986! 5 home occupants with cold & flusymptoms, sore throats, diarrhea, headaches,dermatitis, hair loss, and fatigue! Medical <strong>in</strong>vestigations found no causes! Cold air return duct & area <strong>of</strong> wood fiberboard were contam<strong>in</strong>ated with Stachybotrys! When mold was cleaned up, symptomsresolved! Extracts from the molds were <strong>in</strong>jected <strong>in</strong>toexperimental animals, which died
Johann<strong>in</strong>g, et al., 1996! 39 females and 14 males exposed toStachybotrys <strong>in</strong> a water-damaged <strong>of</strong>ficeenvironment! Comparison group <strong>of</strong> 11 females & 10males! Health effects assessed by questionnaire! Affected persons had significantly morelower respiratory, dermatological, eye,constitutional and chronic fatigue symptoms
Johann<strong>in</strong>g, et al., 1996 (cont)! 3/24 WBC & immunoglobul<strong>in</strong> testsdifferent between exposed and comparison" CD3% = 75.7 <strong>in</strong> comparison & 73.7 <strong>in</strong> exposed" WBC = 6.1 <strong>in</strong> comparison and 6.3 <strong>in</strong> exposed" #NK cells = 42 <strong>in</strong> comparison & 55 <strong>in</strong> exposed! No difference <strong>in</strong> specific IgG/IgE! Air & bulk samples from problem build<strong>in</strong>gpositive for Stachybotrys, Penicillium,Cladosporium and Aspergillus - noassessment performed for comparison group
Hodgson, et al., 1998! Study <strong>of</strong> two build<strong>in</strong>gs with history <strong>of</strong> water<strong>in</strong>cursions! More symptoms were reported amongoccupants <strong>of</strong> problem build<strong>in</strong>g compared tooccupants <strong>of</strong> comparison build<strong>in</strong>gs" Subjects with sx more likely to participate! Response rate, demographic factors,smok<strong>in</strong>g status, or job duties between theoccupants <strong>of</strong> the exposed and comparisonbuild<strong>in</strong>gs were not reported
Hodgson, et al., 1998 (cont)! 17/47 self-selected <strong>in</strong>dividuals had evidence<strong>of</strong> pulmonary disease (test<strong>in</strong>g not done onunexposed)! Neuropsych test<strong>in</strong>g better <strong>in</strong> exposed! Lower concentrations <strong>of</strong> fungi <strong>in</strong>doors thanoutdoors; differences <strong>in</strong> types <strong>of</strong> fungi! Fungal assessment <strong>in</strong> comparison build<strong>in</strong>gswas casual observation only
Hodgson, et al., 1998 (cont)! Satratox<strong>in</strong>s isolated from Stachybotryschartarum contam<strong>in</strong>ated ceil<strong>in</strong>g tiles, butnot air samples! Employees with > 2 symptoms <strong>in</strong> problembuild<strong>in</strong>g did not have higher levels <strong>of</strong>antibodies to fungi identified <strong>in</strong> the build<strong>in</strong>gthan did unexposed
Sudak<strong>in</strong>, 1998! Office build<strong>in</strong>g with health compla<strong>in</strong>ts andhistory <strong>of</strong> moisture <strong>in</strong>cursion! Various bacteria and fungi present <strong>in</strong> air,bulk, and surface samples! Epi study, consist<strong>in</strong>g <strong>of</strong> <strong>in</strong>terviews andquestionnaire adm<strong>in</strong>istration, revealed mostcommon symptoms were fatigue, headache,difficulty concentrat<strong>in</strong>g, & s<strong>in</strong>us congestion! No evidence <strong>of</strong> objective illness amongbuild<strong>in</strong>g occupants was reported
Auger et al., 1994! Several cases <strong>of</strong> chronic fatigue andrecurrent respiratory <strong>in</strong>fections <strong>in</strong> personsliv<strong>in</strong>g <strong>in</strong> homes where certa<strong>in</strong> toxigenicfungi such as Trichoderma, Penicillium, andPhoma were found! Propose that research concern<strong>in</strong>gmycotox<strong>in</strong>s is important <strong>in</strong> the attempts toexpla<strong>in</strong> <strong>in</strong>door environmental qualityproblems
Acute PulmonaryHemorrhage/Hemosiderosis! 8 cases <strong>of</strong> acute pulmonary hemorrhagedur<strong>in</strong>g 1/93-11/94 among <strong>in</strong>fants <strong>in</strong>Cleveland (2 additional cases <strong>in</strong> 12/94)! Case-control study - past water damage tohomes assessed by questionnaire" Cases more likely to reside <strong>in</strong> homes whereparents report water damage <strong>in</strong> the 6 monthsprior to the hemorrhage (OR =16.25; 95% CI=2.55 to <strong>in</strong>f<strong>in</strong>ity)
