CRITICAL ANALYSIS

CRITICAL ANALYSIS

ACOEM POSITION STATEMENT/GUIDELINES

By a Mold Victim who is sick of the lies INTRODUCTION

When reports deliberately focus on only a few known effects of any dangerous substance, the results can be catastrophic for the American public.

The purpose of this critical analysis is to point out misleading information, theory flaws, and to establish a basis that this paper is methodologically flawed. This paper is exclusive of evidence that has been established about the toxic effects of fungi and their metabolites beyond the scope of what is being publicly promoted in a direct attempt to allay the American public’s real concern over a serious physical endangerment to their person, family, and pet(s) health. Due to the self-imposed restrictions of the ACOME statement/guidelines the report itself is of little value in determining the real effects of fungi in regard to Scientific Evidence, Empirical Evidence, Statistical and Practical Application Evidence, and Human Health effects.

The ACOEM report is regularly used as evidence in litigation cases. Reports used for such litigation by their very nature, should be continually updated and reflect full current knowledge. In this introduction several reports dealing with the serious effects of fungi are displayed for prominence.

The uninformed reader has been circumvented from the true facts as presented to the President of the United States of America. The first report verifies the dangers of airborne toxins by scientific and medical, government documentation which will be included in this report.

CDC/NIOSH

Guidance for Protecting Building Environments from Airborne Chemical, Biological, or Radiological Attacks, 2003 * Presented to The White House

HUMAN “Toxins” Toxin categories include bacterial (exotoxins and endotoxins), algae (blue-green algae and dinofiagellates), mycotoxins Trichothocenes and aflatoxins). Botulinum, and plant- and animal-derived toxins. Toxins form an extremely diverse category of materials and are typically most effectively introduced into the body by inhalation or an aerosol. They are much more toxic than chemical agents. Their persistency is determined by their stability in water and exposure to heat or direct solar radiation. Under normal circumstances toxins can be collected using appropriately selected particulate filters as described in the Recommendations section of this document.”

Treatment of Chemical and Biological Warfare Injuries: Insights Derived from the 1984 Iraqi Attack on Majnoon Island Authors: Kadivar H, Adams SC Source: Military Medicine, Vol. 156, No. 4, pages 171-177, 20 references, 1991 Abstract:

HUMAN-WARFARE-FUNGI POISON: Experiences gained during the Iraqi attack on Majnoon Island were reviewed. In March of 1984 chemical and biological weapons systems were employed in a massive attack against Iran. Majnoon Island was particularly heavily hit. Exposure to these weapons resulted in skin burns, ocular damage and pulmonary distress. The clinical presentation following exposure to a number of these agents was quite similar, which made identification of the specific agent very difficult. Agents in use during this attack included nitrogen-mustard (51752), lewisite (541253), tabun (77816), and tricothecene mycotoxins. Therapeutic methods used included decontamination, airway maintenance, fluid replacement, sedation, antibiotic therapy, tetanus prophylaxis, escharotomy, fasciotomy, gastric decompression, evacuation, debridement, and topical chemotherapy. Because medical treatment must be dispensed rapidly and proficiently under extremely adverse conditions, potential care givers must receive thorough advance training. A general treatment plan has to be instituted promptly, then modified as specific information becomes available. The authors note that a vital lesson learned from this particular attack is that the complications from toxic gas exposures is increased when temperatures are extremely high, 120 degrees-F. The administration of atropine and the need to wear protective suits increase the risk of heat stroke. *

Overwhelming evidence by the top scientists and health workers include extensive procedures to eliminate the health hazards presented to an under, or deliberately misinformed public. The extensive documentation of death and injury due to fungi and mycotoxins is so well documented as to make one question the entire premise of a report that deliberately ignores factual reports readily available from government agencies and health professionals on a wide-spread basis. If a report is so urgent and critical that it needs the attention of the President of the United States, why is this information being covered and withheld from the people most affected by it? Especially criminal is the inability for parents to properly access the danger to their children, many of whom have died as a result.

The condition(s) which allow growth of one fungi always welcome many other fungi and bacteria which greatly accelerate the harm done to the person inhaling the fungi. Slanted reports continuously attempt to hide the compounded effect of these multiple-growth organisms humans are exposed to at one time or in a continuous low-dose extended period of time. The end result is that physicians are faced with so many multiple, overlapping destructions of various parts of the human body as well as the neurodegenerative and cognitive effects which leave the sickened and weakened person with so many confusing symptoms that they are very difficult, if not impossible, to treat and return to physical and mental well-being.

Given the time, the studies/reports used to validate the ACOEM statement/guidelines will be reviewed. Anything from the studies/reports used by the ACOEM that is beneficial to this critical review will be included. This will include any part of these studies/reports not included that validate the premise of this critical review. The hypotheses being that if the reports/studies or any section of the reports/studies is credible enough for the ACOEM it is viable for this analysis.

The latest studies and studies prior to the ACOEM policy/statement/guidelines from various government agencies will be included that have been peer-reviewed and/or published by; government agencies, doctors, medical and chemical, poison experts representing government facilities, hospitals, educational facilities, and for the most part have been placed in the National Library of Medicine (with the exception of the latest updated reports) which will clearly reveal the misleading premise of the ACOEM policy/statement/guidelines.

Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences Since mycotoxins, a byproduct of fungi are the most toxic (poisonous) substances known to man and are far more lethal than chemical poisons, a standard for human safety has been established in several industrial settings that should also qualify for home, office and schools regarding fungi/mycotoxin load. Since many contaminated homes, offices, and schools meet or exceed the standards set by OSHA and NIOSH it is reasonable that the major health issues created by the condition of prolific fungi are responsible for the associated complaints and developed underlying illnesses, both, well accepted, still being defined, and not well publicized. At present there are studies that state fungi and mycotoxins exposure in the “field” does have effect at much lower doses than previously though which may lead to NIOSH and OSHA having to set even lower levels than are presently verified as acceptable. Of special interest is Aspergillus as the only fungi monitored and regulated for feed for animal and human consumption world wide and monitored for human inhalation levels in industry in the U.S.A.

NIOSH AND OSHA PERMISSIBLE EXPOSURE LIMITS

Health Hazard Evaluation Report No. HETA-94-0033-2552, Ladish Malting Company, Jefferson, Wisconsin Authors: Knutti E, Kullman GJ, Source: Respiratory Disease Hazard Evaluations and Technical Assistance Program, NIOSH, U.S. Department of Health and Human Services, Morgantown, West Virginia, Report No. HETA-94-0033-2552, 31 pages, 36 references, 1996 Abstract:

HUMAN-FUNGI POISON; In response to a confidential request, worker exposures to mycotoxins during barley storage and malting operations at Ladish Malting Company (SIC-2083), Jefferson, Wisconsin were investigated. Medical and industrial hygiene surveys were conducted, and viable fungi were identified from all collected barley, malt, and dust samples. The most abundant genus cultured from the barley and dust samples was Fusarium. Barley samples also contained the tricothecene mycotoxins Deoxynivalenol (51481108) (DON) and 15-acetyl-deoxynivalenol (88337966). Settled dust samples also contained DON mycotoxin. Operations involved the blowing and sweeping of dust and caused the aerosolization of mycotoxin containing dust. Some personal breathing zone and area levels of airborne grain dust were high compared with the OSHA permissible exposure limit of 10mg/m3 and the NIOSH recommended exposure level of 4mg/m3. Respiratory protection was used by all workers; however, the type of protection used was inadequate for protection against some of the higher levels of dust and mycotoxin. Employee medical evaluations identified symptoms of eye irritation, tiredness, and throat irritation that appeared after the start of the work shift. The onset of at least one symptom within 24 hours of beginning work was reported by 62% of those surveyed. No significant increases in body temperature were identified in the workers. The authors conclude that the potential for the development of hypersensitivity or toxic syndrome exists in this facility. The authors recommend control measures to prevent such occurrences.

CDC

Health Hazard Evaluation Report No. HETA-95-0160-2571, Centers for Disease Control and Prevention, National Center for Environmental Health Authors: Kullman GJ, Sorenson W, Source: Respiratory Disease Hazard Evaluations and Technical Assistance Program, NIOSH, U.S. Department of Health and Human Services, Morgantown, West Virginia, Report No. HETA-95-0160-2571, 48 pages, 18 references, 1996 Abstract:

HUMAN HABITAT; In response to a request from the Centers for Disease Control and Prevention, National Center for Environmental Health, the presence of Stachybotrys-atra fungi and associated mycotoxins was assessed in 42 homes in the Cleveland, Ohio area to support an investigation of acute pulmonary hemorrhage (hemosiderosis) among infants in this area. Air, bulk, and surface samples were obtained from homes with cases of hemosiderosis and homes without such cases. Mean levels of total fungi were higher in homes with hemosiderosis cases compared to homes without such cases. Homes without hemosiderosis cases had higher levels of Aspergillus and Cladosporium fungi compared with homes with cases. In contrast, S-atra fungi were much more abundant in homes with cases of hemosiderosis. The mean concentration of S-atra in surface samples was significantly higher in homes with cases compared with those without. The authors conclude that homes with infants with hemosiderosis had higher concentrations of total fungi and Stachybotrys atra than homes without.

NIOSH

Elevated Airborne Concentrations of Fungi in Residential and Office Environments Authors: Reynolds SJ, Streifel AJ, McJilton CE, Source: American Industrial Hygiene Association Journal, Vol. 51, No. 11, pages 601-604, 19 references, 1990 Abstract: AIHAAP Entry Month: July, 1991 Year of Publication: 1990 Secondary Source ID: NIOSH /00197036

HUMAN HABITAT-FUNG: A review was presented of the general results obtained from six case studies conducted in response to health complaints related to exposure to indoor airborne fungi. The rationale for the sampling protocol was described with the concentrations and types of organisms detected. Six residential and office environments were tested to determine the airborne concentrations of fungi present there. Volumetric samples were collected using Andersen sieve samplers. Reference samples were taken outside of all buildings. Collections were also made of swab samples from surfaces and bulk samples of materials, such as carpeting and ceiling tiles. Gross colony morphology and microscopic examination was used to identify the predominant fungi present. The airborne concentrations of fungi detected inside each of the buildings significantly exceeded outdoor concentrations. It was determined that the contamination was caused by either water damage or buildup of dust. The movement of air through contaminated fans, the ventilation system, the fireplace, or human activity caused the fungi to become aerosolized from contaminated materials. The reduction of airborne concentrations of fungi by remedial means was demonstrated by air sampling taken at a later date.

Toxigenic fungi in a water-damaged building: An Intervention Study. Authors: SUDAKIN DL Author Address: Public Health General Preventive Med., Oregon Health Sci. Univ., 3181 SW Sam Jackson Park Road, CB-669, Portland, OR 97201-3098, USA. Source: AMERICAN JOURNAL OF INDUSTRIAL MEDICINE; 34 (2). 1998. 183-190. Abstract: Entry Month: September, 1998 Year of Publication: 1998 Secondary Source ID: BIOSIS /98/22568 BIOSIS COPYRIGHT: BIOL ABS. Behavioral Biology-Human Behavior, Respiratory System-General, Nervous System-General

HUMAN HABITAT-OFFICE-FUNGI POISON: In an investigation of health complaints among employees of a water-damaged office building, the environment showed evidence of fungal contamination with the isolation of Stachybotrys chartarum in one of five bulk samples tested for fungal growth. In response, a public health official recommended that employees be relocated from the building. Employees were subsequently moved to a different environment. A focused environmental investigation of microbial growth within the building followed, revealing moderate to high levels of fungi (Penicillium, Aspergillus versicolor) and bacteria in bulk and surface samples. S. chartarum was identified in one of 19 (5%) environmental samples using Czapek agar A health survey of building occupants revealed a high prevalence of multiple symptoms, with a predominance of neurobehavioral and upper respiratory tract complaints. The majority of symptoms were significantly less prevalent after relocation from the water-damaged environment. Th—.

DEPARTMENT OF ENVIRONMENTAL HEALTH

Measurements of Airborne aflatoxins during the Handling of 1979 Contaminated Corn, Toxnet, 1990 Authors: BURG WR, SHOTWELL OL, SALTZMAN BE Author Address: Dep. of Environmental Health, Univ. of Cincinnati, Cincinnati, Ohio 45267. Source: AM IND HYG ASSOC J; 43 (8). 1982. 580-586.

HUMAN-HIGH EXPOSURE EXAMPLE-FUNGI POISON; “The potential health hazard of aflatoxin (1402682) contaminated corn grain dusts to agricultural workers was investigated. The average aflatoxin level in all three farm areas was 42.7 parts per billion while the average aflatoxin level from airborne dust samples collected at the grain elevator was 172.8ppb (settled dust average, 222ppb). The author concluded that farmers, truckers, and grain handlers may experience significant exposure to aflatoxin contaminated dust in regions where the Aspergillus-flavus mold thrives, particularly in the southern regions of the United States. They recommend the use of respiratory protection when handling corn know to be contaminated with aflatoxin.”

Exposure to airborne microbes during the repair of moldy buildings. Authors: RAUTIALA S, REPONEN T, HYVARINEN A, NEVALAINEN A, HUSMAN T, VEHVILAINEN A, KALLIOKOSKI P, Author Address: Department Environmental Sciences, University Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. Source: AMERICAN INDUSTRIAL HYGIENE ASSOCIATION JOURNAL; 57 (3). 1996. 279-284. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Entry Month: June, 1996 Public Health-Public Health Administration and Statistics Public Health: Environmental Health-Occupational Health Public Health: Epidemiology-Communicable Diseases Public Health: Disease Vectors-Inanimate Public Health: Microbiology Year of Publication: 1996 Secondary Source ID: BIOSIS /96/12825

HUMAN HABITAT-REMEDIATION-FUNGI; Concentrations of airborne microbes, studied during the repair of seven moldy buildings, showed that concentrations of airborne fungi increased during the repair work. This was especially true during the demolition of moldy building materials, even though the total dust levels remained low. Concentrations of viable fungi sampled with a six-stage cascade impactor were 103 - > 1.9oncentrations of fungal propagules, as determined by the Camnea method (i.e., air filtration method with epifluorescence microscopic counting of acridine-stained organisms) showed 105 - 106 counts/m3 during the demolition. Penicillium was the main genus throughout. Concentrations of viable total bacteria also increased, but this change proved less noticeable than that of the fungi. However, rather high concentrations of viable actinomycetes up to 104 cfu/m3 were detected during the demolition. Results show that construction workers are exposed to high concentrations of microbes, perhaps causi ----.

NIOSH

Fungal Spores; Hazardous to Health? Division of Respiratory disease Studies, National Institute for Occupation and Health, 1999 Authors: SORENSON WG NOTE: ACOME Expert # 1. Author Address: Immunology Section, NIOSH, 1095 Willowdale Road, Morgantown, WV, 26505, USA. Source: ENVIRONMENTAL HEALTH PERSPECTIVES; 107 (SUPPL. 3). 1999. 469-472.

HUMAN DISABILITIES AND DISEASES; “–INHALATION OF FUNGAL SPORES INCLUDE: TOXIC PNEUMONITIS, HYPER PNEUMONITIS, TREMORS, CHRONIC FATIGUE SYNDROME, KIDNEY FAILURE, AND CANCER..”

Studies concerning the metabolites produced by Stachybotrys atra, Pencillium islandicum, penicillium viridicatum and aspergillus-versicolor. PubMed, 1977 Ann Nutr Aliment. 1977;31(4-6):663-84. Pohland AE.

HUMAN DEATH-FUNGI POISON; “Over the past ten years it has become quite apparent that mycotoxins, or toxins produced by fungi, are responsible for a wide variety of human and animal illnesses and, in many cases, deaths.”

IAQ and human toxicosis: empirical evidence and theory, Concordia, 2001 ACOEM Expert # 56, #57. Author: Ammann, H. M. Year 2001 Source In "Bioaerosols, Fungi and Mycotoxins: Health Effects, Assessment, Prevention and Control", Edited by Johanning, E., Boyd Printing, Albany, New York Citation: Ammann, H. M., (2001), "IAQ and human toxicosis: empirical evidence and theory", In "Bioaerosols, Fungi and Mycotoxins: Health Effects, Assessment, Prevention and Control", Edited by Johanning, E., Boyd Printing, Albany, New York. HUMAN EXPOSURE-IMMUNE SYSTEM-FUNGI POISON; “Studies of injury, illness and death occurring in mold-exposed animals and people in the field, observe that the illness called mycotoxicosis results from more complex exposures than can be observed in laboratory experiments with pure mold toxins. Response in field exposures occurs at lower exposure concentrations than those from controlled experiments.

Changes in the immune system, often reflected as increased susceptibility to infectious illness, are a common finding of low level exposure to toxigenic molds that inhibit protein synthesis. Changes in the immune system are extremely complex, but changes in the endocrine and nervous system accompany them and may reflect changes in the central neuroendocrine-immune control system.

Prudent public health practice recognizes the potency of the toxic agents produced by toxigenic molds, and seeks to protect occupants of buildings once moisture incursion with resultant microbial growth has been discovered.”

USDA-1977

HUMAN EXPOSURE-DISEASE-FUNGI POISON; “A healthy individual is more able to fight the toxins than a one that starts out malnourished or diseased. The very young and very old have weakened immune systems that are less able to fight the effects of toxicoses. In general female animals, and to a degree female humans, seem to be more susceptible to the effects of mycotoxicosis. Hosts exposed to harsh living conditions of neglect or squalor have an added burden on their systems. Very high doses of aflatoxin attack the host quicker than lower doses. A very short time of exposure (a single dose) allows the host time to fight the infection where a continued exposure tends to have cumulative effects. Areas that lack the means to regulate and monitor the presence of mycotoxins in genera, and aflatoxin in particular, leave the inhabitants open to unknown poisonings that can continue over long periods of time unchecked. Aspergillus species produce toxins that exhibit a wide range of toxicities, with the most significant effects being long term.

The toxins produced by Penicillium species can be placed in two general groups; those that affect the liver and kidney function, and those that are neurotoxic. The penicillium toxins that affect liver or kidney function are asymptomatic or cause generalized debility in humans or animals while the neurotoxins are characterized by sustained trembling.

The main human disease associated with F. moniliforme is esophageal cancer. -Alternaria toxins-that have been grown or corn or rice and fed to rats, chicks, turkey poults, and ducklings have been shown to be quite toxic.”

1: ScientificWorldJournal. 2003 Nov 13;3:1128-37. The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures. Anyanwu E, Campbell AW, Jones J, Ehiri JE, Akpan AI. Neurosciences Research, Cahers Inc., Conroe, TX, USA. ebereanyanwu@msn.com PMID: 14625399 [PubMed - in process] HUMAN HABITAT-NEUROIMMUNOLOGIC-BEHAVIORAL-DISEASE-FUNGI PRODUCE; Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures.

Immunol Allergy Clin North Am. 2003 Aug;23(3):519-31. Assessment of the indoor environment: evaluation of mold growth indoors. Horner WE. Publication Types: Review Review, Tutorial PMID: 14524389 [PubMed - indexed for MEDLINE] Air Quality Sciences, 1337 Capital Circle, Atlanta, GA 30067, USA. NOTE: ACOEM Expert #2. HUMAN HABITAT-NONATOPIC: Much attention has been focused on indoor molds; resulting in modest amounts of new research. There is strong evidence of respiratory effects. Although mechanisms are disputed, some of the effect (but not all) is likely to be allergy related. There is some evidence that atopic individuals may be more affected, but many nonatopic individuals also are affected. This area needs more general research and specific research on exposure measures (such as what fungal components should be measured) and on health-effect mechanisms. It is worthwhile to emphasize the practical knowledge that is readily available. Buildings should be designed, built, operated, and occupied so that the buildings stay dry. When this situation does not occur, the environmental and clinical aspects that are observed by competent professionals should both be considered when determining causal relationships.

Appl Environ Microbiol. 2002 Apr;68(4):1743-53. Profiles of airborne fungi in buildings and outdoor environments in the United States. Shelton BG, Kirkland KH, Flanders WD, Morris GK. PathCon Laboratories, Norcross, Georgia 30092, USA. PMID: 11916692 [PubMed - indexed for MEDLINE] HUMAN-INDOOR-OUTDOOR AIR SAMPLES; We examined 12,026 fungal air samples (9,619 indoor samples and 2,407 outdoor samples) from 1,717 buildings located across the United States; these samples were collected during indoor air quality investigations performed from 1996 to 1998. For all buildings, both indoor and outdoor air samples were collected with an Andersen N6 sampler. The culturable airborne fungal concentrations in indoor air were lower than those in outdoor air. The fungal levels were highest in the fall and summer and lowest in the winter and spring. Geographically, the highest fungal levels were found in the Southwest, Far West, and Southeast. The most common culturable airborne fungi, both indoors and outdoors and in all seasons and regions, were Cladosporium, Penicillium, nonsporulating fungi, and Aspergillus. Stachybotrys chartarum was identified in the indoor air in 6% of the buildings studied and in the outdoor air of 1% of the buildings studied. This study provides industrial hygienists, allergists, and other public health practitioners with comparative information on common culturable airborne fungi in the United States. This is the largest study of airborne indoor and outdoor fungal species and concentrations conducted with a standardized protocol to date.

Mold allergy: Fungal airborne spores in the homes of allergic and non-allergic subjects. Authors: FADDA ME, COSENTINO S, ATZORI C, DEPLANO M, CARDIA P, PALMAS F Author Address: Ricercatori del Dipartimento di Biologia Sperimentale, Univesita degli Studi di Cagliari. Source: FOLIA ALLERGOL IMMUNOL CLIN; 37 (6). 1990. 335-342. Entry Month: March, 1992 Year of Publication: 1990 Secondary Source ID: BIOSIS/92/03758 Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN HABITAT-SKIN TESTS-FUNGI: A survey was carried out to compare the incidence of fungal spores in the homes of patients with allergic manifestations and positive skin tests for fungi with spore assessment in the homes of non-allergic subjects. Particularly, the spores which have been more frequently found to give skin-positive reactions in the allergic patients were considered. Cladosporium and Penicillium were the most frequent fungi recovered from both groups of homes, whereas spore counts of yeasts, Alternaria, Aureobasidium, Aspergillus and Fusarium, were significantly higher in allergic patients homes. This survey confirms that spore assessments in the air of residential buildings can have direct application in determining the exposure to the various spore types and therefore in the management of allergic patients. Moreover, this kind of study permits to compare the environmental findings with the skin reaction of the patients to extracts of several of the fungal species isolated.

NOTE; THIS STUDY HAS SOME VERY IMPORTANT INFORMATION; (could cortisone treatment cause vulnerability in humans?)

Pathogenic potential of fungal insecticides. Authors: Pore RS, Goodman N, Larsh HW, Source: Am. Rev. Respirat. Disease; 101(4): 627-8 1970; (REF:22) Abstract: HAPAB Entry Month: December, 1973 Year of Publication: 1970 Secondary Source ID: HAPAB /71/00719

HUMAN-INSECTICIDES MADE FROM FUNGI-CORTISONE: A study to explore the pathogenic potential for man of Beauveria bassiana (agent of white muscardine in numerous insects) and other fungi-insecticides has been made. B. bassiana spores were introduced into cultures of mouse peritoneal macrophages maintained by a slightly modified Howard (1965) method. In cultures maintained at 35 C, the spores germinated and in the mouse-derived macrophages formed budding hyphal bodies resembling those observed in the pathogenic process of the fungus in the hemocoels of infected insects. Similar growth occurred in cultures of HeLa cells. Neither in HeLa nor in mouse macrophage cultures held at 37 C, would the spores of B. bassiana germinate. The hyphal bodies of the fungus are considered the pathogenic phase. B. bassiana showed collagenase and elastase activity to a decided degree, as did Trichophyton rubrum and T. mentagrophytes. Entomophthora coronata showed good collagenase production regardless of inoculation route, B. bassiana failed to produce progressive infection in normal mice. Although Aspergillus flavus is pathogenic for mice and rats, cortisone treatment was needed to predispose rats to infection by the respiratory route. Normal animals and man usually resist infection by ,opportunistic' fungi. Application of fungi for insecticidal purposes might lead to more than ,moderate' exposure. At present, several lb of spores/acre are required for insect control. Victims of chronic pulmonary disease have altered resistance. Many fungi are allergenic, a factor that should be taken into account in evaluating fungi for insecticidal use. B. bassiana has been reported as causing intense allergic response in man. Mixtures of bacterial and fungal insecticides have been proposed and are being investigated but they constitute a problem for human health. Many variables, dealing with fungi and hosts, remain to be studied before fungal insecticides can come into use for insect control. 1970

The insurance industry’s inability to financially provide for the remediation for all the damaged structures without additional expenses of medical complications has been well documented in Claim’s Magazine and in the measures taken to protect themselves from future litigation and liability concerning fungal infestation in personal and business properties in and of itself is a form of “evidence,” and has been utilized to avoid the financially catastrophic ramifications of dealing with fungi contamination. Since some reports estimate between 600,000 and 800,000 homes, businesses, and public buildings have fungal infestation, this problem is not going away.

The blue ink is the report by the ACOEM and to highlight the experts used in their report. In all instances if the documentation used by ACOEM could not be provided in this paper, it is noted. Due to the use of specific experts by ACOEM, whenever possible, published, peer-reviewed studies, documents, reviews, tutorials, case history(s), etc., by the same experts will be used. The black ink is the critical analysis and peer-reviewed, published documentation. Red ink is an immediate notice that the study pertains to Human(s) or has critical information. Green ink is used for primate, animal, and rodent studies.

CHAPTER ONE -- PARAGRAPH ONE

“Human Health Effects Associated with Molds in the Indoor Environment”

PARAGRAPH 1, sentence 1 and 2.

“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 believe they have been harmed by exposure to indoor molds.”

A) The red flag “toxic Mold” is a coin-phrase misused and is designed to be inflammatory.

B) Any “Evidence Based Statements” that starts out with a statement concerning a “basis for litigation” should be immediately suspect for having a bias, pro or con.

PARAGRAPH 1, sentence 3.

“This evidence-based statement from the American College of Occupational and Environmental Medicine (ACOEM) discusses the state of scientific knowledge as to the nature of fungal-related illnesses while emphasizing the possible relationships to indoor environments.”

A) “discusses the state of scientific knowledge,” is misleading. This critical review is to provide a wider scope and extensive “scientific knowledge” that the ACOEM does not provide or address in the very limited and slanted view included in the ACOEM’s “state of scientific knowledge”.

B) The proof that the American College of Occupational and Environmental Medicine is exploring all “Scientific Knowledge” is yet to be proved and is disclaimed in sentence 5 of this paragraph. (See Paragraph 1, sentence 5)

C) The general attitude of this paper in the first paragraph give the impression of prejudice due to the phrasing of the sentences, i.e.; “So-called “toxic mold,” and, ”while emphasizing the possible relationships to indoor environments.”

SAMPLE STUDIES THAT VERIFY INDOOR ENVIRONMENTS AND “TOXIC MOLD”

Whenever possible experts used by ACOEM will be used for valid proof of this critical review. See Introduction for some of the more stunning statements concerning fungi and human health effects. At the end of this “critical review” is the majority of verification studies done by Experts used by ACOEM.

NIOSH

Health Hazard Evaluation Report No. HETA-83-327-1402, Weatherwax Golf Course, Middletown, Ohio Authors: Liss GM ,Moseley CL Source: Hazard Evaluation and Technical Assistance Branch, NIOSH, U.S. Department of Health and Human Services, Cincinnati, Ohio, Report No. HETA-83-327-1402, 18 pages, 10 references, 1984 Abstract:

HUMAN-FUNGI; In response to a request from the City Health Department of Middletown, Ohio, an investigation was begun into an outbreak of acute respiratory illness in workers at the Weatherwax Golf Course (SIC-7992). Workers had experienced an outbreak of acute respiratory illness following the unloading of a truck filled with wood chips. Five employees experienced fever, chills, weakness, cough, chest tightness, and headaches, while six employees were not ill. Chips in the front of the truck may have been stored there for about a year. The fungi growing from the wood chips included species of Thermoactinomyces, Aspergillus, Mucor and Candida. Workers who were ill had worked unloading the front part of the truck. Symptoms began to appear approximately 13 hours after the work had been performed. The affected workers were well within 3 days. No diagnostically meaningful serological responses were identified. The authors conclude that the outbreak may have been pulmonary mycotoxicosis brought on by a toxic reaction to the inhalation of large amounts of fungi. Several recommendations were made to avoid this problem in the future.

