Read Microsoft Word - Mold Statement-WITHOUT QUALIFICATIONS.doc text version

HEALTH EFFECTS OF MOLDS IN INDOOR ENVIRONMENTS

STUART M. BROOKS, MD

HEALTH EFFECTS OF MOLDS IN INDOOR ENVIRONMENTS

STUART M. BROOKS, MD

COLLEGES OF PUBLIC HEALTH AND MEDICINE UNIVERSITY OF SOUTH FLORIDA

Human Health Effects of Molds in Indoor Environment

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

TABLE OF CONTENTS TOPIC PAGES

1. STATEMENT OF PROBLEM

3

2. DEFINITION OF TERMS

3

3. CHARACTERIZING MOLD EXPOSURE IS CRITICAL

9

4. CHARACTERIZING STACHYBOTRYS EXPOSURE IS CRITICAL

13

5. HEALTH EFFECTS FROM MOLD/FUNGI

15

6. HEALTH EFFECTS FROM STACHYBOTRYS

19

7. ASTHMA AND INDOOR EXPOSURES

23

8. CONCLUSIONS

24

9. REFERENCES

26

Page 2 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

1. STATEMENT OF PROBLEM In recent years the growth of molds in home, school, and office environments has been cited as the cause of a wide variety of human ailments and disabilities. So-called "toxic mold" has become a prominent topic in the lay press and is increasingly the basis for litigation when individuals, families, or building occupants allege they have been harmed by exposure to indoor molds. The present alarm over human exposure to molds in the indoor environment derives from a belief that inhalation of molds in someway causes a toxicity or illness to the body. It is believed by some that a toxicity or illness is derived from some unknown element of the mold spores or perhaps from released by-products such as mycotoxins or volatile organic compounds. Presumably, these exposures then cause an acute or chronic illness; the illness often consists of nonspecific symptoms or conditions. 2. DEFINITION OF TERMS A." Fungi" are eukaryotic, filamentous organisms that absorb food from the environment after external digestion ("absorptive nutrition"). Their rigid cell wall is made up of chitin fibrils embedded in a matrix of (1 3)-D-glucans and/or mannans. They are found in every ecological niche, and are necessary for the recycling of organic building blocks that allow plants and animals to live. Fungi need external organic food sources and water in order to grow. They release new enzymes and secondary metabolites that help digest a food source making it more soluble for absorption. The Figure below is a diagrammatic representation of potential major mold/fungi chemical releases.

Mold spore and hyphae

Microbial volatile organic compounds (MVOCs) Trichothecenes Mycotoxin Allergens Glucans

There are more than 1,000,000 species of fungi, 200 different types to which people are routinely exposed. Included in the group "fungi" are yeasts, molds and mildews, as well as large mushrooms, puffballs and bracket fungi that grow on dead trees. Many species live as commensal organisms in or on the surface of the human body. Fungi can cause superficial skin or nail infections of the feet (tinea pedis), groin (tinea cruris), dry body skin (tinea corporus), or nails (tinea onchomycosis). Fungal spores contain chemical constituents that can cause an allergic response; allergic type reactions including asthma, allergic rhinitis and allergic sinusitis. However, of the hundreds of thousands of different kinds of fungi, only a few have been tested for allergic potential. Fungal allergy (e.g., allergy skin testing) is common in the general population. Perhaps 10% of the general population and about 40% of asthmatic patients show evidence of allergic sensitization (e.g., allergy skin testing) to various fungi. Immunologically compromised persons (e.g., cancer patients receiving chemotherapy, organ transplant patients receiving immunosuppressive drugs, AIDS patients, and patients with uncontrolled diabetes) are at

Page 3 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

increased risk for acquiring an opportunistic fungal infection. Exposure to molds and other fungi and their spores is unavoidable except when the most stringent of air filtration, isolation, and environmental sanitation measures are observed, e.g., in organ transplant isolation units. There are special types of outdoor fungi in certain parts of the United States that cause pulmonary infections (e.g., Histoplasmosis, Coccidiomycosis). These latter fungi do not reside indoors. Very high occupational concentrations of fungal dusts spores can cause the acute febrile illness of organic dust toxic syndrome. B. "Mold", a subset of fungi, is ubiquitous on our planet. Molds are multicellular fungi that grow as a mat of intertwined microscopic filaments (hyphae). Molds and other fungi are ubiquitous in indoor and outdoor environments. Aspergillus, Penicillium and Cladosporium are predominant mold found indoors. The molds Fusarium, Bacillus mycoides, and Ulocladium are commonly found in damp indoor environments. Molds can grow on cloth, carpets, leather, wood, sheet rock, insulation (and on human foods) when moist conditions exist (Gravesen et al., 1999). Because molds grow in moist or wet indoor environments, it is possible for people to become exposed to molds and their products, either by direct contact on surfaces, or through the air, if mold spores, fragments, or mold products are aerosolized. Many molds reproduce by making spores, which, if they land on a moist food source, can germinate and begin producing a branching network of cells called hyphae. Molds have varying requirements for moisture, food, temperature and other environmental conditions for growth. Indoor spaces that are wet, and have organic materials that mold can use as a food source, can and do support mold growth. Mold spores or fragments that become airborne can potentially expose people indoors through inhalation or skin contact. Molds can have an impact on human health, depending on the nature of the species involved, the metabolic products being produced by these species, the amount and duration of individual's exposure to mold parts or products, and the specific susceptibility of those exposed. C. Mycotoxins" are secondary metabolites produced by fungi during metabolizing of a food source; they do not nourish the fungi and have no apparent physiologic function; they probably interfere with other organisms competing for the same food source. Mycotoxins are relatively stable chemicals, and are usually low molecular weight. Several of them are lipophilic and accumulate in the fat fractions of plants and animals. The history of mycotoxins is related to several outbreaks of the associated diseases (Eskola, 2002). One of the first known diseases in humans caused by mycotoxins was ergotism in the Middle Ages. In around 944, about 40,000 habitants died in France. The outbreak of this mycotoxicosis was due to consumption of rye contaminated with ergot mycotoxins. The last major mycotoxicosis caused by ergot was in France in 1935 and since then several sporadic cases of mycotoxicosis in humans and animals have been reported. Probably the most recent outbreak affecting humans occurred in China in 198485. Hundreds of thousands of turkeys and ducklings died due to feed contaminated with aflatoxin in Great Britain in 1960, launching rapid expansion in mycotoxin research. Cereals are the most important source of human food. The annual world crop of cereals exceeds 2000 million tons meaning over 160 kg per inhabitant and the production of cereals is still growing. It is estimated that 10-30% of the harvested grains are lost due to mold infection (Eskola, 2002). The Food and Agriculture Organization of the United Nations (FAO) estimates that about 25% of the world's food crops are affected by mycotoxins. Usually, and especially in developing countries, the best quality cereals are exported while the crop with poorer quality is consumed in the homeland. Hence the citizens in developing countries, mainly living in rural areas, are especially sensitive to adverse health effects of mycotoxins especially because of malnutrition and low standard of living.

Page 4 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

Mycotoxins are found in all parts of the fungal colony, including the hyphae, mycelia, spores, and the substrate on which the colony grows. Some mycotoxins have medical uses as antibiotics (e.g., penicillin, cyclosporine). The amount (if any) and type of mycotoxin produced is dependent on factors such as nutrition, growth substrate, moisture, temperature, maturity of the fungal colony, and competition from other microorganisms. Even under similar growth conditions, the profile and quantity of mycotoxins varies widely from one isolate to another. Because of all of the variables, the identification of fungal spores does not necessarily mean that mycotoxins are also present. Mycotoxins are of relatively large molecular weight and do not evaporate or "offgas" (e.g., low volatility) into the environment, nor do they migrate through walls or floors independent of a particle. Thus, mycotoxins are not likely to be inhaled and generally there are no significant inhalation risks from mycotoxin presence. Mycotoxin inhalation occurs only under the conditions when there is generation of an aerosol of fungal substrate, fragments, or spores. Generating an aerosol requires mechanical disturbance or physical energy and does not occur spontaneously. There is no skin permeation of mycotoxins because fungal spores and fragments do not pass through the skin. There may be skin irritation after direct contact to large amounts of fungi or contaminated substrate material. The Table below lists some common fungi, mycotoxins and possible health effects from ingestion, skin or inhalation (breathing in) exposures. The information on liver, kidney, neurologic, hemotoxic, and hemorrhagic effects are almost exclusively from animal studies, cases of massive human exposures from ingestion of contaminated food or grain, or very large occupational inhalational exposures. The Table is modified from a paper by Burge (Burge, 2001). Trichothecenes are a type of mycotoxin. FUNGUS

Alternaria alternata Phoma sorghina Aspergillus flavus A. parasiticus Aspergillus fumigatus Aspergillus ochraceus Phoma viridicatum Trichophyton verrucosum Aspergillus nidulans A. versicolor Cochliobolus sativus Cladisporium sp. Fusarium poae F. sporotrichiodes Fusarium moniliforme Pencillium griseofulvum P. viridicatum Pencillium expansum Pithomyces chartarum Stachybotrys chartarum (atra)

MYCOTOXIN

Tenuazoic acid Tenuazoic acid Aflatoxin Aflatoxin Fumitremorgens, Giliotoxin Ochratoxin A Ochratoxin A Ochratoxin A Sterigmatocystin Sterigmatocystin Sterigmatocystin Epicladosporic acid T-2 toxin T-2 toxin Fumonisins Griseofulvin Griseofulvin Patulin, Roquefortine C, Citrinin Sporidesmin Satratoxins, Verrucarins, Roridins

POSSIBLE HEALTH EFFECTS

Kidney, liver, hemorrhagic Kidney, liver, hemorrhagic Mutagenic, carcinogenic, liver Mutagenic, carcinogenic, liver Tremorgenic, cytotoxic Kidney, liver, carcinogenic Kidney, liver, carcinogenic Kidney, liver, carcinogenic Liver, carcinogenic Liver, carcinogenic Liver, carcinogenic Immunosuppressive Hemorrhagic, immunosuppressive. Nausea, vomiting Hemorrhagic, immunosuppressive. Nausea, vomiting Neurologic, liver, kidney, cancer Neurologic, liver, kidney, cancer Neurologic, liver, kidney, cancer Kidney, cancer Kidney, photosensitivity, eczema Inflammation, immunosuppression, dermatitis, hemotoxic, hemorrhagic

Page 5 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

D. Immediate hypersensitivity refers to a type of allergic response in which there is an immediate allergic reaction to an agent to which a person has become immunologically sensitized. The hypersensitivity can be documented by finding elevated levels of specific immunoglobulin E (IgE) antibodies (in the blood) against the sensitizing agents. This type of hypersensitivity has been reported after breathing in mold spores or hyphal fragments. Clinically, immediate hypersensitivity manifests as allergic asthma or allergic rhinitis. Individuals with mold allergy are usually "atopic" persons (e.g., they have a genetic predisposition to develop allergies and manifest specific allergic (IgE) antibodies to a wide range of allergens with molds being one of the participant allergens). E. Bronchial asthma is an inflammatory disorder of the tracheobronchial tract characterized by repeated attacks of coughing, wheezing, chest tightness and breathlessness. During the attacks, there is variable and reversible airflow limitation. There is heightened airway responsiveness to a variety of irritant (aerosol sprays, smoke, Clorox, etc.), odors (perfumes, cologne), physical factors (excessive cold and heat) and pharmacologic agents (methacholine, histamine). In most cases the cause of asthma is on an allergic basis. Mold and fungi can exacerbate symptoms of asthma in persons suffering from pre-existing asthma and who show allergic sensitization to the specific fungal allergen. It has not been established that indoor fungi mold actually causes (e.g., induces a new case) asthma in persons previously not sensitized and who do not suffer from asthma. F. Allergic rhinitis and sinusitis is a disorder of the nasal passages characterized by runny and stuffy nose, headache and nasal congestion. There is inflammation, edema and secretions present. Sometimes, there is a secondary infection of the sinuses. The cause is allergic in origin. Mold and fungi can cause an exacerbation of symptoms in person previously sensitized to fungal allergens. G. Atopy is the genetic predisposition to develop allergies of the IgE type. About 40% of the USA population (e.g., approximately 90,000,000 persons) are atopic; maybe 25 % (e.g., 22,500,000) have allergic antibodies to common inhalant aeroallergens including molds; perhaps 50% of persons with allergic IgE antibodies actually manifest allergic symptoms (e.g., about 11,250,000 persons). Symptomatic persons with circulating specific IgE antibodies to mold can be identified through allergy skin tests or blood tests. If the tests are negative, then the likelihood that these persons suffer immediate hypersensitivity allergic symptoms due to mold is markedly lessened. G. Uncommon allergic syndromes are unusual variants of allergic (IgE-mediated) reactions include allergic bronchopulmonary aspergillosis (ABPA) and allergic fungal sinusitis (AFS). Allergic bronchopulmonary aspergillosis develops in an allergic/atopic individual with prior airway damage usually from a previous illness. Consequently, this prior affliction leads to bronchial irregularities that impair normal drainage, e.g., bronchiectasis. The damaged site allows fungal growth. Aspergillus may colonize on these sites without invading adjacent tissues. Such fungal colonization is without adverse health effects unless the subject is allergic to the specific fungus that takes up residence. In these cases, the subject suffers immediate-type hypersensitivity reactions caused by allergic reactions to fungal allergens. It has more recently been appreciated that a similar process may affect the sinuses: allergic fungal sinusitis (AFS). This condition also presents in subjects who have underlying allergic disease and in whom, because of poor drainage, a fungus colonizes the sinus cavity. Aspergillus and Curvularia are the most common forms although the number of fungal organisms involved continues to increase. There is no evidence to link specific exposures to fungi in residential or office settings to the establishment of fungal colonization that leads to APBA or AFS.

Page 6 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

H. Hypersensitivity pneumonitis (HP) is an immunologically-induced pneumonia that develops after repeated episodes of inhaling foreign (fungal or other) material. Both circulating immunoglobulin G and cellular immunity are operative in the pathogenesis. The vast majority of cases of HP result from occupational exposures, although cases have also been attributed to pet birds, humidifiers, and HVAC systems. The predominant organisms in the latter two exposures are thermophilic actinomyces, which are not molds but rather are filamentous bacteria that grow at higher temperatures (116 degrees F). It has not been substantiated that HP can develop from residential exposures without an underlying mechanical source for aerosolizing fungal/mold antigens. Stachybotrys does not cause HP. I. "Mold hypersensitivity state" represents a belief held by some health practitioners and members of the public that claims that there is a relationship between mold colonization, molds in foods, and an alleged "mold hypersensitivity state." The condition was originally proposed in the lay press as the "Chronic Candida Syndrome" or "Candida Hypersensitivity Syndrome," but now has been generalized to other fungi. Adherents may claim that individuals are "colonized" with the mold(s) to which they are sensitized and that they react to these endogenous molds as well as to exposures in foods and other materials that contain mold products. The claim of mold colonization is generally not supported by any scientific evidence, e.g., cultures or biopsies, to demonstrate the actual presence of fungi in or on the subject. Instead, proponents claim colonization or infection based solely on the finding of a wide variety of nonspecific symptoms and antibodies detected in serologic tests; the latter represents no more than evidence of past exposure to normally occurring environmental fungi. The existence of this alleged disorder is not supported by reliable scientific data; lacks biological plausibility and is not supported by human epidemiologic studies or toxicological experimentation (Hardin, 2002, personal communication). J. Serious fungal infections involves deep tissue fungal infection and are restricted to severely immunocompromised subjects (e.g., patients with lymphoproliferative disorders including acute leukemia, cancer patients receiving intense chemotherapy or persons undergoing bone marrow or solid transplantation who get potent immunosuppressive drugs). Uncontrolled diabetics and persons with advanced AIDS are also at increased risk. For severely immune compromised persons residing outside the hospital, fungi are so ubiquitous (including Aspergillus) that few recommendations can be made beyond avoidance of known sources of indoor and outdoor amplification; this includes exposures to indoor plants and flowers because vegetation is a natural fungal growth medium. Candida albicans is a ubiquitous commensal organism on humans that becomes an important pathogen mainly for the immunocompromised. However, it and other environmental fungi that infect immunocompromised subjects (e.g., Cryptococcus, Histoplasma, and Coccidiomycosis) are not normally found growing in the office or residential environment, although they can gain entry from outdoors. K. Superficial mold infections include infections of the skin or mucosal surfaces and are extremely common in normal subjects. These superficial infections include infection of the feet (tinea pedis), nails (tinea onychomycosis), groin (tinea cruris), dry body skin (tinea corporis) and infection of the oral or vaginal mucosa. Some of the common organisms involved, e.g., Trychophyton rubrum can be found growing as an indoor mold. Others, such as Microsprum canis and Trichophyton mentagrophytes can be found on indoor pets (e.g., dogs, cats, rabbits, and guinea pigs). Candida albicans can be cultured from mucosal surfaces of more than half of the population that shows no evidence of active infection. Candida albicans infections are particularly common when the normally resident microbial flora at a mucosal site is removed by antibiotic use (Hardin, 2002, personal communication).

