Indoor Molds

Characteristics

Fate and Transport in the Environment

Methods for Monitoring in the Environment

Exposure Pathways

Methods for Measuring Human Exposure

Strategies for Preventing or Controlling Mold Exposure


Harmful Effects

Absorption, distribution, metabolism, and sites of toxicity

Biomarkers

Molecular mechanism of action

Risk Assessment

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Molecular mechanism of action

Initial events

Molecular action of mold spores from inhalation exposure starts in the alveolar regions of the lungs. Mold particles embed themselves in the alveoli and are attacked by macrophages. Phagocytosis, engulfing and ingesting particulate matter by macrophages, is the first step when absorbing or digesting particles. Large numbers of macrophages are present on the alveolar walls. If particles are digestible, the macrophages will dissolve the particles and release the products into the lymph. Initial phases of this process, and the reactions involved, are not completely understood for mold toxins. Generally, the receptors on the macrophage cell surface recognize the particles, which leads to a series of internal cell changes. Macrophages change metabolic pathways that lead to alteration of the cell surface characteristics. Due to the changes, a production of a variety of proteins called cytokines take place. These proteins have the ability to induce activity in other cell systems. Some of the agents released by the macrophages are chemotactic and introduce neutrophils from the blood into the lungs and later into the airways. A buildup of platelets also occurs in the pulmonary capillary bed.


Diagram of lungs and alveoli (www.nlm.nih.gov/medlineplus/ency/imagepages/8675.htm)

Molds produce many substances that can be harmful with excessive exposure. Generally, these agents fall into two classes:

  • Secondary products of metabolism (mycotoxins)
  • Structural components (beta-1,3-D glucans)

Mycotoxins

Most of the toxicological studies related to mold mycotoxin exposure involves case studies of ingestion exposure. Extrapolation to realistic indoor inhalation exposure has not been clearly established. At this time, inadequate data exists to accurately predict the risk associated with human inhalation exposure to mycotoxins in indoor environments.

Mycotoxins are by-products of fungal metabolic processes. Their function has not been clearly established but appear to be related to competing with other microbes and helping parasitic fungi invade host tissues. Hundreds of mycotoxins have been identified that are produced by fungi. Mycotoxins are secondary metabolites because they are natural products that are not necessary for fungal growth. Mycotoxins have no molecular features in common and therefore do not constitute a chemical category. The chemical structures of mycotoxins include polyketides, terpenes, and indoles. Some mycotoxins have more toxic effects than others.

Most studies have investigated mycotoxins that are produced by species of Aspergillus, Fusarium, Penicillium, Stachybotrys, and Myrothecium. More than one species of fungi may produce a single mycotoxin, and conversely, one fungus may produce a variety of mycotoxins. The kinds and amounts of toxins a fungus produces depend on the following factors:

  • The fungal strain
  • The growth substrate it is metabolizing
  • The presence or absence of other organisms
  • Environmental conditions (e.g. temperature, pH)

Indoors, the most common exposure to mycotoxins is through inhalation. Fungi that produce the most potent mycotoxins are rarely found in the outdoor ambient air.

Cellular effects

Many mycotoxins are potent cytotoxins that cause cell disruption and interfere with essential cellular processes. Additionally, some mycotoxins are carcinogens, some are vasoactive, and some penetrate the blood-brain barrier. Commonly a single mycotoxin can cause more than one type of toxic effect. There are hundreds of different mycotoxins and only the most common known mycotoxic effects will be covered.

Pulmonary macrophage cells, which are part of the immune systems nonspecific line of defense, actively ingest and remove foreign particles in the alveolar region of the lungs. Studies have shown that mycotoxins including patulin, penicillic acid, aflatoxin, T-2 toxin and satratoxins interfere with macrophage functioning or selectively kill macrophages. Additionally, Aspergillus fumigatus contains a toxin in the spore wall that diffuses rapidly into water and inhibits macrophage function. This and other toxins may facilitate colonization of the airways of asthmatics leading to allergic bronchopulmonary aspergillosis (ABPA).