NIOSH

Health Hazard Evaluation Report No. HETA-93-1110-2575, Martin County Courthouse and Constitutional Office Building, Stuart, Florida Authors: Weber AM, Martinez KF Source: Hazard Evaluation and Technical Assistance Branch, NIOSH, U.S. Department of Health and Human Services, Cincinnati, Ohio, Report No. HETA-93-1110-2575, 27 pages, 15 references, 1996 Abstract:

HUMAN HABITAT-COURTHOUSE-FUNGI & POISON: In response to a request from the Martin County Board of County Commissioners, an investigation was begun into possible exposure to toxicogenic fungi during the renovation of microbiological contaminated areas of the Martin County Courthouse Complex (SIC-9211) in Stuart, Florida. Severe contamination was present, consisting predominantly of Aspergillus, Penicillium, and Stachybotrys. Due to occupant health complaints the Courthouse complex was not occupied. Prior to beginning remediation efforts, an initial environmental assessment had been made in September of 1993, by NIOSH investigators. Follow up site visits were conducted in October and November. After completion, a final visit was made in June of 1994. Containment areas with dedicated supply and exhaust ventilation systems were used in the remediation activities. While containment areas reduced the dissemination of spores, potentially toxicogenic fungal spores were identified on 56% of the filter samples collected outside the containment areas. The authors conclude that workers were exposed to a potential health hazard during removal of the microbiologically contaminated building materials. The authors note that workers performing renovations in buildings contaminated with fungi may unknowingly put themselves and other occupants of the buildings at risk for exposure.

NIOSH

Health Hazard Evaluation Report No. HETA-97-0048-2641, Cowlitz County Health Department, Longview, Washington Authors: Boudreau Y, Perkner J Source: Hazard Evaluations and Technical Assistance Branch, NIOSH, U.S. Department of Healt and Human Services, Cincinnati, Ohio, Report No. HETA-97-0048-2641, 19 pages, 43 references, 1997 Abstract: (EVACUATION OF BUILDING)

HUMAN HABITAT-FUNGI POISON; In response to a request from the Service Employees International Union, a health hazard evaluation was performed at the former Cowlitz County Health Department Building (CCHDB) (SIC-9431) in Longview, Washington. Concern was voiced over employee reports of upper respiratory problems, aches and pains in joints and muscles, and skin rashes, perhaps related to toxins and molds in the building. After an inspection by the Washington State Department of Health revealed the presence of fungi including Stachybotrys, Aspergillus, and Penicillium, the building was evacuated. Twenty nine of the 341 current employees and eight former employees participated in medical interviews and responded to a symptoms questionnaire. Employees reported a decrease in all symptoms after leaving the CCHDB. There was a statistically significant decreased prevalence in most symptoms after leaving the old building. The authors recommend that the new building be inspected once renovations are complete. Employees should see their personal physician for health concerns and should inform that person of any problems they feel may be work related.

NIOSH

Elevated Airborne Concentrations of Fungi in Residential and Office Environments Authors: Reynolds SJ, Streifel AJ, McJilton CE Source: American Industrial Hygiene Association Journal, Vol. 51, No. 11, pages 601-604, 19 references, 1990 Entry Month: July, 1991 DCN-192469 Year of Publication: 1990 Secondary Source ID: NIOSH/00197036 Abstract:

HUMAN HABITAT-ACTIVITY-FUNGI: A review was presented of the general results obtained from six case studies conducted in response to health complaints related to exposure to indoor airborne fungi. The rationale for the sampling protocol was described with the concentrations and types of organisms detected. Six residential and office environments were tested to determine the airborne concentrations of fungi present there. Volumetric samples were collected using Andersen sieve samplers. Reference samples were taken outside of all buildings. Collections were also made of swab samples from surfaces and bulk samples of materials, such as carpeting and ceiling tiles. Gross colony morphology and microscopic examination was used to identify the predominant fungi present. The airborne concentrations of fungi detected inside each of the buildings significantly exceeded outdoor concentrations. It was determined that the contamination was caused by either water damage or buildup of dust. The movement of air through contaminated fans, the ventilation system, the fireplace, or human activity caused the fungi to become aerosolized from contaminated materials. The reduction of airborne concentrations of fungi by remedial means was demonstrated by air sampling taken at a later date.

Laboratory experiments on Membrane Filter Sampling of Airbourne Mycotoxins Produced by Stachybotrys atra Corda, Toxnet, 1993, 21 references Authors: PASANEN A-L, NIKULIN M, TUOMAINEN M, BERG S, PARIKKA P, HINTIKKA E-L Author Address: Univ. Kuopio, Dep. Environ. Sci., P.O. Box 1627, SF-70211 Kuopio, Finland. Source: ATMOS ENVIRON PART A GEN TOP; 27 (1). 1993. 9-13.

HUMAN HABITAT; ”Sixty-six air samples were collected on the filters,. Only one of the 27 air samples collected in methanol was toxic in both the cell culture and rabbit skin tests. All samples collected on a cellulose-nitrate filter were negative in the biological tests, whereas less than half of the samples on a polycarbonate filter and more than half of the samples on a polycarbonate filter were toxic. Twenty-five percent of the air samples collect from contaminated grain and 42% of the samples collected from contaminated wallpaper were toxic. None of the air samples collected from contaminated hay and straw were toxic, even when the original material was toxic.”

NIOSH

Trichothecene mycotoxins in the dust of ventilation systems of office buildings, Toxnet, 1994 Smoragiewicz W ; Cossette B ; Boutard A ; Krzystyniak K International Archives of Occupational and Environmental Health, Vol. 65, No. 2, pages 113-117, 25 references, 1993 [NIOSH]

HUMAN HABITAT; “–reportedly affected by the “sick buildings syndrome”, were analyzed. The dust samples contained at least four trichothecenes; T-2 toxin, diacetoxyscirpenol, roridene A and T-2 tetraol. Screening of dust samples from air ventilation systems of reportedly affected buildings provided direct evidence of trichothecene mycotoxins, with the detection limit estimated at 0.4-4 ng/mg dust.”

Trichothecene Mycotoxins in Aerosolized Conidia of Stachybotrys atra, Toxnet, 1987, 24 references.

HUMAN HABITAT; “A dose depended inhibition of protein synthesis in rat alveolar macrophages was noted within 1 hour–was greatly inhibited by Satratoxin-H and the spore extracts. Each filter contained one or more of the specific trichothecenes.–Trichothecene mycotoxins are acutely toxic to a variety of mammalian species, strongly inhibit protein, DNA, and RNA synthesis in eucaryotic cells, and are immunotoxic in rats and mice. -- Demonstrates the possibility for pulmonary exposure of workers to these toxins contained in moldy hay, contaminated ductwork, and carpets heavily contaminated by S-atra.

Correlation between the prevalence of certain fungi and sick building syndrome. Authors: COOLEY JD, WONG WC, JUMPER CA, STRAUS DC, Author Address: Dep. Microbiol. Immunol., Texas Tech Univ. Health Sci. Center, Lubbock, TX 79430, USA. Source: OCCUPATIONAL AND ENVIRONMENTAL MEDICINE; 55 (9). 1998. 579-584.Entry Month: November, 1998Year of Publication: 1998 Secondary Source ID: BIOSIS/98/30276

Abstract: BIOSIS COPYRIGHT: BIOL ABS. Objective-

HUMAN HABITAT-SCHOOLS-FUNGI; To examine the role of fungi in the production of sick building syndrome. Methods-A 22 month study in the United States of 48 schools (in which there had been concerns about health and indoor air quality (IAQ)). Building indoor air and surface samples, as well as outdoor air samples were taken at all sites to look for the presence of fungi or their viable propagules. Results-Five fungal genera were consistently found in the outdoor air and comprised over 95% of the outdoor fungi. These genera were Cladosporium (81.5%), Penicillium (5.2%), Chrysosporium (4.9%), Alternaria (2.8%), and Aspergillus (1.1%). At 20 schools, there were significantly more colony forming units per cubic metre (CFU/m3) (p<0.0001) of propagules of Penicillium species in the air samples from complaint areas when compared with the outdoor air samples and the indoor air samples from noncomplaint areas. At five schools, there were more, although not significant (p=0.10), Penicillium propag—.

Microfungal contamination of damp buildings--examples of risk constructions and risk materials. Gravesen S, Nielsen PA, Iversen R, Nielsen KF. Energy and Indoor Climate Division, Danish Building Research Institute, Horsholm, Denmark. PMID: 10347000 [PubMed - indexed for MEDLINE] HOUSING MATERIALS-FUNGI POISONS: To elucidate problems with microfungal infestation in indoor environments, a multidisciplinary collaborative pilot study, supported by a grant from the Danish Ministry of Housing and Urban Affairs, was performed on 72 mold-infected building materials from 23 buildings. Water leakage through roofs, rising damp, and defective plumbing installations were the main reasons for water damage with subsequent infestation of molds. From a score system assessing the bioavailability of the building materials, products most vulnerable to mold attacks were water damaged, aged organic materials containing cellulose, such as wooden materials, jute, wallpaper, and cardboard. The microfungal genera most frequently encountered were Penicillium (68%), Aspergillus (56%), Chaetomium (22%), Ulocladium, (21%), Stachybotrys (19%) and Cladosporium (15%). Penicillium chrysogenum, Aspergillus versicolor, and Stachybotrys chartarum were the most frequently occurring species. Under field conditions, several trichothecenes were detected in each of three commonly used building materials, heavily contaminated with S. chartarum. Under experimental conditions, four out of five isolates of S. chartarum produced satratoxin H and G when growing on new and old, very humid gypsum boards. A. versicolor produced the carcinogenic mycotoxin sterigmatocystin and 5-methoxysterigmatocystin under the same conditions.

Aspergillosis in immunocompromised pediatric patients: Associations with building hygiene, design, and indoor air. Authors: ANDERSON K MORRIS G KENNEDY H CROALL J MICHIE J RICHARDSON MD GIBSON B Author Address: Department Respiratory Medicine, Western Infirmary, Glasgow G11 6NT, UK. Source: THORAX; 51 (3). 1996. 256-261. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Entry Month: June, 1996 Year of Publication: 1996 Secondary Source ID:BIOSIS/96/14024 (Six children in 1 year, 1 hospital ward)

HUMAN-HOSPITAL; Background: Nosocomial aspergillosis is a well known complication of immunosuppression in cancer patients and those undergoing transplantation and has usually been associated with major building construction or demolition. An observational study is reported of the hospital environment associated with an outbreak of aspergillosis in a pediatric oncology ward. Methods: All cases of aspergillosis were identified from the hospital records and categorized as definite or probable according to the extent of supportive clinical and laboratory findings. All relevant aspects of building ventilation, air filtration, and aerosol generation considered relevant were examined and air samples for fungi were taken in triplicate at 25 sites using a slit sampler with appropriate culture media. Results: Six cases of aspergillosis were identified over one year out of the 148 patients who attended the unit - the only part of the hospital where cases were found.

Fusariosis associated with pathogenic fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections. Anaissie EJ, Kuchar RT, Rex JH, Francesconi A, Kasai M, Muller FM, Lozano-Chiu M, Summerbell RC, Dignani MC, Chanock SJ, Walsh TJ. Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. PMID: 11692299 [PubMed - indexed for MEDLINE] (8 patients) HOSPITAL-FUNGI; We sought the reservoir of Fusarium species in a hospital with cases of known fusarial infections. Cultures of samples from patients and the environment were performed and evaluated for relatedness by use of molecular methods. Fusarium species was recovered from 162 (57%) of 283 water system samples. Of 92 sink drains tested, 72 (88%) yielded Fusarium solani; 12 (16%) of 71 sink faucet aerators and 2 (8%) of 26 shower heads yielded Fusarium oxysporum. Fusarium solani was isolated from the hospital water tank. Aerosolization of Fusarium species was documented after running the showers. Molecular biotyping revealed multiple distinct genotypes among the isolates from the environment and patients. Eight of 20 patients with F. solani infections had isolates with a molecular match with either an environmental isolate (n=2) or another patient isolate (n=6). The time interval between the 2 matched patient-environment isolates pairs was 5 and 11 months, and 2, 4, and 5.5 years for the 3 patient-patient isolate pairs. The water distribution system of a hospital was identified as a reservoir of Fusarium species.

An indoor mycoaerological investigation at home of allergic patients

Authors: DI BERARDINO L ANGRISANO A BAIO G COMPOSTELLA R Author Address: Div. di Pediatrica, Ospedale di Bollate, Mich. Source: FOLIA ALLERGOL IMMUNOL CLIN; 36 (6). 1990. 431-436.

HUMAN HABITAT-IgE mediated respiratory-FUNGI; The etiopathogenetic role of molds in the respiratory allergic syndromes is now well accepted. To better define the correlation between fungi and allergic diseases we investigated over a period of one year, by gravimetric method, the presence of six genera of moulds (Alternaria, Aspergillus, Candida, Penicillium, Mucor and Cladosporium) inside the house of 20 children affected with an IgE mediated respiratory disease (rhinitis and/or asthma) and skin-test positive to one or more of the six genera of fungi. We evaluated that total aspecific mycoallergenic burden and the global distribution of each mold genus over the period of study. Cladosporium and Penicillium make up the 88% of identified colonies and are constantly present in considerable concentration, with a decrease during winter months for Cladosporium and an increase from November to April for Penicillium. Alternaria was detected particularly in September and October; Aspergillus is constantly present in low co (NEED REST OF REPORT) Medical Subject Headings (MeSH): Entry Month: February, 1991 Year of Publication: 1990 Secondary Source ID: BIOSIS/91/01090.

A Review of Mycotoxins in Indoor Air Authors: ,Hendry KM Cole EC , Source: Journal of Toxicology and Environmental Health, Vol. 38, No. 2, pages 183-198, 48 references, 1993 Abstract: HUMAN HABITAT-FUNGI POISONS; A review of the sources and health effects of mycotoxins that have been found in indoor air was presented. Discussions were presented on the origins and health effects of classes of mycotoxins that have been identified in dust. These included aflatoxins, trichothecenes, zearalenone (17924924), and secalonic-acid-D (35287695). Exposure sources for mycotoxins have included agricultural products such as cereal grains, nuts, and rice, and components of homes and buildings such as heating, ventilation, and air conditioning systems, and burning wood chips. Another source of mycotoxins has been commercial facilities involved in the processing of contaminated materials such as grains or nuts and livestock feed. Fungal growth has been identified in wood drying kilns and two cases of cancer in laboratory workers with repeated exposure to mycotoxins have been reported. Factors conducive to the growth of fungi and the relationship between such growth and the subsequent production of mycotoxins was reviewed. The use of viable and particulate impactors, high volume filtration samplers, or liquid impingers have been recommended by the American Conference of Governmental Industrial Hygienists for the sampling of airborne mycotoxins. The use of thin layer chromatography, high performance liquid chromatography, and a chicken embryo bioassay for the analysis of mycotoxins was discussed. Epidemiological studies on the association between exposures to mycotoxins and the development of human disease were reviewed. Needs for future research in this area were outlined.

NIOSH

Trichothecene Mycotoxins in the Dust of Ventilation Systems in Office Buildings Authors: Smoragiewicz W.

Cossette B, Boutard A, Krzystyniak K Source: International Archives of Occupational and Environmental Health, Vol. 65, No. 2, pages 113-117, 25 references, 1993 Abstract:

HUMAN HABITAT-OFFICE-FUNGI POISON; The presence of trichothecene mycotoxins in dust samples from office buildings suspected of having sick building syndrome was studied. Dust samples were obtained from the ventilation systems or drapes, carpets, and ceiling fiberboards of office spaces from three buildings whose technical and medical records indicated the presence of sick building syndrome and analyzed using thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). TLC proved superior to HPLC for the detection of trichothecene mycotoxins. Dust samples obtained from the ventilation system of one of the buildings had mycotoxins identified as T-2-toxin (21259201), diacetoxyscirpenol (2270408), roridine-A (14729294), and T-2-tetraol (34114993) as well as a fifth mycotoxin that produced a trichothecene specific colored reaction. The dusts obtained from the office spaces of the other two buildings contained six trichothecenes which included two unknown mycotoxins. The authors conclude that the TLC method described is useful for the detection and identification of trichothecene mycotoxins in dust samples.

Relationship of airborne microorganisms with the lung function and leukocyte levels of workers with a history of humidifier fever. Authors: KATEMAN E, HEEDERIK D, PAL TM, SMEETS M, SMID T, SPITTELER M, Author Address: Univ. Wageningen, Dep. Environ. Trop. Health, PO Box 238, 6700 AE Wageningen, Neth. Source: SCAND J WORK ENVIRON HEALTH; 16 (6). 1990. 428-433. Medical Subject Headings Entry Month: May, 1991 Year of Publication: 1990 Secondary Source ID: BIOSIS/91/09345 Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN HABITAT-PLANT-FUNGI ET.AL.; An influenza-like illness appeared recently among workers in a plant processing synthetic yarn. A humidifier, a cold-water spraying system, was the suspected cause. Lung function changes over the day and week and changes in blood leucocytes were studied among the workers from the suspected department and two reference populations. Exposure to colony-forming units of bacteria and fungi and to endotoxins was also monitored. The workers from the suspected department had statistically significantly lower lung functions on the first workday of the week than the referents. Their blood leucocytes were also raised statistically significantly. The exposure to fungi, bacteria, and endotoxins differed significantly between the various departments, but the measured levels were low. It was concluded that the observed effects were suggestive of a "Monday morning fever" type of reaction and that adverse effects occurred at exposure levels lower than those found to date in the literature —.

“Filamentous fungi from walls of “mouldy” dwellings and schools-Penicillium, Aspergillus versicolor, Tiraboschi, A. Flavus Link, Cladosporium sphacrospermum, etc.

HUMAN: “All frequently isolated strains produced secondary metabolites. There are some toxic fungal metabolites in the indoor air not only with the ability to destroy ciliary movement in the upper airways in vitro but, probably, during long-lasting exposure to cause general intoxication of macroorganism via lung tissue.”

1: Inhal Toxicol. 2003 Jan;15(1):23-38. Roponen M, Toivola M, Alm S, Nevalainen A, Jussila J, Hirvonen MR.Department of Environmental Health, National Public Health Institute, PO Box 95, SF-70701 Kuopio, Finland. Inflammatory and cytotoxic potential of the airborne particle material assessed by nasal lavage and cell exposure methods. HUMAN Exposure to bioaerosols in moisture-damaged indoor environments has been shown to be a potential health risk. The aim of the present study was to evaluate the inflammatory and cytotoxic potential of airborne particle material using both the nasal lavage (NAL) method and a cell exposure study. A 24-h sample collection for airborne particles was performed using personal sampling and microenvironmental measurements in homes and an 8-h sample collection in the working places of the studied subjects. At the end of the sampling period, the production of nitric oxide, tumor necrosis factor alpha, interleukin (IL)-1 beta, IL-4, and IL-6 was analyzed in the NAL samples of the subjects. The same mediators, excluding IL-4, were measured in the cell culture medium of mouse RAW264.7 macrophages, which were exposed to the pooled filter extracts representing personal, home, and workplace exposure of each individual during the 24 h before the NAL. Samplings were repeated after 2 wk. The subjects were divided into groups of "low exposure" and "high exposure" according to the concentrations of viable fungi, viable bacteria, or total microbial amount in the pooled extract. Cytokine levels in the NAL samples of subjects with high microbial exposure were slightly increased compared to the corresponding values of the subjects with low exposure. Filter samples collected from the subjects with high microbial exposure induced a significant increase in the production of cytokines in the RAW264.7 macrophages, as compared to those from the subjects with low exposure. The within-subject variation was low in all of the cytokine measurements, but the correlation between the studied methods was poor. In conclusion, both of the methods discriminate at the group level between subjects with high and low microbial exposure. Sampling of airborne particle material and exposure of the mammalian cells to the obtained samples seems to be highly applicable in the environmental monitoring, whereas examination of the exposed subjects directly, for example by using the NAL method, is essential when association between exposure and health effects is evaluated. PMID: 12476358 [PubMed - indexed for MEDLINE]

NIOSH

Mycotoxins as Potential Occupational Hazards Authors: Sorenson WG Source: Developments in Industrial Microbiology, Vol. 31, pages 205-211, 48 references, 1990 Abstract: Entry Month: August, 1992 Year of Publication: 1990 Secondary Source ID: NIOSH /00204894.

HUMAN-FUNGI & POISON: A review was provided to examine the exposure of workers to fungi and the various effects such exposures have on human health. Fungi were noted to affect humans through direct infections, allergy and hypersensitivity and by the production of toxic metabolites. Farmer's lung disease was described as a hypersensitivity reaction which occurs in the lung in response to inhaled thermophilic actinomycetes and certain fungi. Organic dust toxic syndrome was noted to be a new syndrome, possibly associated with the presence of fungi and/or mycotoxins. It was noted that various fungi produce numerous volatile compounds, some of which can be very hazardous. Studies have indicated the inhalation of aflatoxin contaminated dust by chemical engineers working with contaminated peanut dust and biochemists working to purify aflatoxins by preparative thin layer chromatography. Mortality for total cancer and respiratory cancer was shown to be higher than expected among peanut-oil press workers. Airborne dust around combine harvesters of cereal in England has been revealed to consist predominantly of fungus spores and hyphael fragments with spore concentrations as high as 200 million spores/cubic meter. Relatively little information was noted available in the literature pertaining to the effects of specific mycotoxins on the cells and tissues of the lung. A additional studies are needed to determine whether exposure to fungus spores may constitute a significant health risk by virtue of their mycotoxins as well as by their ability to stimulate adverse immunologic response.

Bioaerosols associated with composting facilities. Authors: MILLNER PD, OLENCHOCK SA, EPSTEIN E, RYLANDER R, HAINES J, WALKER J, OOI BL, HORNE E, MARITATO M, Author Address: US Dep. Agric., Agric. Res. Serv., Soil Microbial Systems Lab., Beltsville, MD, USA.Source: COMPOST SCIENCE & UTILIZATION; 2 (4). 1994. 8-57. Abstract:BIOSIS COPYRIGHT: BIOL ABS. Entry Month: May, 1995Year of Publication: 1994 Secondary Source ID: BIOSIS/95/106148.

HUMAN-FUNGI, ETC.: Composting is one of the major treatment processes used to transform wastes into agriculturally useful products. The potential health risks associated with exposure to biological aerosols (hereafter referred to as bioaerosols) generated from the processing and handling of composted organic materials are a major concern in jurisdictions evaluating existing compost installations or planning new ones. Bioaerosols of concern during composting are like those from other organic dusts and they consist of microorganisms (actinomycetes, bacteria and fungi), arthropods, protozoa and organic constituents of microbial and plant origin. Major concerns are the fungus Aspergillus fumigatus (AF), cell walls of gram-negative bacteria (endotoxins), beta-1,3 glucans from the cell walls of fungi and mycotoxins. These biological materials are found in aerosols generated from a wide variety of organic wastes including grass clippings, wood chips, food and household wastes, agricultural waste. *

ACOME EXPERT #1. Solomon WR,

The report used by ACOEM is in a book which costs over $360.00 and not in PubMed. Here are reports from from Solomon WR on related subjects.

1B) 1: Appl Environ Microbiol. 1980 Apr;39(4):840-4. Microbial prevalence in domestic humidifiers. Burge HA, Solomon WR, Boise JR.PMID: 7377779 [PubMed - indexed for MEDLINE]

HUMAN HABITAT-MICHIGAN HOMES: The prevalence of viable thermophilic bacteria and actinomycetes and mesophilic fungi was examined in 145 samples from 110 domestic humidifiers. A total of 72 and 43% of furnace and console humidifier samples, respectively, contained viable thermophilic bacteria, whereas 60 and 72% of these samples produced mesophilic fungal growth. Thermophilic actinomycetes were recovered from seven humidifier samples. Efforts to detect thermophilic actinomycete antigens in 15 humidifier fluid samples were not successful. Antifoulants added to humidifier fluid reservoirs had no apparent effect on microbial frequency. Airborne microbial recoveries did not reflect patterns of humidifier contamination with respect to either kinds or numbers of microorganisms in 20 homes in which volumetric air samples were obtained during humidifier operation.

1C) 1: Monaldi Arch Chest Dis. 1998 Feb;53(1):43-9. b) J Allergy Clin Immunol. 1978 Jul;62(1):56-60. Airborne Aspergillus fumigatus levels outside and within a large clinical center. Solomon WR, Burge HP, Boise JR. PMID: 350933 [PubMed - indexed for MEDLINE] HUMAN HABITAT-HOSPITAL; Most considerations of Aspergillus fumigatus prevalence have implied that patterns of occurrence observed within London hospitals are generally applicable. Since prevalence data are almost nonexistent elsewhere, this assumption remains untested. To provide a comparison relevant to North America, we have monitored thermotolerant fungi outside as well as at two sites within the University Hospital, Ann Arbor, Michigan, during one year. Collections were made with paired Andersen samplers and malt agar for 30- to 40-min periods in a hallway adjacent to 6W, a general medical ward (47 days), and 2W, a lower level service and supply area (40 days); in addition, 10-min outdoor samples (44 days) were taken on an unobstructed hospital rooftop (out). Recoveries were analyzed after 3 and 7 days of 37 degrees C aerobic incubation. Virtually complete suppression of Cladosporium form species at 37 degrees left a mycoflora with A. fumigatus, A. niger, Paecilomyces spp., Mucor spp., and yeast/bacteria predominating. Although the proportions of samples yielding A. fumigatus were 76% for 6W, 57% for 2W, and 56% (out), levels exceeded 40 isolates/m3 only twice and were over 10 isolates/m3 on only 10 of 131 total samples. For 6W, 2W and out, respectively, means were 4.78, 1.97, and 6.25 isolates/m3; medians were 1.20, 1.05 and 1.75/m3 without annual trends indoors and with only a limited outdoor summer increase. Our data fail entirely to show the fall-winter abundance observed in the London report and suggest substantially lower indoor exposure levels of A. fumigatus than those noted in London.

Pathogenic fungi in human dwellings. Authors: STAIB F ,Author Address: Brentanostr. 26, D-1000 Berlin 41, Ger. Source: MYCOSES; 35 (11-12). 1992. 289-292. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Entry Month: July, 1993 Year of Publication: 1992 Secondary Source ID: BIOSIS /93/16604

HUMAN-INDOOR AIR-FUNGI: Airborne invasive fungal infections in various risk groups of people suffering from immunodeficiencies are an increasing problem for modern medicine. Because of the acute and rapid course of invasive infections, prevention is of principal significance. Such prevention mainly concerns the control of fungal spores in indoor air. In this connection the immediate environment offering ecological niches for growth and morphogenesis of infective particles of Aspergillus spp., Mucoraceae, Cryptococcus neoformans and some other yeast-like fungi is of main interest. The current problems of indoor air mycology, i.e. the epidemiology and ecology of pathogenic fungi in indoor air, can only be recognized and interpreted by centres routinely performing mycological diagnosis for all the various risk groups of patients. Models of specific surveillance of the most important fungal pathogens (e.g. Aspergillus spp. and Cryptococcus neoformans) in indoor air will be outlined and discussed.

