Re: More misconceptions From Dr. Ritchie Shoemaker

[Guest guest]

RITCHIE C. SHOEMAKER, M.D., P.A.

CHRONIC FATIGUE CENTER

5OO MARKET STREET

SUITE 102, 1O3

POCOMOKE, MD 21851

TELEPHONE (41O) 957-155O

FAX (41O) 957-393O

H. Bruce Kruger

Managing Director

Practice and Policy

AAAAI

2/28/06

Dear Mr. Kruger,

Re: Bush et al, The medical effects of mold exposure

I am writing to request that you reject the paper by Bush et al on illness

caused by exposure to water-damaged buildings and indoor resident organisms,

including fungi, bacteria and actinomycetes. The paper is not a candidate for

a broad position statement. It cannot be called unbiased, as it is clearly

the self-serving product of a small group of mold-defense witnesses trolling

for support in litigation. The thrust of the statements made in the paper

concerning the reality of human health effects caused by exposure to toxigenic

organisms is just plain wrong.

What gives me the right to say without any hesitation that esteemed

professors from UCLA, Stanford and Oregon are wrong? They have no experience

with

pharmacologic intervention that changes physiologic parameters in the illness

other than to perhaps prescribe some asthma medications. I have 3000 human

reasons why those professors are wrong: my patients with illness. Not in

vitro experiments, not in vivo experiments with mice or rats. Humans! I have

treated over 3000 patients with illness caused by exposure to water-damaged

buildings (WDB). I have testified by invitation in the House of

Representatives

(9/22/04) and in the Senate HELP committee (1/12/06). Our research group has

published the world’s largest series of cases (i) diagnosed; and (ii)

treated. We have published a case definition of “mold illness,†the name

we use

for the syndrome of multiple symptoms from multiple body systems resulting

from exposure to WDB.

We have shown the genetic basis of susceptibility to the illness and the

dramatic number of physiologic abnormalities reproducibly seen in innate immune

responses in these patients. Our most recent paper, presented 2/16/06 at the

American Society for Microbiology conference on Biodefense and Biowarfare,

showed the hyperacute acquisition of illness parameters in previously treated

patients with re-exposure to indoor environments with resident trichothecene

forming fungi. These data once again confirm the dramatic activation of

cascades of biological responses to fungal toxins also demonstrated in animal

studies where as few as 30 spores/gram were capable of increasing TNF

production

by 100,000-fold (see attached references to the work of Dr. Rand). It

is this amplifying biological cascade that confirms that this illness does

not follow traditional dose-response relationships.

Why do I say the paper was produced for use in litigation? You need to know

that while the paper hasn’t been ‘released’ yet, nonetheless an insurance

industry defense attorney sat in my office in Pocomoke, Md on 2/21/06 waving

the Bush missive during my deposition on behalf of a patient, just as though

it were the Ten Commandments. Fortunately, I had read the draft and was

ready for his attempts to manipulate truth in a case in which I was the

treating

physician. I criticized (i) the lack of candor in the paper with its absence

of proper disclosure of conflicts of interest; (ii) the absence of any

citation of papers that showed health effects, including the two from our

group;

(iii) the agreement with and endorsement of the ACOEM report, itself horribly

flawed (see below); (iv) the absence of any human data to support the

dose-response argument; (v) the absence of any controlled studies that

thoroughly

analyzed all symptoms and lab parameters the mold illness patients have; (vi)

the cynical attempt to say that Hurricane Katrina would provide a laboratory to

study remediation (emphasis added), with no statement about illness

acquisition; and (vii) the attempt to discredit analysis of inflammatory

markers,

including cytokines and innate immune responses as if they were just chaff in

the wind and of no consequence.

So, if such sloppy work is so easy to discredit, why would I care if the

AAAAI endorsed it? After all the mold-naysayers, like Drs. Bardana, Saxon and

Terr, are now losing many court cases because they are so wrong. So one might

ask, “what difference does another ‘tobacco-science’ paper actually

make?â€

One main reason is paramount: as physicians we have the duty to help our

patients. We don’t have a duty to make piles of money while perpetuating the

suffering of our patients. The Bush paper violates an important ethical

standard in medical care, one laid down for us since the days of Hippocrates.

Do

no harm to patients. Tell the truth about the science. Do not hide the

academic and clinical work that doesn’t support your ideas. Tell us if you

have

financial interests. Are you self-dealing? Is that so much to ask?

This AAAAI paper would surely do harm to all patients truly sickened

physically and mentally by mold associated illness.

I must assume that you are aware of the bitter battles ongoing between ‘

experts’ in litigation on the topic of “mold illness,†with a recent $22

million

verdict in California sending shock waves throughout the group of

consultants regularly hired by the defense bar and their clients. I must also

assume

that you are aware that several recent papers have been published about mold

illness written by members of your Academy who are highly paid consultants for

defense interests in mold litigation. In particular, the recent publication

in your Journal of a paper written by Dr. Emil Bardana is an egregious abuse

of academic rigor and professional status. I also assume you know that

Bardana’s paper was hailed by several other members of your Academy, namely

Dr.