Page 7 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

L. Microbial volatile organic compounds (MVOCs) are low molecular weight alcohols, aldehydes, and ketones released by fungi. The MVOCs are responsible for the musty, disagreeable odor associated with mold and mildew; also, they may cause the objectionable taste of spoiled foods. The MVOCs, like the mycotoxins, are essentially secondary metabolites and may aid in the competition battle. The production of MVOCs depends on the growth conditions including substrate on which the mold is growing and strain and type of mold. There are qualitative and quantitative modifications in MVOCs. As the mold grows and conditions change, MVOCs indices also may change over time. Even with visually large amounts of mold present, the levels of MVOCs remain low and are less than 1 ug/m3. To date, there has been no clear evidence supporting a relationship between exposure to fungal volatiles and any health outcome. This is true because MVOCs are produced in such minute concentrations that it is unlikely they can cause significant health effects. M. Fungal Glucans are fungal components. The cell wall of the fungi contains - (1-3)-Dglucans. The glucans can cause effects similar to endotoxins. In animal studies, high concentrations of glucans cause irritation and inflammatory effects. Potentially, glucans may act as an irritant to humans. Most epidemiologic studies show only a weak relationship (if any) between symptoms and glucans measurements in dust. N. Trichothecenes are tetracyclic mycotoxins, with a sesquiterpenoid 12, 13epoxytrichothec-9- ene ring system (Eskola, 2002). They are arbitrarily divided into four groups A, B, C and D according to their chemical structure. In type A trichothecenes, the carbonyl group in position C-8 is missing, whereas in type B the carbonyl group appears in position C-8. Type C trichothecenes have a second epoxide group and type D trichothecenes are macrocyclic compounds. Some well known trichothecenes are: diacetoxyscirpenol, T-2 toxin, deoxynivalenol and nivalenol. Deoxynivalenol received its common name, vomitoxin, from the vomiting that generally accompanies poisoning. Some trichothecenes are strong inhibitors of protein synthesis in mammalian cells. The effects of deoxynivalenol are mainly restricted to animal intoxication such as feed refusal in swine. The FDA issued an "advisory" to federal and state officials recommending a level of concern for deoxynivalenol of 2 micrograms of deoxynivalenol / gm for wheat entering the milling process, 1 microgram/ gm in finished wheat products for human consumption, and 4 microgram/ gm for wheat and wheat milling by-products used in animal feed. O. Organic dust toxic syndrome" (ODTS) is condition caused by a massive mold/fungal dust inhalational exposure or from eating contaminated food. Most descriptions of human and veterinary poisonings from molds involve eating moldy foods. Occupational inhalation exposures occur under specific circumstances. For example, acute human inhalation exposures occur among certain agricultural workers handling silage or spoiled grain products. The silage/grain contains high concentrations of fungi, bacteria, and organic debris that release byproducts such as endotoxins, glucans, and mycotoxins. A related condition is called "pulmonary mycotoxicosis," or "grain fever". Exposures associated with ODTS are exposures to a "fog" of particulates; there is a "thick airborne dust" of such intensity it may be impossible to see across a room. Under these circumstances, total fungal counts have ranged between 100,000 and 1,000,000,000 microorganism per cubic meter of air or even 1,000,000,000 -10,000,000,000 spores per cubic meter, These extreme conditions are not ordinarily encountered in the indoor home, school, or office environment (Hardin, 2002, personal communication). P. "Dampness in Building" is a term used to describe water intrusion into a building. This situation often leads to mold growth. "Dampness" in buildings appears to increase the risks of developing symptoms of cough, wheeze and asthma among asthmatic persons. It is not conclusive as to exactly which agent(s) in indoor air equates best to "dampness" and which are

Page 8 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

responsible for the health effects. Mold and dust mites have been implicated. P. "Sick building syndrome" refers to a set of symptoms (usually sensory) or physical complaints that are attributed to occupancy in a building. The complaints are often alleged (in some manner) to be due to the presence of fungal/mold growth. This concern has been especially true when Stachybotrys chartarum (a.k.a. Stachybotrys atra) is identified. "Sick building syndrome" is an inaccurate term because it suggests the building requires investigation and treatment; also, the term suggests there are two populations in a building-sick and healthy. Alternatively, the designation of "healthy building" is wrong because it presumes that in such building, the symptoms of affected persons are not related to building conditions. In many buildings with poor indoor air quality, investigation often finds no specific identifiable cause for the complaints. In contrast, the term "specific building-related illness" refers to a group of illnesses with a fairly homogeneous clinical picture, objective abnormalities on clinical or laboratory evaluation and one or identifiable sources or agents known to cause infectious, immunologic or allergic diseases. The following Table summarizes major specific building-related illnesses and causes (Menzies, 1997). DISEASE INFECTIOUS Legionnaire's disease, Pontiac fever Flu like illness, common cold Tuberculosis IMMUNOLOGIC Hypersensitivity pneumonitis, Humidifier fever ALLERGIC Dermatitis, rhinitis, asthma Rhinitis, contact urticaria, laryngeal edema AGENT OR EXPOSURE Legionella pneumophila Respiratory virus Mycobacterium tuberculosis Multiple bacteria, fungus, actinomycetes, Aspergillus, Penicillium, multiple organisms Dust mites, plant products, animal allergens, fungus, unknown Carbonless copy paper (alkylphenol novolac resin)

IRRITATION Dermatitis, upper and lower respiratory tract Glass fiber, combustion products (e.g., carbon irritation monoxide, nitrogen dioxide) 3. CHARACTERIZING MOLD EXPOSURE IS CRITICAL Concentrations of airborne fungi outdoors routinely vary over several orders of magnitude such as between <10 to > 10,000 colony -forming units (CFU/m3) and from < 1000 to >60,000 spores/ m3. Indoor fungal levels represent a combination of what is outside and what are inside; therefore, changes in outdoor levels has a profound effect on concentrations noted inside. Hourly variations in fungal concentrations are considerable. No precise threshold value has been established for exposure to indoor fungi. In a study of 40 selected Australian houses, both total indoor culturable and total fungal spore levels were observed to be relatively high with 58 % of houses with one or more rooms exceeding 1000 CFU/m3 and 48 % exceeding 10,000 CFU/m3 (Godish, 1996). An evaluation of the/outdoor ratio of selected genera indicated that 50 % of indoor concentrations could be explained by outdoor levels. In another study of 12 schools in Cordoba, Spain (where 456 dust samples were collected), the most frequently identified fungi were Alternaria, Aspergillus fumigatus, Aspergillus niger and several species of Penicillium (Angulo-Romero, 1996).

Page 9 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

The indoor exposure assessment is complex and there are uncertainties. Not documenting the actual exposure is a major impediment to understanding the true health significant of indoor fungi (Burge, 2001). There are sampling concerns such as whether to exclusively measure viable, living organisms rather than particulate fungal components. What is a better indicator of fungal exposure: airborne or settled particulate matter? What is the correct media to use for identifying fungi/mold in the environment? And, when and where are samples to be collected? Unfortunately, there is no standard fungal sampling strategy that is recommended. Sampling for fungi at one point in time is like "taking a snap shot" of that moment. The results of the sampling may not be the same when you sample at another time, nor does it necessarily reflect the exposure when persons complained of illnesses. There may be a difficulty concluding there is a relationship between exacerbation of allergic complaints and a specific exposure. Accurate exposure assessment is usually the missing link for determining an association between the presence of fungi/mold in the environment and the occurrence of human disease. In order for some one to become ill from an exposure, several logical steps must take place. The steps begin at the exposure site and end within the body of the person of concern (Burge, 2001). The generalized pathway for tracking exposure and subsequent responses is summarized in the following Table; it presents an inhalational or airborne type exposure sequence. (Burge, 2001) SOURCE FACTORS The type of fungus Population interaction & dynamics AEROSOL FACTORS Composition of aerosol EXPOSURE FACTORS Time spent in aerosol Breathing rate Particle deposition sites Clearance rates Metabolic destruction of toxin RESPONSE FACTORS Dose reaching appropriate organ Dose needed for effect Metabolism of toxin Human susceptibility factors

Particle size Chemistry, physiology, distribution biology of fungus Dispersion Particle release factors Biologic decay Physical decay Patterns of aerosol concentration

Let us break down the steps required for an exposure to reach and affect a person. First, there must be an exposure/toxin in the environment. For example, a damp section of dry wall contains Stachybotrys growth. This represents a potential exposure source. The next step is the passing of the Stachybotrys toxin into the air; then there is transportation in the air and entrance into the person's body. Once the toxin enters the body, there must be adequate release or distribution of the toxin within the body and into tissues and cells; there must be sufficient amounts of the toxin in contact with target organ cells to cause the observed symptoms. Finally, the observed symptoms must represent a biologically plausible causal relationship with the toxin. We can presume that the more sizeable the fungal growth, the more likely there will be a "significant exposure" to fungal spores. The question becomes: what constitutes a "significant exposure" to indoor mold/fungi? Unfortunately, there is no definitive answer. There is no accepted level or amount of mold growth regarded as a significant human exposure for any type of fungal spores. This "significant exposure" question assumes that the mold growth resides in a site where release and aerosolization (entering into the air) of spores is possible. For the previous dry wall board example, the spores may be hidden behind the wall and not likely to aerosolize into the

Page 10 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

room air. Therefore, there could not be any significant human exposure possible. In order to aerosolize fungal spores, mechanical disruption is necessary. Small air movement may disperse some fungal spores, whereas others fungi require actual mechanical abrasion. For example Penicillium and Aspergillus spores are readily airborne, whereas Stachybotrys chartarum spores require mechanical disturbance, such as brushing against the surface containing the mold or washing the mold growth, or performing renovating activities (Burge, 2001). Stachybotrys spores do not easily enter the air because the spores are relatively large and sticky and tend to settle quickly. Therefore, very few spores are found consistently within the air even in environmental spaces where there is extensive and active fungal growth of Stachybotrys. The important point is that airborne fungi/mold state is dynamic and aerosol characteristics changes over time. What about mycotoxin? The amount of mycotoxin produced by a fungal colony depends on the specific species of fungus, the genetic pattern of the particular strain of the species, the length of time the fungus has been growing, the kind of food source available, the amount water available, the temperature, the amount and wavelength of light, the presence or absence of competition, and other unknown factors. All of these factors are interactive. As mentioned, mycotoxins are not volatile and therefore do not evaporate into the air. Possibly, spores are a source of inhalation exposure to mycotoxins. Spores can enter the air as an aerosol but usually mechanical stimulation is necessary. If one speaks of a particular toxic strain of a fungal species (e.g., Stachybotrys), or a particular food source (e.g., damp dry wall) that stimulates mycotoxin production, it is necessary to measure these specific factors. This means actually measuring the mycotoxin content of the fungus while it is growing on the wall and utilizing its food source. It is important to measure the amount in the air. Using alternative methods such as conditions in culture media may provide irrelevant results. The Table below reproduces data published by Dr. Harriet Burge (Burge, 2001). It shows the very limited data obtainable on particular toxins from spores of several fungal species cultivated on laboratory media and quantified by high-pressure liquid chromatography or thinlayer chromatography. The Table shows the amount of toxin present as nanogram per unit of spores. Data is expressed in units of nanograms of toxin per gram, and as nanograms of toxin per one million spores. FUNGUS Aspergillus fumigatus Aspergillus fumigatus TOXIN(S) Fumigaclavine C Fumitremorgen B + verruculogen Aurasperone C Aflatoxin B1 Secalonic acid D Norsolorinic acid NG/G SPORES 930,000 ------NG/ MILLION SPORES 9.890 6-80

Aspergillus niger 460,000 0.114 Aspergillus parasiticus 16,600 0.976 Penicillium oxalicum 1,890 0.025 Aspergillus parasiticus 280 0.023 (mutant Nor-1) Let us analyze the above Table using the logic and calculations employed by Dr. Burge. An adverse health effect requires the presence of large numbers of spores. The reason for this conclusion is because, the concentration of mycotoxin contained in a single spore is extremely small. Table above demonstrates that the amounts of mycotoxin per spore or per 1,000,000 spores vary. The amount varies by more than 400 times (e.g., comparing 9.8 ng vs. 0.023 ng). For Aspergillus fumigatus, the concentration of mycotoxin per one million spores is about 10 nanogram (actually, 9.890 nanogram). Let us theoretically assume that a require dose of

Page 11 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

mycotoxin to cause an acute effect in a person is 0.1 mg/kg body weight (a 150 pound man is 70 Kg). By calculating the weight factor (0.1 mg/kg) causing an effect and noting there are 10 ng mycotoxin/one million spores (106), then it would take an exposure of (1 x 105)/ (1 x 10-5) or 1010 spores kg. This figure 1010 is 10,000,000,000 (10 billion). For a 70 kg man an exposure of 700,000,000,000 (7 x 1011) spores kg will cause adverse health effects. This is an immense number of spores and highly unlikely for indoor circumstances. The amount of spores that are inhaled into the respiratory tract is equal to the time spent breathing the aerosol of spores multiplied by the aerosol concentration (the number of spores in the aerosol). The longer the time spent breathing in an aerosol, the more likely there will be sufficient numbers of spores inhaled. If you divide the number of spores generated by ten hours, it would take 70,000,000,000 spores per hour (for the 70 kg man) to make the effects possible. This calculation assumes that the exposure is cumulative. These hypothetical levels are what can be calculated based on experimental scientific data. The amount is an estimate of a dose required for an acute toxic dose per kg of body weight. If we consider other Aspergillus mold, which contain less mycotoxin/million spores, a much greater spore load is required. There is not data on Stachybotrys, but we can assume huge numbers of mold are needed to be airborne. It is known that airborne levels of Stachybotrys spores are routinely very low due to its physical properties. Therefore, it is highly unlikely that humans are affected by inhaling Stachybotrys in indoor/residential environments. To date, there is no study in humans equivocally documenting a connection between inhalation of mycotoxins and disease except for the massive exposures noted with organic toxic dust syndrome. Virtually all of the inhalation information we have concerning mycotoxin is derived from animal studies. A small amount of information is derived from human ingestion data. This is not to say there is not a potential for adverse health effects. There may have been an exposure (in the sense there is visible mold growth) but the necessary dose to cause an effect was not documented or was not likely to occur. Current studies fail to carefully document or measure dose. Even with this statement in mind, when one actually carefully analyzes the available data, it is unlikely that sufficient exposure dose and circumstances occur in an indoor situation. Even if you assume there are a great enough number of spores in the air, you are still missing vital information; the critical point is the amount of mycotoxin actually reaching the affected organ system or target cell. For the inhalation route, not everything breathed stays in the lung. What is not known is the amount of mycotoxin that actually reaches and is retained in the respiratory tract. The amount of mycotoxin reaching the target organ is the product of the number of spores retained in the respiratory tract, the amount of mycotoxin present per individual spore, the rate that the toxin is released from the spores and then enters respiratory cells, and the rate the mycotoxin is removed or deactivated from the respiratory site or is destroyed by internal defense mechanisms of the body. These series of factors are unknown for mycotoxins. However, calculations (as was performed above) demonstrate that huge numbers of spores are needed to cause an effect. Therefore, human inhalational illness from molds does not occur unless there is a massive exposure to spores and accompanying very high levels of mycotoxins. In likelihood, there must be levels of spores in excess of 1,000,000 per cubic meter air over short periods. There must be constant exposures to levels greater than 1,000 toxin-containing spores per cubic meter for many days. These types of exposures occur rarely in certain occupational and agricultural situations. This magnitude of exposure does not occur in indoor, home or office environments. 4. CHARACTERIZING STACHYBOTRYS EXPOSURE IS CRITICAL

Page 12 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

Stachybotrys is a greenish-black, sooty-looking mold that grows on nonliving organic materials, especially cellulose and under conditions of high humidity and low nitrogen content; these properties are similar to Aspergillus fumigatus and niger, Cladosporium herbarum, Alternaria alternata and others. It is a slow-growing organism, both in nature and on laboratory media, where it may compete poorly with other rapidly growing fungi. Stachybotrys is rarely recovered from outdoor air samples but is difficult to find in undisturbed indoor air. Because of its affinity for cellulose, it is found in nature on substrates of plant origin, but under very wet conditions; it favors decaying plant materials (Terr, 2001). Stachybotrys is classified as a Deuteromycetes, in the order of Moniliaceae, family of Dematiaceae, genus Stachybotrys and species atra (chartarum, alternans). There are a number of species, but the one most commonly encountered are Stachybotrys atra, Stachybotrys chartarum, or Stachybotrys alternans. These threes names are for the same species. Although Stachybotrys is rarely found in outdoor air (and when found, is present in low quantities), it is potentially an important contaminant of agricultural produce. The fungus has been cultured from soil and substrates rich in cellulose, such as a hay and straw, cereal grains, plant debris, rice paddy grains, combine harvester wheat and sorghum dusts, and broad bean seeds. When identified, Stachybotrys is accompanied by many other types of fungi and is usually not the dominant one. Stachybotrys has been cultured from the hair of large animals, including cow, dog, donkey and skin surfaces of certain monkeys. As in the case of plant contamination, it is found on these animals along with other fungi, especially Cladosporium. Stachybotrys spores can be recovered from indoor air samples, but generally only when there is significant water damage and visible mold growth on surfaces. Even under these conditions, its concentrations are very low compared with the more common Penicillium and Aspergillus species. Stachybotrys is usually not found in homes. For example, in one study, it was found in the air of 2.9 percent of homes in Southern California; the mean Stachybotrys concentration was only 0.3 spores/m3. Stachybotrys can be sampled from surfaces and air. Air sampling routinely uses either Rotorod or Andersen samplers. Microscopic examination identifies spores by a characteristic morphology; the fungal colonies can be counted on culture plates. Recently polymerase chain reaction technology has been use to identify Stachybotrys when the expected quantity is especially small (Cruz-Perez, 2001; Haugland, 1999; Rath, 2000; Roe, 2001; Zhou, 2000). Stachybotrys spores grow well on organic substrates rich in cellulose. Such substrates are noted in urea-formaldehyde foam insulation, fiber-board, gypsum board, carpets, jute, vinyl and paper wall coverings as well as other indoor building materials especially those containing wood or paper materials. Stachybotrys has been recovered from a variety of dust and lint samples and even from tobacco in cigarettes. In all cases, Stachybotrys is only a minor component of the microflora, which usually features Penicillium, Aspergillus and Trichoderma species, as well as Gram-negative bacteria and even Mycoplasma. Numerous Stachybotrys mycotoxins had been characterized by many laboratories over many years. The Table below lists some Stachybotrys toxins.

