***********************************************************

http://groups.yahoo.com/group/aspartameNM/message/1156
autism linked to mercury from power plants in Texas, Raymond F Palmer et al,
Health and Place 2005: Toxicant-Induced Loss of Tolerance, Claudia S Miller
1997 March, full plain text: Murray 2005.03.19 rmforall

[ Comments by Rich Murray:
"On average, for each 1000 lb of environmentally released mercury, there was
a 43% increase in the rate of special education services and a 61% increase
in the rate of autism."
The 2003 study by RF Palmer and CS Miller, linking mercury from Texas power
plants and autism, is a seminal breakthrough.
I also give the full text of the classic research paradigm, given by CS
Miller in 1997, for successful studies on environmental illnesses, which
must have major implications for research on aspartame (methanol,
formaldehyde, formic acid) toxicity. ]

From: "Gary Greenberg" <Gary.Greenberg@...>
To: <Occ-Env-Med-L@...>
Subject: ENN Houston Chron: Autism from Environmental Hg, Power Plants
Date: Friday, March 18, 2005 9:11 PM

------------------- Information from the mail header -----------------

Sender: Occupational & Environmental Medicine for Clinicians & Public
Health Professionals <Occ-Env-Med-L@...>
Poster: Gary Greenberg <Gary.Greenberg@...>
Subject: ENN Houston Chron: Autism from Environmental Hg, Power Plants
----------------------------------------------------------------------------


Gary N. Greenberg, MD MPH Sysop / Moderator Occ-Env-Med-L MailList
gary.greenberg@... Duke Occupat, Environ, Int & Fam Medicine
OEM-L Maillist Website: http://occhealthnews.net
***********************************************************

http://www.enn.com/today.html?id=7359

Study Links Mercury from Power Plants to Autism

March 18, 2005 - By Todd Ackerman, Houston Chronicle

todd.ackerman@...

After years of debate about whether a nationwide explosion in autism is
related to a mercury-based preservative used in vaccines, Texas researchers
have found a new suspect: mercury from coal-burning power plants.

In a new study, scientists at the University of Texas Health Science Center
at San Antonio are reporting a strong correlation between higher mercury
release levels and the developmental disorder marked by communication and
social interaction problems.

"This is a preliminary study that needs further study but suggests there is
a link," said Raymond F. Palmer, an associate professor in the UT-San
Antonio's department of family and community medicine and the study's lead
author. "If corroborated, it would have pretty severe implications for
policy."

Palmer called the study the first to examine the relationship between
potentially chronic, low-dose exposure to mercury and developmental
disorders such as autism. He stressed it does not prove causation.

The study, to be published in an upcoming edition of the journal Health and
Place and already online, looked at 254 counties and 1,200 school districts
in Texas, comparing 2001 mercury emission levels with rates of autism and
special education services.

Using statistical modeling, Palmer's team found a 17 percent increase in
autism rates for every 1,000 pounds of mercury released.

About 48 tons of mercury are released in the air annually in the United
States from hundreds of coal-burning plants. Texas plants release more than
those in any other state.

The study was undertaken amid uncertainty about a dramatic increase in
autism. Once thought to occur in 1 of every 10,000 children, today it is
estimated to afflict as many as 1 in 250.

The still poorly understood disorder has a strong genetic component, but the
increase in cases has fueled theories the environment is playing a role. To
some, mercury, a neurotoxin that affects the brain, spinal cord, kidneys and
liver, made logical sense.

Suspicion initially fell upon vaccines, many of which use thimerosal, a
mercury-based preservative. During the period reported autism rates grew,
U.S. health authorities expanded the shots given to children, causing many
parents to suspect the vaccine. But no proof was ever found; and last year,
a controversial Institute of Medicine report concluded there is no causal
link.

Dr. Sarah Spence, medical director of the UCLA Autism Evaluation Clinic,
called the UT-San Antonio study "very interesting." She noted that the
mercury released by power plants has known toxic effects on humans, whereas
that's still speculative in the kind of mercury used in vaccines.

"If the statistical modeling in the study is accurate, it's an important
first step," said Spence. "Proving causation would provide important
information to both researchers and clinicians, who know people receiving
treatment to remove mercury."

Susan West Marmagas, director of the Washington, D.C.-based Physicians for
Social Responsibility's environment and health program, called the study
"the kind of research the scientific community needs to better evaluate the
potential links between mercury and autism," but said she would need to
confer with experts before commenting further.