Terr and Dr. Saxon, co-authors of the Bush paper.

It is such a remarkable coincidence that the Bush paper lauds the fatally

flawed ACOEM Position Statement published on line 10/27/02 and written by the

same Dr. Saxon along with two non-physicians Kelman and Hardin, members of a

defense consulting firm, Veritox, Inc.

I see the AAAAI being manipulated and used by the insurance and allied

industries and their attorneys and “expertsâ€. As was ACOEM. The

manipulation of

AAAAI is meant to support the false “evidence-based†statement written for

ACOEM. Therefore my comments on the controversial ACOEM paper, comments

supported by a knowledgeable review of the medical science, follow.

A fundamental question for physicians who examine and treat patients with

acute and chronic illnesses possibly related to exposure to water-damaged

buildings is stated simply: “Is this person’s illness caused by exposure

to

biologically produced toxins, including those made by fungi?â€

As noted above, I will refer to the acute and chronic biotoxin-associated

illnesses acquired by people following exposure to indoor environments with

prior water damage and amplified growth of toxigenic microbes, including fungi,

as “mold illness.â€

My intention here is to show (a) how mold illness is defined, i.e. what is

the case definition; ( how it is further delineated by objective

physiological and neurotoxicological parameters beyond the case definition; and

finally

© to expose the errors of the “dose-response†opinion that holds that a

simple dose threshold is always a necessary element in mold illness causation

–

since it is not.

Answering the case definition / causation question involves a series of

logical steps grounded in long-established basic science. My perspective is

that

of a physician who treats patients every day, and who has treated over 3000

patients with illness caused by exposure to water-damaged buildings. My

methods have evolved over my nearly 30-year medical career in which I have

treated

tens of thousands of patients. A treating physician must be able to explain

why:

(A) one person exposed to buildings with water damage and

mold growth is unaffected by such exposure; but

( another person, equally or perhaps less ‘exposed’, has a

multisystem, multisymptom illness with multiple abnormalities in laboratory

markers of the innate immune response system.

Our data on genetic susceptibility to biotoxin-associated illness accomplish

that goal. Moreover, our databases on over 5000 patients with

biotoxin-associated illnesses show the predictable perturbations

(abnormalities) in

physiology that these patients with pre-existing susceptibility clearly

manifest.

When I am called to testify on my patients’ behalf, my opinion will normally

be opposed by other persons identified as ‘experts’ by defense counsel,

even though those consultants have never treated a patient with an illness

associated with exposure to interior environments of moldy buildings. The

logical

disconnect is quite apparent. On the one hand is the knowledge I have

accumulated by treating thousands of patients exposed to water-damaged

buildings.

On the other are the defense ‘experts’ whose opinions have been formed

without any foundation in clinical experience with these patients.

My first line of enquiry underlying the causation question is

straightforward. Does the patient meet the case definition that our research

group has

published in several peer-reviewed papers? _[1]_

(aoldb://mail/write/template.htm#_ftn1)

Our case definition is restrictive. Before diagnosis it requires every

patient to exhibit a series of reproducible findings in two separate tiers of

criteria. The first tier is a direct application of the case definition for a

biotoxin illness created in 1998 by the US Centers for Disease Control and

Prevention (CDC) when that agency was asked to define the acute and chronic

illness caused by exposure to toxigenic dinoflagellates resident in estuaries,

including Pfiesteria piscicida. The CDC concluded that there must be three

elements present for a person to be considered a “caseâ€: first - the

potential

for exposure; second - the presence of a multisystem, multisymptom illness;

and third - the absence of confounding exposures. The first tier for the

case definition for a mold illness patient is no different.

The first element is established by recognized toxicological sampling and

analytical techniques; the second element by careful and appropriate interview

technique and symptom recording; while the third element, the absence of

confounding exposures, must be ascertained employing the standard medical tool

of

differential diagnosis. While many illnesses could possibly cause individual

symptoms, a biotoxin-associated illness will have multiple symptoms from

multiple body systems simultaneously. Finding reasonable medical certainty

involves a clinical approach that separates the potential diagnoses that are

supported by logic from those potential diagnoses that are merely hypothetical.

The second tier to the biotoxin illness case definition creates additional

objective criteria that must be satisfied. The model for the two-tiered

approach is based on multiple examples accepted for use in clinical medicine,

including case definitions for rheumatic fever and systemic lupus

erythematosis.

Patients must have three or more of the six second tier objective parameters,

including (i) visual contrast sensitivity (VCS) testing; (ii) genetic

susceptibility as determined by a properly analyzed blood specimen for HLA DR

by

PCR; (iii) hypothalamic involvement, as shown by deficiency in levels of

melanocyte stimulating hormone (MSH) using an assay employed by LabCorp, a CLIA

approved, high-complexity lab; (iv) elevated levels of matrix

metalloproteinase-9 (MMP9); (v) dysregulation of simultaneously measured levels

of ADH and

osmolality; and (vi) dysregulation of simultaneously measured levels of ACTH

and

cortisol.