MACROCYCLIC TRICHOTHECENES 3-Acetyl-deoxynivalenol Citrinine

ENZYMES B-Gluanase 1,3-Endoglucanases

Page 13 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

Deoxynivalenol Diacetoxyscirpenol Isosatratoxin F, G, S, H Kampanols Nivalenols Phenylspirodrimanes Roridin A Satratoxin F, G, H T-2-Tetraol T-2 Toxin Verrucarin A Verrucarol Vomitoxin

Famesyl-protein transferase SESQUITEPENES: K-76, K-76 COOH SMTP-3, -4, -5, -6 STACHYBOCINS A, B, C STACHYBOTRAMIDE STACHYBOTRIN C STAPLABIN STAPLABIN ANALOGS: SMTP-7, -8 TRIPRENYL PHENOL METABOLITES

There are more than 40 tetracyclic sesquiterpenes, collectively known as trichothecenes. The same or similar ones are also produced by other fungi. Stachybotrys also synthesizes spirocyclic lactones, cyclosporins, stachybotrylactones, and both constitutive and induced enzymes with potential toxic properties. The biologic effects of many of the chemicals produced by Stachybotrys have been extensively studied. These chemicals show varying effects among different strains of organisms. The various activities investigated (in animal or in vitro studies) include cytotoxicity, metabolic effects, hemolysis, plasmin effects, as well as effects on the lung, immunological system, cytokines, cholesterol, nervous system and other manifestations. Stachybotrys mycotoxins' toxicological effects have been studied in animals and cellular in vitro systems but not in humans (Terr, 2001). For animal/in vitro studies, a number of macrocyclic trichothecenes (satratoxins) are shown to inhibit protein synthesis and cause direct cellular cytotoxicity in animals and plants, both in vitro and in vivo. In some cases, the effect seems mediated through apoptosis with deactivation of protein kinases. In vivo studies, document that major oxidative enzymes are altered by Stachybotrys toxin. Some Stachybotrys display hemolytic activity at 37 degrees C when cultured on sheep's blood agar. Staplabin stimulates plasminogen activation and affects other clotting indicators. There are effects on lung surfactant as measured in fetal rabbit alveolar type II cells. Some mycotoxins inhibit complement activation, reduce natural killer cell activity, influence antibody-dependent cell-mediated cytotoxicity and influence other immunologic responses. Satratoxins affects interleukin production. The mycotoxins inhibit various enzymes and alter neuron cells in cellular investigations (Terr, 2001). Because of their relatively large size, most inhaled Stachybotrys spores are deposited in the upper airways. Possibly, upper airway deposition is important. Hypothetically, there might be mycotoxin absorption into the blood from the initial impact site in the upper airways; this deposition could lead to systemic symptoms occurring later providing the dose was adequate. Of course, these hypotheses are unproven. For Stachybotrys, we can predict that only a very few spores will reach the lower respiratory tract and the dose delivered to the respiratory tract is extremely low. Okay, suppose a few spores reach the lower respiratory tract. What effects do a few spores have on lung cells? Unfortunately, there is very little published data of human studies describing toxicological responses to Stachybotrys toxin. In contrast, there is a large body of published data describing Stachybotrys toxin effects on animals; there are also a few studies of other toxins. One study investigated molds obtained from problem buildings and thereafter grown on six different plasterboards. Subsequently, the spores were harvested, and applied to a special

Page 14 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

type of laboratory macrophage preparations (e.g., RAW264.7). The macrophages were evaluated 24 hours after mold exposure for their ability to cause cytotoxicity and to stimulate production of nitric oxide (NO), interleukin-1 beta (IL-1), tumor necrosis factor alpha (TNF) and interleukin-6 (IL-6). The study compared the macrophage outcomes of four different fungal spores (Streptomyces californicus, Penicillium spinulosum, Aspergillus versicolor and Stachybotrys chartarum) grown on six different types of wallboard (Murtoniemi, 2001). The Table below summarizes the results of this investigation (as number or percent of 12 samples -6 plasterboards with replicates). The effects measured were inflammatory mediators and cytotoxicity of macrophages. NO > 10nmol IL-6 >1500 pg IL-1 >600 pg TNF >2500 pg Cytotoxicity >50% cell death

S. californicus 10 12 7 12 8 P. spinulosum 0 2 0 10 6 A. versicolor 0 6 2 8 12 S. chartarum 0 6 0 9 9 NO = nitric oxide; IL-6= interleukin-6 beta; IL-1= interleukin-1 beta; TNF = tumor necrosis factor-alpha. Stachybotrys chartarum was one of the least toxic to the macrophages. The data is interesting because it points out the wide variability of toxic effects occurring among different species of mold. The effects for each species are different depending on the type of wallboard. The strain of Stachybotrys (used in the study) was among the least inflammatory and toxic when compared to the other fungi/mold. It is possible that other strains of Stachybotrys chartarum are more toxic. In summary, studies involving Stachybotrys chartarum toxin show that the acute toxic effects occur only with very large doses of inhaled or instilled toxin. The very large exposure to millions of airborne spores is not likely to occur in residential/schools/office buildings. Animal investigations commonly used extracted Stachybotrys toxin instead of using intact spores. Experiments utilize this approach because the doses can be more easily controlled. However, this approach of extracting toxin is artificial and does not simulate the real situation. It is also important to emphasize that laboratory animal studies are useful for determining cause and effect relationships, but these animal studies cannot be extrapolated to human situations. Realistic chronic exposures given by the inhalation route have not been studied for any animal and certainly not for humans. Furthermore, certain animals are more or less sensitive to a toxin than are humans. Additionally, interpreting respiratory route exposure pathways derived from animal studies and extrapolating to human respiratory tract is not reliable; animal and human respiratory tracts are each quite different. 5. HEALTH EFFECTS FROM MOLD/FUNGI I conducted a MEDLINE search (published between 1960 and July 2002) using key words such as "allergens/or fungi/or fungal protein/or sick building/ or hypersensitivity/ or mold/ or Aspergillus/ or air pollution, indoors. I restricted my search to papers written in English language, pertaining to humans and accompanied by an abstract. I included other papers considered important (by other authors) or pertinent papers mentioned in critical review. I also included information obtained from governmental documents, authoritative books, personal communications and proceedings from recent meetings and from internet sites. I identified 315

Page 15 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

papers, which are listed in the Reference section. I found six recent critical reviews of indoor fungi/mold/Stachybotrys. These six review papers are listed in the following Table. 1. 2. Burge, H. A. (2001). "Fungi: toxic killers or unavoidable nuisances?" Ann Allergy Asthma Immunol 87 (Suppl): 52-56. Fung, F. and W. G. Hughson (2002). Health effects of indoor fungal bioaerosol exposure. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. Page, E. H. and D. B. Trout (2001). "The role of Stachybotrys mycotoxins in buildingrelated illness." American Industrial Hygiene Association Journal 62(5): 644-648. Shum, M. (2002). An overview of the health effects due to mold. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. Terr, A. I. (2001). "Stachybotrys: relevance to human disease." Annals of Allergy, Asthma, & Immunology 87(6 Suppl 3): 57-63. Weiss, J. S. and M. K. O'Neill (2002). Health effects from Stachybotrys exposure in indoor air: A critical review. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA.

3. 4. 5. 6.

The findings of Fung and Hughson were presented at the recent 9th International Conference on Indoor Air Quality and Climate that took place June 30-July 5, 2002 in Monterey CA (Fung, 2002). The investigators conducted a MEDLINE search and reviewed all English language studies (using keywords of bioaerosols, mold, fungus, mycotoxin, dampness, indoor, indoor environment, health effects, respiratory, and sick building. and human health effects) that were published between 1966 and January 2002. Only human studies related to bioaerosol exposure from fungal sources were included in the selection process. Of the 416 published papers identified under the keyword categories, only 28 met the criteria for applicability for review. Of the 28 papers, five represented case-control studies (CDC, 1997; CDC, 1999; Etzel, 1998; Montana, 1997; Williamson, 1997; Verhoeff, 1995). Of the five papers, three articles discussed the possible association of Stachybotrys chartarum exposure and development of pulmonary hemorrhage/hemosiderosis among infants living in the Cleveland area. Initial data was interpreted as indicating there was a risk to infants (e.g., developing pulmonary hemorrhage/hemosiderosis) who were living in water-damaged houses and sustaining apparent Stachybotrys exposure. However, further analyses by the Centers for Disease Control (including formation of a special study group) reversed the conclusions. The CDC concluded that pulmonary hemorrhage/hemosiderosis among the infants was not proven to be caused by Stachybotrys. A fourth paper was a European case-control study assessing moisture and visible mold in the homes of 102 asthmatic patients and 196 control subjects without asthma. The study reported increased prevalence of moisture and mold problems in the homes of asthmatic patients compared with controls. The fifth case-control paper evaluated 259 children with asthma and respiratory symptoms and compared them with 257 children who did not suffer respiratory symptoms. The study showed higher prevalence of dust mite and mold sensitization and greater prevalence of mold in the homes with water problems of 257 asthmatic children compared to homes of the controls. The health outcomes (pulmonary hemorrhage/hemosiderosis ) for the case-control studies reported increased odds ratios for smoking inside (7.9), water damage house (16.9), dampness in home (~2.0), mold growth in home (~2.0) and Stachybotrys presence

Page 16 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

(1.6). The 16 epidemiological cross-sectional studies utilized either questionnaire or symptoms survey tools to obtain information on mold/fungi (Jarvis, 2001; Ross, 2000; Dales, 1999; Jedrychowski, 1998; Hodgson, 1998; Sudakin, 1998; Li, 1997; Yang, 1997; Johanning, 1996; Cuijpers, 1995; Dales, 1991; Dales, 1991; Stachan, 1990; Brunekreef, 1989; Platt, 1989; Waegemaekers, 1989). There were no standardized methods for collection and quantification of the sampling data. Exposure data cannot be considered accurate when obtained through selfreporting questionnaire. The Table below summarizes the type of responses utilized in the 16 epidemiologic studies. The majority of investigations addressed respiratory complaints, asthma, cough, wheeze and/or breathlessness. Most studies presented no specific diagnosis or case definition. EXPOSURE ASSESSMENTS

SAMPLING VISUAL QUESTIONNAIRE

# CASES

7 7 7

HEALTH ASSESSMENTS

QUESTIONNAIRE/SYMPTOM RATE ER VISITS ASTHMA/RESPIRATORY COMPLAINTS

# CASES

12 1 11

A few studies utilized surface and/or air sampling for mold but these measurements did not necessarily coordinate with health outcomes. Many of the studies evaluated multiple possible associations and therefore increased the likelihood that at least some statistically positive results would occur on a random basis. Nevertheless, many of these studies concluded that there was an association between respiratory symptoms and putative indoor fungal exposures. Despite significant limitations, the epidemiological cross-sectional studies present a trend toward increased respiratory symptoms among those who occupy houses in buildings containing excessive moisture. An association between indoor mold and respiratory symptoms is also suggested but not proven. There were seven case reports associating indoor bioaerosols and mold with adverse health effects (Trout, 2001; Novotny, 2000; Fung, 2000; Elidemir, 1999; Flappan, 1999; Croft, 1986; Kozak, 1980). Among the seven case reports, two involved persons suffering from asthma; two cases were persons describing ill-defined symptoms; and, there were three reported infants with pulmonary hemorrhage/hemosiderosis. Four of the reports concluded that subjects recovered completely after treatment or removal from further mold exposure. The health outcomes measured were: "hypersensitive respiratory illness" (1 study), infant pulmonary hemorrhage (3 studies), "flu symptoms" (1 study), Stachybotrys atra was recovered from bronchoalveolar lavage (1 case) and asthma/allergy (2 studies). The authors recommended that health care professionals, public health officials, media and the public not respond to presence of visible mold with knee-jerk recommendations to "move out of your house" or "vacuuming the building". Such actions introduce significant psychosocial and economic consequences. Excessive moisture is considered a risk factor for mold proliferation and therefore it is prudent to identify the source of moisture and repair and fix water intrusion problems before starting an expensive and usually low-yield environmental investigation. The paper by Shum involved DIALOG database search (which included Elsevier Biobase, Life Sciences Collection, NTIS, Fedrip, Env. Bib., Enviroline, Pollution, Biol & Agric. Index, Paxcal, ICONDA-Intl Construction, Tiosis Previews, Toxfile, TGG health & Wellness, MEDLINE, CAB HEALTH, and ChemEng & Biotec Abs) for studies about mold and health effects; certain

Page 17 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

keywords and analyzing were used and only recently published papers from 1981 to 2001 were assessed (Shum 2002). Of the 57 papers initially identified by Shum, 32 concerned human health and mold exposure/indoor environments. The author then abstracted information about each of the investigation's study design, exposure assessment, population studies, and outcomes ascertained and study findings. Of the 32 studies identified in the search, the majority (26) reported an association between mold/indoor environments and increased respiratory and other health effects. Many of the studies relied on self-reported information about exposure and subsequent health outcomes. In order to better examine cause and effect, Dr. Shum focused on studies that included some quantitative measure of both exposure assessment and health evaluation. There were 13 of these type publications examined in detail (Koskinen, 1999; Bjornsson, 1995; CDC, 2000; Dales, 1998; Dales, 1999; Dotterud, 1995; Garrett, 1998; Hirvonen, 1999; Hodgson, 1998; Huang, 1997; Johanning, 1996; Johanning, 1999; Li, 1997; Stachan, 1990). The Table summarizes information on the 13 investigations reviewed concerning the exposure assessment and health outcomes.