Palmer said his next step will be to look at associations between mercury
emissions and autism rates over time, about 15 years. He will start with
Texas data, then compare that to national numbers.

"If this study is corroborated, I would hope it leads to reductions, just as
studies led to reductions in lead," said Palmer.

The Bush administration Tuesday ordered power plants to cut mercury
pollution from smokestacks by nearly half within 15 years. Environmentalists
complained that the order fell short of what was needed.

A New Culprit

Texas researchers are reporting an alternative to the theory that the
mercury in vaccines is related to the explosion of autism -- mercury
released by coal-burning power plants.

--The increase: Once thought to occur in 1 of every 10,000 children, autism
today is estimated to afflict 1 in 250.

--Suspected cause: Mercury is a neurotoxin that affects the brain, spinal
cord, kidneys and liver. It is released by coal-burning power plants.

--The study numbers: A University of Texas Houston Health Science Center at
San Antonio study found a 17 percent increase in the autism rate for every
1,000 pounds of mercury released into the environment.

Source: Knight Ridder/Tribune Business News
***********************************************************

Sarah Jane Spence, MD, PhD
Assistant Professor in Residence, UCLA Department of Psychiatry &
Biobehavioral Sciences
UCLA Center for Autism Research and Treatment, UCLA Neuropsychiatric
Institute, and Mattel Children's Hospital at UCLA, David Geffen School of
Medicine, Los Angeles, CA, USA.
Medical Director UCLA Autism Evaluation Clinic
Medical Director of the Autism Genetic Resource Exchange (AGRE)

Semin Pediatr Neurol. 2004 Sep; 11(3): 196-204.
The genetics of autism.
Spence SJ. PMID: 15575414

Autism Genetic Resource Exchange Cure Autism Now
5455 Wilshire Blvd., Suite 715, Los Angeles, CA 90036-4234
1-323-931-6577 fax: 1-323-549-0547 info@...
http://www.cureautismnow.org/
888-828-8476 (323) 549-0500 (323) 549-0547 (fax)

Sophia Colamarino Science Director Ext. 26
scolamarino@...
***********************************************************

http://www.sciencedirect.com/science/journal/13538292
doi:10.1016/j.healthplace.2004.11.005
Copyright © 2005 Published by Elsevier Ltd.

Environmental mercury release, special education rates, and autism disorder:
an ecological study of Texas

Raymond F. Palmer a Corresponding author. Tel.: +210 358 3883
palmerr@...

Steven Blanchard b, Associate Professor, Sociology; BA University of
Houston; MPH University of Texas School of Public Health; PhD University of
Texas at Austin

Zachary Stein a,

David Mandell c mandelld@...

and Claudia S. Miller a http://www.uthscsa.edu/faculty/millerc.html
millercs@...
Claudia Miller, M.D. Assistant Professor and Director, STEER
South Texas Environmental Education and Training
Department of Family Practice Location: BCT, Suite 150
Phone: (210) 567-7763 Fax: ÝÝÝÝÝ (210) 567-7764

Research Interests:
Environmental health, especially South Texas, Occupational health, Chemical
sensitivity, Indoor air pollution, Health effects of low level chemical
exposure, Neurotoxicology (pesticides, volatile organics), Limbic
sensitization, Cholinergic sensitivity

Unique Technical and Clinical Research Capabilities/Instrumentation:
Health survey instrument (questionnaire) for sick buildings, changes in
health after a chemical exposure, etc.

Publications:

Ashford NA, Miller CS: Chemical Exposures: Low Levels and High Stakes.
Second edition. New York, Van Nostrand-Reinhold, 1997.

Miller CS: Toxicant-induced loss of tolerance: an emerging theory of
disease? Environmental Health Perspectives. 105(2): 445-453, March, 1997.

Miller CS, Ashford NA, Doty R, Lamielle M, Otto D, Rahill A, Wallace L:
Empirical approaches for the investigation of toxicant-induced loss of
tolerance.
Environmental Helath Perspectives. 105(2): 515-519, March, 1997.

Miller CS: Chemical sensitivity: Symptom, syndrome or mechanism for disease?
Toxicology 111: 69-86, 1996.