This case definition was established in a study twice peer reviewed, once

before its acceptance for presentation to the Fifth International Scientific

Conference on Bioaerosols in Indoor and Work environments in September, 2003 and

again before being published in Johanning E (ed), Bioaerosols, Fungi,

Bacteria, Mycotoxins and Human Health, pg 66-77.). The Johanning work is a

compendium of peer-reviewed papers published in March 2005 with funding support

provided by the EPA. The study (Shoemaker RC, Rash JM, Simon E) “Sick

Building

syndrome in water-damaged buildings: generalization of the chronic biotoxin

associated illness paradigm to indoor toxigenic fungiâ€) looked at what linked

all 156 patients with identified mold illness, links which none of the 111

control patients had. Included in the control group were potential confounders

-

tobacco users, diabetics, people who used alcohol, people with cataracts,

patients on estrogen, patients with nasal allergy, asthma, depression, anxiety,

diverticulosis and other potentially confounding conditions. Since the

initial presentation of the case definition September 12, 2003 we have not

(yet)

found any control patients who meet the case definition, including a control

group of 239 patients presented 9/7/05 at the US EPA International Symposium

on Cyanobacteria, held in Research Triangle Park, NC.

Our next hurdle to complete the causation argument, given the presence of a

patient who meets the case definition, is to show that he is affected by a

given building. We all know that fungi are ubiquitous; how can we demonstrate

the causation link between a water-damaged building and a patient meeting the

case definition?

We do not know which built environment is causing the illness when we first

see a patient with mold illness. As the patient is already ill, the original

cause is not easily ascertainable. What can we do? To answer that question,

we use the techniques of Dr. Koch,_[2]_

(aoldb://mail/write/template.htm#_ftn2) his methods both embodied and honored

as “Koch’s Postulatesâ€. His

procedure is a repetitive exposure protocol - as is ours. We are able to

use Koch’s Postulates because we have a proven method of intervention that

allows us to impact the course of the disease.

What we do first is to alleviate the illness with a series of interventions

that restores better health and corrects / ameliorates physiologic

abnormalities in the patient. We document the reduction of symptoms and the

laboratory

confirmations of the correction of physiologic abnormalities. Once the

alleviation has been established and confirmed we stop the medications and keep

the patient away from the suspect, water-damaged building for three to seven

days. Then we establish and document whether this exposure to the ubiquitous

fungi of the rest of the world (unprotected by ongoing medication), for

example in the home including pets, car, church, garden, shopping and so on,

has

caused re-acquisition of the illness. If it has not - that is (i) the symptoms

remain constant and (ii) neurotoxicological and physiological test results

remain the same, then we re-expose the patient to the suspect water-damaged

building (with informed consent, of course), still without any protective

medication. At this stage we monitor the patient daily.

With time as a factor and no other confounders capable of causing the

illness, if the suspect water-damaged building is the cause, we see

reacquisition

of the illness within three days. We can show the repeatedly observed

abnormalities in inflammatory factors appearing in the same order in the patient

as

they did in patients in a clinical trial (multilab, multi-test,

double-blinded, placebo-controlled, crossover clinical trial). Having

established the

causal role of the WDB, we then treat the patient a second time to re-establish

the previous level of alleviation and go forward with other treatment having

confirmed the diagnosis and the cause.

This prospective acquisition of acute illness, complete with all the

abnormalities seen in the chronic illness, proves beyond any reasonable doubt

that

it is exposure to the indoor air of the suspect water-damaged building that

causes the illness. More importantly, the re-emergence of all the

abnormalities acutely, that are seen in the chronic illness, proves that the

re-acquisition of illness does not follow a simple dose-response relationship.

Three

days of exposure is not the same as, say, three years yet the illnesses

resulting from both durations of exposure are comparable.

This research design, when applied in cases where the individuals are not

involved in a research study, enables us to return to our case definition to

answer the question, “Is this person a case?†We can do so with academic

certainty without forcing all patients to run the risk of potential injury by

returning to the source of illness.

Our data in multiple patients has documented the role played by cascades of

biological responses in mold illness. The effects of biotoxin exposures are

collectively seen as activation of innate immune responses. As opposed to the

acquired immune responses, an arm of immune protection that involves

manufacture of antibodies, the innate immune responses involve pre-formed

elements,

including cytokines, complement, vascular growth factors and more. These

response elements are capable of hyperacute response, much as a guard on duty

patrolling a perimeter can react immediately to perceived threats from an

intruder, sounding the alarm until the slower to respond support troops

acquired)

can arrive. Each of these innate responders can activate hundreds of other

innate responders, which in turn activate hundreds more, involving more and

more of the various response mechanisms. As an example, following just three

hours of biotoxin exposure, levels of C4a in susceptible patients will rise

nearly 10-fold, from normal at 600 to over 6000.