PulmonaryHemorrhage/Hemosiderosis! Aggressive air sampl<strong>in</strong>g <strong>in</strong> follow-up<strong>in</strong>vestigation! S. chartarum detected more <strong>of</strong>ten & <strong>in</strong>greater quantity <strong>in</strong> case homes than controls! Cases more likely to be black, male, livewith a relative who coughed blood, exposedto tobacco smoke, and not to be breast fed! Cases had significantly lower birth weight
PulmonaryHemorrhage/Hemosiderosis! <strong>The</strong> CDC has recently released the detailedf<strong>in</strong>d<strong>in</strong>gs <strong>of</strong> both <strong>in</strong>ternal and externalreviews which concluded that a possibleassociation between pulmonaryhemorrhage/hemosiderosishemosiderosis <strong>in</strong> <strong>in</strong>fants andexposure to molds, specificallyStachybotrys, , was not proven
Flappan, 1999! Infant with respiratory distress & shock! Pulmonary hemorrhage noted on <strong>in</strong>tubation! Elevated WBC, PT; cultures negative! Home was evaluated soon after illness! Stachybotrys & other fungal spores found <strong>in</strong>air & surface samples <strong>in</strong> <strong>in</strong>fant’s bedroom! Tricothecenes, <strong>in</strong>clud<strong>in</strong>g rorid<strong>in</strong> &satratox<strong>in</strong> found on closet ceil<strong>in</strong>g <strong>of</strong> <strong>in</strong>fant’sbedroom
Elidemir, et al., 1999! Stachybotrys isolated from BAL fluid <strong>of</strong> 7y.o. boy with LLL pneumonia andhemosider<strong>in</strong>-laden macrophages! Cough, fatigue, & recurrent pneumonias<strong>in</strong>ce age 5! Surface cultures <strong>of</strong> bronchoscopy suite &mycology lab negative for Stachybotrys! Stachybotrys found <strong>in</strong> samples from home! Pt. relocated & symptoms resolved with<strong>in</strong> 1month
Pulmonary Hemorrhage –Chicago (unpublished)! 7 <strong>in</strong>fants with acute pulmonary hemorrhage from4/92-11/94! Case-control study - questionnaire, environmentalsurvey, laboratory evaluation! No significant difference <strong>in</strong> race, gender, birthweight, breast feed<strong>in</strong>g, exposure to tobacco smoke,recent water leakage or flood<strong>in</strong>g <strong>in</strong> home! Stachybotrys more common <strong>in</strong> control homes,Trichoderma <strong>in</strong> case homes! Overall, more fungi <strong>in</strong> control homes
Methodologic Issues! Case def<strong>in</strong>itions are generally absent orpoorly def<strong>in</strong>ed! Documentation <strong>of</strong> exposure to a potentialcausative agent(s) lack<strong>in</strong>g! Both
Cl<strong>in</strong>ical <strong>Illness</strong>! Wide spectrum <strong>of</strong> health effects! Case def<strong>in</strong>itions generally absent or poorlydef<strong>in</strong>ed" Cr<strong>of</strong>t et al. - nonspecific symptoms &uncleardescription <strong>of</strong> medical evaluations" Hodgson et al. - undef<strong>in</strong>ed cl<strong>in</strong>ical diagnosesand epidemiological case def<strong>in</strong>itions" Johann<strong>in</strong>g et al. - did not def<strong>in</strong>e cases;compared employees <strong>of</strong> problem build<strong>in</strong>g withnon-problem build<strong>in</strong>g, f<strong>in</strong>d<strong>in</strong>g an excess <strong>of</strong>nonspecific symptoms <strong>in</strong> the study population
Exposure Characterization! Pulmonary hemorrhage –Pulmonary hemorrhage – no systematicevaluation <strong>of</strong> water damage, aggressivesampl<strong>in</strong>g months after onset <strong>of</strong> illnessunlikely to be representative <strong>of</strong> actualexposures to fungi <strong>in</strong> those homes! Johann<strong>in</strong>g et al. & Hodgson et al. - antibodytest<strong>in</strong>g, ? measure <strong>of</strong> fungal (not mycotox<strong>in</strong>)exposure; found no <strong>in</strong>creased exposure toany specific fungus among problembuild<strong>in</strong>g occupants compared to comparison
Exposure Characterization! Several studies have detected mycotox<strong>in</strong>s <strong>in</strong>samples from walls, ceil<strong>in</strong>g tiles, and airducts! Identification <strong>of</strong> mycotox<strong>in</strong> on a wall or <strong>in</strong>air duct demonstrates only a potential forexposure, and does not alone provideevidence <strong>of</strong> exposure, much less evidencel<strong>in</strong>k<strong>in</strong>g reported symptoms to the fungi orfungal products