Overstreet DH, Miller CS, Janowsky DS, Russell RW: A potential animal model
of multiple chemical sensitivity with cholinergic supersensitiviy.
Toxicology 111: 119-134, 1996.

a University of Texas Health Science Center, San Antonio Department of
Family and Community Medicine, 7703 Floyd Curl Drive, San Antonio, Texas
78229-3900, USA

b Department of Sociology, Our Lady of the Lake University, San Antonio,
Texas, USA

c Department of Psychiatry, Center for Mental Health Policy and Services
Research, University of Pennsylvania School of Medicine, Philadelphia 19104

Accepted 1 November 2004. Available online 17 February 2005. $ 30

Abstract

The association between environmentally released mercury, special education
and autism rates in Texas was investigated using data from the Texas
Education Department and the United States Environmental Protection Agency.
A Poisson regression analysis adjusted for school district population size,
economic and demographic factors was used.
There was a significant increase in the rates of special education students
and autism rates associated with increases in environmentally released
mercury.
On average, for each 1000 lb of environmentally released mercury, there was
a 43% increase in the rate of special education services and a 61% increase
in the rate of autism.
The association between environmentally released mercury and special
education rates were fully mediated by increased autism rates.
This ecological study suggests the need for further research regarding the
association between environmentally released mercury and developmental
disorders such as autism.
These results have implications for policy planning and cost analysis.

Keywords: Mercury; Special education; Autism; Environmental toxins;
Ecological
***********************************************************

http://www.tldp.com/issue/210/toxicantin.htm

Toxicant-Induced Loss of Tolerance - An Emerging Theory of Disease?
by Claudia S. Miller Department of Family Practice
The University of Texas Health Science Center, San Antonio, Texas

Reprinted from Environmental Health Perspectives, Vol. 105, Supplement 2,
March 1997

This paper attempts to clarify the nature of chemical sensitivity by
proposing a theory of disease that unites the disparate clinical
observations associated with the condition.
Sensitivity to chemicals appears to be the consequence of a two-step
process:
loss of tolerance in susceptible persons following exposure to various
toxicants, and subsequent triggering of symptoms by extremely small
quantities of previously tolerated chemicals, drugs, foods, and food and
drug combinations including caffeine and alcohol.
Although chemical sensitivity may be the consequence of this process, a term
that may more clearly describe the observed process is toxicant-induced loss
of tolerance.
Features of this yet-to-be-proven mechanism or theory of disease that affect
the design of human exposure studies include the stimulatory and
withdrawal-like nature (resembling addiction) of symptoms reported by
patients and masking.
Masking, which may blunt or eliminate responses to chemical challenges,
appears to have several components:
apposition, which is the overlapping of the effects of closely timed
exposures, acclimatization or habituation,
and addiction.
A number of human challenge studies in this area have concluded that there
is no physiological basis for chemical sensitivity.
However, these studies have failed to address the role of masking.
To ensure reliable and reproducible responses to challenges, future studies
in which subjects are evaluated in an environmental medical unit, a
hospital-based facility in which background chemical exposures are reduced
to the lowest levels practicable, may be necessary.
A set of postulates is offered to determine whether there is a causal
relationship between low-level chemical exposures and symptoms using an
environmental medical unit.
Environ Health Perspect 105(Suppl 2): 445-453 (1997)

Key words: adaptation, chemical sensitivity, masking, multiple chemical
sensitivity, sensitivity, sensitization, tolerance, addiction, habituation

Introduction

Clinical observations in North America (1-7) and Europe (8) point to an
expanding group of patients who report sensitivities to extraordinarily low
levels of environmental chemicals. This phenomenon, termed chemical
sensitivity or multiple chemical sensitivity, appears to develop de novo in
some individuals following acute or chronic exposure to a wide variety of
environmental agents including various pesticides, solvents, drugs, and air
contaminants in so-called sick buildings. Some practitioners have attributed
a broad spectrum of chronic medical conditions involving any and every organ
system to chemical sensitivity (Figure 1). (4)

Efforts to formulate a case definition for chemical sensitivity, to identify
relevant biomarkers, and to explore a variety of mechanisms for the
condition have escalated over the past decade. Several conflicting schools
of thought have evolved with respect to underlying mechanisms, ranging from
the purely psychological to the wholly physiological. In the midst of the
tumult surrounding chemical sensitivity lies a profound but
little-recognized scientific debate concerning the origins of disease. Some
participants in this debate are challenging currently accepted notions
concerning the causes for many chronic illnesses.