I am reminded of the dose-response argument regarding bee stings when I hear

the old mantra, “The poison is in the dose,†from those who won’t

recognize

the true nature of the effect of biological toxins on genetically susceptible

patients. For someone like me, if I am stung by a bee, I’ll have a local

reaction that will become red and inflamed, but otherwise I am not made ill.

But give that same dose of bee venom (yet another biotoxin) to someone with

pre-existing disposition to an over–reaction of innate immune response

elements

and they might develop a systemic anaphylactic response, with multi-organ

failure and circulatory collapse. The dose is the same, but the outcome is

determined by genetic susceptibility. So too with mold toxins.

And so to the ACOEM statement.

I note that there is a common argument made by certain defense consultants

in mold cases that dose-response relationships hold sway in mold illness. The

reference they use is a “consensus†statement published on-line10/27/02 by

the American College of Occupational and Environmental Medicine (ACOEM).

That “consensus†statement was actually produced at the request of two high

ranking members of ACOEM – one of whom arranged free membership for one of

the

authors and then played the role as supervisor of “peer reviewâ€. Two of the

(non-physician) authors are prominent members of a corporation, Veritox, Inc.

(previously known as GlobalTox) that testifies frequently for the defense in

mold liability cases and a non-ACOEM physician and member of AAAAI who also

testifies for defense interests. The “consensus†and “evidence-basedâ€

statement relies heavily for its scientific basis on a study done on rats using

a

single intratracheal exposure to 9.6 million spores from Stachybotrys fungi.

The authors showed significant evidence of damage to the rat. The ACOEM “

consensus†statement authors then suggest with a leap of “insight†that

such

artificial doses are never seen indoors and therefore, mold illness couldn’t

possibly exist.

This is akin to the logic of saying that:

(i) Someone standing a mile away from Ground Zero in a large nuclear

explosion would be vaporized in an instant; and

(ii) Nuclear explosions don’t happen in your backyard; therefore

(iii) You cannot get a sunburn in your backyard over the course of an

afternoon from that far away low dose series of nuclear explosions we call the

sun.

The three ACOEM “consensus†statement authors ignore numerous studies

performed by others that contradict their “insightâ€, including those by Dr.

Rand of Nova Scotia and his group. Dr. Rand has demonstrated

amplification

of cytokine responses by over 100,000 fold from as few as 30 spores per gram

of mouse. These three ACOEM authors also ignore the comments made by the

authors of the very rat study they cite. Those authors clearly state that

exposures in people are chronic, low-dose exposures; and that to gain an

understanding of human causation, investigations into chronic exposures must be

performed. In other words if you want to understand what causes sunburn, study

that

condition, don’t make outrageous statements based on Hiroshima.

Further, the rat study was an early attempt to find a positive relationship

between mold spores and mammalian health - thus a massive dose was used. The

experiment was done without the benefit of all that we have learned since

that time. For example the spores were washed before they were instilled into

the rats, rendering impossible any estimation of the actual amount of toxin

delivered.

Moreover the rat study also omitted any determination of which fungal

toxins, if any, were at that time being produced by the Stachybotrys cultures

selected. No toxin determinations of any kind were performed. No presence was

confirmed, no quantities were measured, no identification was performed -

nothing.

Yet another reason not to irrationally and improperly apply this rat study

to human causation is that recent good science has shown that the majority of

potentially pathogenic fragments of fungi are not visible unless seen with

high magnification of 800-power or more. Screening for these fragments in the

rat study was done at 200-power magnification. It is the ingestion/inhalation

of these fragments that lead to the apparent discovery of serum stachylysins

by the CDC in a cohort of my SBS patients. But the rat study spores were

washed – one set purposively in alcohol (and agitated, then rinsed) and the

other set in the saline solution used to deliver the spores into the rats.

Recent work has shown that toxic nano-particulates, much smaller than mold

spores, outnumber those spores by 300 to 1. Where did they go when the spores

were washed? How were the spores harvested and stored? Maybe the effective

dose given the rats was actually quite small. We don’t know. The Board of

ACOEM

didn’t even ask.

Finally, the rat study didn’t measure any of the innate immune response

elements, the very compounds that solid, repetitive, peer-reviewed and published

studies of animals and humans have proven are critical in the pathogenesis of

the mold illness.

So how can the only scientific support cited for the ACOEM “consensusâ€

statement - the rat study - support the self-serving position its three authors

advance, namely that impossibly massive doses of fungi must be present to cause

human illness? It doesn’t. Not even close. It shows only that the

presence of large amounts of mold spores artificially introduced into the lungs

of

rats makes them ill. Perhaps Shakespeare put it best “it is a tale told by an

idiot, full of sound and fury, signifying nothingâ€.

In fairness to the rat study authors, at the time the study was conceived it

was a tentative first step to see if mold spores and animal illness might be

related. Thus large amounts of spores were used since the study was seeking

to guarantee a positive response. As the study says itself – it was only a

first step and not applicable to humans. But by October 2002 when the

“consensus

†statement was being written for ACOEM (then after a most unusual “peer

review†edited by the same three authors just prior to its online release),

the

relevant science had progressed far beyond the rat study and this later,

better science recognized the flaws in that study – as experimental science

almost always does with the benefit of hindsight. Nonetheless the three

author/editors used the rat study to support a “consensus†statement that

was clearly

incorrect. And they and their colleagues have used it ever since to benefit

their clients in court.