1D) J Allergy Clin Immunol. 1976 Jan;57(1):46-55. A volumetric study of winter fungus prevalence in the air of midwestern homes. Solomon WR. PMID: 942733 [PubMed - indexed for MEDLINE] HUMAN HABITAT-MICHIGAN HOUSES; Volumetric recoveries of airborne, mesophilic microfungi were made during winter months at three specific points in 150 single-family dwellings in southeastern Michigan. Mean levels of total isolates/m3 comprised a range of from less than 10 to over 20,000, although concurrent outdoor levels never exceeded 230/m3. Form species of Penicillium, Aspergillus, Cladosporium, and Rhodotorula as well as non-pigmented yeasts were the types encountered most widely indoors. Certain homes showed high recoveries of other types, including Cephalosporium, Sporobolomyces, Verticillium, and Sporothrix form species. A positive association between indoor fungus prevalence and bedroom relative humidity was strongly suggested, and high levels were observed in well-humidified homes despite the presence of electrostatic air cleaners. The data indicate characteristic patterns of (winter) air spora in specific homes and suggest that humidifying devices may serve as dispersion sources in addition to their permissive role in facilitating fungus growth.

1E) Mycopathologia. 1977 Jul 29;61(1):27-33. Comparative recoveries of airborne fungus spores by viable and non-viable modes of volumetric collection. Burge HP, Boise JR, PMID: 895829 [PubMed - indexed for MEDLINE] Rutherford JA, Solomon WR. The suitability of viable and non-viable volumetric collectors as prevalence indicators for potentially allergenic airborne fungi was studied during 124 paired exposures of the Burkard (Hirst) spore trap and a modified, wind-oriented Andersen sampler. Overall, viable recoveries of several Cladosporium form species varied directly with microscopic spore counts (p less than or equal to 0.0001). However, as spore levels rose, culture plate data progressively underestimated prevailing concentrations (recoveries falling below 5% at levels above 500 spores/M3). Viable collections yielded low estimates of prevalence (20-40%) even at modest Cladosporium levels (less than 100 spores/M3) and substantially understated the abundance and regularity in air of several additional taxa. Spores typical of Penicillium and Aspergillus form species were not sought in spore trap deposits. Careful examination of these failed to reveal typical arthrospores or Fusarium macrospores despite substantial recoveries of corresponding growth in culture. Correlations in the occurrence patterns of arthrospore-forming and non-sporulating colonies with those of Coprinus and 'other basidiospores' (excluding Ganoderma) were noted.

1F) J Allergy Clin Immunol. 1975 Sep;56(3):235-42. Assessing fungus prevalence in domestic interiors.Solomon WR. PMID: 1151016 [PubMed - indexed for MEDLINE] NOTE: IMPORTANT EXAMPLE HUMAN HABITAT-MICHIGAN HOMES; Single-plate, Andersen sampler collections of mesonphilic imperfect fungi were made at three points in and immediately outside a series of midwestern homes. During frost-free periods, emanations of dark-spored form genera predominated at both points with indoor levels averaging 25% of those in outside air. At these times, volumetric recoveries and those by 30-min exposure of open culture plates have correlated tenuously (r = 0.29) in bedroom air of 20 homes. During winter, form species of Penicillium, Aspergillus, Oospora, Sporothrix, yeasts, etc. predominated indoors, with levels exceeding 1,000 particles/M3 noted in over 18% of homes; outdoor concentrations never exceeded 230 particles/M3. Comparisons of volumetric and open-plate recoveries from 50 homes during winter have revealed an almost random relationship (r = 0.06). These findings reflect the case with which outdoor spore clouds may penetrate structures and obscure evidence of internal fungus sources. The data also imply that, because of size-related undersampling, open plates often seriously misrepresent prevalence levels and occasionally can exclude abundant types from recovery. The fungus flora of enclosed spaces merits further critical study by volumetric techniques of calculable efficiency in a setting that minimizes contamination from without.

Toxigenic fungi in a water-damaged building: An Intervention Study. Authors: SUDAKIN DL Author Address: Public Health General Preventive Med., Oregon Health Sci. Univ., 3181 SW Sam Jackson Park Road, CB-669, Portland, OR 97201-3098, USA.Entry Month: September, 1998 AJIMD Year of Publication: 1998 Secondary Source ID: BIOSIS/98/22568 Source: AMERICAN JOURNAL OF INDUSTRIAL MEDICINE; 34 (2). 1998. 183-190. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-BRAIN-FUNGI; In an investigation of health complaints among employees of a water-damaged office building, the environment showed evidence of fungal contamination with the isolation of Stachybotrys chartarum in one of five bulk samples tested for fungal growth. In response, a public health official recommended that employees be relocated from the building. Employees were subsequently moved to a different environment. A focused environmental investigation of microbial growth within the building followed, revealing moderate to high levels of fungi (Penicillium, Aspergillus versicolor) and bacteria in bulk and surface samples. S. chartarum was identified in one of 19 (5%) environmental samples using Czapek agar A health survey of building occupants revealed a high prevalence of multiple symptoms, with a predominance of neurobehavioral and upper respiratory tract complaints. The majority of symptoms were significantly less prevalent after relocation from the water-damaged environment. Th —.

ACOEM EXPERT #2 HOMER WE

Immunol Allergy Clin North Am. 2003 Aug;23(3):519-31. Assessment of the indoor environment: evaluation of mold growth indoors. Horner WE. Air Quality Sciences, 1337 Capital Circle, Atlanta, GA 30067, USA. ehorner@aqs.com Publication Types: Review Review, Tutorial PMID: 14524389 [PubMed - indexed for MEDLINE] HUMAN HABITAT: Much attention has been focused on indoor molds; resulting in modest amounts of new research. There is strong evidence of respiratory effects. Although mechanisms are disputed, some of the effect (but not all) is likely to be allergy related. There is some evidence that atopic individuals may be more affected, but many nonatopic individuals also are affected. This area needs more general research and specific research on exposure measures (such as what fungal components should be measured) and on health-effect mechanisms. It is worthwhile to emphasize the practical knowledge that is readily available. Buildings should be designed, built, operated, and occupied so that the buildings stay dry. When this situation does not occur, the environmental and clinical aspects that are observed by competent professionals should both be considered when determining causal relationships.

ACOEM EXPERT #3 BILLINGS

Immunol Allergy Clin North Am. 2003 Aug;23(3):519-31. Billings CG, Howard P. Dept Medicine and Pharmacology, University of Sheffield, UK. Publication Types: Review Review, Tutorial PMID: 9632907 [PubMed - indexed for MEDLINE] HUMAN HABITAT; An allergic disposition has long been recognized as a risk factor for asthma. However, it has been suggested that, irrespective of genetic factors, exposure to environmental agents is of major importance in the development of asthma. In industrialized countries, people spend most of their time indoors and so environmental conditions inside the home may play an important role in asthma development. A review of studies examining the relationship between housing conditions and health in general or, more specifically, the relationship between respiratory symptoms/asthma and damp housing and mould has been carried out. These studies have shown that damp housing conditions are associated with increased prevalence of respiratory symptoms and asthma. The severity of asthma increases with an increasing quantity of dampness and mould in the home. It is suggested that damp conditions may, by a number of mechanisms, increase the allergenic burden so resulting in the development of asthma.

Biological activities of actinomycetes and fungi isolated from the indoor air of problem houses. Authors: RATY K, RAATIKAINEN O, HOLMALAHTI J, VON WRIGHT A, JOKI S, PITKANEN A, SAANO V, HYVARINEN A, NEVALAINEN A, BUTI I, Author Address: Dep. Pharmaceutical Chem., Univ. Kuopio, P.O. Box 1627, FIN 70211 Kuopio, Finland. Source: INTERNATIONAL BIODETERIORATION & BIODEGRADATION; 34 (2). 1995. 143-154. Abstract: Public Health-Public Health Laboratory Methods Public Health: Environmental Health-Air Public Health: Microbiology BIOSIS COPYRIGHT: BIOL ABS. Entry Month: January, 1996 Year of Publication: 1995 Secondary Source ID: BIOSIS /95/36133.

HUMAN HABITAT-FUNGI; Isolates of actinomycetes (19 strains) and fungi (12 strains) obtained from houses with microbial indoor air problems were tested for antifungal, antibacterial and genotoxic properties. The tests were performed by observing the inhibition zones on the lawn of indicator organisms around agar discs cut from confluent plates of the test strains. A yeast (Candida albicans), a mold (Alternaria brassicicola) and a Gram-positive bacterium (Streptococcus salivarius subsp. thermophilus) were used as indicator organisms for general antifungal and antibacterial properties, while genotoxicity was detected with a DNA repair-deficient Escherichia coli strain CM871. Among the actinomycetes there were four antifungal, eight antibacterial and two genotoxic isolates, while one antibacterial, one antifungal and three geno toxic strains were detected among the fungi. Multiple activities were detected in two actinomycetes and two fungal isolates. Three bioactive actinomycetes were also exam—.

ACOEM EXPERT #4 BURR ML

1A) Rev Environ Health. 2001 Apr-Jun;16(2):97-103. Health effects of indoor molds. Burr ML, Centre for Applied Public Health Medicine, University of Wales College of Medicine, Temple of Peace and Health, Cardiff, UK. michael.burr@bro-taf-ha.wales.nhs.uk Publication Types: Review Review, Tutorial PMID: 11512632 [PubMed - indexed for MEDLINE] HUMAN HABITAT; Molds grow readily indoors in the presence of dampness. Their visibility enables their effects to be investigated by means of questionnaire surveys, although these are subject to imprecision and potential bias. Exposure to airborne mold particles can be measured in various ways that also have disadvantages and limitations. Many surveys have been conducted on the health effects of molds; most have examined the association between molds and symptoms, although some studies have used lung function tests and other objective health indices. Most surveys suggest that indoor mold growth is associated with ill health, particularly of the respiratory tract. Knowing how important mold exposure really is in health terms is difficult, owing to the tendency for mold growth to be associated with other factors that are prejudicial to health.

1B) 1: Clin Exp Immunol. 1984 Jun;56(3):645-52. Total and specific IgG4 antibody levels in atopic eczema. Merrett J, Barnetson RS, Burr ML, Merrett TG. PMID: 6744664 [PubMed - indexed for MEDLINE] (216 PEOPLE STUDY) HUMAN-ALLERGIC REACTION; Total IgG4 and IgG4 antibody levels specific for 10 allergens (three inhaled and seven ingested) were measured by radioimmunoassay of sera taken from three groups of adult patients: (1) 32 cases of atopic eczema, (2) 28 cases of respiratory allergy and (3) 156 normal volunteers. In all three groups IgG4 antibody activity was mainly directed against common foods, and generally the group with atopic eczema had higher total and specific IgG4 levels than the cases of respiratory allergy, who in turn had higher titres than the normal group. There was within each group a tendency for men to have more total IgG4 than women and the difference was statistically significant among the normals. There was evidence of an IgG4 restricted response in atopic eczema because despite the group's elevated total IgG4 its total IgG4 remained within normal limits. Furthermore specific IgG4 was correlated with the corresponding specific IgE level in five of the 10 allergens examined. These results are generally consistent with the view that IgG4 levels are raised in cases of atopic eczema due to prolonged exposure to an allergen which initiated an IgE response.

ACOEM EXPERT #51, BRIOTON WT

1: JAMA. 1987 Sep 4;258(9):1210-2. PMID: 3626005 [PubMed - indexed for MEDLINE]An outbreak of organic dust toxic syndrome in a college fraternity. Brinton WT, Vastbinder EE, Greene JW, Marx JJ Jr, Hutcheson RH, Schaffner W. HUMAN HABITAT-COLLEGE-FUNGI; An explosive outbreak of a febrile respiratory illness occurred among members of a college fraternity. The preponderant signs and symptoms were muscle aches, cough, and low-grade fever. All illnesses occurred within 1.3 to 13 hours of attendance at a party where there was a dense airborne dust from straw that had been laid on the floor. Of the 67 fraternity members who attended the party and answered a questionnaire, 55 became ill (attack rate, 82%). Risk of illness was higher for those who spent more time at the party. Duration of illness ranged from 4.5 hours to seven days. Results of serological studies did not demonstrate an allergic or viral cause for these illnesses. The clinical and epidemiologic features of this outbreak were characteristic of organic dust toxic syndrome, an acute respiratory illness caused by inhalation of molds growing on hay, silage, or other agricultural products.

NIOSH

Field Survey of Mycotoxin-Producing Fungi Contaminating Human Foodstuffs in Japan, with Epidemiological Background. II. Biological Effects of the Mycotoxins Produced by the Fungi Isolated from Foodstuffs Entry Month: March, 1990Year of Publication: 1971 Secondary Source ID: NIOSH/00117155 Source: Symposium on Mycotoxins in Human Health, I. F. H. Purchase, Ed., The Macmillan Press LTD, London, pages 179-183, 4 references, 19711971 Abstract:

MICE TESTING-FUNGI POISON; The toxicity of food contaminating fungi was assayed. Male DDD-mice received injections of 250 strains of fungi for 3 days. Symptoms were observed and body weights were measured. Dead mice and mice sacrificed following the final injection were necropsied. Thirty kinds of toxic fungi 20 of which produce mycotoxins, were isolated. Specific targets of many fungi were the actively dividing cells. Mitotic injury and chromosome abnormalities were seen. The mycotoxins produced hepatotoxicity, nephrotoxicity, and neurotoxicity, and some produced toxic reactions in two or more organs. The authors recommend further development of chemical and biological assays for detection of mycotoxins.

PARAGRAPH 1, sentence 4.

“Particular attention is given to the possible health effects of mycotoxins, which give rise to much of the concern and controversy surrounding indoor molds.”

A) This is a very misleading sentence since it implies that the health effects of mycotoxins are only “possible” rather than established with ongoing research into the less recognized effects of fungi, their byproduct; mycotoxins, their byproducts, and their interactions with blood, tissue, organs, etc.

A SAMPLE OF PUBLISHED, PEER-REVIEWED EVIDENCE

EPA, IAQ News; September 2002

HUMAN-MEDICAL AND PUBLIC HEALTH; “The view that various molds can cause adverse effects for those with compromised immune systems, asthma, allergies, or other heightened sensitivities finds support in the medical and public health communities. In addition, it is accepted that certain mycotoxins in high enough concentrations are toxic (in fact, some have been studied as potential biological weapons).”

“There is, however, support for specific effects on certain populations; allergic effects for agricultural workers exposed to very high levels of dust from moldy hay and other farm products (known as “farmers lung” or “organic toxic dust syndrome”), and for certain highly allergic or sensitized people.”

“When mold problems do arise, they should not be taken lightly. They call for prompt response that may well require professional assistance.”

NIOSH

Fungal Spores: Hazardous to Health? (Note: ACOEM #1 Expert) W.G. SorensonDivision of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, West Virginia USA Environ Health Perspect 107(suppl 3):469-472 (1999). http://ehpnet1.niehs.nih.gov/docs/1999/suppl-3/469-472sorenson/abstract.html Abstract

HUMAN DISEASES; Fungi have long been known to affect human well being in various ways, including disease of essential crop plants, decay of stored foods with possible concomitant production of mycotoxins, superficial and systemic infection of human tissues, and disease associated with immune stimulation such as hypersensitivity pneumonitis and toxic pneumonitis. The spores of a large number of important fungi are less than 5 µμm aerodynamic diameter, and therefore are able to enter the lungs. They also may contain significant amounts of mycotoxins. Diseases associated with inhalation of fungal spores include toxic pneumonitis, hypersensitivity pneumonitis, tremors, chronic fatigue syndrome, kidney failure, and cancer. Key words: mold, fungi, mycotoxin, lung disease, toxic pneumonitis.

CONCORDIA

Personal exposures and micro-environmental concentrations of particles and bioaerosols, Concorida, 2002

HUMAN HABITAT-BIOAEROSOL EXPOSURE: “The results show that particle mass concentrations, absorption coefficient and fungi were higher in personal exposure samples than in home and workplace samples. Our results indicate that personal exposure measurements of bioaerosols in indoor environments are feasible and supplement the information obtained by stationary samples.” (People breathe)

NEIHS.nih.gov (U.S.A.)

Clinical experience and Results of a Sentinel Health Investigation Related to Indoor Fungal Exposure, Eckart Johanning, et al., Environmental Health Perspectives Supplements, June 1999 HUMAN–EXTENSIVE STUDY NOTE; E Johanning ACOEM Expert #56 and 57

Clinical Experience and Results of a Sentinel Health Investigation Related to Indoor Fungal Exposure Eckardt Johanning,¹ Paul Landsbergis,² Manfred Gareis,³ Chin S. Yang,⁴ and Ed Olmsted5 ¹Mount Sinai School of Medicine, New York, New York USA; Eastern New York Occupational and Environmental Health Center, Albany, New York USA; ²Cornell University Medical College, Mount Sinai School of Medicine, New York, New York USA; ³Federal Meat Research, Microbiology and Toxicology, Kulmbach, Germany; ⁴P&K Microbiology Services, Inc., Cherry Hill, New Jersey USA; ⁵Olmsted Environmental Services, Inc., Garrison, New York USA Abstract

HUMAN HABITAT-DISEASE; This is a review of exposure conditions, clinical presentation, and morbidity of children and adults with indoor fungal exposure such as toxic Stachybotrys chartarum. Indoor exposure was characterized using different methods including microscopic, culture, cytotoxicity screening tests, and chemical analyses. Clinical case histories and physical and laboratory findings are presented of children (age < 18 years, n = 22; mean age 9 years; 60% females) and adults (age >18 years, n = 125; mean age 39 years, 67% females) who consulted an environmental health specialty clinic. In the pediatric patients' exposure history, widespread fungal contamination of water-damaged building materials with known toxic or allergic fungi was identified. Primarily disorders of the respiratory system, skin, mucous membranes, and central nervous system were reported. Some enumeration and functional laboratory abnormalities, mainly of the lymphatic blood cells, were observed, although no statistically significant differences were found. IgE or IgG fungi-specific antibodies, used as exposure markers, were positive in less than 25% of all tested cases. In an evaluation of a symptomatic girl 11 years of age (sentinel case investigation) living in an apartment with verified toxigenic fungi (i.e., S. chartarum), several health indicators showed improvement after exposure cessation. Key words: allergy, bioaerosol, exposure, fungi, health, morbidity, mycotoxins, Stachybotrys, toxicity. -- Environ Health Perspect 107(suppl 3):489-494 (1999). http://ehpnet1.niehs.nih.gov/docs/1999/suppl-3/489-494johanning/abstract.html Environmental Health Perspectives Volume 107, Supplement 3, June 1999

NOTE; EPA quotes rat studies are the “Gold Standard” and “There is proof of mycotoxins and human health effects.

Mycotoxins, PubMed, 2003

HUMAN “Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals.”

PARAGRAPH 1, Sentence 5

“Food-borne exposures, methods of exposure assessment, and mold remediation procedures are beyond the scope of this paper.”

A) These are the most well documented and publically accepted areas of information on fungi and their effects so it would not be beneficial to include these areas in the ACOEM policy/statement. Due to the extensive volume of proof in the area of food-borne exposure, methods of exposure assessment, and mold remediation papers only a few more important peer-reviewed articles will be included here.

B) “methods of exposure assessment,” There are many methods of assessment for the levels of fungal contamination, etc.

C) “mold remediation procedures” have been well established and are prejudicial to the premiss of the ACOEM position. Since almost everyone involved in fungi are well aware of mold remediation procedures only a few items will be used in this report to verify the toxicity of mold and their byproducts.

LABORATORY PROCEDURES

Procedures for destruction of patulin in laboratory wastes, Toxnet, 1996 Frääemy JM; Castegnaro MJ; Gleizes E; De Meo M; Laget M Food Addit Contam 1995 May-Jun;12(3):331-6 [EMIC] FOOD ADDITIVES AND CONTAMINANTS; 12 (3). 1995. 331-336. [BIOSIS

HUMAN-POISON FROM FUNGI: “Patulin is immunosuppressive and there is limited evidence of its carcinogenicity in experimental animals. The International agency for Research on Cancer initiated a programme for the development of degradation techniques for the commonly investigated mycotoxins.”

Laboratory decontamination and destruction of carcinogens in laboratory wastes - Some mycotoxins Authors: Castegnaro M, et al. Corporate Name: International Agency for Research on Cancer, Ministry of the Environment (France) Source: Oxford University Press, Walton Street, Oxford OX2 6DP, United Kingdom, 1991. 63p. 99 ref. Publication Types: MONOGRAPH Entry Month: October, 1992 Classification Code: 120 Year of Publication: 1991 Secondary Source ID: CIS/92/01280 Document Number: CIS /92/01280 Abstract:

HUMAN-POISON FROM FUNGI; The following mycotoxins are considered: citrinin, ochratoxin A, patulin, sterigmatocystin, aflatoxins B[1], B[2], G[1] and G[2]. Methods proposed for eliminating the carcinogenic potential of these compounds include: treatment using sodium hypochlorite, ammoniation, and treatment with potassium permanganate under alkaline conditions that does not generate mutagenic species.

A Review of Mycotoxins in Indoor Air Authors: ,Hendry KM Cole EC , Source: Journal of Toxicology and Environmental Health, Vol. 38, No. 2, pages 183-198, 48 references, 1993 Abstract:

HUMAN HABITAT-FUNGI POISONS; A review of the sources and health effects of mycotoxins that have been found in indoor air was presented. Discussions were presented on the origins and health effects of classes of mycotoxins that have been identified in dust. These included aflatoxins, trichothecenes, zearalenone (17924924), and secalonic-acid-D (35287695). Exposure sources for mycotoxins have included agricultural products such as cereal grains, nuts, and rice, and components of homes and buildings such as heating, ventilation, and air conditioning systems, and burning wood chips. Another source of mycotoxins has been commercial facilities involved in the processing of contaminated materials such as grains or nuts and livestock feed. Fungal growth has been identified in wood drying kilns and two cases of cancer in laboratory workers with repeated exposure to mycotoxins have been reported. Factors conducive to the growth of fungi and the relationship between such growth and the subsequent production of mycotoxins was reviewed. The use of viable and particulate impactors, high volume filtration samplers, or liquid impingers have been recommended by the American Conference of Governmental Industrial Hygienists for the sampling of airborne mycotoxins. The use of thin layer chromatography, high performance liquid chromatography, and a chicken embryo bioassay for the analysis of mycotoxins was discussed. Epidemiological studies on the association between exposures to mycotoxins and the development of human disease were reviewed. Needs for future research in this area were outlined.

CDC

Chronic Sequelae of Foodborne Disease, J. Lindsay, Dec. 1997

HUMAN-EXPOSURE-FUNGI POISONS: “Metabolic activation and detoxification play a crucial role in determining the toxic response of humans to mycotoxins exposure. These highly toxic secondary metabolites aare produced by a wide variety of molds including Aspergilllus, Fusarium, and Penicillium. Mycotoxins exhibit properties of acute, subacute, and chronic toxicities with some molecules being carcinogenic, mutagenic, and teratogenic.

Aflatoxins have been implicated in both acute and chronic liver disease in humans; however, other organs (kidney, spleen, pancreas) may also be affected. The best studied chronic effects are those induced by the fumonisins, zearalenone, and trichothecene mycotoxins produced by Fusarium sp.

–Since trichothecenes modulate immune function, over time mycotoxincosis could reduce immune resistance to infectious diseases, facilitate tumor growth through reduced immune function, and cause autoimmune disease.”

HUMAN DNA DAMAGE AND FUNGI POISON

Mutat Res. 1999 Mar 8;424(1-2):167-81.

DNA damage by mycotoxins. Wang JS, Groopman JD. Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. Copyright 1999 Elsevier Science B.V. Publication Types: Review Review, Tutorial PMID: 10064859 [PubMed - indexed for MEDLINE] HUMAN-CANCER-FUNGI POISON; Mycotoxins are toxic fungal metabolites which are structurally diverse, common contaminants of the ingredients of animal feed and human food. To date, mycotoxins with carcinogenic potency in experimental animal models include aflatoxins, sterigmatocystin, ochratoxin, fumonisins, zearalenone, and some Penicillium toxins. Most of these carcinogenic mycotoxins are genotoxic agents with the exception of fumonisins, which is currently believed to act by disrupting the signal transduction pathways of the target cells. Aflatoxin B1 (AFB1), a category I known human carcinogen and the most potent genotoxic agent, is mutagenic in many model systems and produces chromosomal aberrations, micronuclei, sister chromatid exchange, unscheduled DNA synthesis, and chromosomal strand breaks, as well as forms adducts in rodent and human cells. The predominant AFB1-DNA adduct was identified as 8, 9-dihydro-8-(N7-guanyl)-9-hydroxy-AFB1 (AFB1-N7-Gua), which derives from covalent bond formation between C8 of AFB1-8,9-epoxides and N7 of guanine bases in DNA. Initial AFB1-N7-guanine adduct can convert to a ring-opened formamidopyrimidine derivative, AFB1-FAPY. The formation of AFB1-N7-guanine adduct was linear over the low-dose range in all species examined, and liver, the primary target organ, had the highest level of the adduct. Formation of initial AFB1-N7-guanine adduct was correlated with the incidence of hepatic tumor in trout and rats. The AFB1-N7-guanine adduct was removed from DNA rapidly and was excreted exclusively in urine of exposed rats. Several human studies have validated the similar correlation between dietary exposure to AFB1 and excretion of AFB1-N7-guanine in urine. Replication of DNA containing AFB1-N7-guanine adduct-induced G-->T mutations in an experimental model. Activation of ras protooncogene has been found in AFB1-induced tumors in mouse, rat, and fish. More strikingly, the relationship between aflatoxin exposure and development of human hepatocellular carcinoma (HHC) was demonstrated by the studies on the p53 tumor suppressor gene. High frequency of p53 mutations (G-->T transversion at codon 249) was found to occur in HHC collected from populations exposed to high levels of dietary aflatoxin in China and Southern Africa. Furthermore, AFB1-induced DNA damage and hepatocarcinogenesis in experimental models can be modulated by a variety of factors including nutrients, chemopreventive agents, and other factors such as food restriction and viral infection, as well as genetic polymorphisms.

Folia Biol (Praha). 1986;32(6):406-13. Induction of DNA single-strand breaks and DNA synthesis inhibition in CHO and AWRF cells after exposure to sterigmatocystin and penicillic acid. Stetina R. PMID: 3100345 [PubMed - indexed for MEDLINE] FUNGI POISON-RODENTS; Sterigmatocystin is 12 times more toxic to transformed rat fibroblasts (AWRF) than to Chinese hamster ovary cells (CHO). In contrast, penicillic acid is twice more toxic to CHO cells than to AWRF cells. The ability of sterigmatocystin and penicillic acid to inhibit DNA synthesis correlated well with the differences in cytotoxicity of these mycotoxins in the cell lines used. Sterigmatocystin at a concentration of 10 micrograms/ml inhibited DNA synthesis in AWRF cells during a 3-h exposure to 60% of that found in controls, but did not inhibit DNA synthesis in CHO cells. Within the same time interval penicillic acid inhibited DNA synthesis in AWRF cells at concentrations higher than 5 micrograms/ml and in CHO cells at concentrations over 0.5 microgram/ml. Induction of DNA single-strand breaks (SSB) during a 3-h exposure to sterigmatocystin and penicillic acid was comparable in both cell types. The results suggest that sterigmatocystin is metabolized to reactive metabolites that are responsible for the toxicity and DNA synthesis inhibition at a more rapid rate in AWRF cells than in CHO cells. The observed ability to induce SSB indicates that penicillic acid is

potentially carcinogenic.Mutat Res. 1984 Aug-Sep;137(2-3):111-5.

Induction of sister-chromatid exchanges in vivo in mice by the mycotoxins sterigmatocystin and griseofulvin. Curry PT, Reed RN, Martino RM, Kitchin RM. PMID: 6472322 [PubMed - indexed for MEDLINE] FUNGI POISON-MICE; Two naturally occurring fungal mycotoxins, sterigmatocystin and griseofulvin, were tested for induction of sister-chromatid exchanges (SCEs) in bone marrow cells of female Swiss albino mice. Sterigmatocystin gave elevated SCE frequencies at all doses tested (0.06-6.0 mg/kg). In contrast, griseofulvin, tested from 0.4 to 200 mg/kg, elevated the SCE frequency only in those mice which received doses of 100 or 200 mg/kg body weight. These results indicate that both fungal mycotoxins induce SCE in vivo and are potentially mutagenic.