This paper attempts to clarify the nature of chemical sensitivity by
describing a general mechanism that appears to underlie these cases;
proposes a theory of disease based upon this general mechanism; and offers a
set of testable postulates for corroborating or refuting this theory.
Science is not about opinion or belief; it is about "guess and test," that
is, formulating hypotheses and then devising experiments to test them.

Terminology

Phenomenologically, chemical sensitivity appears to develop in two stages.
(3,4)
First is the loss of tolerance (possibly but not necessarily due to
sensitization) following acute or chronic exposure to various environmental
agents such as pesticides, solvents, or contaminated air in a sick building.
Second is the subsequent triggering of symptoms by extremely small
quantities of previously tolerated chemicals, drugs, foods, and food and
drug combinations (Figure 2). Although sensitivity to chemicals may be one
of the consequences of this two-stage process, the term chemical sensitivity
does not appropriately describe the process involved.

There are two principal reasons for this. First, although chemical
sensitivity certainly sounds like an inconvenient problem to have, the words
fail to convey the potentially disabling nature of the condition and its
postulated origins in a toxic exposure. Some researchers balk at using the
word toxic in this manner. However, numerous investigators from different
geographic regions have published strikingly similar descriptions of
individuals who report disabling illnesses after exposure to recognized
environmental contaminants, albeit at levels not generally regarded as
toxic. (1,9-12) Yet, for these individuals, the exposure appears to have
been toxic.
Paracelsus aptly opined that dose makes the poison. However, as our
knowledge has grown, it has become evident that dose + host makes the poison
(for example, pack-years of smoking plus a-1-antitrypsin deficiency).

Similarly, in the case of chemical sensitivity, not everyone exposed in a
sick building or to a chemical spill develops chronic illness. Thus, it may
be concluded that individual susceptibility, whether physiological or
psychological, must play a role in determining who gets sick. The term
chemical sensitivity fails to convey this key observation that chemical
exposures appear to initiate a process that results in chemical sensitivity.
Conceivably, this phenomenon could represent a new type of toxicity.

The second problem with the term chemical sensitivity, is that it suggests
that those afflicted become intolerant of chemical exposures only when, in
fact, caffeine, alcoholic beverages, various drugs, and foods reportedly
trigger symptoms in these individuals once the process has been initiated.
(4,12-15) For the above reasons, chemical sensitivity is a misnomer for the
process under discussion. An alternative term, toxicant-induced loss of
tolerance (TILT), has been proposed. (16) This term offers several
advantages.
First, it describes the process as it has been observed by clinicians and
patients.
Second, it allows for the possibility that various toxicants may initiate
the process. Third, it does not limit the resulting intolerance to
chemicals.
Finally, it sharpens the focus of the current debate over chemical
sensitivity by positing a theory of disease that can be subjected to
objective testing.

Historically, new theories of disease arose when physicians observed
patterns of illness that did not fit accepted explanations for disease at
that time, for example, the germ theory or the immune theory of disease.
Similarly, many of the illnesses under discussion here do not conform to
current accepted explanations for disease or toxicity. Objections to the
concept of chemical sensitivity have included concerns that:
too many different chemicals have been said to cause chemical sensitivity;
patients report too many symptoms involving any and every organ system;
no known physiological mechanism explains chemical sensitivity;
no biomarker has been identified for chemical sensitivity;
and total avoidance of chemicals is impractical.

Theories of disease attempt to explain what is going on inside the patient
(a "black box") before overt illness, as illustrated below:

A theory of disease is a yet-to-be-established, general mechanism for a
class or family of diseases.

For the germ theory of disease, the boxes depicting the general mechanism of
infection would look something like this:

Note that many different kinds of germs cause responses;
there are many different responses involving any and every organ system
(skin, respiratory, gastrointestinal);
specific mechanisms vary greatly - for example, cholera versus AIDS versus
shingles;
there is no single biomarker - identification of specific germs took years;
and prevention (avoidance, antiseptics, sanitation, use of gloves) preceded
knowledge of specific mechanisms.

For the immune theory of disease, the boxes might look like this:

Here, just as for the germ theory of disease:
many different kinds of antigens cause responses;
there are many different responses involving any and every organ system
(skin, respiratory, gastrointestinal);
specific mechanisms vary greatly - for example, poison ivy versus allergic
rhinitis versus serum sickness;
there is no single biomarker - identification of specific antibodies took
years;
and prevention (avoidance, allergy shots) preceded knowledge of
specific mechanisms.