EXPOSURE ASSESSMENTS AIR SAMPLING BULK/DUST SAMPLING VISUAL # CASES 13 5 HEALTH ASSESSMENTS INTERVIEWS SPIROMETRY ALLERGY TEST HUMORAL IMMUNE LYMPHOCYTE TESTING COUGH RECORDER NEUROPSYCH TESTS MD DIAGNOSIS QUESTIONNAIRE NASAL EOSINOPHILS # CASES 1 2 2 2 1 1 1 1 6 1

3

QUESTIONNAIRE

5

Dr. Shum also concluded (that even though there were other cases linking Stachybotrys chartarum to pulmonary hemosiderosis) there was insufficient scientific evidence to conclude an association between Stachybotrys chartarum and idiopathic pulmonary hemosiderosis (CDC, 1997; CDC, 1999; CDC, 2000; Dearborn, 1999; Flappan, 1999; Vesper, 2000; Vesper, 2000) .The author mentioned that the most well-known study were the Cleveland infants (1993-1996) diagnosed with idiopathic pulmonary hemosiderosis. Initial data showed statistically significant association between pulmonary hemosiderosis and Stachybotrys exposure. Subsequently, the CDC reevaluated the data and reached a conclusion that the study was inherently flawed and that the study conclusions were not conclusive or significant. Dr. Shum commented that many of the investigations noted increase in respiratory and other general symptoms for residents who reported having damp or moldy homes. However, (as was concluded by Drs. Fung and Hughson) questionnaire data was used as an indicator for mold exposure. Unfortunately (and as discussed under the Exposure section above) this method of characterizing exposure does really correlate well with actual mold exposure; furthermore, the observation of dampness and visible mold (as observed even by trained inspectors) does not always correlate with actual airborne mold counts. Therefore, individual personal assessment of exposure through visual means is not accurate. My conclusions and the findings reached by the six author(s) of each of the key review papers are similar. My assessment indicates that there seems to be scientific data that suggests an association between allergy/respiratory symptoms and indoor exposure to moisture/mold. Atopic/allergic and asthmatic subjects, as well as young children, may be at increased risk for developing respiratory complaints due to dampness in buildings. For most studies, the exposure

Page 18 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

assessments are inadequate. A majority of sampling methods incorporated only area sampling for short time-periods; therefore, exposure assessments may not capture actual exposure events (as perhaps personal exposure measurements from the breathing zone). It is clear that fungal/mold growth is dynamic and changes with time and is influenced by alterations in the indoor environment and food sources. The approach of quantifying exposure just by questionnaire can not be considered accurate or exact. Quantitative exposure measurements (and dose-response characterization) do not correlate directly with health effects. Essentially all of the investigations provide limited information characterizing mold/fungi exposures. When conclusions are reached about exposure and health effects, usually there is no logical explanation of exposure pathways. All studies do not demonstrate a dose-response exposure effect. This type of response is an expected toxicological outcome and characteristic of all toxic chemical responses. The public perception that fungi/molds are "toxic" to humans, under conditions of poor indoor air quality situations is not founded on scientific facts and remains controversial. More specifically, exposure to Stachybotrys mycotoxin can not cause symptoms in the vast majority, if not all, building/residential situations. Massive numbers of Stachybotrys spores in the air are necessary to induce toxicity. This is not the case. First, Stachybotrys spores are not likely to be come airborne. The finding of significant numbers of indoor airborne Stachybotrys spores is rare. Secondly, mycotoxins have low volatility and do not normally evaporate into the air. Mycotoxins may reside on spore surfaces. However, the number of spores required to cause a toxic effect is massive. Consequently, it is unrealistic to expect actual "toxicity" (e.g., doseresponse) at levels below the massive amount. For the typical indoor environment, massive levels of Stachybotrys spores do no occur. The very high levels are more appropriate for certain occupational exposures. Some epidemiological studies report weak relationships between glucans levels in dust and symptoms. There is no reason to think that it is the glucans itself that is causing the symptoms; glucans may be acting as a surrogate for some other agent. Further, these studies do not meet necessary criteria to reach a definitive conclusion. To date, there is no clear evidence supporting a relationship between MVOCs exposure and any health outcome. The main reason for this conclusion is because the volatiles are produced in such minute concentrations. Without better studies, a causal association between mold and human health outcomes cannot be confirmed at this time. The role of dampness correlates with respiratory symptoms, especially in allergic/atopic/asthmatic person, and children. 6. HEALTH EFFECTS FROM STACHYBOTRYS Original interest in Stachybotrys chartarum was due to its capacity to deteriorate organic fabric fibers and its ability to produce highly cytotoxic macrocyclic trichothecenes; these chemicals caused significant health problems when they contaminated moldy straw in Eastern and Northern Europe. Stachybotryotoxicosis was first described in the 1930s by Russian researchers, and later by Forgacs in the English written literature (Eskola, 2002). Forgacs assisted Russian veterinarians during World War II, where stachybotrystoxicosis in horses was a severe problem for the Russian army. Russian researchers showed that horses were very susceptible to Stachybotrys infested straws (Terr, 2001). The link to indoor air appeared in 1986, when Croft et al described a household in Chicago, where the occupants suffered from symptoms claimed to be similar to stachybotryotoxicosis (Croft, 1986). Filters from air sampling in this home were supposedly black due to the many Stachybotrys spores. Eppley & Bailey were the first to isolate trichothecenes from Stachybotrys chartarum; they found the known components, trichodermol and roridin E and three novel components, named satratoxins H, G and F (Eppley,

Page 19 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

1975). Sorenson reported that the spores from trichothecene-producing isolates contained approx. 10-40 ppm of a trichothecene and about 40 fentagrams thrichothecene per spore, whereas Nikulin et alfound 140 fentagrams /spore. Thus, Stachybotrys chartarum is capable of producing extremely potent trichothecene toxins, as evidenced by one-time lethal doses in mice (LD50) as low as 1.0 to 7.0 mg/kg, depending on the toxin and the exposure route. Depression of immune response, and hemorrhage in target organs are characteristic for animals exposed experimentally and in field exposures. The public and lay press have been concerned about health effects from its mycotoxin. Lay press reports have referred to Stachybotrys as the "fatal fungus", "toxic fungus" or "toxic mold". A number of investigations addressed the role of bioaerosols from Stachybotrys chartarum and related symptoms of mucous membrane irritation of eyes, nose, throat and tracheobronchial tract, gastrointestinal and flu-like complaints, increased headaches, fatigue, dizziness, neurocognitive problems, onset or worsening of pre-existing allergies and asthma, and also increase in sinusitis and upper and lower respiratory illnesses. There are three excellent review papers (Weiss, 2002; Page, 2001; Terr, 2001). My review indicates that to date, no case of human systemic or local infection has been reported, even in immunosuppressed patients. There are no cases of hypersensitivity pneumonitis caused by Stachybotrys in the published literature. While allergy and asthma have been proposed, there is no good documentation with allergy testing showing Stachybotrys sensitivity in persons reporting asthma. There have been cases of Stachybotryotoxicosis from ingesting very large concentrations in occupational exposures (Tantaoui-Elaraki, 1994; Schneider, 1979; Harrach, 1983; Akkmeteli, 1977; Terr, 2001). There have been reports of toxicity from ingesting contaminated grain and food sources. This has been true for animals and there is a condition called "alimentary toxic aleukia" (ATA) in animal. For example, there is the 1930s report in Siberia of horses fed barley, corn, and wheat stored under winter snow. The horses developed gastrointestinal hemorrhages and ulcerations, agranulocytosis, mouth ulcers, respiratory tract inflammation, fever and failure of blood clotting. The disease was traced to Stachybotrys infestation of fodder and later the condition was reported experimentally by feeding horses Stachybotrys organisms added to freshet or by feeding them a pure culture of the fungus. It has also been reported to affect other large farm animals. There was one isolated observation involving veterinarians and later similar disease in some of the local farmers in contact with the mold-contaminated hay and straw. Since the 1940s, however, no additional human case report or epidemics have been published, although it remains a potential threat to farm animals. Since these early ingestion cases, subsequent reports of possible human disease are largely restricted to a variety of illnesses allegedly caused by water damaged buildings. These reports fall into two distinct categories of illness: [1] Presumed excess number of "health complaints", rather than a specific disease; and, [2] A specific disease-acute pulmonary hemorrhage such hemosiderosis very young infants (Terr, 2001).My critical review of the published reports about human disease following inhalation of Stachybotrys spores does not establish a clear-cut positive effect relationship. The paucity of human scientific data does not justify the untoward degree of concern now expressed by many of the public. Several studies have examined medical literature. For example, one investigation (Weiss, 2002) involved analysis of a computerized database of MEDLINE from January 1965 through January 2002. This investigation is instructive because of the methodology utilized in analyzing the cases. A total of 190 articles were identified and fell into the categories of human case reports, letters to the editor, review articles, case reports, animal experimental studies, epidemiological investigations, methods development for quantification of Stachybotrys and its

Page 20 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

mycotoxins and other types of investigations. Only publications written in English and with abstracts, case reports, letters the editor, opinions, review articles and other non-epidemiological reports were used. All epidemiological studies were assessed by criteria developed by the Evidence Based Medicine Working Group of the Journal of the American Medical Association for articles on Causation/Harm/Etiology (Guyette, 1992). In finality, there were 31 relevant articles, which consisted of 15 animal experiments and 16 epidemiological studies. Of the 16 epidemiologic studies, six studies involved the initial assessment and then re-analysis of a single group of infant pulmonary hemorrhage/hemosiderosis cases in Cleveland; these six cases were treated as a single analysis (CDC, 1994; CDC, 1999; CDC, 2000; Montana, 1997; Etzel, 1998; Dearborn, 1999). Two other publications referred to studies completed on the same group exposed in a water-damaged building were also analyzed as a single study (Johanning, 1993; Johanning, 1996).There were a total of nine epidemiologic studies evaluated according to JAMA criteria (Etzel, 1998; Johanning, 1996; Cooley, 1998; Sudakin, 1998; Walinder, 2001; Landers, 2001; Thorn, 2001; Platt, 1989; Norback, 2000). The articles were assessed for study design, methodological biases, doseresponse, consistency, strength of association and exclusion of alternative medical explanations. The studies were graded on a primary scale as to whether they fulfill the JAMA criteria. Panel studies were evaluated to assess issues of biological plausibility. In general, the epidemiologic studies suffered from methodological problems and most were found to be lacking in one or more areas. The most significant of the problems were lack of reliable exposure assessment taken by scientifically sound methodology or corroboration of medical conditions. Environmental assessments were frequently undertaken only after case outcomes were known. Some were undertaken substantially beyond the clinically relevant time period and after environmental conditions had been modified. Few assessed individualized exposure and typically relied on small numbers of areas samples that were not specifically related to a particular participant's exposure. Of the 15 animal studies, there were five determined to be most in keeping with the criteria (Nikulin, 1996 #1072; Nikulin, 1997; McCrae, 2001; Rao, 2000; Rao, 2000). Animal studies supported evidence of adverse reproductive effects, hemorrhage, necrosis of the gastrointestinal tract and adverse effect on lymphoid tissue when Stachybotrys toxin and spores are ingested in high dosages. Intranasal and intratracheal installation of high doses of Stachybotrys spores lead to pulmonary parenchymal damage. No studies documented Stachybotrys spore infectivity. The animal studies provide very interesting information and give some indication of the amount of dose needed to cause an effect. The studies showed that observed pulmonary changes were due to a prominent mass effect from the physical presence of large numbers of spores deposited in the lungs (as well as possible adverse effect due to endotoxins and other cell wall compounds). The use of such large doses in animals makes it difficult to extrapolate animal single high dose (given as a single or subacute but massive dose) to findings noted after chronic low-level exposures. Another interesting finding of animal investigations revealed the Stachybotrys spores were rapidly cleared from the respiratory tract by tissue macrophages; this response was noted even with different methods of spores' introduction into the lungs. This finding of effects noted with very large doses suggests that the immune system in animals can effectively dispose of spores, and that pathologic findings likely occur when the animal's normal physiological system is overwhelmed (as may be the case when massive doses of spores are introduced).

Page 21 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

At the lower end of the dose-response curves, the Non Observed Adverse Effects Levels (NOAEL) level (both for rats and mice) are actually pretty high and are in dose ranges of 1,0001,000,000 spores. These are two important observations: [1] rapid spore clearance and [2] confirmation of NOAEL level both in rats in mice. The two findings suggest that Stachybotrysrelated disease reported in high-dose animal studies may not be applicable to the substantially lower inhalation exposures of humans. The experimental animal data supports the conclusion that ingestion of high doses of Stachybotrys spores causes generalized disease. This may be similar to what has been described in human ingestion of contaminated food. Unlike ingestion studies, there were no animal investigations demonstrating that when spores were introduced into the respiratory tract it caused systemic changes. No animal study documented antibody formation, change in blood cell parameters, or alteration in lymphoid tissue. The results of high dose tracheal installation studies suggest that perhaps there is a constituent of the spores themselves (factors other than tricothicene mycotoxin) that may be implicated in development of lung pathology. The cell wall constituent may possibly act as an endotoxin (rather than as a secondary metabolite mycotoxin). Clearly, high-dose tracheal instillation studies result in changes due to a prominent mass effect; instilled spores take up considerable alveolar space in rats' lung and consequently inhibit gas exchange. The animal experimental studies utilized massive levels of spores to demonstrate induction of inflammatory changes. The combination of the mass effect from lots of spores and the accumulation of fungal/mold cell wall elements (e.g., endotoxins) in the lungs may be important in the pathogenesis of pathological changes. The review paper by Page and Trout included a MEDLINE search (1965-2001) and information from a literature database maintained by the National Institute for Occupational Safety and Health (e.g., NIOSHTIC) (Page, 2001). This strategy yielded more than 150 articles from which relevant articles were selected. Page and Trout concluded "the literature review indicates that currently there is inadequate evidence supporting a causal relationship between symptoms and illness among building occupants and exposure to mycotoxins. Research involving the identification and isolation of specific fungal toxins in the environment and in humans is needed before a more definitive link between health outcomes in mycotoxins can be made". There were other comprehensive reviews dealing with Stachybotrys (Terr, 2001; Page, 2001). Both investigators reached similar conclusions. Dr Terr concluded that "the current public concern for adverse health effects from inhalation of Stachybotrys spores in water-damaged buildings is not supported by published reports in the medical literature". The paper by Dr. Harriet Burge presented information not found in many other papers (Burge, 2001). She is considered a leading authority in the field. Her assessment of exposure was very insightful. In her paper, she mentions "key cases" that "have stimulated concern" (Croft, 1986; Etzel, 1998; Montana, 1997; Sorenson, 1987). One paper involved four family members and a maid (Croft, 1986). The author hypothesized that trichothecene toxins were causing an illness described as cold/flu symptoms, sore throat and skin rashes. High volume air sampling tested positive for trichothecene toxins. Stachybotrys atra was cultured from a suspension of 6,000 liters of air. A poorly described "crude test" was said to show the presence of trichothecene. Fungal spores were measured by impinger sampling. However, no objective evidence of specific disease was detected. The author used an ethanol extract of Stachybotrys atra ­containing debris from an air duct, which caused death when injected into young rats and adult mice; there were no controls. There was no dose-response information available. The authors concluded the family's illness was caused by airborne trichothecenes from Stachybotrys. Reportedly, there were no further complaints after the home was cleaned. The hypothesis that trichothecene toxins might

Page 22 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

cause an illness is plausible but is definitely not proven given the experimental design and methodology. The other papers deal with infant pulmonary hemorrhage/hemosiderosis (Etzel, 1998; Montana, 1997; Sorenson, 1987). The hypothesis was that Stachybotrys exposure, which was isolated from reservoirs, in some way lead to pulmonary capillary fragility (over the time period) and caused infant pulmonary hemorrhage/hemosiderosis. However, for all studies, cassette sampling revealed very low to zero concentrations (less than10 per cubic meter of air) of Stachybotrys chartarum. While houses were found to be moldy, no logical pathway for exposure was demonstrated. In addition, there was no documentation of spores in the air. There was no explanation of how sufficient dose entered the lungs of infants. There were problems with the experimental design. Cigarette smoking was a greater risk factor than other factors. Over the past five years, there have been about 100 additional cases of acute infant idiopathic pulmonary hemorrhage (with and without hemosiderosis) reported where Stachybotrys is found present in the home. These case reports included cases where the organism was also recovered from the patient's lung (Jarvis, 1998; Dearborn, 1999; Elidemir, 1999; Vesper, 2000). The Cleveland experience has been discounted by two expert panels commissioned by the CDC (CDC, 2000; CDC, 1999). The specific errors in the study design were discussed in the report by the CDC and by publications (Terr, 2001). 7. ASTHMA AND INDOOR AIR EXPOSURES A number of papers have addressed asthma and mold growth (Bardana, 2001; Bjornsson, 1995; Brunekreef, 1992; Dharmage, 2001; Engvall, 2001; Fung, 2000; Gehring, 2001; Hodgson, 1998; Hoffman, 1993; Immonen, 2001; Jarvis, 2001; Koch, 2000; Landers, 2001; Lawrence, 2001; Li, 1995; Norback, 2000; Ross, 2000; Seuri, 2000; Su, 2001; Thorn, 2001; Wijnands, 2000; Cox-Ganser, 2002; Li, 2002; Platts-Mills, 2002) Fungi produce an array of compounds that are potential allergens. Each fungus produces many different allergens of a range of potency. The Table below lists the major defined allergens isolated from fungi (Committee for the Assessment of Asthma and Indoor Air (Institute of Medicine), 2000).