IMMUNE DEFICIENCY

SOCIAL SECURITY ADMINISTRATION

Notice of Proposed Rulemaking Revised Medical Criteria for Evaluating Immune System Disorders [Federal Register: May 9, 2003 (Volume 68, Number 90)] [Proposed Rules] [Page 24896-24898] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr09my03-30] SOCIAL SECURITY ADMINISTRATION 20 CFR Parts 404 and 416 [Regulations Nos. 4 and 16] RIN 0960-AF33 Revised Medical Criteria for Evaluating Immune System Disorders AGENCY: Social Security Administration. ACTION: Advance notice of proposed rulemaking. regulations@ssa.gov Date posted: 05/12/2003 Comment period opens:05/09/2003 Comment period closes: 07/08/2003 Summary And Background:

HUMAN; We are planning to update and revise the rules that we use to evaluate immune system disorders of adults and children who apply for, or receive, disability benefits under title II and Supplemental Security Income (SSI) payments based on disability under title XVI of the Social Security Act (the Act). The rules we plan on revising are sections 14.00 and 114.00 in the Listing of Impairments in appendix 1 to subpart P of part 404 of our regulations (the listings). We invite you to send us comments and suggestions for updating and revising these rules.

After we have considered your comments and suggestions, as well as information about advances in medical knowledge, treatment, and methods of evaluating immune system disorders, and our program experience, we intend to publish for public comment a Notice of Proposed Rulemaking (NPRM) that will propose specific revisions to the rules. As part of our long-term planning for the disability programs, we are also interested in your ideas for how we may be able to improve our programs for people who have immune system disorders, especially those who would like to work.

Immunology _?2 2002 Yuldasheva I. A.

Changes in immune status and lipid peroxidation in asthmatics

HUMAN; Cellular and humoral immunity was assessed in patients with asthma. T-lymphocyte content normalized during remissions. Analysis of immunoregulatory subpopulations showed hyposuppressive immunodeficiency in asthmatics. Evaluation of T-helper levels showed their significant decrease during exacerbation and increase during remission.

Autoimmune diseases e.g. pernicious anaemia, Autoimmune thyroid disease, Thrombocytopenic purpura, and SLE can be seen with selective IgA and common variable antibody deficiency

In vitro exposure of human lymphocytes to trichothecenes: Individual variation in sensitivity and effects of combined exposure on lymphocyte function. Authors: THUVANDER A, WIKMAN C, GADHASSON I, Author Address: Division of Toxicology, National Food Administration, 751 26, Uppsala, Sweden. Source: FOOD AND CHEMICAL TOXICOLOGY; 37 (6). 1999. 639-648. Entry Month: December, 1999 Year of Publication: 1999 Secondary Source ID: BIOSIS/99/25859 Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-FUNGI POISON; The trichothecenes are mycotoxins produced by fungi of the genus Fusarium, which are commonly present in foods and feed of cereal origin. Owing to the lack of sufficient toxicological data for most of the trichothecenes, in vitro studies may contribute to risk assessments of these toxins. In the present report, human lymphocyte cultures were used to study the individual variation in sensitivity among humans and the effects on in vitro Ig production. Furthermore, proliferative responses of cells e blood donors. The individual variation in sensitivity, evaluated as the range of IC50 values, was rather limited (within a factor of 3 to 4). Immunoglobulin production by pokeweed-stimulated human lymphocytes was also effectively inhibited with IC50 values similar to the IC50 values in the proliferation tests for DON and NIV. However, IC50 values for Ig synthesis in cultures exposed to T2 were approximately two to three times higher than the corresponding IC50 values found in the proliferation could have been expected from the inhibition produced by the individual toxins. In conclusion, the tested trichothecenes inhibited both proliferation and Ig production in human lymphocytesin a dose-dependent manner with limited variation in sensitivity between individuals. Enhanced Ig production was observed in cell cultures exposed to the lower doses of the toxins. Combined exposure to two of the toxins resulted mainly in additive or antagonistic effects, although synergistic effects cannot be—.

Immunology _?3 2002 Mokronosova M. A., Lyaporova T. V., Kochetova Yu. I.

Study reactivity to allergen from C. albicans yeast-like fungi in patients with atopic dermatitis (115 people)

HUMAN; Candida fungi are highly prevalent in nature and belong to opportunistic microflora. Patients with atopic dermatitis (AD) often develop sensitization to yeast-like fungi, which manifests by allergic IgE-mediated reactivity. C. albicans antigenic extract together with tuberculin and tetanus toxin is acknowledged as a marker characterizing cell-mediated immunity. We investigated immediate and delayed type skin reactivity to intracutaneous injection of C. albicans extract 20 min, 24, 48, and 72 h postinjection in 115 patients with AD and 29 subjects without AD. Patients with newly detected serum IgE to C. albicans aged 5-40 years (mean age 19.5 years) with AD of different severity were observed. Patients with AD were characterized by a high incidence of immediate positive reactions (20 min postinjection), which were observed in 60% vs. 16% in the reference group (p < 0.01). The incidence of immediate type hyperergic reactions increased with AD severity: from 11% in healthy subjects and 40% in patients with slight AD to 80% in patients with severe AD. The incidence of delayed type positive reactions was 2-fold higher in patients with severe AD in comparison with those with slight AD. Severe AD is characterized by changed skin reactivity to candidine, increased incidence and extent of immediate reactions and decreased mean area of delayed reactions. Intracutaneous test with C. albicans allergen can serve as an objective marker of AD severity.

IgG Subclass

Guidelines for evaluating Adult Immune Deficiency Syndromes--IgA, IgG-4, and IgG-2

HUMAN DISEASE-IMMUNE SUPPRESSION; “Ataxia-Telangiectasis,- progressive cerebellar, oculoculaneous telangiectasis, recurrent sinopulmonary infections, and predisposition to neoplasis. Complex immune deficiency that involves abnormal functions of both T and B lymphocytes. Serum IgA level is low in about 70%.”

From Infections in Medicine® Immunology Management of IgG Subclass Deficiency in Adults Posted 01/05/2004 Maeve E. O'Connor, MD; Charles H. Kirkpatrick, MD Abstract and Introduction Abstract

HUMAN-IMMUNE SYSTEM; An intact immune system is essential for prevention of injury from infectious microorganisms, toxins, tumor cells, and autoimmunity. The importance of antibodies is clearly demonstrated by the recurrent acute infections in patients with antibody deficiency syndromes. IgG, the major immune globulin in serum, is composed of 4 subclasses, and each has its own properties. Although some patients with deficiencies of 1 or more of the IgG subclasses have recurrent infections, others are healthy. This has led to controversies over the clinical significance of IgG subclass deficiencies and their relationship to susceptibility to recurrent infections.

NIOSH

Autoimmunity Induced by Chemicals, Toxnet 1990 Bigazzi PE Journal of Toxicology, Clinical Toxicology, Vol. 26, Nos. 3/4, pages 125-156, 113 references, 1988 [NIOSH]

HUMAN “Chemical induced autoimmunity was reviewed.—Autoimmune responses to autoantigens can occur in healthy persons and do not necessarily result in the development of an autoimmune disease.–These included systemic lupus erythematosus induced by hydralazine (86544), procainamide (51069), isoniazid (54853), penicillamine (52675, and other drugs, autoimmune hemolytic anemia and thrombocytopenia induced by methyldopa (555306), myasthenia gravis resulting from treatment with penicillamine, pemphigus type skin lesions induced by penicillamine, glomerulonephritis mediated by immune complexes and renal antigens.----hepatitis induced by a variety of drugs and environmental toxins.”

NIOSH

B lymphocyte precursor cells represent sensitive targets of T2 Mycotoxin exposure, Toxline, 1995 Holladay SD ; Smith BJ ; Luster MI Toxicology and Applied Pharmacology, Vol. 131, No. 2, pages 309-315, 31 references, 1995 [NIOSH] Entry Month: November, 1995 Year of Publication: 1995 Secondary Source ID: NIOSH/00226865 Document Number: NIOSH/00226865

HUMAN-IMMUNE SYSTEM-FUNGI POISON: “Exposure of experimental animals and humans to the Fusarium Trichothecene metabolite, T2 toxin, has been associated with a variety of immunosuppressive effects, including altered parameters of humoral-mediated immunity. -resulted in significant and selective depletion of fetal liver cells expressing low levels of surface CD44 and CD45 antigens, suggestive of possible lymphoid progenitor cell sensitivity to this agent. -reduction in fetal liver B lymphocytic cells in animals exposed to T2 toxin.

Allergy and other hypersensitivity reactions “Allergic and other hypersensitivity responses to indoor molds may be immunoglobulin E (IgE) or immunoglobulin G (IgG) mediated, and both types of response are associated with exposure to indoor molds.”

Effects of sterigmatocystin, deoxynivalenol and aflatoxin G1 on apoptosis of human peripheral blood lymphocytes in vitro, PubMed, 2002 Sun XM, Zhang XH, Wang HY, Cao WJ, Yan X, Zuo LF, Wang JL, Wang FR.Department of Experimental Pathology, Hebei Medical University, Shijiazhuang 050017, Hebei, China. HUMAN: “CONCLUSION; ST, DON and AFG1 can induce apoptosis of HPBLs in vitro and may have some negative effects on human immunosystem.”

NOTE: Many people exposed to fungi and mycotoxins from fungi show these types of blood problems=. IgG, IgA, et al. IVIG replacement therapy costs about $20,000.00 per month. Asthma, etc. can be IgG, IgA mediated.

Humoral Immunodeficiency Practice Parameters Reprinted with permission from: The Annals of Allergy, Asthma, and Immunology Most recent update: October 27, 1996 Webbed by Jay Portnoy, MD. The Children's Mercy Hospital III. Management of Humoral Immune Deficiencies

HUMAN; Intravenous immunoglobulin (IVIG) replacement therapy should only be given to patients with specific antibody deficiency involving IgG.

IVIG therapy for patients with normal humoral immunity but recurrent infections, particularly upper respiratory infections, has no scientific rationale.

IVIG replacement therapy should be initiated with a dose of 200 to 400 mg/kg/3 to 4 wk in most circumstances; adjustment to higher doses and shorter intervals may benefit some patients.

IVIG replacement therapy in humoral immunodeficient patients is usually life-long.

Concomitant therapy with systemic antibiotics is necessary in patients receiving IVIG who develop infections, such as chronic lung and sinus disease.

Avoidance of live viral vaccines is mandatory in patients with complete absence of serum immunoglobulins.

Patient/parent education and genetic counseling are essential for adjustment of the patient to a chronic disease.

It is important to determine what type of agammaglobulinemia is present in a patient. The carrier state of females with some X-linked forms of humoral immunodeficiency can now be determined. Prenatal diagnosis of some forms of humoral immune deficiency can now be accomplished, giving parents information on reproductive choices. The advent of gene therapy for newly discovered molecular lesions in humoral immunodeficiencies may revolutionize patient management in the future.

Patients with recurrent infections should be considered for referral to an allergist/immunologist for evaluation of humoral immunodeficiency.

The allergist/immunologist has special expertise in evaluating, diagnosing, and managing patients with humoral immune defects.

Because humoral immune defects are a form of chronic disease, communication and follow-up consultation on a continuing basis between the referring physician and the allergist/immunologist is essential.

In certain circumstances the allergist/immunologist and the primary care physician will need to consult specialists in otorhinolaryngology, infectious diseases, metabolism, hematology/oncology, pulmonology, rheumatology, gastroenterology, surgery, and other fields.

Role of Mycotoxins in Human and Animal Nutrition and Health, Toxnet, 1995

NOTE: ACOEM Experts; #1, #36, Authors: SMITH JE, SOLOMONS G, LEWIS C, ANDERSON JG Author Address: Dep. Biosci. Biotechnol., Univ. Strathclyde, 204 George St., Glasgow G1 1XW, UK. Source: NATURAL TOXINS; 3 (4). 1995. 187-192.

HUMAN-FUNGI POISON; “Mycotoxin entry to the human and animal dietary systems is mainly by ingestion but increasing evidence also points at entry by inhalation. –mycotoxins can be mutagenic, carcinogenic, ,embryotoxic, teratogenic, or oestrogenic. Analysis of mycotoxin adducts in human populations can act as a surrogate for human genotoxicity. Mycotoxins can also be immunosuppressive and appear to involve cellular immune phenomena and non-specific humoral factors associated with immunity.”

Role of Mycotoxin in Human and Animal Nutrition and Health, Toxnet, 1995

Authors: SMITH JE SOLOMONS G LEWIS C ANDERSON JG Author Address: Dep. Biosci. Biotechnol., Univ. Strathclyde, 204 George St., Glasgow G1 1XW, UK. Source: NATURAL TOXINS; 3 (4). 1995. 187-192.

NOTE; ACOEM Expert #36

HUMAN “Mycotoxin entry to the human and animal dietary systems is mainly by ingestion but increasing evidence also points at entry by inhalation. Mycotoxins exhibit a wide array of biological effects and individual mycotoxins can be mutagenic, carcinogenic, embryotoxic, teratogenic, or oestrogenic. Analysis of mycotoxin adducts in human populations can act as a surrogate for human genotoxicity. Mycotoxins can also be immunosuppressive and appear to involve cellular immune phenomena and non-specific humoral factors associated with immunity.”

Use of Cell culture for predicting the biological effects of Mycotoxins, 1987, 29 references

Robbana-Barnat S ; Lafarge-Frayssinet C ; Frayssinet C Cell Biology and Toxicology, Vol. 5, No. 2, pages 217-226, 29 references, 1989 [NIOSH] CELL BIOL TOXICOL 5:217-226,1989 [EMIC] CELL BIOL TOXICOL; 5 (2). 1989. 217-226. [BIOSIS]

HUMAN “The biological effects of some trichothecenes, a representative family of mycotoxins, were assessed and compared in normal and transformed lymphoid cells, hepatic cells and/or neoplastic fibroblasts to illustrate the utility of a test designed for toxicological analysis using cells derived from different target organs.-first group-no effects, second group-acted preferentially on hepatoma cells, and third group showed preferential lymphotrophic effects.” NOTE: Lymphotropic effects=immune system effects.

Ochratoxins and toxicological consequences. Authors: CREPPY EE BAUDRIMONT I BETBEDER AM Author Address: Lab. Toxicol. d'Hygiene Appliquee, Univ. de Bordeaux II, 3 ter Place de la Victoire 33000 Bordeaux, France. (In TOXNET) Source: CRYPTOGAMIE MYCOLOGIE; 16 (3). 1995. 195-221. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN; Ochratoxin A (OTA), a contaminant found in foods such as cereals, meat of animals fed with contaminated feed, and dried fruits, is a mycotoxin produced by molds from the genera Aspergillus and Penicillium. OTA is now considered to be the principal causal agent of endemic nephropathy in the Balkans, particularly in the rural zones of Bulgaria, Croatia, Slovenia, Bosnia, and Romania. OTA was also detected in the blood of people living in Germany, France, Scandinavia, Canada, Japan, and North Africa. The nephropathy involves a slow-evolving tubulointerstitial nephritis often associated with urinary tract tumors. In addition to glucose metabolism and blood coagulation disturbances, other toxic effects include immunosuppression, genotoxicity, and teratogenesis. OTA is metabolized in vitro and in vivo by P-450 cytochrome subfamilies in several metabolites. 4R-4-hydroxyochrotoxin-A presents a cytotoxicity analogous to that of OTA. Chronic and acute toxicity are linked to OTA's

Review: Toxicological and nutritional implications of T-2 toxin. Authors: LEAL M GONZALEZ DE MEJIA E Author Address: Univ. Autonoma Queretaro, Fac. Quim., Centro Univ., Cerro Campanas, Queretaro, Qro. 76049, Mexico. Source: FOOD SCIENCE AND TECHNOLOGY INTERNATIONAL; 3 (4). 1997. 241-250. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Entry Month: November, 1997 Year of Publication: 1997 Secondary Source ID: BIOSIS/97/27639 Document Number: BIOSIS/97/27639

HUMAN; Trichothecenes are mycotoxins produced by species of the genus Fusarium. These toxins are associated with health problems in humans and animals. The most common trichothecenes in cereals are deoxynivalenol, HT-2 toxin, diacetoxyscirpenol, nivalenol, neosolaniol and T-2 toxin; the latter is the most widely studied because it is easy to produce in the laboratory. The effects of T-2 toxicosis include dermatonecrosis, reduced body weight and efficiency of food utilization, severe diarrhoea, hemorrhage, necrosis of the upper alimentary tract, anaemia, immunosuppression; and in birds, poor feathering. This paper reviews the latest information about the occurrence, chemical characteristics, toxicity, metabolic alterations, biotransformation and detoxification methods of the T-2 toxin.

B lymphocyte precursor cells represent sensitive targets of T2 mycotoxin exposure. (Toxnet) Authors: HOLLADAY SD SMITH BJ LUSTER MI Author Address: Dep. Biomedical Sci. Pathobiology, Virginia-Maryland Regional Coll. Veterinary Med., Virginia Polytechnic Inst. State Univ., Blacksburg, VA 24061-0442, USA. Source: TOXICOLOGY AND APPLIED PHARMACOLOGY; 131 (2). 1995. 309-315. Abstract: BIOSIS COPYRIGHT: BIOL ABS. TXAPA Entry Month: September, 1995 Year of Publication: 1995 Secondary Source ID: BIOSIS EnglishCoden:/95/19579 CAS Registry Numbers: 21259-20-1

HUMAN; Exposure of experimental animals and humans to the Fusarium trichothecene metabolite, T2 toxin, has been associated with a variety of immunosuppressive effects, including altered parameters of humoral-mediated immunity. Although T2 toxin is cytotoxic in vitro to lymphocytic cells, limited information is presently available regarding the contribution of such a mechanism to immunosuppression in vivo, or to potential immune cell targets. In the present report, subchronic T2 toxin treatment of timed-pregnant B6C3F1 mice resulted in significant and selective depletion of fetal liver cells expressing low levels of surface CD44 and CD45 antigens, suggestive of possible lymphoid progenitor cell sensitivity to this agent. Evaluation of CD45R antigen expression in fetal liver supported such a hypothesis, demonstrating a significant reduction in fetal liver B lymphocytic cells in animals exposed to T2 toxin. Subsequent in vitro T2 toxin exposure of fetal liver cells enriched for–.

Stachybotryotoxicosis and immunosuppression. Authors: DANKO G Source: INT J ENVIRON STUD; 8 (3). 1975 (RECD 1976) 209-211 Abstract: HEEP COPYRIGHT: BIOL ABS. Entry Month: July, 1976 Year of Publication: 1975 Secondary Source ID: HEEP /76/11420

CATTLE: Stachybotryotoxicosis in cattle is caused by straw and hay that is contaminated with the mold Stachybotrys alternans. Upon autopsy, large hemorrhages, ulcers (some dried), dried necrotic foci and degenerate areas, mycelia and Mucor-type fungi have been discovered. S. alternans did not grow in the internal organs, as determined by experimental infection and field studies. Development of lesions may be caused by secondary molds. The toxin S. alternans reduces the number of immunocompetent leukocytes, hindering the immunoreactions of the organism and the formation of immunoglobulins and thus immunosuppression. An immunosuppressive effect must be considered in regard to other fungal toxicosis. Facultative pathogenic microorganisms can cause mass diseases and death of animals fed with toxic food, and this is in consequence of an immunosuppressive effect. The active immunization (vaccination) of such animals is unsuccessful.

NOTE: This sounds like what happens to many humans exposed to Stachybotrys. Does this report validate that there have been experiments with vaccinations against fungi? Lowered immune system=disease.

Studies of immune function of CD-1 Mice exposed to Aflatoxin B1, Toxnet, 1987, 26 references.

“AFB1 suppressed both B-cell and T-cell functions, with a greater effect on T-cells.”

Experimental T-2 toxicosis in swine following inhalation exposure, clinical signs and effects on hematology, serum biochemistry, and immune response. PubMed, 1988

“ The lymphocyte count decreased while the neutrophil count increased.+++++”

PATIENTS ALREADY IMMUNOCOMPROMISED

NOTE: Immune suppression can be caused by many diseases. EXAMPLE’S: Cancer, AIDS, diabetes, liver disease, and from something as simple as a cold.

20 Clinical Pearls Fungal Infections Posted 10/24/2003 Carol A. Kauffman, MD Abstract and Introduction

Carol A. Kauffman, MD, Ann Arbor (Michigan) Veterans Affairs Healthcare System, University of Michigan Medical School, Ann Arbor. Dr Kauffman is chief, infectious diseases, Ann Arbor Veterans Affairs Healthcare System, and professor of internal medicine, University of Michigan Medical School, Ann Arbor.

Abstract

HUMAN; Opportunistic fungal infections in immunocompromised patients are associated with a high mortality rate. Endemic mycoses are often asymptomatic, but in appropriate hosts, fungi can cause severe and even fatal infection. Skin lesions and multiple nodules or mass-like lung lesions seen on CT scans or radiographs may be clues to specific types of fungal infections. Some fungi grow better in the presence of iron and may cause infection in patients being treated with deferox amine. Face pain in an immunocompromised patient may signify invasive fungal sinusitis. Treatment with antifungal agents needs to be individualized according to factors such as the fungus involved, presence of renal failure, or pregnancy. Combining antifungal agents or addition of other approaches, such as surgical debridement or steps to control intracranial pressure, may be needed for adequate treatment of certain types of fungal infections.

Introduction; Opportunistic fungal infections constitute an increasing proportion of infections seen in immunocompromised patients; these infections are associated with a very high mortality rate. On the other hand, the endemic mycoses affect tens of thousands of persons who encounter the fungi that cause these infections in the course of every day activities in certain geographic areas. These infections are often asymptomatic, but endemic fungi can cause severe and even fatal infection in the appropriate host.

Infections in Medicine®^® (ISSN: 0749-6524) Selections from 2000 - Volume 17, Number 7

Case Report - Primary Sternal Aspergillus Osteomyelitis from Infections in Medicine ®®

Jose L. Baez-Escudero, John N. Greene, MD, Ramon L. Sandin, MD, Universidad San Francisco de Quito, Ecuador; University of South Florida College of Medicine; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla Abstract and Introduction Introduction

HUMAN: Aspergillus is a ubiquitous mold that rarely causes disease in healthy people. Immunocompromised individuals, on the other hand, are susceptible to Aspergillus infection, which causes significant morbidity and mortality in this population.^[1] Neutropenic patients are the most vulnerable to invasive infection, which usually affects the lungs and sinuses after inhalation and colonization of the organism.^[2]

Although fungi are seldom implicated in hematogenous bone infection, several cases of primary Aspergillus osteomyelitis have been reported.^[3] Bone aspergillosis also may result from contiguous spread and inoculation of extensive trauma regions and open skin wounds. Although the spine is the most commonly affected site, sternal involvement has also been reported.^[4] In this article, we present an unusual case of primary Aspergillus fumigatus sternal osteomyelitis. We review 6 additional cases from the literature and discuss the epidemiology and treatment of bone aspergillosis.

CHAPTER TWO -- PARAGRAPH TWO

PARAGRAPH TWO, Sentences 1 through 5.

“The fungi are eukaryotic, unicellular, or multicellular organisms that, because they lack chlorophyll, are dependent upon external food sources. Fungi are ubiquitous in all environments and play a vital role in the Earth's ecology by decomposing organic matter. Familiar fungi include yeasts, rusts, smuts, mushrooms, puffballs, and bracket fungi. Many species of fungi live as commensal organisms in or on the surface of the human body. "Mold" is the common term for multicellular fungi that grow as a mat of intertwined microscopic filaments (hyphae).”

A) This is the first description of fungi that I have personally read that included fungi living on the surface of the human body.

PARAGRAPH TWO, Sentence 6.

“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, eg, in organ transplant isolation units. “

A) It is reasonable to assume that this sentence is correct for the most part. The question arises as to the sentences’ accuracy since many people under these very “stringent” environments develop fungal infections that are life-threatening. Documentation of contamination under these conditions can be added as to mode of exposure if necessary. (Hospital exposure)

B) The “exposures to mold and other fungi and their spores is unavoidable,” can be simply answered – it is not a matter of “unavoidable”-- it is a matter of how much is a threat to human health and safety. Documentation of present standards and standards used in industry is presented in the Introduction as well as here, there are guidelines and common sense (empirical)).

Studies concerning the metabolites produced by Stachybotrys atra, Pencillium islandicum, penicillium viridicatum and aspergillus-versicolor.Pohland AE. PubMed, 1977 Ann Nutr Aliment. 1977;31(4-6):663-84.

HUMAN “Over the past ten years it has become quite apparent that mycotoxins, or toxins produced by fungi, are responsible for a wide variety of human and animal illnesses and, in many cases, deaths.”

CDC/NIOSH

Guidance for Protecting Building Environments from Airborne Chemical, Biological, or Radiological Attacks, 2003

HUMAN-FUNGI POISON: “Toxins” Toxin categories include bacterial (exotoxins and endotoxins), algae (blue-green algae and dinofiagellates), mycotoxins Trichothocenes and aflatoxins). Botulinum, and plant- and animal-derived toxins. Toxins form and extremely diverse category of materials and are typically most effectively introduced into the body by inhalation or an aerosol. They are much more toxic than chemical agents. Their persistency is determined by their stability in water and exposure to heat or direct solar radiation. Under normal circumstances toxins can be collected using appropriately selected particulate filters as described in the Recommendations section of this document.”

NIOSH

Health Hazard Evaluation Report No. HETA-94-0033-2552, Ladish Malting Company, Jefferson, Wisconsin, Toxnet1997

HUMAN-FUNGI EXPOSURE LEVEL: “Operations involved the blowing and sweeping of dust and caused the aerosolization of mycotoxin containing dust. Some personal breathing zone and area levels of airborne grain dust were high compared with the OSHA permissible exposure limit of 10mg/m3 and the NIOSH recommended exposure level of 4mg/m3. –The authors conclude that the potential for the development of hypersensitivity or toxic syndrome exists in this facility.”

NIOSH

Measurements of Airborne aflatoxins during the Handling of 1979 Contaminated Corn, Toxnet, 1990 Burg WR ; Shotwell OL ; Saltzman BE University of Cincinnati, Department of Environmental Health, Cincinnati, Ohio, Grant No. R01-OH-00796, 20 pages, 12 references, 19821982 [NIOSH]

HUMAN; “The potential health hazard of aflatoxin (1402682) contaminated corn grain dusts to agricultural workers was investigated. The average aflatoxin level in all three farm areas was 42.7 parts per billion while the average aflatoxin level from airborne dust samples collected at the grain elevator was 172.8ppb (settled dust average, 222ppb). The author concluded that farmers, truckers, and grain handlers may experience significant exposure to aflatoxin contaminated dust in regions where the Aspergillus-flavus mold thrives, particularly in the southern regions of the United States. They recommend the use of respiratory protection when handling corn know to be contaminated with aflatoxin.”

NOTE: The above report shows that there are standard tests used to test the levels of aflatoxin used regularly.

Laboratory experiments on membrane filter sampling of airborne mycotoxins produced by Stachybotrys atra Corda.

Authors: PASANEN A-L NIKULIN M TUOMAINEN M BERG S PARIKKA P HINTIKKA E-L Author Address: Univ. Kuopio, Dep. Environ. Sci., P.O. Box 1627, SF-70211 Kuopio, Finland. Source: ATMOS ENVIRON PART A GEN TOP; 27 (1). 1993. 9-13. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Entry Month: June, 1993 Year of Publication: 1993 Secondary Source ID: BIOSIS/93/13074

Document Number: BIOSIS /93/13074

A membrane filter method for sampling of airborne stachybotrystoxins was studied in the laboratory. Toxigenic strains of Stachybotrys atra on wallpaper, grain, hay and straw were used as toxin sources in the experiments. Air samples were collected on cellulose nitrate and polycarbonate membrane filters at air flow rates of 10-20 l min-1. After the filter sampling, the air was passed through methanol. The results showed that stachybotrystoxins (trichothecenes) were concentrated in airborne fungal propagules, and thus can be collected on filters. Polycarbonate filters with a pore size of 0.2 mum collected the highest percentage of toxic samples. The laboratory experiments indicated that polycarbonate filter sampling for the collection of airborne mycotoxins is a promising method for extension to field measurements.