So why are courts permitting physicians who have no experience treating mold

patients to testify that the ACOEM statement (written by 2 non-physicians

and 1 non-treating physician) is determinative of the issue of illness

causation? They shouldn’t. The courts have been fooled by words, words

issued under

the aegis of a trade organization that should have known better. Words that

many members of ACOEM now regret. Words that ACOEM will undoubtedly have to

retract if it is to regain credibility.

These words are “Levels of exposure in the indoor environment, dose-response

data in animals, and dose-rate considerations suggest that delivery by the

inhalation route of a toxic dose of mycotoxins in the indoor environment is

highly unlikely at best, even for the hypothetically most vulnerable

subpopulations.†Other words used include “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

…†(emphasis added). The only “evidence†referenced in the 3 authors’

ACOEM

statement for “dose-response data in animals, and dose-rate considerationsâ€

was the deeply flawed rat study. Moreover it was then taken out of context

and used in a way that its own authors specifically stated that it ought not

to be used. There is no scientific knowledge discussed.

* The simple truth is that mold illness is readily identified by

simple measures and readily available lab tests.

* Treatment according to published protocols is highly effective if a

correct diagnosis is made.

Mold illness is based on inflammation. We can measure the changes in

inflammation beginning rapidly after exposure and continuing until treatment is

instituted. Measures that help allergic conditions, including removal from

exposure, use of antihistamines and steroids are of no benefit in mold illness

without concomitant therapy for toxin-induced inflammatory cascades. Since

mold illness invokes inflammation from the innate immune response, and

antihistamines and steroids have nothing to do with the innate immune response,

we

wouldn’t expect those medications to help. And they don’t.

Now that we can identify the symptom clusters and laboratory abnormalities

found in hundreds of affected patients that separate them from thousands of

control patients, we don’t have to pay any more attention to biased,

self-serving statements from defense interests. So ends my comment on ACOEM’s

embarrassing and financially driven misadventure.

I am interested that Bardana M.D. and Kelman Ph.D. both reassured a nervous

American public the week of 9/23-9/37/05, telling all of us that the massive

mold growth in New Orleans homes with water damage from Hurricane Katrina wasn

’t a health problem at all. Our data from a screening clinic (attached)

held 2/9-2/12/06 shows the incidence of mold illness in 193 patients exceeds

50%. The Bush paper is already being used by the defense industry and their

attorneys because AAAAI has posted it. Innocent mold victims are already being

harmed. If you do not deny the AAAAI seal of approval to this paper, you will

lend support to defense interests that are trying to deny the reality of

mold illness and you will contribute to ongoing chronic illness in a large

number of people who are made ill by exposure to water-damaged buildings. If

you

require further time to make a determination on these issues, you must now

take down the paper and post an appropriate retraction and explanation to

prevent further harm. The fact that the AAAAI posted this paper on a public web

site shows considerable naiveté. I strongly suggest that my letter and any

other comments that you receive are circulated in full to your membership

through use of your website coupled with an email alert. ACOEM are in the

process

of being exposed for suffering a breakdown in their internal processes and I

would hope that AAAAI will not go down the same road.

Mold illness is readily diagnosed and readily treatable if caught early on.

I have included two papers our group has published in peer-reviewed

literature. The experimental design permits an assessment of prospective

exposure

that proves causation of illness by exposure to interior environments of

water-damaged buildings. I have not included the manuscript of our double

blinded,

placebo controlled crossover clinical trial that confirms benefit of

therapies and documents the role of innate immune response elements in mold

illness,

as we are still double-checking references. The paper will be finished in a

matter of days. I have included abstracts from two recent presentations our

group has made, the first being documentation of what physiologic

abnormalities are seen in 288 known adult cases of mold illness and 152

children with

mold illness compared to over 4000 controls; the second paper shows the

sequence of acquisition of physiologic abnormalities in 15 patients with

hyperacute

exposure to WDB with presence of known formers of trichothecenes.

I have also included a slide regarding IgE levels in my patients. Mold

illness as I see it in patients does not involve acquired immune responses and

it

is not allergy. Whenever I see someone discussing the pulmonary involvement

of patients with illness following exposure to WDB and I don’t hear the

discussant reviewing elevated levels of MMP9 or C4a and not discussing

deficiencies in MSH, VEGF and VIP, I know that the speaker has no first hand

insight

into the physiology of pulmonary involvement in mold illness. When I read that

the Institute of Medicine thinks that cytokines and genetics have something

to do with hypersensitivity pneumonitis, that’s true, they do, but to not

follow up those statements remains the single biggest failure of the IOM

statement. Once again, there is not one person on the IOM panel who has

presented

any data on treatment, not even a small cohort of 30 adults and 30 children

with mold illness.