FUNGUS Aspergillus fumigatus Aspergillus oryzae Alternaria alternata Cladosporium herbarum Penicillium citrinum Penicillium chrsogenum Trichophyton tonsurans Malassezia furfur Psilocybe cubenis MAJOR ALLERGEN Asp f I, Asp f III Alt a I, Alt a II Cla h I

Tri t I Mal f I Psi c II

Fungi allergen production varies by strain, species and genera. The source of the allergen is contained within the spores, mycelium, and culture medium. The substrate medium significantly influences the amount and pattern of allergen production. For example allergen content of Alternaria spores growing on ceiling tiles likely differs from that of spores produced on dead grass. There is cross-reactivity but the data is inconsistent and appears to depend on the specific strain used and on methods of allergen extraction. It has been estimated that about 6-10% of the population and 15-50% of atopics are sensitized to fungal allergens. In studies where Alternaria extracts were used alone, overall rates for allergy patients ranged from 3% to 36%; for asthmatics the rate was 7-39%. A study of California allergy patients showed nine different fungal extracts were necessary to detect 90% of

Page 23 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

mold allergy patients (Committee for the Assessment of Asthma and Indoor Air (Institute of Medicine), 2000). Fungal skin sensitivity rates increased with age. Because fungal allergens can cause a strong IgG response, it may block IgE allergy skin responses; this could lead to an underestimation of prevalence of fungal allergy in population studies. Population studies of persons suffering from asthma report relationships to mold exposure (Committee for the Assessment of Asthma and Indoor Air (Institute of Medicine), 2000). Many of studies investigated Alternaria as a risk factor for asthma. There have been reports linking indoor Aspergillus and asthma in school children. Associations between asthma and other mold/fungi have been published; Penicillium, Cladosporium and Bacillus have been incriminated (Committee for the Assessment of Asthma and Indoor Air (Institute of Medicine), 2000). Other types of correlation between asthma and indoor parameters have been explored. Studies have mentioned "visible mold", "dampness indicators", "mold growth indicators", "total dampness" as showing relationships with asthma. In one study, homes having: musty odor, visible mold growth, water intrusion, high humidity and limited ventilation showed higher fungal spore counts than dry homes. Visible mold has been correlated with high concentrations of Cladosporium spores (but not total spores) in one investigation. Damp conditions are associated with the existence of physician-diagnosed asthma and with the presence of symptoms considered to reflect asthma. Therefore, dampness may exacerbate existing asthma. Symptoms prevalence among asthmatics is also related to home dampness indicators. Supposedly, dampness may exacerbate existing asthma. The factors related to dampness that actually leads to the development of symptoms and asthma exacerbation are not yet confirmed but likely relate to dust mites and fungal allergens. The Institute of Medicine concluded that there is sufficient evidence of an association between fungal growth exposure and symptom exacerbation in sensitized asthmatics. Exposure may also be related to nonspecific chest symptoms. There is inadequate or insufficient evidence to determine causation of asthma; in other words, whether or not there is an association between fungal exposure and development of asthma in persons without previous allergy to mold and without previous asthma. 8. CONCLUSIONS Molds are common and important allergens. Molds are not the dominant allergens for most people. For example, dust mite, plant allergens and furry pets are much more potent causes of allergy. The molds that reside outdoor are far more important than indoor ones. Normal building materials and furnishings provide ample nutrition for many species of molds but they can grow and amplify indoors. Where mold grows indoors, there is an inappropriate source of water that must be corrected before remediation of the mold colonization can succeed. Mold/fungi can exacerbate allergic symptoms in persons sensitized to the mold. Moisture and dampness are very important factors for causing exacerbation of symptoms in these persons. Dust mites are also influenced by humidity and moisture and may also be a factor in the exacerbation of symptoms. As of date, there is no conclusive proof that indoor mold actually causes asthma in persons previously not sensitize to mold and without asthma symptoms. For most allergic individuals the reactions will be limited to rhinitis, sinusitis, or asthma. Superficial fungal infections of the skin and nails are relatively common in normal individuals, but those infections are readily treated and generally resolve without complication. This type of infection is not believed to be caused by mold growth indoors. Mold growth in home, school, or office environments is not a source of infections or "mycotoxicosis". Fungal infections of deeper tissues are rare and in general are limited to persons with severely impaired immune systems. The leading pathogenic fungi for persons with impaired immune function, Candida,

Page 24 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

Cryptococcus, Histoplasma, and Coccidioides, may find their way indoors with outdoor air but normally do not grow or propagate indoors. Due to the ubiquity of fungi in the environment, it is not possible to prevent immune-compromised individuals from being exposed to molds and fungi outside the confines of hospital isolation units. These individuals can only be advised to avoid recognizable reservoirs, e.g., dead vegetation both indoors and outdoors. Occupational diseases are recognized in association with inhalation exposure to fungi, bacteria, and other organic matter, usually in very special industrial or agricultural settings. Despite a voluminous literature on the subject, the causal association between breathing in mycotoxin and development of human disease remains weak and unproven. One mold in particular, Stachybotrys chartarum is blamed for an array of maladies when it is found indoors. Despite its well-known ability to produce mycotoxins under appropriate growth conditions (in culture media), years of intensive study have failed to conclusively establish that exposure to Stachybotrys chartarum in home, school, or office environments is a cause of serious adverse human health. Levels of mycotoxin exposure in the indoor environment, the limited ability of Stachybotrys spores to become airborne and the dose-response data in animals suggest that disease caused by breathing in a "toxic dose" of Stachybotrys mycotoxins is highly unlikely at best, even for the hypothetically most vulnerable subpopulations. The term "toxic mold" is a misnomer. In humans, mold does not cause unusual syndromes such as chronic fatigue, chemical sensitivity, toxic encephalopathy or neurotoxic manifestations. Mold growth in the home, school, or office environment should not be tolerated because mold physically destroys the building materials on which it grows, mold growth is unsightly and may produce offensive odors, and mold may produce allergic responses in susceptible individuals. When mold colonization is discovered in the home, school, or office, it should be remediated after the source of the moisture that supports its growth is identified and eliminated.

Page 25 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

9. REFERENCES 1. Abbas, H. K., C. J. Mirocha, et al. (1984). "Mycotoxins produced from fungi isolated from foodstuffs and soil: comparison of toxicity in fibroblasts and rat feeding tests." Applied & Environmental Microbiology 48(3): 654-61. Abdel-Hafez, S. I., I. A. el-Kady, et al. (1987). "Mycoflora and trichothecene toxins of paddy grains from Egypt." Mycopathologia 100(2): 103-12. Abdel-Hafez, S. I., A. H. Maubasher, et al. (1978). "Cellulose-decomposing fungi of salt marshes in Egypt." Folia Microbiologica 23(1): 37-44. Abdel-Hafez, S. I., A. H. Moubasher, et al. (1990). "Fungal flora associated with combine harvester wheat and sorghum dusts from Egypt." Journal of Basic Microbiology 30(7): 46779. Abdel-Hafez, S. I. and A. A. Shoreit (1985). "Mycotoxins producing fungi and mycoflora of air-dust from Taif, Saudi Arabia." Mycopathologia 92(2): 65-71. Abdel-Hafez, S. I., A. A. Shoreit, et al. (1986). "Mycoflora and mycotoxin-producing fungi of air-dust particles from Egypt." Mycopathologia 93(1): 25-32. Aerts, G. M. and C. K. De Bruyne (1981). "Effects of alcohols on hydrolysis catalyzed by beta-D-glucosidase from Stachybotrys atra." Biochimica et Biophysica Acta 660(2): 31724. Ahman, M., A. Lundin, et al. (2000). "Improved health after intervention in a school with moisture problems." Indoor Air-International Journal of Indoor Air Quality & Climate 10(1): 57-62. Akkmeteli, M. A. (1977). "Epidemiological features of the mycotoxicoses." Annales de la Nutrition et de l'Alimentation 31(4-6): 957-75.

2. 3. 4.

5. 6. 7.

8.

9.

10. Alberti, C., A. Bouakline, et al. (2001). "Relationship between environmental fungal contamination and the incidence of invasive aspergillosis in haematology patients." Journal of Hospital Infection 48(3): 198-206. 11. American Conference of Governmental Industrial Hygienists, I. (1999). Bioaerosols: Assessment and control. Cincinnati, ACGIH. 12. Anderson, K., G. Morris, et al. (1996). "Aspergillosis in immunocompromised paediatric patients: associations with building hygiene, design, and indoor air." Thorax 51(3): 256-61. 13. Andersson, M. A., M. Nikulin, et al. (1997). "Bacteria, molds, and toxins in water-damaged building materials." Applied & Environmental Microbiology 63(2): 387-93. 14. Andersen, B., K. F. Nielsen, et al. (2002). "Characterization of Stachybotrys from waterdamaged buildings based on morphology, growth, and metabolite production." Mycologia 94: 392-403. 15. Andriienko, O. V. and O. M. Zachenko (1997). "Certain peculiarities of biological action of the stachybotryotoxin preparations." Mikrobiolohichnyi Zhurnal 59(3): 41-6. 16. Angulo-Romero, J., F. Infante-Garcia, et al. (1996). Pathogenic and antigenic fungi in school dust of the south of Spain. Aerobiology. M. Muilenberg and H. A. Burge. Baco Raton, FL, CRC Press, Inc-Lewis Publishers.

Page 26 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

17. Anonymous (1996). "Molds, fungi cause sick building syndrome [news]." Occup Health Safety 65(1): 13-4. 18. Apostolakos, M. J., H. Rossmoore, et al. (2001). "Hypersensitivity pneumonitis from ordinary residential exposures." Environmental Health Perspectives 109(9): 979-81. 19. Archambault, C., G. Coloccia, et al. (1998). "Characterization of an endo-1,3-beta-Dglucanase produced during the interaction between the mycoparasite Stachybotrys elegans and its host Rhizoctonia solani." Canadian Journal of Microbiology 44(10): 989-97. 20. Auger, P. L., P. Goudreau, et al. (1994). "Clinical experience with patients suffering from a chronic fatigue like syndrome and repeated upper respiratory infections in relation to airborne molds." Am J Indust Med 25: 41-42. 21. Bagy, M. M. (1986). "Fungi on the hair of large mammals in Egypt." Mycopathologia 93(2): 73-5. 22. Bagy, M. M. and Y. M. Gohar (1988). "Mycoflora of air-conditioners dust from Riyadh, Saudi Arabia." Journal of Basic Microbiology 28(9-10): 571-7. 23. Bardana, E. J., Jr. (1997). "Sick building syndrome--a wolf in sheep's clothing." Annals of Allergy, Asthma, & Immunology 79(4): 283-93; quiz 293-4. 24. Bardana, E. J., Jr. (2001). "Indoor pollution and its impact on respiratory health." Annals of Allergy, Asthma, & Immunology 87(6 Suppl 3): 33-40. 25. Barnes, C., J. Tuck, et al. (2001). "Allergenic materials in the house dust of allergy clinic patients." Annals of Allergy, Asthma, & Immunology 86(5): 517-23. 26. Barth, E., N. Talbott, et al. (2002). "Evaluation of bioaerosol exposures during conditioning of biofilter organic media beds." Applied Occupational & Environmental Hygiene 17(1): 104. 27. Bascom, R. (1992). "Differential responsiveness mechanisms." Ann N Y Acad Sci 641: 225-47. to irritant mixtures. Possible

28. Bata, A., B. Harrach, et al. (1985). "Macrocyclic trichothecene toxins produced by Stachybotrys atra strains isolated in Middle Europe." Applied & Environmental Microbiology 49(3): 678-81. 29. Baur, X., G. Richter, et al. (1992). "Increased prevalence of IgG-induced sensitization and hypersensitivity pneumonitis (humidifier lung) in nonsmokers exposed to aerosols of a contaminated air conditioner." Respiration 59(4): 211-4. 30. Bellin, P. and J. Schillinger (2001). "Comparison of field performance of the Andersen N6 single stage and the SAS sampler for airborne fungal propagules." Indoor Air-International Journal of Indoor Air Quality & Climate 11(1): 65-8. 31. Berardi, B. M. and E. Leoni (1993). "Indoor air climate and microbiological airborne: contamination in various hospital areas." Zentralbl Hyg Umweltmed 194(4): 405-18. 32. Betina, V. (1991). "Mycotoxins, analysis, and significance." Med Lab Sci 48: 271-282. 33. Bhat, R. V., S. R. Ramakrishna, et al. (1989). "Outbreak of trichothecene mycotoxicosis associated with consumption of mold-damaged wheat products in Kashmir Valley, India." Lancet 1 (8628): 35-37.

Page 27 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

34. Bissett, J. (1987). "Fungi associated with urea-formaldehyde foam insulation in Canada." Mycopathologia 99(1): 47-56. 35. Bjornsson, E., D. Norback, et al. (1995). "Asthmatic symptoms and indoor levels of microorganisms and house dust mites." Clin Exp Allergy 25(5): 423-31. 36. Bornehag, C. G., G. Blomquist, et al. (2001). "Dampness in buildings and health. Nordic interdisciplinary review of the scientific evidence on associations between exposure to "dampness" in buildings and health effects (NORDDAMP)." Indoor Air-International Journal of Indoor Air Quality & Climate 11(2): 72-86. 37. Breborowicz, A. and M. Bartkowiak (1992). "Analysis of hypersensitivity to airborne allergens in children with bronchial asthma using FAST." Pneumonol Alergol Pol 60(Suppl 1): 33-6. 38. Brooks, S. M. (1994). "Host susceptibility to indoor air pollution." J Allergy Clin Immunol 94: 344-51. 39. Brunekreef, B. (1992). "Damp housing and adult respiratory symptoms." Allergy 47(5): 498-502. 40. Brunekreef, B., D. W. Dockery, et al. (1989). "Home dampness and respiratory morbidity in children." Am Rev Respir Dis 140: 1363-1367. 41. Burge, H. A. (1995). "Aerobiology of the indoor environment." Occup Med 10(1): 27-40. 42. Burge, H. A. (2001). "Fungi: toxic killers or unavoidable nuisances?" Ann Allergy Asthma Immunol 87 (Suppl): 52-56. 43. Burge, H. A., D. L. Pierson, et al. (2000). "Dynamics of airborne fungal populations in a large office building." Current Microbiology 40(1): 10-6. 44. Burr, M. L. (2001). "Health effects of indoor molds." Reviews on Environmental Health 16(2): 97-103. 45. Buttner, M. P. and L. D. Stetzenbach (1993). "Monitoring airborne fungal spores in an experimental indoor environment to evaluate sampling methods and the effects of human activity on air sampling [published erratum appears in Appl Environ Microbiol 1993 May;59(5):1694]." Appl Environ Microbiol 59(1): 219-26. 46. Caldas, F., R. Fox, et al. (1995). Indoor Air Pollution. Environmental Medicine. S. Brooks, Gochfeld, M, Schenker, M, Year Books Mosby: 419-437. 47. CDC, Centers for Disease Control and Prevention. (1994). "Acute pulmonary hemorrhage/hemosiderosis among infants-Cleveland, January 1993-November 1994." MMWR - Morbidity & Mortality Weekly Report 43: 881-883. 48. CDC, Centers for Disease Control and Prevention. (1997). "Update: pulmonary hemorrhage/hemosiderosis among infants--Cleveland, Ohio, 1993-1996." MMWR Morbidity & Mortality Weekly Report 46(2): 33-5. 49. CDC, Centers for Disease Control and Prevention. (1999). Report of members of the CDC External Expert Panel on Acute Idiopathic Pulmonary Hemorrhage in Infants-A synthesis 1999. Atklanta GA, CDC, Centers for Disease Control and Prevention: 1-96.