Fungal Spores; Hazardous to Health? Division of Respiratory disease Studies, National Institute for Occupation and Health, 1999 SORENSON WG ENVIRONMENTAL HEALTH PERSPECTIVES; 107 (SUPPL. 3). 1999. 469-472. [BIOSIS]

HUMAN “–inhalation of fungal spores include toxic pneumonitis, hyper pneumonitis, tremors, chronic fatigue syndrome, kidney failure, and cancer.”

Role of Mycotoxins in Human and Animal Nutrition and Health, Toxnet, 1995 SMITH JE ; SOLOMONS G ; LEWIS C ; ANDERSON JG NATURAL TOXINS; 3 (4). 1995. 187-192. [BIOSIS]

HUMAN “Mycotoxin entry to the human and animal dietary systems is mainly by ingestion but increasing evidence also points at entry by inhalation. –mycotoxins can be mutagenic, carcinogenic, ,embryotoxic, teratogenic, or oestrogenic. Analysis of mycotoxin adducts in human populations can act as a surrogate for human genotoxicity. Mycotoxins can also be immunosuppressive and appear to involve cellular immune phenomena and non-specific humoral factors associated with immunity.”

IAQ and human toxicosis: empirical evidence and theory, Concordia, 2001

HUMAN: “Studies of injury, illness and death occurring in mold-exposed animals and people in the field, observe that the illness called mycotoxicosis results from more complex exposures than can be observed in laboratory experiments with pure mold toxins. Response in field exposures occurs at lower exposure concentrations than those from controlled experiments.

USDA-1977

HUMAN “A healthy individual is more able to fight the toxins than a one that starts out malnourished or diseased. The very young and very old have weakened immune systems that are less able to fight the effects of toxicoses. In general female animals, and to a degree female humans, seem to be more susceptible to the effects of mycotoxicoses. Hosts exposed to harsh living conditions of neglect or squalor have an added burden on their systems. Very high doses of aflatoxin attack the host quicker than lower doses. A very short time of exposure (a single dose) allows the host time to fight the infection where a continued exposure tends to have cumulative effects. Areas that lack the means to regulate and monitor the presence of mycotoxins in genera, and aflatoxin in particular, leave the inhabitants open to unknown poisonings that can continue over long periods of time unchecked. Aspergillus species produce toxins that exhibit a wide range of toxicities, with the most significant effects being long term.

The toxins produced by Penicillum species can be placed in two general groups; those that affect the liver and kidney function, and those that are neurotoxic. The penicillium toxins that affect liver or kidney function are asymptomatic or cause generalized debility in humans or animals while the neurotoxins are characterized by sustained trembling. The main human disease associated with F. moniliforme is esophageal cancer. ==Alternaria toxins-that have been grown or corn or rice and fed to rats, chicks, turkey poults, and ducklings have been shown to be quite toxic.”

CHAPTER THREE, PARAGRAPH THREE

PARAGRAPH 3, Sentence 1.

“Molds and other fungi may adversely affect human health through three processes: 1) allergy; 2) infection; and 3) toxicity.”

A) “may adversely affect human health,” Do affect human health. Allergy is an immune system reaction, outright infection by certain types of fungi are about 80% fatal, and toxicity means poisoned. Fungi poisons are in the category of the most poisonous substances known to mankind and far exceed any level of chemical poison–there are studies that say that fungi poisons are 200 times stronger than anything in a cigarette.

B) The one area of human health effects which should be labeled “process 4" is immune suppression since immune suppression leads to mutiple health effects as well as diseases as immune suppression causes humans to be unable to fight disease. The other possible area to be clearly addressed is Cancer.

C) Another area of human health effects which should be labeled “process 5" neurological and Central Nervous System effects since so much of human health and mental well being is directly effected by fungi poison.

CANCER

IARC Activities in Mycotoxins Research. Authors: CASTEGNARO M, WILD CP, Author Address: Unit Environ. Carcinogenesis, Int. Agency Res. Cancer, 150 cours A. Thomas, 69372 Lyon Cedex 08, France. Source: NATURAL TOXINS; 3 (4). 1995. 327-331. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

The creation of the International Agency for Research on Cancer (IARC) in May 1965 occurred only two years after publication of the chemical structure of the aflatoxins, and the investigation of a possible link between exposure to these compounds and liver cancer incidence was initiated by IARC as early as 1968. Thus, mycotoxins were one of the first topics of research at IARC and the Agency's special interest in cancer in developing countries has contributed to a sustained effort in this research field. The work performed comprises a number of aspects including laboratory research into mechanisms of action and methods for destruction of mycotoxins, epidemiological studies, and through evaluation of the carcinogenic potency of these toxins in the 'IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans.' A particular feature has been the integration into epidemiological studies of biomarkers of mycotoxin exposure (e.g., to aflatoxin, ochratoxin A) develope

Complications of Cancer Therapy in Children: A Radiologist's Guide Marguerite T. Parisi, MD, MSEd1,2, Jana L. Fahmy, MD1, Cornelia K. Kaminsky, MD1 and Marcio H. Malogolowkin, MD3 1 Departments of Radiology (M.T.P., J.F., C.K.K.) 2 Pediatrics (M.T.P.), Childrens Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027 and the University of Southern California School of Medicine 3 Department of Pediatrics, University of California Los Angeles (M.H.M.).

HUMAN; With the exception of accidents, childhood cancer is the most common cause of death in persons under 15 years of age (excluding the neonatal period) in the United States (1,2). In this country, approximately 6,000 new cases of childhood cancer——or 126 cases per million children less than 15 years of age——are diagnosed annually. Although incidence rates have remained stable, advances in the treatment of childhood malignancies have resultedin dramatically increased rates of patient survival. Currently,60%––75% of children with cancer are being cured (2). By the year 2000, approximately one of 1,000 adults between theages of 20 and 29 years will be a survivor of childhood cancer (3).

Etiological role of Alternaria alternata in human esophageal cancer. Authors: LIU G,, QIAN Y-Z, ZHANG P, DONG WH, QI Y-M, GUO H-T, Author Address: Dep. Pathophysiol., Henan Med. Univ., Zhengzhou 450052. Source: CHIN MED J (ENGL ED); 105 (5). 1992. 394-400. Entry Month: December, 1992 Year of Publication: 1992 Secondary Source ID: BIOSIS /92/30310 Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-THROAT CANCER-FUNGI POISON: In this paper, the mutagenicity and carcinogenicity of alternariol monomethyl ether (AME), alternariol (AOH), and their relevance to the etiology of human esophageal cancer were studied. These mycotoxins were produced by Alternaria alternata which was the main contaminating fungi isolated from the grain in Linxian County, an area with high incidence of esophageal cancer. This study demonstrated that: 1. AME and AOH might cause cell mutagenicity and transformations; 2. AME and AOH could combine with the DNA isolated from human fetal esophageal epithelium, activate the oncogens, c-H-ras and c-mys in it, and promote proliferation of human fetal esophageal epithelium in vitro; 3. squamous cell carcinoma of the fetal eosphagus could be induced by AOH. According to the results of the studies of AME and AOH mentioned above, we consider that Alternaria alternata plays an important role in the etiology of human esophageal cancer.

Transplacental transfer of genotoxins and transplacental carcinogenesis. (Toxnet) Authors: Autrup H Author Address: Department of Environmental and Occupational Medicine, University of Aarhus, Denmark. Source: Environ Health Perspect 1993 Jul;101 Suppl 2:33-8 Abstract:

HUMAN; A number of chemical compounds induce cancer in the offspring of animals treated with these compounds. The fetus is sensitive to the toxic and teratogenic effects of chemicals in the early embryonic stages, whereas it is sensitive to carcinogenic effects during late fetal stages. Carcinogens may be direct acting or may require metabolic oxidation such as those in tobacco smoke. Activation can occur in utero. Animal experiments indicate that tumors can be initiated in utero, commonly by activation of cellular proto-oncogenes, and that promotion can occur after birth by postnatal treatment with tumor promoters. This may have important implications for humans. The initial peak of cancer incidence during the first 5 years of life may be due to prenatal exposure of either parent to mutagens, but the role of paternal exposure in relation to childhood cancer is controversial. There is an increased risk of cancer in children whose fathers work in heavy industry or whose mothers work in medical or dental services. The exact etiological agents have not been unequivocally identified. Information on human transplacental exposure to carcinogens and genotoxins is limited and based on measurement of maternal plasma concentrations or analysis of cord blood. Transplacental transfer of carcinogens in smoke and smoke-related damage to fetal tissue have been demonstrated. The mycotoxin aflatoxin B1 or its metabolites have been detected in cord blood, as have metabolites of pesticides and polychlorinated biphenyls. New biomarkers may provide important information on the transplacental transfer of genotoxic compounds.

Cancer Res. 1992 Apr 1;52(7 Suppl):2114s-2118s. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Wogan GN. Division of Toxicology, Whitaker College of Health Sciences and Technology, Cambridge, Massachusetts. PMID: 1311989 [PubMed - indexed for MEDLINE] On a global basis, primary liver cancer (PLC) is a very prevalent form of cancer. Wide variation of PLC incidence in different areas of the world suggests the involvement of environmental factors in its etiology. Two major classes of risk factors have been identified. Extensive evidence indicates the importance of infection by the hepatitis B virus as a major risk factor for PLC. Because many organic chemicals induce liver cancer in experimental animals, those to which human exposure is known to occur are also of interest with respect to their possible involvement as risk factors for PLC. Particular emphasis has been placed on aflatoxins because of the frequency with which they occur as food contaminants, together with their potency as liver carcinogens for a large number of experimental animals, including subhuman primates. Other mycotoxins, notably sterigmatocystin and fumonisin, also are relatively potent carcinogens for the liver of animals, but little is known about human exposure to them. Epidemiological surveys carried out over the past 25 years in Asia and Africa have revealed a strong statistical association between aflatoxin ingestion and PLC incidence. The combined experimental and epidemiological evidence has led to designation of aflatoxins as human carcinogens according to International Agency for Cancer Research criteria. Collectively, current evidence strongly suggests that PLC is of multifactorial origin, with probable interactions between viral and chemical agents in populations concurrently exposed to both classes of risk factors. Recently developed methods that permit individual monitoring of aflatoxin exposure, hepatitis B virus infection, and genetic damage caused by these agents are being applied in the design of molecular and biochemical epidemiological studies of the etiology of the disease. Application of this methodology may contribute to elucidation of the relative importance of interacting etiological agents in different populations.Adv Exp Med Biol. 1991;283:525-32. PMID: 1906226 [PubMed - indexed for MEDLINE]

Bisfuranoid mycotoxins: their genotoxicity and carcinogenicity. Hsieh DP, Atkinson DN. Department of Environmental Toxicology, University of California, Davis 95616. Based on the mode of action of AFB1 and the activities of its biologically active intermediates, one may conclude that: 1. The mode of toxic action of the bisfuranoid mycotoxin is through epoxidation of the vinyl ether double bond of their dihydrobisfuran functionality. 2. The DNA and plasma albumin adducts formed in vivo may be useful in the molecular dosimetry of these environmental carcinogens. 3. There appears to be a linear correlation between the steady state levels of AFB1-FAPy-DNA adducts and the carcinogenicity of AFB1. Elucidation of the molecular basis of this correlation may shed light on the mechanism of AFB1-induced carcinogenesis. 4. Consistent appearance of AFB1-DNA adducts in the livers of liver cancer patients tested is supportive of the IARC conclusion that AFB1 is a human carcinogen involved in human primary liver cancer.Cancer Res. 1977 Jun;37(6):1786-93. PMID: 192462 [PubMed - indexed for MEDLINE] Repair of DNA in human cells after treatment with activated aflatoxin B1. Sarasin AR, Smith CA, Hanawalt PC. HUMAN; Repair replication was examined in cultured human cells exposed to the hepatocarcinogen aflatoxin B1 using the combined bromodeoxyuridine density label and radioisotopic label method. Semiconservative DNA synthesis was strongly inhibited, and the repair replication mode was stimulated in diploid fibroblasts (W138) and in their SV40 transformants (VA13) only when exposure to aflatoxin B1 was in the presence of an activating system containing rat liver microsomal enzymes. The maximum amount of repair synthesis was about 20% of that obtained after saturating doses of ultraviolet light (UV). The time course of repair synthesis was similar to that seen after UV, and most of the synthesis was in 30- to 50-nucleotide "short patches." A line of SV40-transformed xeroderma pigmentosum cells (Group A) deficient in repair after exposure to UV was similarly deficient in repair replication after aflatoxin treatment. Treatment with aflatoxin resulted in a 25 to 45% inhibition of UV-induced repair replication, suggesting that in addition to producing lesions in DNA, which are substrates for the excision repair system, the toxin also inhibits excision repair. CsC1 gradients of DNA treated in vitro with activated aflatoxin demonstrated binding of the drug to DNA. Alkaline sucrose gradient sedimentation gave no indication that single-strand breaks or alkali labile bonds were introduced into DNA by treatment of cells with activated aflatoxin.

Transplacental transfer of aflatoxin in humans. Denning DW ; Allen R ; Wilkinson AP ; Morgan MRA (Toxnet)Carcinogenesis, Vol. 11, No. 6, pages 1033-1035, 31 references, 1990 [NIOSH] Authors: DENNING DW ALLEN R WILKINSON AP MORGAN M RA Author Address: Dep. Infectious Dis., Santa Clara Valley Med. Cent., 751 South Bascom Ave., Stanford Univ., San Jose, Calif. 95128. Source: CARCINOGENESIS (LOND); 11 (6). 1990. 1033-1036. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN; This study quantified aflatoxin (AFB1, AFG1 and AFQ1) by enzyme-linked immunosorbent assay in human cord sera obtained at birth and in serum obtained immediately after birth from the mother. The subjects of the study were residents of Songkhla, Thailand. Of the 35 samples of cord sera, 17 (48%) contained aflatoxin in concentrations from 0.064 to 13.6, mean 3.1 nmol/ml. By comparison only two (6%) of 35 maternal sera contained aflatoxin (mean 0.62 nmol/ml). These results demonstrate transplacental transfer and concentration of aflatoxin by the feto-placental unit which may be of biological importance. Aflatoxins are mutagenic, carcinogenic and teratogenic and cause immunosuppression in animals. The implications of these findings are potentially profound and deserve further study.

Olsen JH, et al: Br J Cancer 58 (3); 392-396 (1988) **PEER REVIEWED** TOXNET Authors: OLSEN JH, DRAGSTED L, AUTRUP H Source: BR J CANCER; 58 (3). 1988. 392-396.

CANCER RISK AND OCCUPATIONAL EXPOSURE TO AFLATOXINS IN DENMARK

HUMAN: “Variable concentrates of aflatoxin–Risk was established on the basis of cancer cases among male workers–Elevated risks for liver cancer and for cancers of the biliary tract were observed, which increased by two- to three-fold significance after a 10-year latency. Exposure to aflatoxins - - was judged to be the most probable explanation for these findings. Increased risks for salavatory gland tumors and mutilpe myeloma were also detected. A decreased risk for lung cancer was observed; despite possible negative confounding due to the smoking habits of the employees, the lung does not seem to be a target organ for the carcinogenic effect of inhaled aflatoxins in humans.”

Cancer Risk and Occupational Exposure to Aflatoxins in Denmark Authors: Olsen JH Dragsted L Autrup H Source: British Journal of Cancer, Vol. 58, No. 3, pages 392-396, 25 references, 19881988 Abstract:

HUMAN; The risk for cancers of the liver, biliary tract, and respiratory system was studied in relation to occupational exposure to aflatoxins among male Danish workers employed in 241 livestock feed processing facilities. The cancer cases were identified through the Danish Cancer Registry, and employment histories for identified subjects were obtained back to 1964. Levels of aflatoxins in Danish crops have been below the limit of detection, but imported products such as cotton seed, soybean, coconut and palm kernel oilcakes may contain substantial aflatoxin levels. The average aflatoxin-B1 (1162658) content of processed cattle feed during the period of the study was 140 micrograms per kilogram, yielding a daily respiratory intake per worker of approximately 170 nanograms. There were 398 cancer cases identified; an elevated risk for cancer was determined for the pancreas, liver, gallbladder and extrahepatic bile ducts, larynx, mediastinum, salivary glands, skin, lymphatic and hematopoietic systems, multiple myeloma, and thyroid and endocrine glands. The increase in the cancer risk among the men with the longest employment in the Danish feed processing companies was determined to be statistically significant for the liver, gall bladder and extrahepatic bile ducts, salivary glands, and thyroid, and a significant decrease in the cancer risk was determined for the lung among the same population. The authors conclude that long term exposure to aflatoxins increases the risk for primary liver cancer.

Cancer Morbidity among Employees in a Danish Pharmaceutical Plant Authors: Hansen J Olsen JH Larsen AI Source: International Journal of Epidemiology, Vol. 23, No. 5, pages 891-898, 26 references, 1994 Abstract:

HUMAN; Site specific cancer morbidity was investigated among workers at a large pharmaceutical factory in Denmark. The company produced hormones, antibiotics, industrial enzymes, and some synthetic drugs. Using the records of the nationwide Supplementary Pension Fund, 10,889 persons were identified who had worked at a pharmaceutical factory between April 1, 1964 and December 31, 1988. Data on cohort members were linked to files of the Danish Cancer Registry. Individuals were followed up through December 31, 1989. The national incidence rates of site specific cancers by sex, 5 year age group and years under observation were compared to those for the cohort, and Standardized Incidence Ratios (SIR) were determined. A significant increase in overall SIR was found for women in the study. There was an excess risk for breast cancer (SIR 1.5). The SIR in men reflected that seen in the nationwide population. There were three cases of breast cancer in men, compared with 0.4 expected. There was no association between intensity of occupational exposure to hormones and the risk for breast cancer.

Int J Oncol. 2000 Oct;17(4):737-42. Absence of p53-mediated G1 arrest with induction of MDM2 in sterigmatocystin-treated cells. Xie TX, Misumi J, Aoki K, Zhao WY, Liu SY. Department of Public Health and Hygiene, Oita Medical University, Hasama, Oita 879-5593, Japan. PMID: 10995885 [PubMed - indexed for MEDLINE] HUMAN; P53 plays a critical role in G1 checkpoint after DNA damage. MDM2 gene is a p53 target gene and its protein forms a feedback loop with p53 and inhibits p53-mediated G1 arrest. Sterigmatocystin (ST) is a mycotoxin and carcinogen. In this study we show that exposure of cells to ST for 12 or 24 h resulted in failure of G1 arrest at both time points. Accordingly, p53 protein was not increased and p21WAF1 expression was inhibited at 12 h, and both proteins were weakly induced at 24 h after treatment with ST. Meanwhile, MDM2 protein was induced in a p53-dependent fashion by ST at both 12 and 24 h. The induction of MDM2 was coincident with the cellular responses of p53 and p21WAF1, and might contribute to the failure of G1 arrest in ST-treated cells. In addition, ST-treated cells exhibited G2M arrest, regardless of p53 status. Our results indicate that the carcinogenic effects of ST seem to be mediated by failure of p53-mediated G1 checkpoint.

Tumor incidence in a chemical carcinogenesis study of nonhuman primates, PubMed, 1994 Authors: THORGEIRSSON UP, DALGARD DW, REEVES J, ADAMSON RH Author Address: Div. Cancer Etiol., Natl. Cancer Inst., Natl. Inst. Health, Bethesda, MD 20892, USA. Source: REGULATORY TOXICOLOGY AND PHARMACOLOGY; 19 (2). 1994. 130-151. Abstract: BIOSIS COPYRIGHT: BIOL ABS. Coden: RTOPD Entry Month: July, 1994 Year of Publication: 1994 Secondary Source ID: BIOSIS/94/16201 Document Number: BIOSIS/94/16201

MONKEY “ –a 32-year period of an ongoing chemical carcinogenesis study in nonhuman primates which was initiated by the National Cancer Institute in 1961. After 22 years of continuous dosing, neither cyclamate nor saccharin have shown any evidence of carcinogenic effects. Similarly, the tumorigenic potential of arsenic and DDT was negligible–. In contrast, the fungal food contaminants, aflatoxin B1 (AFB1) and sterigmatocystin (SMT), were

found to be potent hepatocarcinogens. AFB1 also induced adenocarcinomas of the pancreas, osterosarcomas, and other tumors.”

SYNERGY EFFECT SAMPLE

Carcinogenesis. 1995 Sep;16(9):2187-91. 2,3,7,8-Tetrachlorodibenzo-p-dioxin sensitization of cultured human epidermal cells to carcinogenic heterocyclic amine toxicity. Walsh AA, deGraffenried LA, Rice RH. Department of Environmental Toxicology, University of California, Davis 95616-8588, USA. PMID: 7554073 [PubMed - indexed for MEDLINE] HUMAN-SYNERGY EFFECTS-FUNGI POISON and TCDD; Treatment of cultures of spontaneously immortalized human epidermal cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitized them to carcinogen toxicity. While the tryptophan pyrolysis product 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the mycotoxin sterigmatocystin were highly toxic to the cultures at moderate concentration (1 microgram/ml), the potency of each agent was increased > or = 10-fold in the presence of TCDD. A toxicity increase was also evident in the several-fold stimulation by TCDD of protein and DNA adducts formed by Trp-P-1. In contrast, the cells were insensitive to toxicity from 3-amino-1-methyl-5H-pyrido[4,3-b]indole. DNA damage mediated by Trp-P-1 was capable of producing inheritable effects, as judged by the induction of hprt mutants in a TCDD-stimulated fashion. Northern blotting showed that TCDD strongly stimulated expression of P4501A1 and 1B1 in the cells, enzymes important for xenobiotic metabolism. These findings demonstrate the potential usefulness of SIK cultures as a model for studying keratinocyte responses to carcinogens activated by TCDD-induced cytochromes P450.

NOTE; TOO MANY STUDIES TO INCORPORATE.

LIVER & KIDNEYS

NOTE: PKD is the #4 killer.

Polycystic Kidney Disease: An Unrecognized Emerging Infectious Disease?

Marcia A. Miller-Hjelle,* J. Thomas Hjelle,* Monica Jones,* William R. Mayberry,†† Mary Ann Dombrink-Kurtzman,‡‡ Stephen W. Peterson,‡‡ Deborah M. Nowak,* and Frank S. Darras* *University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA; ††East Tennessee State University, Johnson City, Tennessee, USA; and ‡‡U.S. Department of Agriculture, Agricultural Research Service, Peoria, Illinois, USA

HUMAN; Polycystic kidney disease (PKD) is one of the most common genetic diseases in humans. We contend that it may be an emerging infectious disease and/or microbial toxicosis in a vulnerable human subpopulation. Use of a differential activation protocol for the Limulus amebocyte lysate (LAL) assay showed bacterial endotoxin and fungal (13)-ßß-D-glucans in cyst fluids from human kidneys with PKD. Fatty acid analysis of cyst fluid confirmed the presence of 3-hydroxy fatty acids characteristic of endotoxin. Tissue and cyst fluid from three PKD patients were examined for fungal components. Serologic tests showed Fusarium, Aspergillus, and Candida antigens. IgE, but not IgG, reactive with Fusarium and Candida were also detected in cyst fluid. Fungal DNA was detected in kidney tissue and cyst fluid from these three PKD patients, but not in healthy human kidney tissue. We examine the intertwined nature of the actions of endotoxin and fungal components, sphingolipid biology in PKD, the structure of PKD gene products, infections, and integrity of gut function to establish a mechanistic hypothesis for microbial provocation of human cystic disease. Proof of this hypothesis will require identification of the microbes and microbial components involved and multifaceted studies of PKD cell biology.

GENE ACTIVITY IN THE DEVELOPMENT OF POLYCYSTIC KIDNEYS, PubMed,

HUMAN “PKD can be inherited as an autosomal dominat (ADPKD) or autosomal recessive (SRPKD) trait, or can be provoked by environmental factors (acquired cystic disease).”

Hepatic Cysts emedicine 2002

HUMAN: “differential diagnosis of cystic lesions of the liver includes simple cysts, multiple cysts in the setting of congenital polycystic liver disease, parasitic or hydatid (echinococcal) cysts, cystic tumors, and abscesses. Polycystic liver disease can arise in childhood or adult life as a part of a congential disorder associated with polycystic kidney disease (often results in renal failure)*. A number of tumors can manifest as cystic hepatic lesions including cystadenoma and cystadenocarcinoma.”

NOTE: *Polycystic Kidney Disease, adult onset, is now considered as a infectious disease due to endotoxin/mold/mycotoxin discoveries in the cysts. (People live in same houses=same exposures–generations--must be taken into consideration.)

NOTE: Since fungi cause allergies, asthma, pass the brain barrier, enter infants before birth, cause immune suppression, DNA changes, soft-tissue damage, heart, liver, lung, nervous system, endocrine system, are clearly linked to numerous diseases including diabetes, cancer, etc al the effects of fungi deserve far more attention than they are given. This is in no way a complete rundown of cause and effect of fungi.

DNA damage by mycotoxins, Toxnet, 1999 Wang JS; Groopman JD Mutat Res 1999 Mar 8;424(1-2):167-81 [EMIC]

HUMAN “More strikingly, the relationship between aflatoxin exposure and development of human hepatocellular carcinoma (HHC) was demonstrated by the studies on the p53 tumor suppressor gene.”

Ochratoxin A in human sera in the area with endemic nephropathy in Croatia. Authors: RADIC B, FUCHS R, PERAICA M, LUCIC A, Author Address: Dep. Toxicol., Inst. Medical Res. Occup. Health, Ksaverska c. 2, 10000 Zagreb, Croatia. Source: TOXICOLOGY LETTERS (SHANNON); 91 (2). 1997. 105-109. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-DISEASE-FUNGI POISON; Ochratoxin A (OA) is nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxin porcine nephropathy, a disease comparable with a human kidney disease called endemic nephropathy (EN). In this paper we presented results obtained over a 10-year period in the hyperendemic village Kaniza, and in control villages where no clinical cases of nephropathy had been found. In the hyperendemic village Kaniza and non-endemic villages the incidence of OA in human blood was up to 4.5% (range 2-50 ng/ml) and up to 2.4% (range 2-10 ng/ml), respectively. Almost all samples of food and feed, collected randomly in the hyperendemic village were found to contain OA. Considering marked exposure to OA in Kaniza, it was assumed that incidence of EN in this population could be related to OA contamination of food and feed.

1148 Nephrotoxicity of Penicillium aurantiogriseum, a possible factor in the aetiology of Balkan endemic nephropathy. Yeulet SE, Mantle PG, Rudge MS, Greig JB. Mycopathologia. 1988 Apr;102(1):21-30. Water-soluble components of a nephrotoxic isolate of Penicillium aurantiogriseum have been fractionated by sequential ion-exchange, size-exclusion gel filtration, reverse-phase silica chromatography and HPLC. Nephrotoxicity in the rat was confined to a size-exclusion fraction approximating to 1,500 daltons, which also inhibited DNA synthesis in cultured kidney cells. The more sensitive in vitro assay allowed toxicity to be followed to a sub-fraction from gradient-elution HPLC which in further HPLC resolved into a small group of glycopeptides. Recent Yugoslavian P. aurantiogriseum isolates, from a village in which the idiopathic human disease Balkan Nephropathy is hyperendemic, elicited a similar nephropathology and were acutely cytotoxic, reinforcing a need to regard this novel Penicillium nephrotoxin as a potential factor in human nephropathy.

1143 Verrucofortine, a major metabolite of Penicillium verrucosum var. cyclopium, the fungus that produces the mycotoxin verrucosidin. Hodge RP, Harris CM, Harris TM. J Nat Prod. 1988 Jan-Feb;51(1):66-73. Verrucofortine [8], an alkaloid derived from tryptophan and leucine, has been isolated from the fungus Penicillium verrucosum var. cyclopium. The structure and absolute configuration have been established by a combination of spectroscopic and chemical techniques. Its structure is unrelated to that of other major metabolite of the organism, the highly toxic pyrone-type polyketide verrucosidin [1], which was previously reported to be a tremorgen. A second novel metabolite, normethylverrucosidin [3], has also been isolated and identified. Small quantities of several other secondary metabolites, ergosterol, cyclopenin [4], cyclopenol [5], and 3-O-methylviridicatin [6], were isolated. They are known fungal metabolites but had not previously been obtained from this fungus. Studies of verrucofortine toxicity in mice showed no apparent toxic effects at doses as high at 160 mg/kg ip.