Conclusions! Molds are a potential health hazard" Allergy" Infection" Toxicosis# Evidence <strong>of</strong> cl<strong>in</strong>ical illness (<strong>in</strong> humans and animals)from <strong>in</strong>gestion <strong>of</strong> significant quantities <strong>of</strong>mycotox<strong>in</strong>-contam<strong>in</strong>ated foodstuffs# <strong>Illness</strong> associated with bioaerosol exposures <strong>in</strong>agricultural or <strong>in</strong>dustrial environments has also beenreported# Relevance <strong>of</strong> these f<strong>in</strong>d<strong>in</strong>gs to the <strong>in</strong>door (non<strong>in</strong>dustrial)environment is unclear
Conclusions! Inadequate evidence that mycotox<strong>in</strong>s <strong>in</strong><strong>in</strong>door (non-<strong>in</strong>dustrial) environments causessymptoms or illness among build<strong>in</strong>goccupants! Identification & isolation <strong>of</strong> fungal tox<strong>in</strong>s <strong>in</strong>the environment & humans is needed! Objective measures <strong>of</strong> adverse healtheffects must be associated with somemeasure <strong>of</strong> mycotox<strong>in</strong> exposure! Comparisons made with appropriatecontrols
EnvironmentalAssessment 2Rule out <strong>in</strong>fectious causesHRCT 3 ChestCXR, sputum cultures/smear, CBC with differential 1If <strong>in</strong>fectious process unlikelyPFT with DLCO 4Methachol<strong>in</strong>e Challenge TestSk<strong>in</strong> Prick Test<strong>in</strong>g 5Precipitat<strong>in</strong>g Ab 6Total IgEESR 7Interstitial InfiltrateRestrictive PatternDecreased DLCOObstructive Pattern and/orHyperreactive AirwaysSupportive F<strong>in</strong>d<strong>in</strong>gsPrecipitat<strong>in</strong>g AbElevated ESR“Pneumonitis”“Asthmatic”Supportive F<strong>in</strong>d<strong>in</strong>gsSpecific HypersensitivityElevated Total IgEBronchoscopy withbronchoalveolor lavage and biopsy 8Peak expiratory flow test<strong>in</strong>gat work and away from work1Also consider: serology for histoplasmosis; Lp1 antigen (ur<strong>in</strong>e) to evaluate for Legionella <strong>in</strong>fection2Extent <strong>of</strong> environmental assessment will depend on multiple factors3High-resolution computed tomography - should be performed even with normal CXR4Pulmonary function test (with bronchodilator adm<strong>in</strong>istration) with lung volumes and diffus<strong>in</strong>g capacitycorrected for alveolar volume5Evaluation for IgE-mediated immediate hypersensitivity6Evaluation for precipitat<strong>in</strong>g antibodies to antigens present <strong>in</strong> the environment7Erythrocyte sedimentation rate8Also CD 4/CD 8ratio, fungal/bacterial cultures, histology*Trout, et al. [2001].Environ Health Perspect109:641-644
Indoor Mold Remediation! Follow the guidel<strong>in</strong>esdescribed <strong>in</strong> theEnvironmental ProtectionAgency’s document,“Mold Remediation <strong>in</strong>Schools and CommercialBuild<strong>in</strong>gs” available athttp://www.epaepa.gov/iaq/molds/toctoc.html! Identification <strong>of</strong> mold notnecessary
Fungal RequirementsMoistureSubstrateTemperature
Indoor Mold Prevention
Indoor Mold Prevention! <strong>The</strong> key is to control <strong>in</strong>terior moisture" Repair leaks" Prevent condensation through <strong>in</strong>sulation,<strong>in</strong>creas<strong>in</strong>g surface temperature, or <strong>in</strong>creas<strong>in</strong>g aircirculation" Vent any moisture-produc<strong>in</strong>g equipment orappliances to the outdoors" Ma<strong>in</strong>ta<strong>in</strong> <strong>in</strong>terior relative humidity below 60%(ideally between 30% and 50% to m<strong>in</strong>imizemold growth)
Indoor Mold Prevention (cont)" Ensure that air condition<strong>in</strong>g systems areadequately dra<strong>in</strong>ed to prevent stand<strong>in</strong>g water" Clean up and dry any wet or damp spots with<strong>in</strong>48 hours" Ensure that water dra<strong>in</strong>s away from thebuild<strong>in</strong>g foundation" Rout<strong>in</strong>ely <strong>in</strong>spect and ma<strong>in</strong>ta<strong>in</strong> the build<strong>in</strong>g andbuild<strong>in</strong>g systems