Page 28 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

50. CDC, Centers for Disease Control and Prevention. (2000). "Update: Pulmonary hemorrhage/hemosiderosis among infants--Cleveland, Ohio, 1993-1996." MMWR Morbidity & Mortality Weekly Report 49(9): 180-4. 51. Chew, G. L., J. Douwes, et al. (2001). "Fungal extracellular polysaccharides, beta (1-->3)glucans and culturable fungi in repeated sampling of house dust." Indoor Air-International Journal of Indoor Air Quality & Climate 11(3): 171-8. 52. Ciegler, A. (1978). "Fungi that produce mycotoxins: Conditions and occurrence." Mycopathologia 65: 5-11. 53. Committee for the Assessment of Asthma and Indoor Air (Institute of Medicine) (2000). Clearing the Air. Washington, DC, National Academy Press. 54. Cooley, J. D., W. C. Wong, et al. (1998). "Correlation between the prevalence of certain fungi and sick building syndrome." Occupational & Environmental Medicine 55(9): 579-84. 55. Coulombe, R. A. (1993). "Symposium: Biological action of mycotoxins." J dairy Sci 76: 880-891. 56. Cox-Ganser, J. M., C. Y. Rao, et al. (2002). Work-related asthma symptoms correlate with environmental measures in a healthcare facility. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 57. Croft, W. A., B. B. Jarvis, et al. (1986). "Airborne outbreak of tricholthecene toxicosis." Atmosph Environ 20: 549-552. 58. Cruz-Perez, P., M. P. Buttner, et al. (2001). "Specific detection of Stachybotrys chartarum in pure culture using quantitative polymerase chain reaction." Molecular & Cellular Probes 15(3): 129-38. 59. Cuijpers, C. E., G. M. Swaen, et al. (1995). "Adverse effects of the indoor environment on respiratory health in primary school children." Environ Res 68: 11-23. 60. Custovic, A., S. C. Taggart, et al. (1996). "Exposure to house dust mite allergens and the clinical activity of asthma." J Allergy Clin Immunol 98(1): 64-72. 61. D. Amato, G. and F. T. Spieksma (1995). "Aerobiologic and clinical aspects of mould allergy in Europe." Allergy 50(11): 870-7. 62. Dales, R. and e. al (1998). "Influence of residential fungal contamination on peripheral blood lymphocyte populations in children." Arch Environ Health 53: 190-195. 63. Dales, R., Burnett, R, Zwanenburg, H (1991). "Adverse health effects among adults exposed to home dampness and molds." Am Rev Respir Dis 143: 505-509. 64. Dales, R., Miller, D (1999). "Residential fungal contamination and health: microbial cohabitants as covariates." Environ Health Perspect 107 (Suppl): 481-483. 65. Dales, R., Zwanenburg, H, Burnett, R, Franklin, CA (1991). "Respiratory health effects of home dampness and molds among Canadian children." Am J Epidemiol 134: 196-203. 66. Dales, R. E., D. Miller, et al. (1999). "Testing the association between residential fungus and health using ergosterol measures and cough recordings." Mycopathologia 147: 181186.

Page 29 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

67. de Gussem, R. L., G. M. Aerts, et al. (1978). "Purification and properties of an induced beta-D-glucosidase from Stachybotrys atra." Biochimica et Biophysica Acta 525(1): 14253. 68. Dearborn, D. G., I. Yike, et al. (1999). "Overview of investigations into pulmonary hemorrhage among infants in Cleveland, Ohio." Environmental Health Perspectives 107(Suppl 3): 495-9. 69. Dharmage, S., M. Bailey, et al. (2001). "Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure." American Journal of Respiratory & Critical Care Medicine 164(1): 65-71. 70. Dose, K., A. Bieger-Dose, et al. (2001). "Survival of microorganisms under the extreme conditions of the Atacama Desert." Origins of Life & Evolution of the Biosphere 31(3): 287303. 71. Dotterud, L. K., L. H. Vorland, et al. (1995). "Viable fungi in indoor air in homes and schools in the Sor-Varanger community during winter." Pediatr Allergy Immunol 6(4): 1816. 72. Eskola, M. (2002). Study on Trichothecenes, Zearalenone and Ochratoxin A in Finnish Cereals: Occurrence and Analytical Thechniques. Agriculture and Forestry. Helsinki, University of Helsinki: 78. 73. Elidemir, O., G. N. Colasurdo, et al. (1999). "Isolation of Stachybotrys from the lung of a child with pulmonary hemosiderosis." Pediatrics 104(4 Pt 1): 964-6. 74. el-Kady, I. A., S. S. el-Maraghy, et al. (1991). "Mycotoxin production on different cultivars and lines of broad bean (Vicia faba L.) seeds in Egypt." Mycopathologia 113(3): 165-9. 75. El-Kady, I. A. and M. H. Moubasher (1982). "Some cultural conditions that control production of verrucarin J, a cytotoxic metabolite of Stachybotrys chartarum." Zentralblatt fur Mikrobiologie 137(3): 241-6. 76. Ellringer, P. J., K. Boone, et al. (2000). "Building materials used in construction can affect indoor fungal levels greatly." Aihaj 61(6): 895-9. 77. el-Maghraby, O. M. and M. A. Abdel-Sater (1993). "Mycoflora and natural occurrence of mycotoxins in tobacco from cigarettes in Egypt." Zentralblatt fur Mikrobiologie 148(4): 25364. 78. el-Maghraby, O. M., G. A. Bean, et al. (1991). "Macrocyclic trichothecenes produced by Stachybotrys isolated from Egypt and eastern Europe." Mycopathologia 113(2): 109-15. 79. Engvall, K., C. Norrby, et al. (2001). "Asthma symptoms in relation to building dampness and odour in older multifamily houses in Stockholm." International Journal of Tuberculosis & Lung Disease 5(5): 468-77. 80. Engvall, K., C. Norrby, et al. (2001). "Sick building syndrome in relation to building dampness in multi-family residential buildings in Stockholm." International Archives of Occupational & Environmental Health 74(4): 270-8. 81. Environmental Health Issues Forum (1998). "Fatal fungus [news]." Environ Health Perspect 106: A11-A12. 82. Eppley, R. M. (1975). "Methods for the detection of trichothecenes." Journal - Association of Official Analytical Chemists 58(5): 906-8.

Page 30 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

83. Etzel, R. A., E. Montana, et al. (1998). "Acute pulmonary hemorrhage in infants associated with exposure to Stachybotrys atra and other fungi." Archives of Pediatrics & Adolescent Medicine 152(8): 757-762. 84. Fekete, C., A. Logrieco, et al. (1997). "Screening of fungi for the presence of the trichodiene synthase encoding sequence by hybridization to the Tri5 gene cloned from Fusarium poae." Mycopathologia 138(2): 91-7. 85. Fischer, G., T. Muller, et al. (2000). "Exposure to airborne fungi, MVOC and mycotoxins in biowaste-handling facilities." International Journal of Hygiene & Environmental Health 203(2): 97-104. 86. Flappan, S. M., J. Portnoy, et al. (1999). "Infant pulmonary hemorrhage in a suburban home with water damage and mold (Stachybotrys atra)." Environmental Health Perspectives 107(11): 927-30. 87. Fujioka, T., K. Yao, et al. (1996). "Epi-cochlioquinone A, a novel acyl-CoA : cholesterol acyltransferase inhibitor produced by Stachybotrys bisbyi." Journal of Antibiotics 49(5): 409-13. 88. Fung, F., R. Clark, et al. (1998). "Stachybotrys, a mycotoxin-producing fungus of increasing toxicologic importance." Journal of Toxicology - Clinical Toxicology 36(1-2): 7986. 89. Fung, F. and W. G. Hughson (2002). Health effects of indoor fungal bioaerosol exposure. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 90. Fung, F., D. Tappen, et al. (2000). "Alternaria-associated asthma." Applied Occupational & Environmental Hygiene 15(12): 924-7. 91. Garrett, M. H. and e. al (1998). "Indoor airborne fungal spores, house dampness and associations with environmental factors and respiratory health in children." Clin Exp Allergy 28 (4): 459-467. 92. Garrison, R. A., L. D. Robertson, et al. (1993). "Effect of heating-ventilation-air conditioning system sanitation on airborne fungal populations in residential environments." Ann Allergy 71(6): 548-56. 93. Garvey, J. (1994). "Developing an integrated approach to SBS (Sick Building Syndrome)." Occup Health (Lond) 46(2): 50-3. 94. Gehring, U., G. Bolte, et al. (2001). "Exposure to endotoxin decreases the risk of atopic eczema in infancy: a cohort study." Journal of Allergy & Clinical Immunology 108(5): 84754. 95. Gehring, U., J. Douwes, et al. (2001). "Beta(1-->3)-glucan in house dust of German homes: housing characteristics, occupant behavior, and relations with endotoxins, allergens, and molds." Environmental Health Perspectives 109(2): 139-44. 96. Gehring, U., J. Heinrich, et al. (2001). "Respiratory symptoms in relation to indoor exposure to mite and cat allergens and endotoxins. Indoor Factors and Genetics in Asthma (INGA) Study Group." European Respiratory Journal 18(3): 555-63. 97. Gereda, J. E., M. D. Klinnert, et al. (2001). "Metropolitan home living conditions associated with indoor endotoxin levels." Journal of Allergy & Clinical Immunology 107(5): 790-6.

Page 31 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

98. Godish, R. K., T. Godish, et al. (1996). "Airborne mold levels in Australian houses." Indoor Built Environ 5: 148-154. 99. Gonzalez-Vila, F. J., C. Saiz-Jimenez, et al. (1978). "13C nuclear magnetic resonance spectra of fungal melanins." Zeitschrift fur Naturforschung. Section C. Journal of Biosciences 33(3-4): 291-3. 100. Gorny, R. L., J. Dutkiewicz, et al. (1999). "Size distribution of bacterial and fungal bioaerosols in indoor air." Annals of Agricultural & Environmental Medicine 6(2): 105-13. 101. Gravesen, S., P. A. Nielsen, et al. (1999). "Microfungal contamination of damp buildings-examples of risk constructions and risk materials." Environmental Health Perspectives 107(Suppl 3): 505-8. 102. Gustafsson, D., K. Andersson, et al. (1996). "Significance of indoor environment for the development of allergic symptoms in children followed up to 18 months of age." Allergy 51(11): 789-95. 103. Guyette, G., D. Rennie, et al. (1992). "User guide to the medical literature: A manual for evidence-based clinical practice." JAMA 268: 2420-2425. 104. Haijtos, I., B. Harrach, et al. (1983). "Stachybotryotoxicosis as a predisposing factor of ovine systemic pasteurellosis." Acta Vet Hung 31: 181-188. 105. Hardin, D., B. J. Kelman, et al. (2002). Adverse human health effects associated with molds in the indoor environment. Personal communication. 106. Harrach, B., A. Bata, et al. (1983). "Isolation of satratoxins from the bedding straw of a sheep flock with fatal stachybotryotoxicosis." Applied & Environmental Microbiology 45(5): 1419-22. 107. Harrach, B., C. J. Mirocha, et al. (1981). "Macrocyclic trichothecene toxins produced by a strain of Stachybotrys atra from Hungary." Applied & Environmental Microbiology 41(6): 1428-32. 108. Harrison, J., C. A. Pickering, et al. (1992). "An investigation of the relationship between microbial and particulate indoor air pollution and the sick building syndrome." Respir Med 86(3): 225-35. 109. Haugland, R. A. and J. L. Heckman (1998). "Identification of putative sequence specific PCR primers for detection of the toxigenic fungal species Stachybotrys chartarum." Molecular & Cellular Probes 12(6): 387-96. 110. Haugland, R. A., J. L. Heckman, et al. (1999). "Evaluation of different methods for the extraction of DNA from fungal conidia by quantitative competitive PCR analysis." Journal of Microbiological Methods 37(2): 165-76. 111. Haugland, R. A., S. J. Vesper, et al. (1999). "Quantitative measurement of Stachybotrys chartarum conidia using real time detection of PCR products with the TaqMan(TM)fluorogenic probe system." Molecular & Cellular Probes 13(5): 329-40. 112. Heidelberg, J. F., M. Shahamat, et al. (1997). "Effect of aerosolization on culturability and viability of gram-negative bacteria." Applied & Environmental Microbiology 63(9): 3585-8. 113. Hendry, K. M. and E. C. Cole (1993). "A review of mycotoxins in indoor air." J Toxicol Environ Health 38(2): 183-98.

Page 32 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

114. Hinkley, S. F., E. P. Mazzola, et al. (2000). "Atranones A-G, from the toxigenic mold Stachybotrys chartarum." Phytochemistry 55(6): 663-73. 115. Hirsch, T. (1999). "Indoor allergen exposure in west and East Germany: a cause for different prevalences of asthma and atopy?" Reviews on Environmental Health 14(3): 15968. 116. Hirsch, T., M. Hering, et al. (2000). "House-dust-mite allergen concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows and central heating systems." Allergy 55(1): 79-83. 117. Hirvonen, M. R. and e. al. (1999). "Nitric oxide and proinflammatory cytokines in nasal lavage fluid associated with symptoms and exposure to mold microbes." Am J Respir Crit Care Med 160 (6): 1943-1946. 118. Hodgson, M. J., P. Morey, et al. (1998). "Building-associated pulmonary disease from exposure to Stachybotrys chartarum and Aspergillus versicolor." Journal of Occupational & Environmental Medicine 40(3): 241-9. 119. Hoffman, R. E., R. C. Wood, et al. (1993). "Building-related asthma in Denver office workers." Am J Public Health 83(1): 89-93. 120. Horvath, E. P. (1997). "Building-related illness and sick building syndrome: from the specific to the vague." Cleveland Clinic Journal of Medicine 64(6): 303-9. 121. Hu, W., R. Narasaki, et al. (2001). "Selective production of staplabin and SMTPs in cultures of Stachybotrys microspora fed with precursor amines." Journal of Antibiotics 54(11): 962-6. 122. Huang, J., K. Aoyama, et al. (1995). "Respiratory effects and skin allergy in workers exposed to tetrachloroisophthalonitrile." Bull Environ Contam Toxicol 55(2): 320-4. 123. Huang, S. W. and J. W. Kimbrough (1997). "Mold allergy is a risk factor for persistent coldlike symptoms in children." Clin Pediatr (Phila) 107 (Suppl 3): 489-494. 124. Immonen, J., T. Meklin, et al. (2001). "Skin-prick test findings in students from moistureand mould-damaged schools: a 3-year follow-up study." Pediatric Allergy & Immunology 12(2): 87-94. 125. Jarvis, B. B., Y. W. Lee, et al. (1986). "Trichothecenes produced by Stachybotrys atra from Eastern Europe." Applied & Environmental Microbiology 51(5): 915-8. 126. Jarvis, B. B., J. Salemme, et al. (1995). "Stachybotrys toxins. 1." Natural Toxins 3(1): 10-6. 127. Jarvis, B. B., W. G. Sorenson, et al. (1998). "Study of toxin production by isolates of Stachybotrys chartarum and Memnoniella echinata isolated during a study of pulmonary hemosiderosis in infants." Applied & Environmental Microbiology 64(10): 3620-5. 128. Jarvis, B. B., Y. Zhou, et al. (1996). "Toxigenic molds in water-damaged buildings: dechlorogriseofulvins from Memnoniella echinata." Journal of Natural Products 59(6): 5534. 129. Jarvis, J. Q. and P. R. Morey (2001). "Allergic respiratory disease and fungal remediation in a building in a subtropical climate." Applied Occupational & Environmental Hygiene 16(3): 380-8.

Page 33 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

130. Jedrychowski, W. and E. Flak (1998). "Separate and combined effects of the outdoor and indoor air quality on chronic respiratory symptoms adjusted for allergy among preadolescent children." Int J Occup Med Environ Health 11: 19-35. 131. Joffe, A. Z. (1983). "Environmental conditions conducive." 132. Joffe, A. Z. (1983). "Environmental conditions conducive to Fusarium toxin formation causing serious outbreaks in animals and man." Vet Res Comm 7: 187-193. 133. Johanning, E., R. Biagini, et al. (1996). "Health and immunology study following exposure to toxigenic fungi (Stachybotrys chartarum) in a water-damaged office environment." International Archives of Occupational & Environmental Health 68(4): 207-18. 134. Johanning, E., P. Landsbergis, et al. (1999). "Clinical experience and results of a Sentinel Health Investigation related to indoor fungal exposure." Environmental Health Perspectives 107(Suppl 3): 489-94. 135. Johanning, E., P. Morey, et al. (1993). Clinical-epidemiological investigation of health effects caused by Stachybotrys atra building contamination. 1993. Indoor Air '93 Proceedings. 136. Karunasena, E., N. Markham, et al. (2001). "Evaluation of fungal growth on cellulosecontaining and inorganic ceiling tile." Mycopathologia 150(2): 91-5. 137. Kaufman, T. S., R. P. Srivastava, et al. (1995). "Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors." Journal of Medicinal Chemistry 38(9): 1437-45. 138. Kawai, S., K. Takatori, et al. (1991). "Mycological examination on skin surface of cynomolgus monkeys (Macaca fasicularis) [in Japanese]." Jikken Dobutsu 40: 549-551. 139. Khan, Z. U., M. A. Khan, et al. (1999). "Aspergillus and other moulds in the air of Kuwait." Mycopathologia 146(1): 25-32. 140. Klanova, K. (2000). "The concentrations of mixed populations of fungi in indoor air: rooms with and without mould problems; rooms with and without health complaints." Central European Journal of Public Health 8(1): 59-61. 141. Koch, A., K. J. Heilemann, et al. (2000). "Indoor viable mold spores--a comparison between two cities, Erfurt (eastern Germany) and Hamburg (western Germany)." Allergy 55(2): 176-80. 142. Kordula, T., A. Banbula, et al. (2002). "Isolation and properties of stachyrase A, a chymotrypsin-like serine proteinase from Stachybotrys chartarum." Infection & Immunity 70(1): 419-21. 143. Koskinen, O. M., T. M. Husman, et al. (1999). "The relationship between moisture or mould observations in houses and the state of health of their occupants." European Respiratory Journal 14(6): 1363-7. 144. Kozak, P. P., Jr., J. Gallup, et al. (1980). "Currently available methods for home mold surveys. II. Examples of problem homes surveyed." Annals of Allergy 45(3): 167-76. 145. Kreiss, K. (1993). "The sick building syndrome in office buildings--a breath of fresh air [editorial; comment]." N Engl J Med 328(12): 877-8.