Occurrence of a primary liver carcinoma in a Rhesus Monkey fed Aflatoxin B1

1973, 50 references

Induction of Cholangiocarcinoma following treatment of a Rhesus Monkey with Aflatoxin

1975, 13 references

Influence of aflatoxin B1 and Aflatoxin B2 on rat liver lysosomal acid deoxyribonuclease, 1973

“-studied on the permeability of isolated rat liver lysosomes-Only AB1 altered the lysosomal membrane with the consequent release of lysosomal enzymes. Dnase in liver lysosomes was markedly decreased in rats with AB1 While the specific activity of cytoplasmic acid Dnase or nonsedimentable acid Dnase, was dramatically increased.-discussed in relation to a hypothesis concerning the role of lysosomes in carcinogenesis.”

Malignancy in natural and experimental hepatic cysts: experiments with aflatoxin in rats and malignant transformation of cysts in HUMAN LIVERS. 1971 J. Pathology, PubMed,

Variability in aflatoxin B(1)-macromolecular binding and relationship to biotransformation enzyme expression in human prenatal and adult liver. Toxicology Appl. Pharmacol, PubMed, 2002

HUMAN: “Mixtures of cytosolic and microsomal proteins from prenatal and adult livers catalyzed the formation of AFB(1)-DNA and AFB(1) -protein adducts at relatively similar rates, although greater individual variability in AFB(1) adduct formation was observed in adult tissues the in vivo toxicity of mycotoxins are scant. Frequently cited are the inhalation LC₅₀ values determined for mice,.

TOO MANY STUDIES TO INCORPORATE

PARAGRAPH 3, Sentence 2.

“One can estimate that about 10% of the population has allergic antibodies to fungal antigens. Only half of these, or 5%, would be expected to show clinical illness.”

A) Seems good on the surface and falls in line with many studies but lets look at the present data to the contrary. There is some statistical evidence that can show a pattern as well as the easily disproved “estimate.”

GENERAL STATISTICAL EVIDENCE

According to the Census Bureau there are approximately 328 Million people in America.

Mayo Clinic – the reported incident of sinusitis/rhinitis fungal infection is 97% of all sinusitis with 2.7 types of fungi growing in the sinus cavity. A study from 1996 – Chronic sinusitis is the most commonly reported chronic disease affecting 12.6 percent of people (approximately 38 million) in the United States in 1996. In that year the health care expenditures attributed to sinusitis were more than $5.8 billion.

Invasive fungal infections are responsible for one-fifth of the infectious deaths in children with ALL.

Mycoses. 2003 Dec;46(11-12):441-6. PMID: 14641615 [PubMed - indexed for MEDLINE] J Wound Care. 2003 Jul;12(7):265-70.

Penicillin is a common cause of drug allergy. One clinic found 2.5 percent of their study group reacted to penicillin allergy skin tests (IgE antibodies) Anaphylactic reactions to penicillin cause 400 deaths annually among Americans, making penicillin allergy a more common cause of death than food allergy.

Allergy Statistics – facts and figures, National Institute of Allergy and Infectious Diseases, January, 2002

Each year more than 50 million Americans suffer from allergic diseases. Allergies are the 6^th leading cause of chronic disease in the United States, costing the health care system $18 billion annually. Atopic dermatitis (caused by fungi) is one of the most common skin diseases, particularly in infants and children. The estimated prevalence in the United States is 9%.

CDC, Asthma data – Number of adults who were diagnosed and still have asthma; 14 million (2001), 6.9% adults (2001), Number of children who were diagnosed and still have asthma; 6.3 million (2001), 8.7% (2001).

©© 2003 Canadian Lung Association. All Rights Reserved.The Canadian Lung Association site strives to provide you with timely, accurate information, which is not intended for diagnosis or self treatment. 1-888-566-LUNG (5864) HUMAN; HISTOPLASMOSIS: Histo –– the short name for histoplasmosis –– is a deceiver. It used to be thought rare. Only 71 cases were known to doctors in the United States up to 1945. Today an estimated fifty million Americans are believed to have been infected with it. Histoplasmosis used to be considered a fatal disease. Today, among the millions infected, there are very few fatalities. Histoplasmosis is a masquerader. The "summer flu" that Midwesterners used to get often is now thought to he been histoplasmosis. The disease is not "catching" from someone who has it, as tuberculosis is –– but many times it has been mistaken for TB, as well as other diseases.

What Causes Histoplasmosis? Histoplasmosis is caused by a fungus (mold), an extremely simple form of plant life. (Other familiar fungi are mushrooms, yeast and mildew.) The particular fungus, or plantææ, that causes this disease is known as histoplasmosisplasma capsulatum. It is tiny and light enough to float in the air when stirred up with dust. Once it is breathed in, the fungus gets down into the lungs. In effect, it takes root there like a seed and continues to live. The tiny plants increase in number within the lungs simply by dividing themselves in two –– over and over again. Although histoplasmosis is not as uniformly serious as was once believed, it infects millions of people all over the country, many of them living in the Mississippi, Ohio, Missouri and other river valleys.

It took years of detective work and the patient tracking down of clues to unmask and identify histoplasmosis. There are still many mysteries about the disease, but certain facts are known.

Where Histoplasmosis is Found Histoplasmosis has gone to town. It used to be considered a rural Midwestern disease. But it has been discovered recently in small towns and even cities in the East and other parts of the country. Because the histoplasmosis seeds, called spores, are living things, they need certain conditions in which to flourish. There must be warmth, moisture, and preferably some darkness. These conditions are found most often in accumulated droppings from chickens, pigeons, starlings, and other birds, as well as bats. Therefore, the place of infection for many people has often been old chicken houses, barns, belfries, pigeon lofts, caves and in parks under trees where many birds have roosted.

One outbreak of histoplasmosis involved a troop of Boy Scouts who had worked hard cleaning up an old city park in which many starlings roosted. The dank, damp undergrowth of the park was disturbed for the first time in years –– and the boys breathed in a sufficient quantity of fungus-bearing dust to get the disease.

In one celebrated instance, a number of schoolchildren came down with what eventually was diagnosed as histoplasmosis. The source of the disease was painstakingly traced to a window of the schoolroom. Several weeks before a load of coal had been dumped under the window. The coal, it is believed, came from a mine in which the histoplasmosis fungus had grown. Who Gets Histoplasmosis? Most persons who come in contact with a heavy barrage of histoplasmosis spores are infected. But fortunately in most persons the infection produces no symptoms. Usually people do not even know they have been infected, but some do get sick.

Schoolchildren of both sexes are frequent victims. More men than women, however, get the disease as adults. Very young children and old men are the most susceptible to the generalized form of histoplasmosis that spreads from the lungs to other parts of the body.

What Happens Within the Lungs? When the fungus-bearing dust is breathed in, the tiny histoplasmosis spores are carried into the bronchial tubes (the air passages in the lungs). Some of the spores eventually reach deep down into the very tiny air sacs of the lung –– where the air we breathe in finally winds up before it is exhaled. Then various things happen. In the air sacs some of the spores are arrested by wandering police cells called phagocytes. They are taken to the lungs’’ lymph nodes, where they are trapped and held. But they may find the lymph nodes an excellent place in which to stay and multiply. The lymph tissue reacts to this invasion. A sensitivity –– actually an allergic reaction –– develops. The area becomes inflamed. The tissues of the nodes may be damaged, as well as nearby lung cells. Scars and calcium deposits may form. Others of the spores that reach the air sacs are attacked by the body’’s defenses right there. As it does tuberculosis germs, the body walls up most of these spores in calcified tubercles. (On an X-ray these look just like the tubercles of tuberculosis.) The little plants in their calcium prison become starved for oxygen and nutrition. Though remaining in the body, they are harmless and cannot multiply. Spores that escape these defenses may damage lung tissue and even form cavities –– also much like those of tuberculosis. But, unless the spore invasion is enormous in quantity, these various reactions actually do the patient little harm in by far the majority of cases. Some feel no symptoms at all, others suffer a brief and relatively mild illness. Only when the spores spread throughout the body –– as happens only rarely –– is there real trouble. The "disseminated" form of histoplasmosis is often fatal.

What Histoplasmosis Does Depending on the number of spores the patient has taken in, the symptoms of histoplasmosis vary widely in intensity. The symptoms, when they appear, are usually almost identical with those of flu. Fever, tiredness, sometimes a slight cough or chest pains. Actually, histoplasmosis takes four possible forms:

Mild infection. This is often without symptoms. The patient may not ever know he has had it. It lasts from one to three days.

Acute lung infection. This is usually self-limiting and confined to the lungs. The patient feels fever, recurring chills, cough, chest pain and labored breathing. Even without treatment, this clears up in two weeks to three months.

Chronic lung infection. Looking much like TB on an X-ray, this form shows cavities, calcium nodules and other TB-like signs. Illness hangs on. Treatment, when indicated, usually helps.

Disseminated form. A large number of the fungus spores spreading outside the lungs mean more serious symptoms: loss of weight, extreme tiredness, anemia and weeks or months of convalescence. Without treatment, a great portion of these patients die within four to ten months after their exposure to the fungus. Fortunately, this is a rare form of the disease.

How Histoplasmosis is Diagnosed There are both skin tests and blood tests that can reveal the presence of histoplasmosis infection and disease. Histoplasmosis also shows up on chest x-rays, but since x-ray findings are almost indistinguishable from those of tuberculosis, this may be undependable. Healthy young men who once unknowingly had histoplasmosis were kept out of military service during World War II because their x-rays suggested extensive tuberculosis scars. Today there are a variety of specific skin tests –– and also tests in which the organisms are examined under the microscope –– that differentiate other fungus diseases and tuberculosis from histoplasmosis.

Treatment Most cases of histoplasmosis require little or no treatment. After their flu-like symptoms, patients recover of their own accord. A drug, amphotericin B, has been found effective in the more severe cases of histoplasmosis. Its use requires hospitalization, however, because the drug must be introduced into the bloodstream almost daily for a period of weeks or months. Side effects have to be carefully monitored. Surgery –– removal of sections of the lung that are imbedded with histoplasmosis spores –– may sometimes be indicated when there has been extensive damage.

NOTE: Histoplasmosis is the leading cause of blindness in endemic areas of the USA.

Chlamydia Data Reported in 2001 – 783,242 chlamydial infections were reported to CDC – (of special interest they only keep track of the female cases so there must be a significant number of men infected or carrying Chlamydia). I did not find any information on how many infants and children develope Thush each year.

TITLE: Otitis Externa: A Personal Perspective SOURCE: Grand Rounds Of The UTMB Department Of Otolaryngology DATE: April 19, 1995 FACULTY: Francis B. Quinn, Jr., M.D. DISCUSSANT: J. R. B. Hutchinson, M.D., Atlanta GA SERIES EDITOR: Francis B. Quinn, Jr., M.D.

"This material was prepared for resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." (1,118 cases of fungal ear infections in this study)

HUMAN; 1.C.3. Fungal external otitis As many as 61 different fungal species have been identified in cases of external otitis, but the most common are Candida and Aspergillus. Fungi were identified in more than 9% of 12000 cases of external otitis in one study. Penicillin species are sometimes found as well. Many cases are actually mixed fungal and bacterial infections, usually S. aureus, Psuedomonas species and Proteus species. Often the symptoms are indistinguishable from bacterial external otitis. Physical presentation is that of a red canal, somewhat swollen and tender, with white, black, gray, or brown debris deep within the canal, usually right up against the drum, having been driven there by the patient's attempts at cleaning the canal with q-tips. Sometimes the fungal growth can be mistaken for the cotton tip of a q-tip itself. The disorder fails to respond to the usual antibacterial topical medications, and that is often the physician's first clue to the diagnosis. Laboratory identification of the fungi is of questionable benefit, for antifungal sensitivity tends to be inconsistently related to fungal species.

Lucente FE (Otolar. Clin N.A. v20 no6 Dec 1993 995-1006) collected 15 species of yeast and fungi from patients with external otitis during the course of one year. He obtained antifungal sensitivities on these specimens, using clotrimazole, nystatin, tolnaftate, amphotericin B, miconazole, natamycin, and flucytosine. (see handout) Clotrimazole consistently had the largest zone of inhibition aginst common fungi. Nystatin, amphotericin B, miconazole, and natamycin were also effective, but to a lesser extent. Only clotrimazole and miconazole showed antibacterial effects against Staphylococcus epidermidis and aureus.

Infect Dis Clin North Am. 2002 Dec;16(4):935-64, vii.

Fungal infections in nontransplant patients with hematologic malignancies. Segal BH, Bow EJ, Menichetti F.Division of Infectious Diseases, SUNY at Buffalo, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. PMID: 12512188 [PubMed - indexed for MEDLINE] Fungal infections are a major cause of morbidity and mortality in patients with hematologic malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Dimorphic fungi can cause serious infection in immunocompetent persons, but infection is more likely to be disseminated in patients with compromised cell-mediated immunity. Cryptococcus neoformans and Pneumosystis carinii typically cause infections in persons with severe T-cell suppression. The frequency of rare pathogenic fungi commonly resistant to amphotericin B has significantly increased over the past 20 years among patients with hematologic malignancies. Examples of such emerging pathogens include Trichosporon, Fusarium, and Scedosporium species, and dark-walled molds. This article reviews the epidemiology, clinical manifestations, diagnostic evaluation, and treatment of the major fungal pathogens in nontransplant patients with hematologic malignancies.

These statistics far exceed the more than “expected 10% of the population” and this is only based on a few of the more obvious effects of fungi in human health.

B) “only half of these, or 5%, would be expected to show clinical illness.” The above data clearly refutes this seemingly innocent assumption. I could not find statistics for how many sinus surgeries are performed.

PARAGRAPH 3, Sentence 3

“Furthermore, outdoor molds are generally more abundant and important in airway allergic disease than indoor molds —— leaving the latter with an important, but minor overall role in allergic airway disease.”

A) This sentence makes the assumption that there is more mold outside than in a contaminated enviroment as well as, “more important.”

B) Is the mold causing the disease airborne, is it from mold byproducts, or can it be landing on food people consume in their houses?

C) Are the molds outside different from the molds in the contaminated environment?

1) This brings into question the “mix” of molds and known effects.

D) “minor” Is anything minor when it comes to human health?

PARAGRAPH 3, Sentence 4.

“Allergic responses are most commonly experienced as allergic asthma or allergic rhinitis ("hay fever").”

A) This sentence may be true but what does that mean to the sufferer, the economy, et. al.? A clinical description of what a person suffers though, i.e., symptoms, lost days of income, expenses, side effects of the medications taken to relieve the problem, and the inability to enjoy activities.

“A rare, but much more serious immune-related condition, hypersensitivity pneumonitis (HP) may follow exposure (usually occupational) to very high concentrations of fungal (and other microbial) proteins.”

A) This type of problem is ignored (since it is being downplayed) in the medical profession and can be assumed to be generally overlooked and/or diagnosed as something else unless there is a clear suspicion of a fungal connection.

BRAIN

Brain abscess, Medline plus: “A brain abscess is a mass of immune cells, pus, and other material that can occur when the brain is infected by bacteria or fungus.

Neuropsycological performance of patients following mold exposure 2002 PubMed Appl Neuropsychol. 2002;9(4):193-202. Baldo JV, Ahmad L, Ruff R. Veterans Affairs Northern California Health Care System, Martinez, California 91711-3948, USA.

HUMAN-BRAIN-FUNGI POISON: Showed Axis I and Axis II Pathology-correlation on Beck Depression Inventory, complex interactions of impaired cognition, psycho stressors, poor physical health, and emotional functioning.

ACOEM EXPERT #52, MAY JJ

3-Nitropropionic acid's lethal triplet: Cooperative pathways of neurodegeneration. Authors: ALEXI T, HUGHES PE , FAULL R LM , WILLIAMS CE Author Address: Res. Centre Dev. Med. Biol., Starship Hosp., Level 1, Univ. Auckland, Private Bag 92019, Auckland, New Zealand. Source: NEUROREPORT; 9 (11). 1998. R57-R64. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN BRAIN-FUNGI POISON: 3-Nitropropionic acid (3-NP) is a mitochondrial toxin which interferes with ATP synthesis. Accidental ingestion of 3-NP by humans as well as other mammals results in neuronal degeneration within the basal ganglia and movement dysfunction characterized by dystonia, chorea, and hypokinesia. The selective degeneration of structures of the basal ganglia occurs despite the nonselective impairment of energy metabolism throughout the brain and body. These effects of 3-NP are shared with the genetic disorder Huntington's disease (HD), which is characterized by progressive neurodegeneration of the basal ganglia and choreic motor dysfunction. These similarities have prompted further investigation of 3-NP as an animal model of HD. Metabolic compromise with 3-NP causes neurodegeneration that involves three interacting processes: energy impairment, excitotoxicity, and oxidative stress. This triplet of cooperative pathways of neurodegeneration helps to explain 3-NP's regional selecti

Metabolic compromise with 3-NP causes neurodegeneration that involves three interacting processes; energy impairment, excitotoxicity, and oxidative stress.”

On the Etiology and Pathogenesis of Chemically Induced Neurodegenerative Disorders

Authors: Spencer PS , Allen CN , Kisby GE , Ludolph AC , Source: Neurobiology of Aging, Vol. 15, No. 2, pages 265-267, 13 references, 1994 Abstract:

HUMAN-ENCEPHALOPATHY-FUNGI POISON; In order to find chemical triggers of neuronal disease, the etiology and pathogenesis of progressive neurodegenerative disorders must be more clearly understood. Motor system disorders associated with xenobiotics are examined and it appears in each case clinical deficits appear during or shortly after exposure to the neurotoxin. Some of the disorders reach a plateau and may remain static for some period of time. In others the degradation is rapid and progressive neurodegenerative disease like amyotrophic lateral sclera develops. Much information is available concerning the astrocytic metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289545) (MPTP) and the neuronal degeneration associated with parkinsonism. 3-Nitropropionic-acid (504881) (NPA) is less well known but appears to produce encephalopathy, seizures, and irreversible dystonia in children who eat sugarcane contaminated with the fumigant. Repeated ingestion of a diet with L-beta-N-oxalylamino-L-alanine (5302454) (L-BOAA) induces central motor deficits and mild spasticity in macaques. Rodents treated with L-BOAA demonstrate convulsant behavior, and prominent excitotoxic pathology. L-BOAA and NPA induce specific patterns of self limiting neuronal disease as does domoic-acid (14277975) (DOA), largely held responsible for memory loss and lower motor neuron weakness in consumers of mussels contaminated with the toxin. Other chemicals discussed briefly in this review include beta-N-methylamino-L-alanine and methylazoxymethanol (590965). The authors suggest that either a metabolic abnormality occurs resulting in the presence of a compound with the ability to serve as an excitotoxic neurotransmitter or an energy depleting agent, or an irreversible or incompletely reversible change in a critical cell function may be responsible for the mechanisms underlying the etiology and pathogenesis of progressive neurodegenerative disorders.

TOXIC LEUKOENCEPHALOPATHY, Department of Psychiatry, Washington University, St. Louis, 2001NEJM 345:425-432, 2001

HUMAN “Leukoencephalopathy is a structural alteration of cerebral white matter in which myelin suffers the most damage. Toxic leukoencephalopathy may be caused by exposure to a wide variety of agents, including cranial irradiation, therapeutic agents, drugs of abuse, and environmental toxins.–clinical features; inattention, forgetfulness, and changes in personality to dementia, coma, and death. This review focuses on white-matter damage caused by toxins as distinguished from that caused by disorders such as MS, cerebrovascular disease, and metabolic disturbances.”

The effect on motor cortical neuronal development of focal lesions to the subcortical white matter in the neonatal rat; a model for periventricular leukalacia, PubMed, 2003

HUMAN “Periventricular leukomalacia (PVL) is either a diffuse or cystic lesion of the periventricular white matter that leaves the overlaying cortical grey matter largely intact. It is believed to result from hypoxia occurring per-or perinatally and is a major cause of cerebral palsy.

3-Nitropropionic acid injections caused small focal lesions restricted to the sub-cortical white matter. 3-Nitropropionic acid treatment initially increased expression of the apoptosis promoting proteins Bax and cJun, as well as not-phosphorylated neurofilaments in cortical layer V overlying the injection site. Non-phosphorylated neurofilament expression distal to the lesion was decreased representing a loss of cortical axons, but persisted and even increased with time withing the cortex, demonstration persistence of the parent cell bodies and local sprouting of neurites.

These persistent differences in expression of activity sensitive calcium binding proteins suggest alterations in local cortical circuitry without substantial loss of grey matter as is characteristic of periventricular leukomalacia.”

NOTE: Cyclosporin is made from fungi.

Cyclosporin leukoencephalopathy induced by intravenous lipid solution

Authors: Author Address: Dept. of Neurol., Acad. Ziekenhuis, Free Univ. of Brussels, B1090 Brussels, Belgium Source: Lancet; VOL 339 ISS May 2 1992, P1114, (REF 5) Comments: Letters Abstract: IPA COPYRIGHT: ASHP

A severe case of leukoencephalopathy associated with cyclosporine (cyclosporin) induced by intravenous (IV) lipid solution is reported in a 48-yr-old renal transplant recipient who was receiving 150 mg of cyclosporine and other immunosuppressive agents. The patient had developed pulmonary edema necessitating intubation and ventilation for 3 days, during which fentanyl and propofol were administered IV. Propofol was dissolved in soybean oil (Intralipid). The patient's serum triglycerides rose from 3.16 to 6.01 mmol/l and cholesterol from 3.63 to 5.75 mmol/l, and at the same time blood cyclosporine concentrations rose from 250 to 997 ng/ml. Cyclosporine was stopped and the patient's strength and mental function improved. Renal function became normal 4 days after cyclosporine was discontinued. It was concluded that IV administration of lipid solutions should be avoided in patients on cyclosporine.

On the Etiology and Pathogenesis of Chemical Induced Neurodegenerative Disorders, Toxnet, 1994, 13 references

HUMAN “Motor system disorders associated with xenobiotics are examined and it appears in each case clinical deficits appear during or shortly after exposure to the neurotoxin. Some of the disorders reach a plateau and may remain static for some period of time. In others the degradation is rapid and progressive neurodegenerative diseases like amyotropic lateral sclera developes.

3-Nitropropionic-acid (504881)(NPA) is less well known but appears to produce encephalopathy, seizures, and irreversible dystonia in children who eat sugarcane contaminated with the fumigant.

The authors suggest that either a metabolic abnormality occurs resulting in the presence of a compound with the ability to serve as an excitotoxic neurotransmitter or an energy depleting agent, or an irreversible or incompletely reversible change in a critical cell function may be responsible for the mechanisms underlying the etiology and pathogenesis of progressive neurodegenerative disorders.”

3-Nitropropionic acid's lethal triplet: Cooperative pathways of neurodegeneration. Authors: ALEXI T, HUGHES PE, FAULL R LM, WILLIAMS CE, Author Address: Res. Centre Dev. Med. Biol., Starship Hosp., Level 1, Univ. Auckland, Private Bag 92019, Auckland, New Zealand. Source: NEUROREPORT; 9 (11). 1998. R57-R64.

Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-FUNGI POISON-BRAIN-DISEASE; 3-Nitropropionic acid (3-NP) is a mitochondrial toxin which interferes with ATP synthesis. Accidental ingestion of 3-NP by humans as well as other mammals results in neuronal degeneration within the basal ganglia and movement dysfunction characterized by dystonia, chorea, and hypokinesia. The selective degeneration of structures of the basal ganglia occurs despite the nonselective impairment of energy metabolism throughout the brain and body. These effects of 3-NP are shared with the genetic disorder Huntington's disease (HD), which is characterized by progressive neurodegeneration of the basal ganglia and choreic motor dysfunction. These similarities have prompted further investigation of 3-NP as an animal model of HD. Metabolic compromise with 3-NP causes neurodegeneration that involves three interacting processes: energy impairment, excitotoxicity, and oxidative stress. This triplet of cooperative pathways of neurodegeneration helps to explain 3-NP's regional selecti--

In northern China, fungi growing on sugarcane stored over winter for the New Year Festival were responsible for at least 885 poisonings and 88 deaths over the period 1972-1989 (He et al., 1995). Nitropropionic acid is produced by various fungi of the genus Arthrinium, as well as Aspergillus and Penicillium, and causes selective neuronal loss in the striatum (Fu et al., 1995).

Ann N Y Acad Sci. 2001 Jun;939:381-92. Biomarkers of 3-nitropropionic acid (3-NPA)-induced mitochondrial dysfunction as indicators of neuroprotection. Scallet AC, Nony PL, Rountree RL, Binienda ZK. Division of Neurotoxicology, National Center for Toxicological Research, USFDA, 3900 NCTR Drive, Jefferson, Arkansas 72079, USA. AScallet@NCTR.FDA.GOV HUMAN-NEUROMUSCULAR DISORDERS-FUNGI POISON; In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3-Nitropropionic acid (3-NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme important for mitochondrial energy production. We have been studying biomarkers of 3-NPA exposure in the expectation that such markers may be useful in the screening process to identify neuroprotective agents against neurotoxicity produced by mitochondrial energy dysfunction. Animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity and measurement of immediate postmortem rectal temperature. 3-NPA-treated rats experienced progressive hypothermia that reached a loss of 3 degrees C or more in core body temperature by three hours after dosing. The optical density of the SDH stain in brain was reduced, following a similar time course, most prominently in the cerebellum and least sharply in the thalamus. Some rats were given injections of L-carnitine (an enhancer of fatty acid transport) either alone, or as a pretreatment prior to a dose of 3-NPA. Although L-carnitine deficiency by itself can produce mitochondrial dysfunction, pretreatment with L-carnitine was of limited efficacy at overcoming the effects of 3-NPA on either body temperature or quantitative SDH histochemistry. Body temperature and SDH histochemistry may be useful biomarkers for evaluating the efficacy of neuroprotective agents against lower doses of 3-NPA, against other pharmacological models of mitochondrial dysfunction, or even against genetic mitochondrial diseases.

Consistent striatal damage in rats induced by 3-nitropropionic acid and cultures of arthrinium fungus.

Authors: FU Y, HE F, ZHANG S, JIAO X, Author Address: Inst. Occupational Med., Chinese Acad. Preventive Med., 29 Nan Wei Road, Beijing 100050, China. Source: NEUROTOXICOLOGY AND TERATOLOGY; 17 (4). 1995. 413-418. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-ENCEPHALOPATHY-FUNGI POISON; Arthrinium fungi were cultivated from the samples of mildewed sugarcane which caused acute encephalopathy and delayed dystonia in children. The Arthrinium cultures (AC) contained 5 mg/ml 3-nitropropionic acid (3-NPA) after being inactivated and concentrated. A neuropathological study was carried out in rats intoxicated with 3-NPA and AC, respectively. Consistent bilateral striatal necrosis was found in rats with both poisonings, and the severity was well correlated with persistent recumbency which was a clinical indicator of the development of morphological brain lesions. A reproducible animal model of striatal damage has been produced in rats by IP injections of 10 mg/kg 3-NPA, 6 times a day, with an interval of 1.5 h for 3-5 days. The clinical and neuropathological manifestations in rats dosed with AC were nearly the same as those dosed with 3-NPA. The striatal lesions induced by 3-NPA and AC in poisoned rats were in accordance with the bilateral lenticular hypodensit

Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid; Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption? Journal of Neuroscience, 2003

“We conclude that early expression and activation of MMP-9 by ROS may be involved in early BBB disruption and progressive striatal damage after 3-NP treatment.”