Collaboration among defense consultants; deliberate exclusion of papers that

are “key†to proving mold illness parameter; recklessly wrongheaded

statements about illness causation; a complete lack of first-hand knowledge of

treatments; complete lack of any data on physiologic abnormalities in mold

patients – these all support my request that you reject the Bush paper as

academically unacceptable. This paper must be withdrawn.

The above statements are made to a reasonable degree of medical certainty.

I have no personal bias against any of the authors or supporters of the Bush

paper, but I do have strong feelings that persons in powerful positions of

trust are betraying academic integrity and our patients.

Sincerely,

Ritchie C. Shoemaker MD

Pocomoke, Md

As follows are several series of references used to support my opinions.

Fungal Articles

1. Kelk P, Claesson R, Hanstrom L, Lerner UH, Kalfas S, Johansson A.

Abundant secretion of bioactive interleukin-1b by human macrophages induced by

Actinobacillus actinomycetemcomitans leukotoxins. Inf and Immunol 2005;

73(1): 453-8.

2. Peltola J, Andersson MA, Haahtela T, Mussalo-Rauhamaa H, Rainey FA,

Kroppenstedt RM, Samson RA, Salkinoja-Salonen MS. Toxic-metabolite-producing

bacteria and fungus in an indoor environment. Appl Environ Microbiol 2001;

67(7): 3269-74.

3. Solfrizzo M, Visconti A, Avantaggiato G, A, Chulze S. In

vitro and in vivo studies to assess the effectiveness of cholestyramine as a

binding agent for fumonisins. Mycopathologia 2001; 151(3): 147-53.

4. -Ganser JM, White SK, R, Hilsbos K, Storey E, Enright PL,

Rao CY, Kreiss K. Respiratory morbidity in office workers in a water-damaged

building. Env Health Perspect 2005; 113(4): 485-90.

5. Gent JF, Ren P, Belanger K, Triche E, Bracken MB, Holford TR,

Leaderer BP. Levels of household mold associated with respiratory symptoms in

the

first year of life in a cohort at risk for asthma. Env Health Perspect 2002;

110(12): A781-92.

6. Jussila J, Komulainen H, Huttunen K, Roponen M, Livaninen E, Torkko

P, Kosma VM, Pelkonen J, Hirvonen MR. Mycobacterium terrae isolated from

indoor air of a moisture-damaged building induces sustained biphasic

inflammatory

response in mouse lungs. Env Health Perspect 2002; 110(11): 1119-25.

7. PC, SE, Hall AJ, Prentice AM, Wild CP. Modification of

immune function through exposure to dietary alfatoxin in Gambian children.

Env Health Perspect 2003; 111(2): 217-20.

8. Apostolakos MJ, Rossmoore H, Beckett WS. Hypersensitivity

pneumonitis from ordinary residential exposures. Env Health Perspect 2001;

109(9):

979-81.

9. Trout D, Bernstein J, ez K, Biagini R, Wallingford K.

Bioaerosol lung damage in a worker with repeated exposure to fungi in a

water-damaged building. Env Health Perspect 2001; 109(6): 641-4.

10. Brasel TL, DR, SC, Straus DC. Detection of

airborne Stachybotrys chartarum macrocyclic trichoecene mycotoxins on

particulates

smaller than conidia. Appl Env Microbiol 2005; 71(1): 114-22.

11. Romani L. Immunity to fungal infections. Imunol 2004; 4: 11-23.

12. Peltola J, Ritieni A, Mikkola R, Grigoriev PA, Poscfalvi G,

Andersson MA, Salkinoja-Salonen MS. Biological effects of Trichoderma

harzianum

peptaibols on mammalian cells. Appl Env Microbiol 2004; 70(8): 4996-5004.

Fungal/Inflammation

12/28/05

1. Gorny RL, Reponen T, Willeke K, Schmechel D, Robine E, Boissier M,

Grinshpun SA. 2002; 68 (7): 3522-3531. Applied and Environmental Microbiology.

Fungal fragments as indoor air biocontaminants.

2. Murtoniemi T, Nevalainen A, Hirvonen MR. Applied and Environmental

Microbiology. 2003;69 (7): 3751-3757. Effect of plasterboard composition on

Stachybotrys chartarum growth and biological activity of spores.

3. Nieminen SM, Karki R, Auriola S, Toivola M, Laatsch H, Laatikainen

R, Hyvarinen A, AV. Applied and Environmental Microbiology. 2002; 68

(10): 4871-4875. Isolation and identification of Aspergillus fumigatus

mycotoxins on growth medium and some building materials.

4. Engelhart S, Loock A, Skutlarek D, Sagunski H, Lommel A, Farber H,

Exner M. Applied and Environmental Microbiology. 2002; 68 (8): 3886-3890.

Occurrence of toxigenic Aspergillus versicolor isolates and sterigmatocystin in

carpet dust from damp indoor environments.