Page 34 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

146. Krishnamurthy, T. and E. W. Sarver (1988). "Mass spectral investigations on trichothecene mycotoxins. V. Direct analysis of satratoxins by tandem mass spectrometric techniques." Biomedical & Environmental Mass Spectrometry 15(4): 185-91. 147. Land, C. J., H. Lundstrom, et al. (1993). "Production of tremorgenic mycotoxins by isolates of Aspergillus fumigatus from sawmills in Sweden." Mycopatholgia 124: 87-93. 148. Landers, F., H. W. Meyer, et al. (2001). "Serum IgE specific to indoor moulds, measured by basophil histamine release, is associated with building-related symptoms in damp buildings." Inflammation Research 50(4): 227-31. 149. Larsen, F. O., L. H. Christensen, et al. (1996). "Microfungi in indoor air are able to trigger histamine release by non-IgE-mediated mechanisms." Inflamm Res 45(Suppl 1): S23-4. 150. Lass-Florl, C., P. Rath, et al. (2000). "Aspergillus terreus infections in haematological malignancies: molecular epidemiology suggests association with in-hospital plants." Journal of Hospital Infection 46(1): 31-5. 151. Lau, S., S. Illi, et al. (2000). "Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group." Lancet 356(9239): 1392-7. 152. Lawrence, R. and D. Martin (2001). "Moulds, moisture and microbial contamination of First Nations housing in British Columbia, Canada." International Journal of Circumpolar Health 60(2): 150-6. 153. Lee, H. B. and N. Magan (2000). "Impact of environment and interspecific interactions between spoilage fungi and Aspergillus ochraceus on growth and ochratoxin production in maize grain." International Journal of Food Microbiology 61(1): 11-6. 154. Lee, M. G., S. Li, et al. (1999). "Effects of satratoxins and other macrocyclic trichothecenes on IL-2 production and viability of EL-4 thymoma cells." Journal of Toxicology & Environmental Health. Part A 57(7): 459-74. 155. Li, C. S., C. W. Hsu, et al. (1997). "Dampness and respiratory symptoms among workers in daycare centers in a subtropical climate." Archives of Environmental Health 52(1): 6871. 156. Li, C. S., C. W. hsu, et al. (1997). "Indoor pollution and sick building syndrome symptoms among workers in day-care centers." Arch Environ Health 52: 200-207. 157. Li, C. S. and L. Y. Hsu (1996). "Home dampness and childhood respiratory symptoms in a subtropical climate." Arch Environ Health 51(1): 42-6. 158. Li, C. S. and L. Y. Hsu (1997). "Airborne fungus allergen in association with residential characteristics in atopic and control children in subtropical region." Arch Environ Health 52 (1): 72-79. 159. Li, C. S., L. Y. Hsu, et al. (1995). "Fungus allergens inside and outside the residences of atopic and control children." Arch Environ Health 50(1): 38-43. 160. Li, D.-W., B. Kendrick, et al. (2002). Causal Influences of airborne fungi and other factors on symptoms of respiratory allergies. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 161. MacNeil, L., T. Kauri, et al. (1995). "Molecular techniques and their potential application in monitoring the microbiological quality of indoor air." Can J Microbiol 41(8): 657-65.

Page 35 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

162. Mahmoudi, M. and M. E. Gershwin (2000). "Sick building syndrome. III. Stachybotrys chartarum." Journal of Asthma 37(2): 191-8. 163. Mansour, M., B. P. Lanphear, et al. (2001). "A side-by-side comparison of sampling methods for settled, indoor allergens." Environmental Research 87(1): 37-46. 164. Mason, C. D., T. G. Rand, et al. (2001). "Effects of Stachybotrys chartarum on surfactant convertase activity in juvenile mice." Toxicology & Applied Pharmacology 172(1): 21-8. 165. Mason, C. D., T. G. Rand, et al. (1998). "Effects of Stachybotrys chartarum (atra) conidia and isolated toxin on lung surfactant production and homeostasis." Natural Toxins 6(1): 2733. 166. McCrae, K. C., T. Rand, et al. (2001). "Analysis of pulmonary surfactant by Fouriertransform infrared spectroscopy following exposure to Stachybotrys chartarum (atra) spores." Chemistry & Physics of Lipids 110(1): 1-10. 167. Mendell, M. J. (1993). "Non-specific symptoms in office workers: a review and summary of the literature." Indoor Air-International Journal of Indoor Air Quality & Climate 3: 227-236. 168. Menetrez, M. Y., K. K. Foarde, et al. (2001). "An analytical method for the measurement of nonviable bioaerosols." Journal of the Air & Waste Management Association 51(10): 143642. 169. Menzies, D. and J. Bourbeau (1997). "Building-related illnesses." N Engl J Med 337: 15241531. 170. Menzies, D., P. Comtois, et al. (1998). "Aeroallergens and work-related respiratory symptoms among office workers." Journal of Allergy & Clinical Immunology 101(1 Pt 1): 38-44. 171. Menzies, D., R. M. Tamblyn, et al. (1996). "Exposure to varying levels of contaminants and symptoms among workers in two office building." Am J Public Health 86: 1629-1633. 172. Miller, J. (1992). "Fungi as contaminants in indoor air." Atmosph Environ 26A: 2163-2172. 173. Miller, J. D., P. D. Haisley, et al. (2000). "Air sampling results in relation to extent of fungal colonization of building materials in some water-damaged buildings." Indoor AirInternational Journal of Indoor Air Quality & Climate 10(3): 146-51. 174. Milton, D. K., K. U. Alwis, et al. (2001). "Enzyme-linked immunosorbent assay specific for (1-->6) branched, (1-->3)-beta-D-glucan detection in environmental samples." Applied & Environmental Microbiology 67(12): 5420-4. 175. Minkwitz, A. and G. Berg (2001). "Comparison of antifungal activities and 16S ribosomal DNA sequences of clinical and environmental isolates of Stenotrophomonas maltophilia." Journal of Clinical Microbiology 39(1): 139-45. 176. Miyazaki, W., H. Tamaoka, et al. (1980). "A complement inhibitor produced by Stachybotrys complement, nov. sp. K-76, a new species of fungi imperfecti." Microbiology & Immunology 24(11): 1091-108. 177. Montana, E., R. A. Etzel, et al. (1997). "Environmental risk factors associated with pediatric idiopathic pulmonary hemorrhage and hemosiderosis in a Cleveland community." Pediatrics 99: E5.

Page 36 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

178. Moritz, M., H. Peters, et al. (2001). "Capability of air filters to retain airborne bacteria and molds in heating, ventilating and air-conditioning (HVAC) systems." International Journal of Hygiene & Environmental Health 203(5-6): 401-9. 179. Moter, A. and U. B. Gobel (2000). "Fluorescence in situ hybridization (FISH) for direct visualization of microorganisms." Journal of Microbiological Methods 41(2): 85-112. 180. Murtoniemi, T., A. Nevalainen, et al. (2001). "Induction of cytotoxicity and production of inflammatory mediators in raw264.7 macrophages by spores grown on six different plasterboards." Inhalation Toxicology 13(3): 233-47. 181. Nakamura, M., Y. Ito, et al. (1995). "Stachybocins, novel endothelin receptor antagonists, produced by Stachybotrys sp. M6222. I. Taxonomy, fermentation, isolation and characterization." Journal of Antibiotics 48(12): 1389-95. 182. Nasman, A., G. Blomquist, et al. (1999). "Air sampling of fungal spores on filters. An investigation on passive sampling and viability." Journal of Environmental Monitoring 1(4): 361-5. 183. National Institute for Occupational Safety and Health (NIOSH) (1996). Hazard Evaluation and Technical Assistance Report (HHE 95-0160-2571). Cleveland, Ohio, CDC/NIOSH. 184. Nelson, N. A., J. D. Kaufman, et al. (1995). "Health symptoms and the work environment in four nonproblem United States office buildings." Scand J Work Environ Health 21: 51-59. 185. Newberne, P. M. (1974). "Mycotoxins: toxicity, carcinogenicity and influence of various nutritional conditions." Environ Health Perspect 9: 1-32. 186. Niels, K. F. and U. Thran (2001). "Fast methods for screening of trichothecenes in fungal cultures using gas chromatography-tandem mass spectrometry." Journal of Chromatography. A. 929(1-2): 75-87. 187. Nikulin, M., K. Reijula, et al. (1996). "Experimental lung mycotoxicosis in mice induced by Stachybotrys atra." International Journal of Experimental Pathology 77(5): 213-8. 188. Nikulin, M., K. Reijula, et al. (1997). "Effects of intranasal exposure to spores of Stachybotrys atra in mice." Fundamental & Applied Toxicology 35(2): 182-8. 189. Noble, J. A., S. A. Crow, et al. (1997). "Allergic fungal sinusitis in the southeastern USA: involvement of a new agent Epicoccum nigrum Ehrenb. ex Schlecht. 1824." Journal of Medical & Veterinary Mycology 35(6): 405-9. 190. Nolles, G., M. O. Hoekstra, et al. (2001). "Prevalence of immunoglobulin E for fungi in atopic children." Clinical & Experimental Allergy 31(10): 1564-70. 191. Norback, D., R. Walinder, et al. (2000). "Indoor air pollutants in schools: nasal patency and biomarkers in nasal lavage." Allergy 55: 163-170. 192. Norback, D., G. Wieslander, et al. (2000). "Asthma symptoms in relation to measured building dampness in upper concrete floor construction, and 2-ethyl-1-hexanol in indoor air." International Journal of Tuberculosis & Lung Disease 4(11): 1016-25. 193. Novotny, W. E. and A. Dixit (2000). "Pulmonary hemorrhage in an infant following 2 weeks of fungal exposure." Archives of Pediatrics & Adolescent Medicine 154(3): 271-5.

Page 37 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

194. Nozawa, Y., K. Yamamoto, et al. (1997). "Stachybotrin C and parvisporin, novel neuritogenic compounds. I. Taxonomy, isolation, physico-chemical and biological properties." Journal of Antibiotics 50(8): 635-40. 195. Nummi, N. and M. L. Niku-Paavola (1977). "Water soluble toxins of Stachybotrys alternans." Annales de la Nutrition et de l'Alimentation 31(4-6): 761-70. 196. Ogawa, K., M. Nakamura, et al. (1995). "Stachybocins, novel endothelin receptor antagonists, produced by Stachybotrys sp. M6222. II. Structure determination of stachybocins A, B and C." Journal of Antibiotics 48(12): 1396-400. 197. Ohm, M., J. E. Juto, et al. (1997). "Nasal histamine provocation of tenants in a sickbuilding residential area." American Journal of Rhinology 11(2): 167-75. 198. Omar, S. A. and m. A. Ismail (1999). "Microbial populations, ammonification and nitrification in soil treated with urea and inorganic salt." Folia Microbiologica 44: 205-212. 199. Ooi, P. L. and K. T. Goh (1997). "Sick building syndrome: an emerging stress-related disorder?" International Journal of Epidemiology 26(6): 1243-9. 200. Oren, I., N. Haddad, et al. (2001). "Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters." American Journal of Hematology 66(4): 257-62. 201. Page, E. H. and D. B. Trout (2001). "The role of Stachybotrys mycotoxins in buildingrelated illness." American Industrial Hygiene Association Journal 62(5): 644-8. 202. Palmgren, M. S. and L. S. Lee (1986). "Separation of mycotoxin-containing sources in grain dust and determination of their mycotoxin potential." Environ Health Perspect 66: 105-108. 203. Paoletti, P. (1995). "Application of biomarkers in population studies for respiratory nonmalignant diseases." Toxicology 101(1-2): 99-105. 204. Park, J. H., D. L. Spiegelman, et al. (2001). "Predictors of airborne endotoxin in the home." Environmental Health Perspectives 109(8): 859-64. 205. Pasanen, A. L. (2001). "A review: fungal exposure assessment in indoor environments." Indoor Air-International Journal of Indoor Air Quality & Climate 11(2): 87-98. 206. Pei-Chih, W., S. Huey-Jen, et al. (2000). "Characteristics of indoor and outdoor airborne fungi at suburban and urban homes in two seasons." Science of the Total Environment 253(1-3): 111-8. 207. Pfeiffer, R., Jr. (1993). "Flood-related upper respiratory infections [letter]." Iowa Med 83(10): 372-3. 208. Pieckova, E. and Z. Jesenska (1995). "The effect of chloroform-extractable secondary metabolites of filamentous fungi on the movement of respiratory tract cilia of one-day-old chicks in vitro." Folia Microbiologica 40(1): 123-7. 209. Pieckova, E. and Z. Jesenska (1999). "Microscopic fungi in dwellings and their health implications in humans." Annals of Agricultural & Environmental Medicine 6(1): 1-11. 210. Pieckova, E. and Z. Jesenska (1999). "Occurrence of itraconazole-tolerant micromycetes in the soil and food products." Folia Microbiologica 44(6): 677-82.

Page 38 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

211. Pitten, F. A., M. Scholler, et al. (2001). "Filamentous fungi and yeasts on mattresses covered with different encasings." European Journal of Dermatology 11(6): 534-7. 212. Platt, S. D., C. J. Martin, et al. (1989). "Damp housing, mould growth and symptomatic health state." British Medical Journal 289: 1673-1678. 213. Platts-Mills, T. A. E., N. Custis, et al. (2002). Asthma and indoor air. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 214. Pohland, A. E. (1977). "Studies concerning the metabolites produced by Stachybotrys atra, Penicillium islandicum, Penicillium viridicatum and Aspergillus versicolor." Annales de la Nutrition et de l'Alimentation 31(4-6): 663-84. 215. Prahl, P. (1992). "Reduction of indoor airborne mould spores." Allergy 47(4 Pt 2): 362-5. 216. Price, D. L. and D. G. Ahearn (1999). "Sanitation of wallboard colonized with Stachybotrys chartarum." Current Microbiology 39(1): 21-6. 217. Rainer, J., U. Peintner, et al. (2001). "Biodiversity and concentration of airborne fungi in a hospital environment." Mycopathologia 149(2): 87-97. 218. Rand, T. G., M. Mahoney, et al. (2002). "Microanatomical changes in alveolar type II cells in juvenile mice intratracheally exposed to Stachybotrys chartarum spores and toxin." Toxicological Sciences 65(2): 239-45. 219. Rao, C. Y., H. A. Burge, et al. (2000). "Reduction of pulmonary toxicity of Stachybotrys chartarum spores by methanol extraction of mycotoxins." Applied & Environmental Microbiology 66(7): 2817-21. 220. Rao, C. Y., H. A. Burge, et al. (2000). "The time course of responses to intratracheally instilled toxic Stachybotrys chartarum spores in rats." Mycopathologia 149(1): 27-34. 221. Rath, P. M. and R. Ansorg (2000). "Identification of medically important Aspergillus species by single strand conformational polymorphism (SSCP) of the PCR-amplified intergenic spacer region." Mycoses 43(11-12): 381-6. 222. Raunio, P., M. Karkkainen, et al. (2001). "Preliminary description of antigenic components characteristic of Stachybotrys chartarum." Environmental Research 85(3): 246-55. 223. Rayner, K. F. (1996). "Condensation and mould: the Canadian experience." J R Soc Health 116(2): 83-6. 224. Redlich, C. A., J. Sparer, et al. (1997). "Sick-building syndrome." Lancet 349(9057): 10136. 225. Reinikainen, L. M. and J. J. Jaakkola (2001). "Effects of temperature and humidification in the office environment." Archives of Environmental Health 56(4): 365-8. 226. Reinikainen, L. M., J. J. Jaakkola, et al. (1992). "The effect of air humidification on symptoms and perception of indoor air quality in office workers: a six-period cross-over trial." Arch Environ Health 47(1): 8-15. 227. Ren, P., T. M. Jankun, et al. (2001). "The relation between fungal propagules in indoor air and home characteristics." Allergy 56(5): 419-24. 228. Restrepo, A., D. J. Baumgardner, et al. (2000). "Clues to the presence of pathogenic fungi in certain environments." Medical Mycology 38(Suppl 1): 67-77.