Selective toxicity of ochratoxin A in primary cultures from different brain regions, PubMed 1999

HUMAN: (Aspergillus, Penicillium) “OTA passes into the blood of both humans and animals and accumulates in several organs, such as the kidney and the brain with selective toxicity in the ventral mesencephalon and the cerebellum. (Rat brain) a significant increase in levels of MDA and LDH release were noted. –indicate that OTA is also a neurotoxic substance in addition to its well-documented nephrotoxicity and that the effects are likely to be restricted within particular structures of the brain.”

23 Y) 1: Neurology. 1985 Nov;35(11):1654-7. ACOEM EXPERT #23 Fungal infections of the central nervous system: comparative analysis of risk factors and clinical signs in 57 patients. Walsh TJ, Hier DB, Caplan LR. HUMAN; Risk factors and clinical manifestations of fungal infections of the CNS were analyzed in 57 autopsied patients. Aspergillosis occurred in 16, candidiasis in 27, and cryptococcosis in 14. Nine of 31 variables studied showed significant difference (p less than 0.01). Cryptococcosis was community-acquired in 93%; whereas, aspergillosis and candidiasis were nosocomial in more than 95%. Focal neurologic deficits developed in 50% with CNS aspergillosis, but in only 4% with candidiasis. Meningeal signs occurred in 86% with CNS cryptococcosis, but in only 6% with aspergillosis and 7% with candidiasis. Discriminant analysis demonstrated that CNS aspergillosis was most frequently a nosocomial infection with focal neurologic deficits, pulmonary infiltrates, and hypercortisolemia. Cryptococcosis was generally a non-nosocomial infection with meningeal signs presenting in an ambulatory population. CNS candidiasis was a clinically occult nosocomial fungal infection with generally no deficits or meningismus, occurring most frequently in the neonate, the elderly, and surgical patients. The discriminant functions, which correctly classified 91% of these CNS fungal infections, may be applicable in clinical diagnosis. PMID: 4058755 [PubMed - indexed for MEDLINE]

23 Z) 1: Ann Neurol. 1985 Nov;18(5):574-82. ACOEM EXPERT #23 Aspergillosis of the central nervous system: clinicopathological analysis of 17 patients. Walsh TJ, Hier DB, Caplan LR. HUMAN; The clinical, laboratory, and pathological features of aspergillosis of the central nervous system (CNS) were studied in a series of 17 autopsied patients. Two groups were defined. Group A consisted of 8 patients with diseases commonly associated with CNS aspergillosis: leukemia, lymphoma, aplastic anemia, and renal transplantation. Group B contained 9 patients with various illnesses not generally known to be associated with CNS aspergillosis. CNS aspergillosis was diagnosed and treated before death in only 1 patient. Patients in Group A received cytotoxic drugs, often had granulocytopenia, less commonly had focal neurological deficits, and seldom had seizures. Group B patients were not granulocytopenic, received no cytotoxic agents, underwent nontransplant surgery, and more frequently had focal neurological deficits. Eleven of the 17 patients (65%) had focal deficits, most of them hemiparesis. Meningeal signs were rare, but the cerebrospinal fluid was usually abnormal. The principal neuropathological process was Aspergillus invasion of blood vessels causing hemorrhagic infarction. Focal clinical deficits correlated neuroanatomically with Aspergillus lesions. In 2 patients, such lesions were detected by 99mTc-DTPA or cerebral angiography before computed tomographic scanning. The lungs were the usual portal of entry, but isolated CNS lesions occurred in 2 patients. CNS aspergillosis should be considered as a cause of new onset of focal neurological deficits in patients with illnesses that are more diverse than has generally been appreciated. PMID: 3935042 [PubMed - indexed for MEDLINE]

ANTIBIOTIC PRODUCTION--HUMAN DISEASE-NERVOUS SYSTEM-BRAIN

Some characteristic of current forms of occupational nervous system diseases of chemical aetiology, Toxnet, Authors: Antonjuzenko VA Gnesina EA Gnelickij GI Karacarova SV Kalistova VV Source: Gigiena truda i professional'nye zabolevanija Feb. 1987, No.2, p.19-22. 9 ref. 1987 Entry Month: August, 1989 Classification Code: 130 Year of Publication: 1987 Secondary Source ID: CIS/89/00569 Document Number: CIS/89/00569

HUMAN “Follow-up of 214 patients with the most commonly encountered types of poisoning–as well as with occupational pathology due to antibiotics (penicillin and streptomycin). Neurological symptoms–antibiotics produce circulatory disorders confirmed by visual disorders.”

Role of allergic factor in the development of nervous system pathology in occupational diseases due to exposure to penicillin and streptomycin, Toxnet, 1982 GERASIMOVA MM Author Address: Inst. Ind. Hyg. Occup. Dis., Gorki, USSR. Source: GIG TR PROF ZABOL; 0 (8). 1981. 23-26. 1984 Entry Month: October, 1982 Year of Publication: 1981 Secondary Source ID: HEEP/82/11930 Document Number: HEEP/82/11930

HUMAN: “ 76 persons with nervous system pathology due to antibiotic exposure. The allergic factor resulting from exposure to antibiotics played the main role in the development of nervous system pathology; candidiasis antigen plays a minor role. Basophil degranulation tests were conducted on 76 persons with nervous system pathology due to antibiotic exposure; penicillin, streptomycin and Candida antigen were tested as allergens. Although dysbacteriosis and candidiasis are frequent consequences of excessive exposure to antibiotics, allergy to penicillin and streptomycin, rather than Candida, seemed to be most highly correlated with nervous disorders in the given group of hospital and antibiotic-production workers.”

Relationships between some adverse occupational exposure and the incidence of allergies on operators engaged in the production of ampicillin, Toxnet, Karpenko LZ Gigiena truda i professional'nye zabolevanija Oct. 1986, No.10, p.37-40. Illus. 1 ref. [Russian] [CIS]

HUMAN: “Neurological symptoms often develop in combination with symptoms of organic lesions of different parts of the brain. Simultaneous entry of antibiotics into the workers’ bodies through the respiratory tract and through the skin was reflected in damage to both systems.”

Clinical and experimental study of the relationship between allergic reactions to yeast-like fungi and penicillin. Toxnet, 1989 Sosedova LM Gigiena truda i professional'nye zabolevanija June 1987, No.6, p.12-15. 7 ref. [Russian] [CIS]

HUMAN “Examinations of 40 workers engaged in yeast protein production revealed both hypersensitivity to yeast-like fungi of the Candida group and to penicillin. Initially, hypersensitivity developes as a delayed reaction. An immediate reaction appears with increasing length of exposure.”

Age dependence of striatal neuronal death caused by mitochondrial dysfunction. Authors: BOSSI SR, SIMPSON JR , ISACSON O Author Address: Neuroregeneration Lab., McLean Hosp., Belmont, MA 02178. Source: NEUROREPORT; 4 (1). 1993. 73-76. Abstract: BIOSIS COPYRIGHT: BIOL ABS.

HUMAN-FUNGI POISON; Several lines of evidence point to a decline in mitochondrial deficiency with age. The relationship between age and sensitivity of Huntington disease-like neuronal death in the striatum induced by the mitochondrial inhibitor 3-nitropropionic acid (3-NP) was examined. 3-NP has been shown to cause degeneration of striatum, hippocampus, and thalamus in rat and of caudate-putamen in humans. We administered single doses of 3-NP intraperitoneally to rats of various ages. Animals older than 4 months exhibited a far greateer susceptibility to striatal neurotoxicity and mortality compared with younger animals. These results are discussed in the context of age-dependent metabolic impairment, which may be a key factor in the etiology of neurodegenerative disorders such as Huntington's disease and Alzheimer's disease.

Int J Dev Neurosci. 2003 Jun;21(4):171-82.

The effect on motor cortical neuronal development of focal lesions to the sub-cortical white matter in the neonatal rat: a model for periventricular leukomalacia. Gibson CL, Clowry GJ. Brain Development, Plasticity and Repair Group, School of Clinical Medical Sciences (Child Health), University of Newcastle upon Tyne, UK. HUMAN-DISEASE-FUNGI POISON; Periventricular leukomalacia (PVL) is either a diffuse or cystic lesion of the periventricular white matter that leaves the overlying cortical grey matter largely intact. It is believed to result from hypoxia occurring pre- or perinatally and is a major cause of cerebral palsy. We have modelled PVL in rats comparing the effects of discrete injections of 3-nitropropionic acid (3-NP), a mitochondrial toxin, ibotenic acid (IBA), a glutamate analogue, or saline into the sub-cortical white matter on postnatal day 7 (P7). Following recovery times ranging from 3 days to 4 weeks, forebrain sections were Nissl stained or immunostained for Bax, cJun, calbindin (CB), parvalbumin (PV) or non-phosphorylated neurofilaments (NPNF). Compared to saline injections, ibotenic acid caused large lesions of both grey and white matter not characteristic of periventricular leukomalacia. 3-Nitropropionic acid injections caused small focal lesions restricted to the sub-cortical white matter. 3-Nitropropionic acid treatment initially increased expression of the apoptosis promoting proteins Bax and cJun, as well as non-phosphorylated neurofilaments in cortical layer V overlying the injection site. Non-phosphorylated neurofilament expression distal to the lesion was decreased representing a loss of cortical axons, but persisted and even increased with time within the cortex, demonstrating persistence of the parent cell bodies and local sprouting of neurites. There were significantly fewer calbindin and parvalbumin positive neurones in the motor cortex (MC) side ipsilateral to the 3-nitropropionic acid injection compared to the contralateral side. These persistent differences in expression of activity sensitive calcium binding proteins suggest alterations in local cortical circuitry without substantial loss of grey matter as is characteristic of periventricular leukomalacia. Changes in expression of Bax, cJun and non-phosphorylated neurofilaments during normal development are also described.

Biochemical Effects of Topical Application and Decontamination of T-2 Toxin in Rats. Authors: Jovanovic D,

Milovanovic ZA, Jacevic V, Bocarov-Stancic A, Kilibarda V, Author Address: MILITARY MEDICAL ACADEMY BELGRADE (YUGOSLAVIA) NATIONAL POISON CONTROL. Source: Govt Reports Announcements & Index (GRA&I), Issue 15, 2003 Abstract:

Original contains color plates: All DTIC reproductions will be in black and white. Pres: The First World Congress on Chemical and Biological Terrorism, Dubrovnik, Croatia, 21-27 Apr 2002. p295-299 This article is from ADA411272 Chemical and Biological Medical Treatment Symposium - Industry II World Congress on Chemical and Biological Terrorism.

HUMAN-WARFARE-FUNGI POISON; T-2 toxin is a mycotoxin - a natural product of Fusarium Fungi. It was used in the Indochina as a chemical warfare agent and certainly has a 'terrorist' dimension. It is very complicated to treat; currently the best antidotes are corticosteroid hormones, compounds with significant adverse effects. These properties make T-2 toxin a very dangerous potential terrorist agent. This research describes our research in decontaminating T-2 on skin.

Annu Rev Pharmacol Toxicol. 1999;39:191-220.

Inhibition of nitric oxide synthase as a potential therapeutic target. Hobbs AJ, Higgs A, Moncada S. Wolfson Institute for Biomedical Research, University College London, Rayne Institute, United Kingdom. HUMAN; Nitric oxide (NO) regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states. This provides the rationale for the design of therapies that modulate NO concentrations selectively. A well-characterized family of compounds are the inhibitors of NO synthase, the enzyme responsible for the generation of NO; such agents are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including septic shock, neurodegenerative disorders, and inflammation. This article provides an overview of NO synthase inhibitors, focusing on agents that prevent binding of substrate L-arginine.

Fumonisin B1 in developing rats alters brain sphinganine levels–myelination.

“–(CNP) activities were decreased significantly–The hypomyelination associated with FB1 may be mediated by limited nutrition.”

Actions of tremorgenic fungal toxins on neurotransmitter release. Toxnet 1980

“The neurochemical effects of the tremogenic mycotoxins Verrucvlogen and Penitrem A, which produce a neurotoxic syndrome characterized by sustained tremors, were studied using sheep and rat synaptosomes.–Penitrrem A increased the spontaneous release of endogenous Glu, GABA; and Asp by 231%, 455%, and 277%, respectively, from cerebrocortical synaptosomes. Verruculogen increased the spontaneous release of Glu and Asp by 1300 and 1200%, respectively but not GABA from cerebrocortical synaptosomes.

Biochemical correlates for behavioral deficits induced by secalonic acid D in developing mice, Toxnet, 1992 (Penicillium)

“Humoral signals (neurotransmitters and hormones) control cell division, migration, and differentiation processes which define the organization of brain pathways.–mycotoxin, causes behavioral and neurochemical deficits in developing mice following prenatal or postnatal exposure. SAD-induced functional abnormalities include delays in reflex behaviors, integrated eneuromuscular activity and strength, stress adaptation responses, and sensory discrimination. These behavioral changes are associated with reductions of brain monoamine neurotransmitter levels–.”

Aflatrem, the temorgenic mycotoxin from Aspergillus flavus, Toxnet, 1979

“Recently identified as an indole-mevalonate metabolite. Several strains of A. flavus produced a tremorgenic toxin–mice caused several behavioral changes, including a pronounced trembling that sometimes persisted for 3 days. Larger doses caused the initial trembling to be replaced abruptly by convulsive seizures that frequently proved fatal. Guinea pigs and rats were also susceptible to oral or i p administration of the toxin.”

Biological and Chemical Characterization of Metabolites of Fusarium Moniliforme Isolates, 1990, 17 references, Toxnet

“In all groups of treated rats hemorrhages and edema were detected in the brain and intestine.”

Age-related differences in the toxicity of ochratoxin A in female rats, PubMed 2001

“Vacuolation of the white brain matter (cerebellar medulla and ventral parts of the brain stem) was significantly increased in young rats.–Kidney and possibly the brain being primary target organs–old rats are more sensitive.”

Regional selectivity to ochratoxin A, distribution and cytotoxicity in rat brain, PubMed, 1998

“–is a mycotoxin found as a contaminant in foodstuffs and shown to be nephrotoxic, teratogenic, immunosuppresive, genotoxic, mutagenic, and carcinogenic in rodents.–teratogenic effects in neonalse–accumulate in the brain according to the duration of exposure to doses in the range of natural contamination of feedstuff.—detected at 0.1nglg–lactate dehydrogenase (LDH) was increased–ventral mesencephalon, hippocampus, striatum and cerebellum as the main OTA targets in the brain of adult rats.”

Cigarette smoking and silent brain infarction in normal adults, Toxnet, 1996

HUMAN “Cigarette smoking was not related to the incidence of silent brain infarction or leuko-araiosis in healthy adults in Japan.”

Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults, Toxnet, 1999

HUMAN “Excitotoxicity and mitochondrial impairment are believed to play major roles in the neuronal degeneration and death that occurs in the brains of patients suffering from both acute brain insults such as stroke and seizures, and chronic neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. We now report that FR (alternate-day feeding regimen for 2-4 months) in adult rats results in resistance of hippocampal neurons to excitotoxin0induced degeneration, and of striatal neuron to degeneration induced by the mitochondrial toxins 3-nitropropionic acid and malonate.”

HUNTINGTON’S DISCOVERY BRINGS HOPE, Feb. 18, 2004, Howard Florey Institute, Dr. Anthony Hannan. *This is not peer-reviewed, It is a public release to the media.

HUMAN “–The disease was inherited by 50 per cent of sufferers’ children, but the DNA expansion can occasionally occur in people whose families had not previously suffered from Huntington’s.

“Despite the strong genetic factor, our recent evidence from a mouse model with a human Huntington’s disease gene mutilation suggests environmental factors play a major role in the disease’s onset and progression,” Dr. Hannan said. This discovery implies that understanding how gene-environment interactions affect the function of networks of nerve cells is important for all brain diseases, including those caused by an inherited mutation in a single gene.”

NOTE: 3-Nitropropionic acid is produced by fungi which in turn produces Nitric Oxide in the brain-causes overproduction.

INHIBITION OF NITRIC OXIDE SYNTHASE AS A POTENTIAL THERAPEUTIC TARGET, Annual Review of Pharmacology and Toxicology, April 199, Vol 39, pp. 191-220

HUMAN “Nitric oxide (NO) regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states. This provides the rational for the design of therapies that modulate NO concentrations selectively. –such agents are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including septic shock, neurodegenerative disorders, and inflammation.”

Mechanisms of Action of Trichothecenes in the Cardiovascular System, Toxnet, 1987

HUMAN “The mycotoxin experiments were consistent with previous observations that autonomic nervous system disturbances are responsible for a substantial part of the cardiovascular collapse reported for trichothecene mycotoxicosis.”

Age dependence of striatal neuronal death caused by mitochondrial dysfunction, Toxnet, 1993

HUMAN “Several lines of evidence point to a decline in mitoxchondrial deficiency with age. The relationship between age and sensitivity of Huntington disease-like neuronal death in the straitum induced by the mitochondrial inhibitor 3-nitropropionic acid (3-NP) was examined. 3-NP has been shown to cause degeneration in striatum, hippocampus, and thalamus in rat and of caudate-putamen in humans.

Animals older than 4 months exhibited a far greater susceptibility to striatal neurotoxicity and mortality compared with younger animals. These results are discussed in the context of age-dependent metabolic impairment, which may be a key factor in the etiology of neurodegenerative disorders such as Huntington’s disease and Alzheimer’s disease.”

Immunology _?4 2002 Ilyinskaya A. N., Pichugina L. V., Bakhus G. O., Klimova S. V., Pinegin B. V.

The influence of Russian cyclosporin A on functional activity of human lymphocytes

HUMAN; Russian drug cyclosporin-A (CSA), as shown in experiments in vitro, is a powerful inhibitor of the functional activity of T-lymphocytes. At a dose 0,1 mg/ml the drug significantly supresses proliferative activity of T-cells induced by PHA. CSA inhibits the first stage of development of proliferative response of T-lymphocytes, i.e. transformation of naive cells into blasts. The preparation reduces the percent of actively dividing cells and, respectively, the number of mitoses, which the cell passes in cultivation. CSA inhibits the production of key indicator of cytokines synthetized by CD4+Th1 and Th2-cells: gamma-interferon and IL-10. But maximal inhibitory effects of CSA is observed in respect of IL-2 (in a dose of 0,01 mg/ml the drug inhibits production of this cytokine by 80%. The inhibitory action of CSA upon the functional activity of T-cells is not related with their cytotoxic influence on leukocytes. In two-day incubation of leucocytes with the maximal dose, used in the experiments (10 mg/ml) there was no fall in cell‘‘s survival.

Images in Infectious Disease: Sputum Conidia Identifying Aspergillus niger Necrotizing Pneumonia from Infections in Medicine ®® Posted 07/21/2003 Jill A. Nord, MD, Vincent J. La Bombardi, PhD Cases and photographs submitted by Jill A. Nord, MD, associate professor of clinical medicine, and Vincent J. La Bombardi, PhD, assistant professor of clinical pathology, Saint Vincent Catholic Medical Centers-St. Vincent's Hospital Manhattan, New York, and New York Medical College, Valhalla, NY. Dr Wingard is professor of medicine, director, blood and marrow transplant program, and associate director, clinical and translational research, division of hematology-oncology, at the University of Florida College of Medicine, Gainesville.

HUMAN-FUNGI-DEATH; Progressive hypocalcemia developed (calcium level, 5.9 mg/dL; creatinine level, 2.2 mg/dL) on the second hospital day, and despite calcium carbonate therapy, the patient's serum calcium level fell to 3.7 mg/dL on the sixth hospital day, with a normal serum magnesium level and an inorganic phosphate level of 6.3 mg/dL. Renal failure, hypotension, oliguria, and massive hemoptysis developed, and the patient died on the sixth hospital day.

A niger is the third most common Aspergillus species to cause pulmonary disease, after Aspergillus fumigatus and Aspergillus flavus.^[1] It is also a rare cause of chronic necrotizing pulmonary aspergillosis.^[1-3] A fermentation by-product of Aspergillus fungi, especially A niger, is oxalic acid, which complexes with calcium from the host to form calcium oxalate crystals. These crystals cause severe tissue necrosis, including damage to blood vessels.^[4,5]

The diagnosis of an invasive Aspergillus pulmonary infection is normally accomplished by finding hyphal fragments in a specimen obtained by bronchoscopy. Rarely, as in this case, only conidia are identified.^[6] Conidia of A niger are darkly pigmented and echinulate and have a diameter of 4 to 5 µμm.

Fungal Infection Aspergillosis: Are We Making Progress? from Infections in Medicine ®® Posted 07/18/2003

John R. Wingard, MD Abstract and Introduction Abstract University of Florida College of Medicine, Gainesville

HUMAN-ADVANCES IN TREATING FUNGI: Advances in treatment have led to a decline in mortality from Candida infections in hospitalized patients in the United States. Unfortunately, similar progress has not occurred in the treatment of patients with aspergillosis. Acute invasive Aspergillus infections are less frequent than Candida infections, but mortality from aspergillosis now surpasses that from Candida infections. Although several new therapeutic agents have been introduced, they have not made a substantial impact in improving outcomes. The most promising one, voriconazole, was recently shown in a randomized trial to be superior to amphotericin B for first-line therapy for aspergillosis, although half of the patients still did not have successful outcomes. Even with more effective and safer therapies, substantial inroads in quelling aspergillosis may not occur until accurate early diagnostic methods are developed and incorporated into strategies to start treatment earlier.

Introduction Invasive fungal infections are increasing causes of morbidity and mortality in hospitalized patients for several reasons:

The widespread use of potent broad-spectrum antibiotics allows fungal overgrowth.The increasing application of critical care services has given rise to larger numbers of patients with indwelling catheters and various host defenses that are compromised in multiple ways.Chemotherapy regimens have intensified, and new immunomodulatory therapies have been introduced for the management of neoplastic diseases.Organ transplantation occurs for ever-increasing indications in modern medical practice.

As a consequence, not only is the pool of susceptible patients growing, but with more effective antibacterial treatments, superinfections by fungi are more likely. During the 1980s, the rate of fungal infections in hospitalized US patients doubled, with increases occurring in both medical and surgical patient populations.^[1] During the 1990s, this trend did not abate. At the same time, mortality from Candida infection in hospitalized patients declined, because of improvements in both early detection (through heightened awareness and improvements in culture techniques) and management of invasive Candida infections.^[2] This trend coincided with the introduction and widespread use of fluconazole, an effective, safe antifungal with excellent activity against most Candida species.

In contrast, there was a relentless rise in mortality from Aspergillus infection, which has now surpassed the mortality rate from Candida infection. The cost attributable to invasive aspergillosis in 1996 exceeded $650 million, an 8-fold increase in 2 decades.^[3] One can rightly ask, therefore: Are we making progress in the fight to quell the growing problem of aspergillosis morbidity and mortality?

Invasive Fungal Infections in the Neutropenic Cancer Patient: Current Approaches and Future Strategies

from Infections in Medicine ®® Posted 09/05/2002 Andreas H. Groll, MD, Thomas J. Walsh, MD Abstract and Introduction Andreas H. Groll, MD, Wilhelms-University, Müünster, Germany; Thomas J. Walsh, MD, National Cancer Institute, Bethesda, Md When this article was written, Dr. Groll was senior clinical fellow, immunocompromised host section, pediatric oncology branch, National Cancer Institute, Bethesda, Md. He is currently senior staff physician, center for bone marrow transplantation, department of pediatric hematology/oncology, Wilhelms-University Medical Center, Müünster, Germany. Dr. Walsh is head, immunocompromised host section, pediatric oncology branch, National Cancer Institute.

Infections in Medicine®^® (ISSN: 0749-6524) Selections from 2000 - Volume 17, Number 9

Aspergillus flavus Isolated in Cerumen by Scanning Electron Microscopy (earwax) from Infections in Medicine ®® Craig N. Burkhart, James Arbogast, PhD, William T. Gunning III, PhD, Vijay Adappa, MD, Craig G. Burkhart, MS, MD, Medical College of Ohio, Toledo Lourdes College, Sylvania, Ohio St Vincent's Medical Center, Toledo

Aspergillus flavus Isolated in Cerumen from Infections in Medicine ®® Craig N. Burkhart is presidential scholar, department of microbiology, Medical College of Ohio, Toledo. Dr Arbogast is head of chemistry, Lourdes College, Sylvania, Ohio. Dr Gunning is associate professor, department of pathology, Medical College of Ohio, Toledo. Dr Adappa is associate, department of surgery, St Vincent's Medical Center, Toledo. Dr Craig G. Burkhart is clinical professor of medicine, Medical College of Ohio, Toledo. Discussion

HUMAN-EAR-FUNGI; Fungi, usually in the form of yeast rather than mycelia, have been reported to exist in most cerumen.^[7,8] Products from fungal metabolism stimulate local release of interferon-like substances by the lymphoid tissue in the ear canal.^[7] Nevertheless, the existence of A flavus as transient flora in the ear was unexpected and raises the question of whether it might be a factor in auricular disease, such as ceruminous plug formation or otomycosis. A flavus frequently inhabits the nasal cavity of normal subjects, but it has been reported to become pathogenic when conditions in the paranasal sinuses become relatively anaerobic following mucosal thickening.^[9] Furthermore, the use of topical corticosteroids and the presence of epidermal cells within earwax increase the chance that transient flora, such as A flavus, will flourish and initiate a pathologic response in the ear canal.

Invasive fungal infections are important causes of morbidity and mortality in patients with hematologic malignancies and those who are undergoing hematopoietic stem cell transplantation (HSCT). The most significant risk factors in these settings are prolonged and profound neutropenia and therapy with high doses of corticosteroids. The overall frequency of invasive fungal infections in patients with acute leukemia and following allogeneic HSCT (the patient populations at highest risk) is between 10% and 25%; the overall case fatality rate exceeds 50% and is close to 100% in disseminated infections or persistent neutropenia. While Aspergillus and Candida species traditionally account for the majority of documented infections, recent epidemiologic trends indicate a shift toward infections by Aspergillus species, non-albicans Candida species, and previously uncommon fungi that often have little susceptibility to current antifungal agents.

Microbiology of CNS infections Patricia Spear, Ph.D. Dept. of Microbiology, Northwestern University Medical School Return to Neurology Education Index This material is the lecture handout for the lecture of the same title for the Scientific Basis of Medicine Course, offered to 2nd Year Medical Students at Northwestern University Medical School.

IV. Different types of CNS disease and the causative agents

HUMAN-DISEASE;

A. Meningitis.

The causes can be bacterial, viral or fungal. Access to the meninges and CSF is most often via a hematagenous route. Bacteria and fungi can grow rapidly in the CSF and secrete toxic products. Viruses infect meningeal and ependymal cells. The causes of acute meningitis are usually bacterial (Table 2) or viral (Table 3). It is extremely important to determine immediately whether the cause is bacterial, because immediate antibiotic therapy is necessary to prevent morbidity and mortality. Viral meningitis is usually less severe and, in general, only supportive therapy is available or necessary. The causes of chronic meningitis are usually bacterial (M. tuberculosis) or fungal (often C. neoformans). Diagnosis is more difficult in part because of difficulties of detecting infectious agent in the CSF.

Chronic infections in cranial bones, ears, sinuses, oral cavity or upper respiratory tract, and the attendant inflammation, can provide conditions that permit spread of infection to the CNS.

Sepsis: its causes and effects. Smith N. Guy's, King's and St Thomas' Hospital, London, UK. Review Review, Tutorial PMID: 12894698 [PubMed - indexed for MEDLINE] HUMAN; Sepsis contracted after malignancy, surgery or trauma is caused by a variety of micro-organisms ranging from viruses and fungi to bacteria. If untreated, it can lead to permanent damage to organs and tissues, or even to the patient's death.

Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington’s disease Mutation, Journal of Neuroscience, 1999

HUMAN “Cognitive decline is apparent in the early stages of Huntington’s disease and progressively worsens throughout the course of the disease.”

TOO MANY STUDIES TO INCORPORATE..