5. Shelton BG, Kirkland KH, Flanders WD, GK. Applied and

Environmental Microbiology. 2002; 68 (4): 1743-1753. Profiles of airborne fungi

in

buildings and outdoor environments in the United States.

6. Levetin E, Shaughnessy R, CA, Scheir R. Applied and

Environmental Microbiology. 2001; 67 (8): 3712-3715. Effectiveness of

germicidal UV

radiation for reducing fungal contamination within air-handling units.

7. RH, Ward E, McCartney HA. Applied and Environmental

Microbiology. 2001; 67 (6): 2453-2459. Methods for integrated air sampling and

DNA

analysis for detection of airborne fungal spores.

8. Vesper SJ, Vesper MJ. Infection and Immunity. 2002; 70 (4):

2065-2069. Stachylysin may be a cause of hemorrhaging in humans exposed to

Stachybotrys chartarum.

9. Kordula T, Banbula A, Macomson J, J. Infection and Immunity.

2002; 70 (1): 419-421. Isolation and properties of stachyrase A, a

chymotrypsin-like serine proteinase Stachybotrys chartarum.

10. Horner WE, Worthan AG, Morey PR. Applied and Environmental

Microbiology. 2004; 70 (11): 6394-6400.Air- and dustborne mycoflora in houses

free of

water damage and fungal growth.

11. Sebastian A, Larsson L. Applied and Environmental Microbiology.

2003; 69 (6): 3103-3109. Characterization of microbial community in indoor

environments: a chemical-analytical approach..

12. Pessi AM, Suonketo J, Penntti M, Kurkilahti M, Peltola K,

Rantio-Lehtimaki A. Applied and Environmental Microbiology. 2002; 68 (2):

963-967.Microbial growth inside insulated external walls as an indoor air

biocontamination

source.

13. Peltola J, Andersson MA, Haahtela T, Mussalo-Rauhamma H, Rainey FA,

Kroppenstedt RM, Samson RA, Salkinoja-Salonen MS. Applied and Environmental

Microbiology. 2001; 67 (7): 3269-3274. Toxic-metabolite-producing bacteria

and fungus in an indoor environment.

14. Brasel TL, AW, Demers RE, Ferguson BS, Fink J, Vojdani A,

SC, Straus DC. Archives of Environmental Health. 2004; 59 (6):

317-323 Detection of trichothecene mycotoxins in sere from individuals exposed

to

Stachybotrys chartarum in indoor environments..

15. Brasel TL, JM, Carriker CG, SC, Straus DC. Applied

and Environmental Microbiology. 2005; 71 (11): 7376-7388. Detection of airborne

Stachybotrys chartarum macrocyclic trichothecene mycotoxins in indoor

environment.

16. Brasel TL, DR, SC, Straus DC. Applied and

Environmental Microbiology. 2005; 71 (1): 114-122. Dectection of airborne

Stachybotrys

chartarum macrocyclic trichothecene mycotoxins on particulates smaller than

conidia.

17. Netea MG, Van der Meer JWM, Sutmuller RP, Adema GJ, Kullberg BJ.

Antimicrobial Agents and Chemotherapy. 2005; 49 (10): 3991-3996. From the

Th1/Th2 paradigm towards a Toll-like receptor/ T-helper bias.

18. Graaf CAAVD, Netea MG, Verschueren I, Meer JWMVD, Kullberg BJ.

Infection and Immunity. 2005; 73 (11): 7458-7464. Differential cytokine

production and Toll-like receptor signaling pathways by Candida albicans

blastoconidia

and hyphae.

19. A, Epps HLV, Hohl TM, Rizzuto G, Pamer EG. Infection and

Immunity. 2005; 73 (11): 7170-7179. Distinct CD4+-T-cell responses to live and

heat-inactivated Aspergillis fumigatus conidia.

20. McCann F, Carmona E, Puri V, Pagano RE, Limper AH. Infection and

Immunity. 2005; 73 (10): 6340-6349. Macrophage internalization of fungal

B-glucans is not necessary for initiation of related inflammatory responses.

Dr. Rand’s group

Flemming, J., B. Hudson and T.G. Rand. 2004. Comparison of inflammatory and

cytotoxic lung responses in mice after intratracheal exposure to spores of

two different Stachybotrys chartarum strains. Toxicological Sciences. In

Press.

Hastings, C.T. Rand, H.T. Bergen, J.A. Thliveris, A. Shaw, H.H. Mantsch and

J.E. . 2004. Stachybotrys chartarum alters surfactant-related

phospholipids synthesis and CTP: cholinephosphate cytidylytransferase activity

in

isolated fetal rat type II cells.

Toxicological Letters. In Press.

, L., D. Dearborn, J. Pestka and T.G. Rand. 2004. Localization of

satratoxin-G in Stachybotrys chartarum spores and spore-impacted mouse lung

tissues using immunocytochemistry. Toxicologic Pathology. 32(1): 26-34.

Yike, I., Rand, T., Walenga, R., and Dearborn, D. 2003. Acute inflammatory

responses to Stachybotrys chartarum in lungs of infant rats: time course and

possible mechanisms. Am. J. Respir. Critical Care Med. 167: A205-206.