Page 39 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

229. Robbins, C. A., L. J. Swenson, et al. (2000). "Health effects of mycotoxins in indoor air: a critical review." Applied Occupational & Environmental Hygiene 15(10): 773-84. 230. Roe, J. D., R. A. Haugland, et al. (2001). "Quantification of Stachybotrys chartarum conidia in indoor dust using real time, fluorescent probe-based detection of PCR products." Journal of Exposure Analysis & Environmental Epidemiology 11(1): 12-20. 231. Roponen, M., M. Toivola, et al. (2001). "Differences in inflammatory responses and cytotoxicity in RAW264.7 macrophages induced by Streptomyces Anulatus grown on different building materials." Indoor Air-International Journal of Indoor Air Quality & Climate 11(3): 179-84. 232. Rose, C. (1994). "Bioaerosols." West J Med 160(6): 566. 233. Ross, M. A., L. Curtis, et al. (2000). "Association of asthma symptoms and severity with indoor bioaerosols." Allergy 55(8): 705-11. 234. Rothman, A. L. and M. I. Weintraub (1995). "The sick building syndrome and mass hysteria." Neurol Clin 13(2): 405-12. 235. Rowan, N. J., C. M. Johnstone, et al. (1999). "Prediction of toxigenic fungal growth in buildings by using a novel modelling system." Applied & Environmental Microbiology 65(11): 4814-21. 236. Rudblad, S., K. Andersson, et al. (2001). "Nasal hyperreactivity among teachers in a school with a long history of moisture problems." American Journal of Rhinology 15(2): 135-41. 237. Ruhl, R. A., C. C. Chang, et al. (1993). "The sick building syndrome. II. Assessment and regulation of indoor air quality." J Asthma 30(4): 297-308. 238. Ruotsalainen, M., A. Hyvarinen, et al. (1995). "Production of reactive oxygen metabolites by opsonized fungi and bacteria isolated from indoor air, and their interactions with soluble stimuli, fMLP or PMA." Environ Res 69(2): 122-31. 239. Ryan, C. M. and L. A. Morrow (1992). "Dysfunctional buildings or dysfunctional people: an examination of the sick building syndrome and allied disorders." J Consult Clin Psychol 60(2): 220-4. 240. Ryan, T. J., L. W. Whitehead, et al. (2001). "Survey of the Asp f 1 allergen in office environments." Applied Occupational & Environmental Hygiene 16(6): 679-84. 241. Rylander, R. (1997). "Airborne (1-> 3)-beta-d-Glucan and airway disease in day-care center before and after renovation." Arch environ Health 52: 281-285. 242. Rylander, R. and R. H. Lin (2000). "(1-->3)-beta-D-glucan - relationship to indoor airrelated symptoms, allergy and asthma." Toxicology 152(1-3): 47-52. 243. Sabir, M., U. Shashikiran, et al. (1999). "Building related illnesses and indoor air pollution." Journal of the Association of Physicians of India 47(4): 426-30. 244. Sakamoto, K., E. Tsujii, et al. (1993). "FR901459, a novel immunosuppressant isolated from Stachybotrys chartarum No. 19392. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities." Journal of Antibiotics 46(12): 1788-98.

Page 40 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

245. Salvaggio, J. E. (1994). "Use and misuse of biomarker tests in "environmental conditions"." J Allergy Clin Immunol 94(2 Pt 2): 380-4. 246. Savilahti, R., J. Uitti, et al. (2000). "Respiratory morbidity among children following renovation of a water-damaged school." Archives of Environmental Health 55(6): 405-10. 247. Scheel, C. M., W. C. Rosing, et al. (2001). "Possible sources of sick building syndrome in a Tennessee middle school." Archives of Environmental Health 56(5): 413-7. 248. Scheff, P. A., V. K. Paulius, et al. (2000). "Indoor air quality in a middle school, Part II: Development of emission factors for particulate matter and bioaerosols." Applied Occupational & Environmental Hygiene 15(11): 835-42. 249. Schneider, D. J., W. F. Marasas, et al. (1979). "A field outbreak of suspected stachybotryotoxicosis in sheep." Journal of the South African Veterinary Association 50(2): 73-81. 250. Sega, K. and N. Kalinic (1994). "Sick building syndrome--a case study in Zagreb." Arh Hig Rada Toksikol 45(1): 1-10. 251. Seltzer, J. M. (1995). "Biologic contaminants." Occup Med 10(1): 1-25. 252. Seuri, M., K. Husman, et al. (2000). "An outbreak of respiratory diseases among workers at a water-damaged building--a case report." Indoor Air-International Journal of Indoor Air Quality & Climate 10(3): 138-45. 253. Shaban, G. M. (1996). "Further studies on Egyptian soil fungi: succession of sugar and osmophilic fungi in soil amended with five organic substrates." Mycopathologia 136(1): 3340. 254. Shinohara, C., K. Hasumi, et al. (1996). "Staplabin, a novel fungal triprenyl phenol which stimulates the binding of plasminogen to fibrin and U937 cells." Journal of Antibiotics 49(10): 961-6. 255. Shum, M. (2002). An overview of the health effects due to mold. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 256. Skov, P. (1992). "The sick building syndrome." Ann N Y Acad Sci 641: 17-20. 257. Skov, P., O. Valibjorn, et al. (1990). "Influence of indoor climate on the sick building syndrome in an office building." Scand J Work Environ Health 16: 363-371. 258. Smith, J. E., J. G. Anderson, et al. (1992). "Cytotoxic fungal spores in the indoor atmosphere of the damp domestic environment." FEMS Microbiol Lett 79(1-3): 337-43. 259. Smoragiewicz, W., B. Cossette, et al. (1993). "Trichothecene mycotoxins in the dust of ventilation systems in office buildings." Int Arch Occup Environ Health 65(2): 113-7. 260. Soine, L. (1995). "Sick building syndrome and gender bias: imperiling women's health." Soc Work Health Care 20(3): 51-65. 261. Sorenson, W. G., D. G. Frazer, et al. (1987). "Trichothecene mycotoxins in aerosolized conidia of Stachybotrys atra." Applied & Environmental Microbiology 53(6): 1370-5. 262. Spaul, W. A. (1994). "Building-related factors to consider in indoor air quality evaluations." J Allergy Clin Immunol 94(2 Pt 2): 385-9.

Page 41 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

263. Stachan, D. P., Flannigan, B., McCabe, E.M., McGarry, F. (1998). "Toxigenic fungi in a water-damaged building: an intervention study." Am J Indust Med 34: 183-190. 264. Stachan, D. P., Flannigan, B., McCabe, E.M., McGarry, F. and e. al (1990). "Quantification of airborne moulds in the homes of children with and without wheeze." Thorax 45 (5): 382387. 265. Stack, M. E. and R. M. Eppley (1980). "High pressure liquid chromatographic determination of satratoxins G and H in cereal grains." Journal - Association of Official Analytical Chemists 63(6): 1278-81. 266. Staib, F. (1992). "Pathogenic fungi in human dwellings." Mycoses 35(11-12): 289-92. 267. Stuart, B. P. and D. M. Bedell (1982). "Mycotoxicosis in swine." Vet Clin North Am Large Animal Pract 4: 377-388. 268. Su, H. J., P. C. Wu, et al. (2001). "Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan." Environmental Research 85(2): 135-44. 269. Su, H. J., P. C. Wu, et al. (2001). "Fungal exposure of children at homes and schools: a health perspective." Archives of Environmental Health 56(2): 144-9. 270. Sudakin, D. L. (1998). "Toxigenic fungi in a water-damaged building: an intervention study." American Journal of Industrial Medicine 34(2): 183-90. 271. Sudakin, D. L. (2000). "Stachybotrys chartarum: current knowledge of its role in disease." Medgenmed [Computer File]: Medscape General Medicine: E11. 272. Summerbell, R. C., F. Staib, et al. (1994). "Household hyphomycetes and other indoor fungi." J Med Vet Mycol 32(Suppl 1): 277-86. 273. Szathmary, C. I., C. J. Mirocha, et al. (1976). "Identification of mycotoxins produced by species of Fusarium and Stachybotrys obtained from Eastern Europe." Applied & Environmental Microbiology 32(4): 579-84. 274. Szponar, B. and L. Larsson (2000). "Determination of microbial colonization in waterdamaged buildings using chemical marker analysis by gas chromatography-mass spectrometry." Indoor Air-International Journal of Indoor Air Quality & Climate 10(1): 13-8. 275. Takahashi, F., K. Hasumi, et al. (1995). "Modulation of the plasma cholesteryl ester transfer by stachybotramide." Biochimica et Biophysica Acta 1258(1): 70-4. 276. Tamblyn, R. M., R. I. Menzies, et al. (1992). "The feasibility of using a double blind experimental cross-over design to study interventions for sick building syndrome." J Clin Epidemiol 45(6): 603-12. 277. Tantaoui-Elaraki, A., S. L. Mekouar, et al. (1994). "Toxigenic strains of Stachybotrys atra associated with poisonous straw in Morocco." Veterinary & Human Toxicology 36(2): 93-6. 278. Teeuw, K. B., C. M. Vandenbroucke-Grauls, et al. (1994). "Airborne gram-negative bacteria and endotoxin in sick building syndrome. A study in Dutch governmental office buildings." Arch Intern Med 154(20): 2339-45. 279. Terr, A. I. (2001). "Stachybotrys: relevance to human disease." Annals of Allergy, Asthma, & Immunology 87(6 Suppl 3): 57-63. 280. Thorn, A. (1998). "The sick building syndrome: a diagnostic dilemma." Social Science & Medicine 47(9): 1307-12.

Page 42 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

281. Thorn, A., M. Lewne, et al. (1996). "Allergic alveolitis in a school environment." Scandinavian Journal of Work, Environment & Health 22(4): 311-4. 282. Thorn, J., J. Brisman, et al. (2001). "Adult-onset asthma is associated with self-reported mold or environmental tobacco smoke exposures in the home." Allergy 56(4): 287-92. 283. Tripi, P. A., S. Modlin, et al. (2000). "Acute pulmonary haemorrhage in an infant during induction of general anaesthesia." Paediatric Anaesthesia 10(1): 92-4. 284. Trout, D., J. Bernstein, et al. (2001). "Bioaerosol lung damage in a worker with repeated exposure to fungi in a water-damaged building." Environmental Health Perspectives 109(6): 641-4. 285. Truscott, J. E., C. A. Gilligan, et al. (2000). "Quantitative analysis and model simplification of an epidemic model with primary and secondary infection." Bulletin of Mathematical Biology 62(2): 377-93. 286. Tuomi, T., K. Reijula, et al. (2000). "Mycotoxins in crude building materials from waterdamaged buildings." Applied & Environmental Microbiology 66(5): 1899-904. 287. Ueno, Y. (1985). "The toxicology of mycotoxins." Crit Rev Toxicol 14: 99-132. 288. Upadhyay, R. C. and M. Hofrichter (1993). "Effect of phenol on the mycelial growth and fructification in some of basidiomycetous fungi." Journal of Basic Microbiology 33(5): 3437. 289. Verhoeff, A. P., R. T. van Strien, et al. (1995). "Damp housing and childhood respiratory symptoms: the role of sensitization to dust mites and molds." Am J Epidemiol 141: 103110. 290. Verhoeff, A. P., J. H. van Wijnen, et al. (1992). "Presence of viable mould propagules in indoor air in relation to house damp and outdoor air." Allergy 47(2 Pt 1): 83-91. 291. Vesper, S., D. G. Dearborn, et al. (2000). "Evaluation of Stachybotrys chartarum in the house of an infant with pulmonary hemorrhage: quantitative assessment before, during, and after remediation." Journal of Urban Health 77(1): 68-85. 292. Vesper, S. J., D. G. Dearborn, et al. (2000). "Quantification of siderophore and hemolysin from Stachybotrys chartarum strains, including a strain isolated from the lung of a child with pulmonary hemorrhage and hemosiderosis." Applied & Environmental Microbiology 66(6): 2678-81. 293. Vesper, S. J., D. G. Dearborn, et al. (1999). "Hemolysis, toxicity, and randomly amplified polymorphic DNA analysis of Stachybotrys chartarum strains." Applied & Environmental Microbiology 65(7): 3175-81. 294. Vesper, S. J., M. L. Magnuson, et al. (2001). "Initial characterization of the hemolysin stachylysin from Stachybotrys chartarum." Infection & Immunity 69(2): 912-6. 295. Vujanovic, V., W. Smoragiewicz, et al. (2001). "Airborne fungal ecological niche determination as one of the possibilities for indirect mycotoxin risk assessment in indoor air." Environmental Toxicology 16(1): 1-8. 296. Waegemaekers, M., N. van Wageningen, et al. (1989). "Respiratory symptoms in damp homes. A pilot study." Allergy 44: 192-198.

Page 43 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

297. Walinder, R., D. Norback, et al. (2001). "Nasal lavage biomarkers: effects of water damage and microbial growth in an office building." Archives of Environmental Health 56(1): 30-6. 298. Wan, G. H. and C. S. Li (1999). "Dampness and airway inflammation and systemic symptoms in office building workers." Archives of Environmental Health 54(1): 58-63. 299. Wan, G. H. and C. S. Li (1999). "Indoor endotoxin and glucan in association with airway inflammation and systemic symptoms." Archives of Environmental Health 54(3): 172-9. 300. Wang, Z., J. Peng, et al. (1993). "Human toxicosis caused by moldy rice contaminated with Fusarium and T-2 toxin." Biomed Environ Sci 6: 65-70. 301. Weber, S., G. J. Kullman, et al. (1993). "Organic dust exposure from compost handling: Case presentation and respiratory exposure assessment." Am J Ind Med 24: 365-374. 302. Weiss, J. S. and M. K. O'Neill (2002). Health effects from Stachybotrys exposure in indoor air: A critical review. Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate, Monterey, CA. 303. Weltermann, B. M., M. Hodgson, et al. (1998). "Hypersensitivity pneumonitis: a sentinel event investigation in a wet building." American Journal of Industrial Medicine 34(5): 499505. 304. Wickman, M., G. Emenius, et al. (1994). "Reduced mite allergen levels in dwellings with mechanical exhaust and supply ventilation [see comments]." Clin Exp Allergy 24(2): 109-14. 305. Wickman, M., S. Gravesen, et al. (1992). "Indoor viable dust-bound microfungi in relation to residential characteristics, living habits, and symptoms in atopic and control children." J Allergy Clin Immunol 89(3): 752-9. 306. Wieslander, G., D. Norback, et al. (1999). "Nasal and ocular symptoms, tear film stability and biomarkers in nasal lavage, in relation to building-dampness and building design in hospitals." International Archives of Occupational & Environmental Health 72(7): 451-61. 307. Wijnands, L. M., W. D. Deisz, et al. (2000). "Marker antigens to assess exposure to molds and their allergens. I. Aspergillus fumigatus." Allergy 55(9): 850-5. 308. Wijnands, L. M., W. D. Deisz, et al. (2000). "Marker antigens to assess exposure to molds and their allergens. II. Alternaria alternata." Allergy 55(9): 856-64. 309. Wilkins, C. K., S. T. Larsen, et al. (1998). "Respiratory effects in mice exposed to airborne emissions from Stachybotrys chartarum and implications for risk assessment." Pharmacology & Toxicology 83(3): 112-9. 310. Wilkins, K., K. Larsen, et al. (2000). "Volatile metabolites from mold growth on building materials and synthetic media." Chemosphere 41(3): 437-46. 311. Williamson, I., C. Martin, et al. (1997). "Damp housing and asthma: a case-control study." Thorax 52: 229-234. 312. Yang, C. Y., H. F. Chiu, et al. (1997). "Damp housing conditions and respiratory symptoms in primary school children." Pediatr Pulmonol 24: 73-77. 313. Yang, G. H., B. B. Jarvis, et al. (2000). "Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation." Toxicology & Applied Pharmacology 164(2): 149-60.

Page 44 of 45

Health Effects of Molds in Indoor Environments

Stuart M. Brooks, MD

314. Yoast, R. and P. Remington (1995). "Wisconsin public opinion regarding clean indoor air policies." Wis Med J 94(11): 624-6. 315. Zhou, G., W. Z. Whong, et al. (2000). "Development of a fungus-specific PCR assay for detecting low-level fungi in an indoor environment." Molecular & Cellular Probes 14(6): 33948.

Page 45 of 45

Information

Microsoft Word - Mold Statement-WITHOUT QUALIFICATIONS.doc

45 pages

Report File (DMCA)

Our content is added by our users. We aim to remove reported files within 1 working day. Please use this link to notify us:

Report this file as copyright or inappropriate

899968

You might also be interested in

BETA
Microsoft Word - Brief_Spoilage_7_07.doc
untitled