Aspergillus

Aflatoxins, produced by several members of the genus Aspergillus are known carcinogens. Aflatoxin B1 is known as the most potent studied natural carcinogen. It is a “pro-carcinogen” that must be transformed to the carcinogenic state within the body. Following ingestion exposure, this transformation occurs in the liver, and the result is liver cancer. Additionally, airway epithelium can activate aflatoxin B1 to the carcinogenic form. Airway instillation also results in binding both in the lung and in the liver, indicating translocation of the active form of the toxin.

Gliotoxin is produced during mycelial growth of Aspergillus fumigatus. This toxin is known to cause fragmentation of DNA. It is potent immunosuppressive agent that stops phagocytosis actions of the macrophages and impairs induction of cytotoxic and alloreactive T-cells. This toxin also disrupts the normal attachment of epithelial cells and fibroblasts, which allows fungal hyphae to grow in human tissue, causing a disease called aspergillosis.

Stachybotrys chartarum

Stachybotrys chartarum varies in its ability to produce mycotoxins depending on the substrate and other environmental factors. Mycotoxins produced from Stachybotrys chartarum can include the trichothecene mycotoxins satratoxins G and H. Satratoxins G and H are potent protein synthesis inhibitors and cause immunosuppression in laboratory animals. Immunosuppression can lead to secondary infections. Research has found that trichothecenes affect lymphatic and hematopoietic tissues as well as skin and mucous membranes. Acute exposure to large amounts of trichothecene toxins results in a rapid release of sequestered white blood cells into circulation. Chronic exposure can destroy granulocytic precursor cells in bone marrow, which leads to white cell depletion. Cellular effects can include:

  • Mitogen B/T lymphocyte blastogenesis suppression
  • Decrease of IgM, IgG, IgA immunoglobulins
  • Impaired macrophage activity
  • Increased spontaneous antibody producing cells in the spleen

Skin reactions have been observed in some asthmatics living or working in Stachybotrys-contaminated rooms, suggesting hypersensitivity to the fungus and that the fungal spores may produce allergenic affects.

Inflammation

Fungi are well-known causes of allergenic disease, stimulating the production of IgE-mediated response as well as hypersensitivity pneumonitis (HP). In addition to the allergen-induced release of inflammatory agents that mediate these responses, some kinds of fungal spores directly stimulate the release of mediators of inflammation. Agents that pulmonary macrophages may release in response to fungal spore exposure include cytokines, reactive oxygen metabolites, and chemotactic factors. The blood distributes these agents from the lungs and spreads them throughout the body.

Exposure to fungi and mycotoxins are likely to be associated with exposure to other agents as well. Organic dust toxic syndrome (ODTS) is a flu-like illness that may follow exposure to complex mixtures of organic dusts. The mixtures may include endotoxin, glucans, antigens, and mycotoxins. Relatively low exposure to complex mixtures can result in release of mediators of inflammation. Laboratory animal studies indicate a synergistic effect between endotoxin and fungal spore components. A family history of environmental allergies confirmed by skin prick test is a risk factor for ODTS, possibly indicating a role of antigens in the disease. The role of mycotoxins in ODTS is still not fully understood. Deposition of mycotoxins with particles seems to amplify adverse effects in the lungs, possibly due to increased toxin retention in the respiratory tract. (Photo: Tomography of the lungs (www.nhslothian.scot.nhs.uk/.../public_health/2002/09)

Mold as an antigen

Molds are considered to be antigens. Antigens are foreign substances that can cause a measurable hypersensitivity or immune response. The immune system is attempting defend the body against a foreign substance. Inhalation of airborne fungal antigens causes a variety of immune illnesses generally referred to as hypersensitivity diseases. An immune response consists of specific antigen recognition and the recruitment of sensitized cells and antibodies. An allergic reaction is a specific immune response caused by an allergen. An allergy is caused by exposure to an allergen, which produces the immune-mediated state of hypersensitivity.

The primary targets for inhaled antigens are the upper and lower respiratory tract.