Menzies, D., Popa, J., Hanly, J., Rand T.G., and Milton, D. 2003. Impact of

Germicidal ultraviolet Lights Installed in the Heating Ventilation and Air

Conditioning Systems of Office Buildings on Workers Health and Well Being.

Lancet. 362: 1885-1791.

, J.D., T.G. Rand and B.B. Jarvis. 2003. Stachybotrys chartarum:

cause of human disease or media darling? Medical Mycology. 41: 271-291.

L., T. G. Rand, D. Dearborn, I Yoke and S. Vesper. 2002.

Immunocytochemical localization of a hemolysins-like protein in Stachybotrys

chartarum

spores and spore-impacted mouse and rat lung tissues. Mycopathologia. 56:

77-85.

Rand, T.G., K. White, A. Logan and L. . 2002. Histological,

immunohistochemical and morphometric changes in lung tissue in juvenile mice

experimentally exposed to Stachybotrys chartarum spores. Mycopathologia. 56:

87-99.

Rand, T.G., M. Mahoney, K. White, M. Oulton. 2002. Microanatomical changes

associated with alveolar type II cells in juvenile mice exposed to

Stachybotrys chartarum and isolated toxin. Toxicological Sciences. 65:

239-245.

MaCrae, K.C., T.G. Rand, R.A. Shaw, C. Mason, M.R. Oulton, C. Hastings, T.

Cherlet, J.A. Thliveris, H.H. Mantsch, J. Mac, and J.E. . 2001.

Analysis of pulmonary surfactant by Fourier-transform infrared spectroscopy

following exposure to Stachybotrys chartarum (atra) spores. Chemistry and

Physics

of Lipids. 110 (1): 1-10.

Mason, C., T.G. Rand, M. Oulton, J. Mac. 2001. The effect of

Stachybotrys chartarum spores and an isolated trichothecene, isosatratoxin F,

on

convertase activity in mice. Toxicology and Applied Pharmacology, 172: 21-28.

Rand T.G. 2004. (In Press). Ecology of molds in building environments. In.

American Industrial Hygiene Association Field Guide for the Determination

of Biological Contamination in Environmental Samples (eds. K. Dillon, P.

Heinsohn, D. ). AIHA Press. Washington, D.C.

Rand, T. G. 2004. Fungi associated with aquatic animals. In G. M.

Mueller, G.F. Bills, and M. S. (eds.), Biodiversity of Fungi, Inventory

and

Monitoring Methods. Academic Press, Toronto.

Rand, T.G. 2000. Diseases of Animals. In Marine Mycology – A Practical

Approach. (eds. K.D. Hyde and S.B. Pointing). Fungal Diversity Research

Series

1, Fungal Diversity press, Hong Kong. Pp. 21-48.

Taboski, M.A.S., T. G. Rand and A. Piorko. 2004. Lead and cadmium uptake in

the marine fungi Corollospora lacera and Monodicyts pelagica. FEMS

Microbiology Ecology.

Hudson, B., Flemming, J., and T.G. Rand. 2004. Comparison of early

inflammatory and cytotoxic lung tissue and BALF responses in mice exposed to

Stachybotrys chartarum spores using quantitative PCR. Clinical and

Experimental

Allergy.

Moser, S., Flemming, J., B. Hudson, J.E. and T.F. Rand. 2004. Alveolar

surfactant surface tension is degraded by Stachybotrys chartarum spore

exposures. American Journal of Physiology. (Lung Cellular and Molecular

Physiology).

Poirrier, L. K. and T. G. Rand 2004. Ultrastructural and morphometric

changes associated with alveolar capillary walls in Stachybotrys chartarum

spore-impacted juvenile mouse lung tissues. Mycopathologia.

____________________________________

_[1]_ (aoldb://mail/write/template.htm#_ftnref1) Shoemaker RC, Rash JM, Simon

EW, pg 66-77, in Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health,

ed by E Johanning; 5/05. Sick Building Syndrome in water-damaged buildings:

generalization of the chronic biotoxin-associated illness paradigm to

indoor toxigenic fungi; Shoemaker RC and House D, Neurotoxicology and Teratology

2005; 27 (1): 29-46. A time series study of sick building syndrome: chronic,

biotoxin associated illness from exposure to water-damaged buildings.

_[2]_ (aoldb://mail/write/template.htm#_ftnref2) Nobel Winner 1905 – he

theorized that all four of his postulates must be fulfilled in order to

establish

a causal relationship between a _parasite_

(http://en.wikipedia.org/wiki/Parasite) and a _disease_

(http://en.wikipedia.org/wiki/Disease) . He applied

these to establish the _etiology_ (http://en.wikipedia.org/wiki/Etiology) of

_anthrax_ (http://en.wikipedia.org/wiki/Anthrax) and _tuberculosis_

(http://en.wikipedia.org/wiki/Tuberculosis) , but they have been generalized to

other

diseases.