Aflatoxins and kwashiorkor in Kenya: A hospital based study in a rural area in Kenya. Authors: DE VRIES HR LAMPLUGH SM HENDRICKSE RG Author Address: Dep. Tropical Paediatrics, Sch. Tropical Med., Liverpool L3 5QA, UK. Source: ANN TROP PAEDIATR; 7 (4). 1987. 249-251. Abstract: BIOSIS COPYRIGHT: BIOL ABS. (41 children)

HUMAN Alfatoxin analyses were undertaken on sera and urines of 41 children admitted to a rural hospital in Kenya with kwashiorkor, marasmus, marasmic kwashiorkor or normal nutrition (Wellcome Classification). Aflatoxins were detected most frequently and at highest concentrations in the sera of kwashiorkors who, conversely, showed aflatoxins least frequently in their urine and in concentrations that were disproportionately low compared with serum/urine aflatoxin levels in other groups. These findings indicate altered aflatoxin metabolism in kwashiorkor and support the hypothesis that there are special relationships between aflatoxins and kwashiorkor. Medical Subject Headings (MeSH): Entry Month: April, 1988 Year of Publication: 1987 Secondary Source ID: BIOSIS/88/09514 /89/25803

NOTE: SEE---Epidemiology of Health and Safety Risks in Agriculture and Related Industries, Practical Applications for Rural Physicians, Toxnet, 1995

LUNGS

Granulomatous lesions in the lung induced by inhalation of mold spores, Toxnet, 1994

“(rats) Aspergillus versicolor to elucidate the mechanism for the lung damage induced by grain dust exposure. One month after exposure to the mold, remarkable proliferation of bronchus-associated lymphoid tissues with germinal centers was induced by aspiration of mold spores.”

Organic Dust Toxicity (Pulmonary Mycotoxicosis) Associated with Silo Unloading, Toxnet, 1986, 20 references

HUMAN: “The authors note that pulmonary mycotoxicosis is a distinct and different disease from farmer’s lung, although it is frequently mistaken for farmer’s lung.”

Organic Dust Toxcity (Pulmonary Mycotoxicosis) Associated with Silo Unloading

1990, 20 references

HUMAN: Twenty nine episodes of pulmonary mycotoxicosis in 25 farmers-

The use of enzyme-linked immunosorbent assay in the diagnosis of farmers lung, Toxnet, 1980

HUMAN: “Thermoactinoyces vulgaris and Micropolyspora faeni, Mycelial—used seperatly to analyze antibodies in 3 study groups: farmer’s lung patients, bronchitis patients, and healthy controls. The prevalence and the titers of antibodies against the 3 microbes detected by ELISA were higher in the farmer’s lung group than in the other 2 groups.

Farmer’s Lung, Long-Term Outcome and Lack of Predictive Value of Bronchoalveolar Lavage Fibrosing Factors, Toxnet, 1993, 32 references

HUMAN: “The authors conclude that chronic airflow obstruction with or without emphysema occurs in about half of the patients with a documented history of farmer’s lung. BAL fluid fibrogenic factors are not predictive of the outcome of farmer’s lung.

CHAPTER 4, PARAGRAPH 4.

PARAGRAPH 4, Sentence 1.

“Most fungi generally are not pathogenic to healthy humans.”

Since there are thousands of types of fungi this is probably true. However, there is increasing evidence that many of the fungi that were not considered pathogenic to healthy humans are.

PARAGRAPH 4, Sentence 2.

“A number of fungi commonly cause superficial infections involving the feet (tinea pedis), groin (tinea cruris), dry body skin (tinea corporus), or nails (tinea onchomycosis)

True, embarrassing, painful, and expensive.

PARAGRAPH 4, Sentence 3.

“A very limited number of pathogenic fungi – such as Blastomyces, Coccidiodes, Cryptococcus, and Histoplasma – infect non-immunocompromised individuals.”

A) A description of what these “pathogenic fungi” do to humans should be inserted.

B) Histoplasma is the #1 cause of blindness in the Mississippi Valley area, beats #1 nationwide–diabetes.

C) Report from Mayo Clinic on fungi in sinuses -- 2.7 types of fungi average growing in noses of 97% of people suffering from sinuosities..

PARAGRAPH 4, Sentence 4.

“In contrast, patients receiving chemotherapy, organ transplant patients receiving immuno-suppressive drugs, AIDS patients, and patients with uncontrolled diabetes, are at significant risk for more severe opportunistic fungal infection.”

A) Over 40, 000,000 Americans suffer from opportunistic fungal infection of the sinuses and the average is 2.7 types of mold per sufferer.

B) Since no statistics have been kept for the number of severe fungal infections, consequences of these infections, and related deaths in the U. S. it is impossible to estimate the deaths caused as a direct result of fungal infection or mycotoxin poisoning that initiated disease (by some mechanism not fully understood, generally understood by the public, medically common practice, empirically accepted, empathically proved, or still unknown) in humans.

C) “patients with uncontrolled diabetes.”

J Environ Sci Health B. 1982;17(2):77-91. Inhibition of pancreatic carboxypeptidase A: A possible mechanism of interaction between penicillic acid and ochratoxin A. Parker RW, Phillips TD, Kubena LF, Russell LH, Heidelbaugh ND. PMID: 7077056 [PubMed - indexed for MEDLINE] HUMAN-FUNGI POISON-SYNERGY EFFECT; Penicillic acid and ochratoxin A are environmentally important toxic fungal metabolites (mycotoxins) that are synergistic in combination. The effects of penicillic acid on the pancreatic enzyme, carboxypeptidase A were investigated in vitro and in vivo. A broad range of inhibition in vitro of the enzyme by PA was demonstrated with a half-maximal inhibitory concentration equal to 1.1 x 10(-4) M PA. Inhibition of carboxypeptidase A was time and temperature dependent, and resulted in decreased conversion of parent ochratoxin A to the non-toxic metabolite, ochratoxin alpha. Studies in vivo demonstrated a penicillic acid-dependent inhibition of pancreatic carboxypeptidase A activity in the mouse and the chicken following multiple oral exposure. It is postulated that the mode of toxic interaction of the two mycotoxins may be due, in part, to impaired detoxification of ochratoxin A through penicillic acid depletion of carboxypeptidase A activity. (Pancreas-diabetes?)

E) This report is very important–causes diabetes, drug made from mold

1: Transplantation. 1999 Aug 15;68(3):396-402.

Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC. Department of Pathology, University of Maryland School of Medicine, Baltimore 21201, USA.

HUMAN-MEDICINE MADE FROM FUNGI;: BACKGROUND: The introduction of the potent immunosuppressive drugs tacrolimus (FK) and cyclosporine (CSA) has markedly improved the outcome of solid organ transplantation. However, these drugs can cause posttransplantation diabetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation. METHODS: We studied 26 pancreas allograft biopsies, performed 1-8 months posttransplantation, from 20 simultaneous kidney-pancreas transplant recipients, randomized to receive either FK or CSA. The biopsies were studied by light microscopy, immunoperoxidase stains for insulin and glucagon, in situ DNA-end labeling for detection of apoptosis, and electron microscopy. The islet morphology was correlated with the mean and peak levels of CSA and FK in serum, with corticosteroid administration and with glycemia. RESULTS: On light microscopy cytoplasmic swelling, vacuolization, apoptosis, and abnormal immunostaining for insulin were seen in biopsies from patients receiving either FK or CSA. The islet cell damage was more frequent and severe in the group receiving FK than in the group receiving CSA (10/13 and 5/13, respectively) but the differences were not statistically significant. Significant correlation was seen between the presence of islet cell damage and serum levels of CSA or FK during the 15 days previous to the biopsy, as well as with the peak level of FK. Toxic levels of CSA or FK and administration of pulse steroids were associated with hyperglycemia when these occurred concurrently (P=0.005). Toxic levels of CSA or FK by themselves were associated with hyperglycemia in a minority of cases (8 and 26%, respectively). Electron microscopy showed cytoplasmic swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in beta cells; the changes were more pronounced in patients on FK. Serial biopsies from two hyperglycemic patients receiving FK and evidence of islet cell damage demonstrated reversibility of the damage when FK was discontinued. CONCLUSIONS: The structural damage to beta cells demonstrated in this study is similar to morphological and functional abnormalities previously described in experimental animal models and can at least partially account for the glucose metabolism abnormalities seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentiate each others' diabetogenic effects.Publication Types: Clinical Trial Randomized Controlled Trial PMID: 10459544 [PubMed - indexed for MEDLINE]

E) more on mold by-product and diabetes 1: Am J Kidney Dis. 1999 Jul;34(1):1-13. Comment in: Am J Kidney Dis. 2000 Mar;35(3):562.

Risk for posttransplant Diabetes mellitus with current immunosuppressive medications.Weir MR, Fink JC. (ACOEM Expert #8) HUMAN; Division of Nephrology, University of Maryland School of Medicine, Baltimore, MDWith improvements in the practice of transplantation and the introduction of new immunosuppressive medications, there has been a substantial increase in 1-year allograft survival rates. Consequently, the pool of potential candidates for organ transplants continues to grow and a greater preponderance of older patients with more comorbidities are undergoing transplantation. As a result, there is interest in such medical complications as posttransplantation diabetes mellitus (PTDM) that develop after the transplantation of a successful allograft. PTDM is an undesirable consequence of transplantation because of its associated morbidity and impairment of both patient and graft survival. Although some controversy exists, it is likely that glucose intolerance after transplantation results in both macrovascular and microvascular disease, and there is an increasing risk for infectious and cardiovascular diseases, to which transplant recipients are already at increased susceptibility. Both experimental and clinical observations have shown that immunosuppressive agents currently used in transplantation account for a large degree of the increased risk for PTDM. Consequently, improved understanding of the effects of currently used immunosuppressive medicines on glycemic tolerance is of interest in clinical transplantation.Publication Types: Review Review, Tutorial PMID: 10401009 [PubMed - indexed for MEDLINE]

G) 1: J Cardiovasc Pharmacol Ther. 2002 Apr;7(2):117-29. Diabetes, heart rate, and mortality. Singh N.Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. HUMAN; A large body of evidence indicates that a persistently high heart rate is associated with a significant risk for higher mortality and sudden death in individuals with a variety cardiovascular disorders, as well as in the general population. Heart rates elevated beyond a certain threshold have been found to be a risk factor for mortality in patients with hypertension, in survivors of myocardial infarction, and in patients with impaired cardiac function. Conversely, a naturally slow heart rate, or one that is slow by virtue of sympathetic blockade induced by pharmacologic agents, may result in longer survival. This is particularly evident in the case of beta-adrenergic blocking drugs, especially in patients after myocardial infarction and in those with acute as well as chronic cardiac failure, a syndrome in which there is a complex neurohormonal disturbance with elevated heart rate. Persistently elevated heart rate is also a feature of diabetes mellitus associated with autonomic neuropathy. Whether this also constitutes an independent risk factor for sudden and augmented mortality is not well defined. In this review, the data on the role of increased heart rate as a risk factor for mortality are examined in the context of other factors that may have therapeutic implications. Publication Types: Review Review, Tutorial

1A) Arthritis Rheum. 1994 Jul;37(7):1101-4. Immediate hypersensitivity reaction to cyclophosphamide.

Knysak DJ, McLean JA, Solomon WR, Fox DA, McCune WJ.University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor

NOTE: This medication is made from fungi. HUMAN We report a case of an acute anaphylactic reaction to intravenous cyclophosphamide in a patient with systemic lupus erythematosus. Skin testing for reactivity to cyclophosphamide and one of its metabolites, 4-hydroperoxycyclophosphamide, was performed on the patient and on 6 controls. The patient exhibited positive skin test responses; all controls had negative responses. The results suggest an acute hypersensitivity reaction related to sensitivity to cyclophosphamide and to 4-hydroperoxycyclophosphamide, through a shared antigenic determinant or dual sensitization. Publication Types: Case Reports PMID: 8024619 [PubMed - indexed for MEDLINE]

CHAPTER FIVE, PARAGRAPH FIVE

PARAGRAPH 5, Sentence 1.

“Some species of fungi, including some molds, are know to be capable of producing secondary metabolites, or mycotoxins, some of which find a valuable clinical use, eg. Penicillin, cyclosporine.”

A) “Penicillin” Put in studies of workers in industry effects and side effects.

Toxicity of Inhaled Mycotoxins, Toxnet, U.S. Department of Health and Human Services, NIOSH, 1990

“(rats)- secalonic acid-D (penicillium)–(Note: these studies lasted for less than 24 hours before exposed rats were killed) T2 toxin. SEC was found to be toxic at lower doses than previously thought. Pathological changes were confined to the lungs and consisted of necrosis of the bronchial epithelium, focal areas of granulomatous inflammation, and hyperplasia of the epithelium. T2 toxin and diacetoxyscirpenol reduced the viability of alveolar macrophages by as much as 50 percent.”

B) “Cyclosporine” Put in studies of side effects of use of cyclosporine. (See Chapter 4 for diabetes caused by cyclosporine use.)

ROLE OF NITRIC OXIDE IN CYCLOSPORINE INDUCED HYPERTENSION

Authors: GOMEZ CA Author Address: UNIV OF MICHIGAN, A7119 UH BOX 0108, ANN ARBOR, MI 48109-0108 Source: Crisp Data Base National Institutes of Health Abstract:

Cyclosporine is a potent immunosuppressive agent and is a mainstay of anti-rejec tion therapy in adult and pediatric heart transplant recipients. However, cyclos porine-induced hypertension remains a major complication of cyclosporine use, an d may occur in up to 96% of pediatric cardiac transplant patients. Cyclosporine -induced hypertension is particularly refractory therapy, and multiple antihyper tensive medications have been used with limited success. The cellular mechanism of cyclosporine induced hypertension remains unknown. Recent in vitro studies have suggested that cyclosporine has a direct effect on peripheral vasculature t o decrease the production of endothelium-derived nitric oxide, a potent vasodila tor, leading to impaired vascular smooth muscle relaxation, elevation of systemi c vascular resistance, and subsequent systemic hypertension. The aim of the pro posed study is to test the typothesis that cyclosporine-induced hypertension in vivo is secondary to decreased endothelial production of nitric oxide. To test this hypothesis, we will investigate the acute effects of intravenous administra tion of L-arginine, the amino acid precursor to nitric oxide, in pediatric cardi ac transplant recipients treated with cyclosporine.

NOTE: Hypercalcemia from drug made from fungi–human.

AMLODIPINE--REDUCING/REVERSING CYCLOSPORIN/TACROLIMUS INDUCED NEPHROTOXICITY

Authors: HEUBI JE Author Address: CHILDREN'S HOSPITAL RES FDN, 3333 BURNET AVE, CINCINNATI, OH 45229-3039 Source: Crisp Data Base National Institutes of Health Abstract:

HUMAN; The current purpose of this protocol is to evaluate the potential value of a long-acting calcium channel blocker (amlodipine) in the prevention of nephrotoxicit y associated with the use of cyclosporin and tacrolimus after orthotopic liver transplantation in children. This project is designed to assess glomerular filtra tion rate before OLT and sequentially afterwards while receiving amlodipine as w ell as during a period when drug is washed out to determine whether the effects of immunosuppressants on the kidney can be prevented/reversed. During the study period, 10 new subjects were enrolled, and 3 are being followed after OLT.

U.S. DEPARTMENT OF HEALTH

DEHP-INDUCIBLE CYTOCHROME P450 FORMS IN KIDNEY AND LIVER

Authors: OKITA RT Author Address: WASHINGTON STATE UNIVERSITY, WEGNER HALL, ROOM 105, PULLMAN, WA 99164-6510 Source: Crisp Data Base National Institutes Of Health Abstract: RPROJ

HUMAN; Members of the cytochrome P450 4A (CYP4A) subfamily catalyze the omega - or penultimate -hydroxylation of saturated and unsaturated fatty acids and prostaglandins. P450 4A forms are induced by peroxisome proliferators and their induction represents one of the earliest cellular events following exposure to these agents. It is thought that P450 4A induction and formation of oxidized fatty acids may be essential for induction of peroxisomal enzymes. There is considerable interest in the cellular effects of peroxisome proliferators, because these chemicals have been shown to cause hepatic tumors and testicular atrophy in rodents. In addition, 4A forms synthesize products which mediate vasoconstriction of renal vessels and an increase in P450-mediated fatty acid omega- hydroxylase activity is reported prior to the elevation in blood pressure in genetically-bred hypertensive rats. P450 4A forms have been identified in many species and one human 4A form has been sequenced. In rats, three members of the 4A family, 4A1, 4A2, and 4A3 have been identified and form specific oligonucleotide probes and an antibody which recognizes the three forms on western blots have been developed. Certain P450 4A forms exhibit organ specific expression and are regulated by sex hormones. The objectives of this competitive grant renewal are: 1) To localize specific 4A forms in distinct segments of the rat nephron by western blot analysis, because there is considerable uncertainty over the identity of renal forms. The localization of renal 4A forms will be compared in male and female rats because expression of renal 4A forms is sex hormone-dependent; 2) To identify 4A forms which are induced by two immunosuppressive drugs, cyclosporine and FK 506. Cyclosporine is an important therapeutic agent used in transplantation surgery and in treatment of autoimmune diseases, but nephrotoxicity is a major side effect. Studies indicate there is a correlation between induction of fatty acid omega-hydroxylase activity by cyclosporine and "the onset of nephrotoxicity; 3) To examine the mechanisms by which calcium channel blockers suppress induction of hepatic enzymes in DEHP (diethylhexyl phthalate), MEHP (monoethylhexyl phthalate) or clofibrate treated rats or isolated hepatocytes and to examine whether 20-hydroxyeicosatetraenoic acid (20-HETE) and other omega- or penultimate- oxidized fatty acids regulate intracellular calcium concentrations in isolated rat hepatocytes; and 4) To examine the interferon-induced suppression of hepatic 4A forms in phthalate or clofibrate treated rats or isolated hepatocytes. Interferon has been shown to inhibit the induction of P450 4A forms and its suppressive effects on peroxisome fatty acyl CoA oxidase will be examined. The long-term goals of this proposal are to determine the function of P450-mediated fatty acid omega-hydroxylases, its role in peroxisome proliferation, and its physiological function in the kidney.

Publication Types: Research Supporting Agency: U.S. DEPT. OF HEALTH AND HUMAN SERVICES; PUBLIC HEALTH SERVICE; NATIONAL INST. OF HEALTH, NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

U.S. DEPARTMENT OF HEALTH

Am J Cardiol. 2001 Apr 1;87(7):927-30.

Effect of arginine on cyclosporine-induced systemic hypertension after cardiac transplantation in the young.Gomez CA, Crowley DC, D'Alecy L, Goldberg CS, Charpie JR.Department of Pediatrics, The University of Michigan Medical Center, Ann Arbor, Michigan, USA. PMID: 11274958 [PubMed - indexed for MEDLINE] Source: Crisp Data Base National Institutes of Health Abstract:

HUMAN; Cyclosporine is a potent immunosuppressive agent and is a mainstay of anti-rejec tion therapy in adult and pediatric heart transplant recipients. However, cyclos porine-induced hypertension remains a major complication of cyclosporine use, an d may occur in up to 96% of pediatric cardiac transplant patients. Cyclosporine -induced hypertension is particularly refractory therapy, and multiple antihyper tensive medications have been used with limited success. The cellular mechanism of cyclosporine induced hypertension remains unknown. Recent in vitro studies have suggested that cyclosporine has a direct effect on peripheral vasculature t o decrease the production of endothelium-derived nitric oxide, a potent vasodila tor, leading to impaired vascular smooth muscle relaxation, elevation of systemi c vascular resistance, and subsequent systemic hypertension. The aim of the pro posed study is to test the typothesis that cyclosporine-induced hypertension in vivo is secondary to decreased endothelial production of nitric oxide. To test this hypothesis, we will investigate the acute effects of intravenous administra tion of L-arginine, the amino acid precursor to nitric oxide, in pediatric cardi ac transplant recipients treated with cyclosporine.

Publication Types: Research Supporting Agency: U.S. DEPT. OF HEALTH AND HUMAN SERVICES; PUBLIC HEALTH SERVICE; NATIONAL INSTITUTES OF HEALTH, NATIONAL CENTER FOR RESEARCH RESOURCES

Comparative Effect of Immunotoxic Chemicals on in Vitro Proliferative Responses of Human and Rodent Lymphocytes. 1993, 41 references

HUMAN and rodent; Cyclosporin-A caused a dose related inhibition of lymphocyte proliferation that was similar across all three species. Hydroquinone caused a biphasic response in mouse and human lymphocytes; stimulation followed by inhibition.

-T2 caused a dose dependent inhibitory response in human lymphocytes.

-Authors conclude that overall similar effects have been observed in rodent and human lymphocytes treated with known immunotoxic agents.

DIABETES and PANCREATIC CANCER (#4 killer in U.S.)

(Beta cell-Pancreas)

Autoimmune diabetes is caused by selective loss of insulin-producing pancreas beta-cells.

University of Maryland Medicine, What are therapies for preventing type-1 diabetes?

HUMAN; “Research is ongoing to develop treatments that use the body’s own immune system to impede or prevent beta-cell destruction. For example, cyclosporine, a drug that suppresses immune factors that worsen diabetes, was shown to help prevent development of the disease in some patients. It has some severe side effects, however and does not work in all people. It also loses effectiveness once it has been stopped.”

Frataxin deficiency in pancreatic islets causes diabetes due to loss of B cell (beta) mass, PubMed, 2003

HUMAN; “Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing b (beta) cells. (Description of cell death) These observations might provide insight into the deterioration of the B (beta) cell function observed in different subtypes of diabetes in humans.”

The relationship between diabetes and pancreatic cancer, PubMed, 2000

HUMAN “About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes. This observation has led to the following two hypotheses; 1. Pancreatic cancer causes the associated diabetes, and 2. The conditions associated with diabetes promote the development of pancreatic cancer. Evidence supporting both hypotheses has been accumulated in previous studies.”

Fluconazole Penetration into the Pancreas, May 2000, AAC

HUMAN “In recent years, however, it has been noticed that antibiotic prophylaxis in necrotizing pancreatitis causes a significant shift towards fungi in the microbial spectrum of the infected necrotic pancreatic tissue. Although the overall frequency of fungal contamination was approximately 7% of all pancreatic infections in the period before antibiotics were used prophylactically, this frequency has increased to 40% since the use of prophylactic antibiotic regimens.”

Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes, American Diabetes Association, 1999

HUMAN “Diabetes has been reported as being more common in Huntington’s disease and other triplet repeat disorders.”

Isolation of a metastasizing cancer cell line from an aflatoxin B1-induced rat liver tumor, PubMed, 1992

RAT “An attempt was made to isolate cancer cell lines from liver tumors that had been induced by aflatoxin B1 (AFB1) in rats. A clonal cell line named AFB-1 was isolated from a liver tumor that was histologically diagnosed as hepatocellular carcinoma.

–they metastasized from the site of inoculation into the abdominal cavity to form may tumor nodules throughout the serous membrane and metastatic foci in the kidney and pancreas. They also metastasized into the thoracic cavity to form metastic foci in the lung.”

PARAGRAPH 5, Sentence 2.

“Serious veterinary and human mycotoxicoses have been documented following ingestion of foods heavily overgrown with molds.”

They certainly have.

KOJIC ACID – THROYD, TESTOSTERONE, ETC.

Induction of thyroid tumours in (C57BL/6N x C3H/N)F1 mice by oral administration of Kojic acid PUBMED 1998

Effects of Fungal Metabolites on Testosterone Secretion in Vitro, 1990, 22 refereces.

“A significant but not dose dependent inhibition of testosterone secretion was noted in the presence of Kojic-acid. Rat

Changes in thyroid function during development of thyroid hyperplasia induced by kojic acid in F344 rats.

“–Inhibition of organic iodine formation was only observed after 3 weeks treatment.–TSH levels became evident with 48 h in both sexes.–interrupts thyroid function, primarily by inhibiting iodine intake, consequently causing a decrease in serum T(3) and %(4). Increased TSH from the pituitary glands in turn stimulates thyroid hyperplasia.”

Several thyroid lesion studies NOTE: SEVERAL STUDIES–CAUSES LESIONS, SAME RESULTS

PARAGRAPH 5, Sentence 3.

“In agricultural settings, inhalatation exposure to high concentrations of mixed organic dusts – which include bacteria, fungi, endotoxins, glucans, and mycotoxins – is associated with organic dust toxic syndrome, an acute febrile illness.”

Epidemiology of Health and Safety Risks in Agriculture and Related Industries, Practical Applications for Rural Physicians, Toxnet, 1995

HUMAN “In a discussion of risks in agriculture based on the finding of epidemiological studies emphasizing diseases and conditions that rural physicians are likely to encounter, the principal exposures and medical conditions associated with agricultural work were reviewed. These include respiratory system disorders, cancer, neurological problems, accidents, hearing loss, skin disorders, and stress. Typical pulmonary disorders include chronic bronchitis, asthma, hypersensitivity pneumonitis, and organic dust toxic dust syndrome caused by exposure to organic dust, microbes, molds, fungi, endotoxins, and various allergens.—Neurologic disorders, including acute intoxication, peripheral neuritis, and acute and chronic encephalopathy, can be caused by exposures to pesticides, solvents, and fumigants. Skin problems such as dermatitis, dermatophytic infections, and cancer can be caused by exposure to pesticides, fuels, fungi, sunlight, mites, or parasites.”

“The present alarm over human exposure to molds in the indoor environment derives from a belief that inhalation exposures to mycotoxins cause numerous and varied, but generally nonspecific, symptoms.”

A) “a belief that inhalation exposures to mycotoxins causes numerous and varied, but generally nonspecific, symptoms” is still not addressing the true effects from fungi and their byproducts. There are very specific and many nonspecific results from fungi and their byproducts.

B) Since the first thing that happens when a person is exposed to fungal byproducts is that they get ill and develop neurological symptoms, it is not surprising that patients are dismissed as “emotionally unstable” and fungi causes are notably overlooked by most practicing physicians.

HUMAN: “Peipheral blood from four health subjects, two men and two women, was used to prepare lymphocyte cultures. Breaks in--Chromosomes 1,2,3,4, and 5 were most affected by aflatoxin-G1, while chromosomes 2,11,19, and 20 were most affected by aflatoxin B1. =Aflatoxin B1 had higher mutagenic activity.”

Immunological shifts in workers due to contact with biological factors in the industrial environment, Toxnet 1989

HUMAN “Ninty-six workers occupationally exposed to a range of biological factors (length of exposure: 1 month to 8 years or more) were examined for changes in the immune system. All had positive skin reactions to Candida maltosi and depression of all elements of the immune system. This case shows a typical combination of increased sensitization with depression of the immune system. Disturbances in certain elements of the immune system in patients with skin and pulmonary pathology indicated direct and active participation of immune reactions in the pathogenesis of these diseases.”

A mechanistic analysis of nitric oxide-induced cellular toxicity. Burney S, Tamir S, Gal A, Tannenbaum SR. Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139-4307, USA. PMID: 9701052 [PubMed - indexed for MEDLINE]

HUMAN; Nitric oxide (NO.)-induced toxicity was investigated in two different cell lines, Chinese hamster ovary (CHO-AA8) and human lymphoblastoid (TK6), over a range of NO. doses (0-9 mM) delivered for an exposure of 2 h. To determine both short-term and delayed effects leading to death, a range of assays was employed to decipher the major mechanisms of cytotoxicity. Examples of damage parameters measured in this study include inhibition of DNA synthesis, damage to mitochondria, loss of cell membrane integrity, apoptosis, changes in cell cycle distribution, and the occurrence of DNA strand breaks. Our results indicate that NO.-induced toxicity is an extremely complex process involving multiple pathways generally leading to apoptotic cell death. Results consistently demonstrate that TK6 cells are much more susceptible to NO.-induced toxicity than CHO-AA8 cells. This difference in sensitivity could be seen for all types of cellular damage examined. The earliest observable effect of NO. exposure is inhibition of DNA synthesis which is not the result of inhibition of ribonucleotide reductase but may be the result of DNA damage leading ultimately to cell cycle arrest.

“Current scientific evidence does not support the proposition that human health has been adversely affected by inhaled mycotoxins in the home, school, or office environment.”

NOTE: The basis for the rest of this report has already been established as being biased and of little scientific value. It is therefore unnecessary to continue for the validity of this critical analysis.