The mechanism of all hypersensitivity diseases involves:

  • Repeated antigen exposure
  • Immunological sensitization of a body to an antigen
  • Immune-mediated damage to the body
  • A latency period between the initial exposure and the second exposure in order to develop an immunological sensitization

The immune response depends on the specific antigen and the duration and intensity of the exposure. Antibodies produced in response to specific antigens belong to a group of molecules called immunoglobulins. Immunoglobulins are broken down into five classes: IgA, IgD, IgE, IgG, and IgM. Antigens produce IgE mediated responses. People without allergies produce small amounts IgE antibodies, but allergy sufferers produce abnormally large quantities as a reaction to allergens.

The IgE antibodies bind to two types of cells. One type of cell is the basophil, a white blood cell (leukocyte) containing granules that circulates in blood. Another cell that antibodies bind to is a mast cell, which is found in the lungs, skin, tongue, lining of the nose, intestinal tract and connective tissue. Mast cells also contain basophilic granules. Both types of cells release substances such as histamine, heparin and other chemicals in response to injury or inflammation of bodily tissues. These chemicals produce allergic symptoms.

When the allergic individuals confront the same allergen, it attaches to the IgE antibodies already bound to basophils and mast cells, which starts the same chain reaction that results in allergic symptoms. Allergic reactions become more severe with repeated exposure because more basophils and mast cells are already bound to the IgE antibodies.


Diagram of an allergic reaction from http://www.niaid.nih.gov/final/immds/allergy.htm

Allergic asthma and rhinitis

Exposure to fungal spores or hyphal fragments results in the formation of IgE antibodies. The IgE antibodies can cause inflammation mediators and histamine to be released in the blood. This leads to allergenic rhinitis (hay fever) and/or asthma. Symptoms for rhinitis are characterized by a runny or congested nose, sneezing, irritated and inflamed throat and eyes. Allergic asthma is an inflammation of the airways most likely from acute reactions.

Allergic bronchopulmonary mycoses and allergenic sinusitis

Fungal colonization of the central airways can occur in individuals with long-standing, severe asthma. This can lead to a syndrome known as allergic bronchopulmonary mycoses (ABPM). ABPM is called allergic bronchopulmonary aspergillosis (ABPA) when the exposure is due to Aspergillus fumigatus and other Aspergillus species. Symptoms from this disease include:

  • Fever
  • Malaise
  • Brownish mucus plugs containing fungal hyphae in sputum
  • An abnormal increase in eosinophils (a type of white blood cell)
  • Expectoration of blood from the respiratory tract

Allergenic sinusitis can also be caused by localized fungal growth in the nasal sinuses. This condition is characterized by chronic sinus symptoms and increased fungal specific serum IgE, most commonly to Aspergillus fumigatus.

Hypersensitivity pneumonitis (HP)

HP is an inflammatory lung disease caused by continuous or repeated exposures to various antigenic substances. Once sensitized to the bioaerosol, individuals respond to very low exposures to environmental antigens. Although HP is usually a concern for exposures to dusty environments, HP can be a concern for occupants of offices and residences, which are not a problem for nonsensitized occupants. Antigenic bioaerosols have been traced to contaminated ventilation systems and microbial contamination due to flooding.

SEM of Penicillium (www.cosmiclight.com/ galleries/sem1.htm)

beta-1,3-D glucans

Glucans are glucose polymers, which are structural components of most fungal cell walls. The structures consist of unbranched or branched chains that may be chemically bound to chitin. Glucans may contribute to virulent and opportunistic fungal infections. They may also be involved in the development of hypersensitivity pneumonitis (HP) by affecting the inflammation-regulating capacity of airway macrophages, probably by influencing T cell lymphocytes. In insoluble form, glucans cause a gradual decrease in the number of macrophages and lymphocytes in the lung wall and appear to have an effect on the lung similar to that of endotoxin. In guinea pigs, exposure to glucans was found to increase breathing rate and increase in neutrophils, lymphocytes and red blood cells in the lungs.

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