For toxicant-induced loss of tolerance, the boxes might look like this:

For toxicant-induced loss of tolerance,
as for the germ and immune theories of disease:
many different kinds of chemicals may cause responses;
there may be many different responses involving any and every organ system;
specific mechanisms may vary greatly;
it is conceivable that there is no single biomarker for response -
identification of biomarkers may take years;
and prevention (avoidance of initiators or triggers) may precede knowledge
of specific mechanisms.

Although the concept 'loss of tolerance' may sound vague, in fact it is not.
What these individuals report is a loss of specific tolerance to particular
chemicals, foods, and drugs. (16) Note that this theory does not exclude
the possibility that toxicant-induced loss of tolerance could turn out to be
a special kind of toxicity or a variation on the immune theory of disease
just as allergy and delayed-type hypersensitivity are special cases that
fall under the general classification of immunologic disorders.

A consequence of viewing TILT as a theory of disease would be a shift in
perspective from chemical sensitivity as a syndrome to chemical sensitivity,
now TILT, as a class of disorders parallel to infectious diseases or
immunologic diseases. Much effort has been devoted to developing a case
definition for chemical sensitivity, with a singular lack of success. This
lack of success would not be surprising if in fact TILT represented a new
class or family of disorders. Certainly, it would not be feasible to develop
a single clinical case definition that would embrace all infectious or all
immunologic diseases.

Theories of disease that withstand scientific scrutiny arise infrequently.
The past century has witnessed the inculcation of the germ and immune
theories of disease into medical practice. Equating toxicant-induced loss of
tolerance to either one of these theories, both of which have been widely
corroborated, would be premature and presumptuous. On the other hand,
toxicant-induced loss of tolerance has certain earmarks of an emerging
theory of disease, including the vituperative professional disputes that
surround it. (16)

Features of TILT Relevant for Its Testing

As described by many investigators, this phenomenon appears to involve a
two-stage process. Because of ethical considerations, the first stage
(initiation) is more difficult to model in humans than the second stage
(triggering). Ultimately, epidemiologic studies and animal models may
elucidate the first stage.

Fortunately, the second stage readily lends itself to testing via direct
human challenges, a potent form of scientific evidence. However, in the
design of human challenge studies in this area, certain key clinical
observations must be taken into account.
First, the commonly reported biphasic, stimulatory-and-withdrawal-like
pattern of the patients' symptoms, particularly those symptoms involving the
central nervous system, must be understood to perform meaningful test
challenges on these patients.
Second, a related phenomenon called masking (to be described further) may
hide responses to low-level chemical challenges and therefore may need to be
minimized before testing. Controlling masking may be analogous to
controlling background noise in studies on sound.

The following sections will discuss these clinical features, their
incorporation in experimental designs, and how failure to do so might
threaten research outcomes.

Stimulatory and Withdrawal Symptoms

Randolph first described the time course of the responses of these
individuals to chemicals and foods. (17) He reported striking parallels
between their symptoms and those associated with alcohol and drug addiction.
Randolph viewed the food and caffeine addictions his patients exhibited as
the bottom rungs in a hierarchy of addiction, proceeding from foods and food
and drug combinations such as caffeine and alcohol on the lower rungs upward
to nicotine and other naturally occurring and synthetically derived drugs.
(14)

Chemically sensitive patients resemble drug addicts in that members of both
groups often report intense cravings and debilitating withdrawal symptoms.
However, chemically sensitive patients' responses are not primarily to
drugs. These individuals more commonly report addictions to caffeine or
certain foods. While drug addicts manifest ad-dicted behaviors (Latin ad
"toward" + dicare "proclaim"), chemically sensitive patients respond as
though they were ab-dicted (Latin ab "away from" + dicare "proclaim") and
assiduously avoid the very substances addicted persons favor, including
alcohol, drugs and nicotine.

The stimulatory and withdrawal symptoms reported by chemically sensitive
patients are frequently identical to those reported by normal persons
exposed to much greater amounts of the same substances.

For example, after drinking one cup of coffee, chemically sensitive patients
may report feeling hyperactive, jittery, talkative, nervous, anxious, or
experiencing panic-like symptoms (stimulatory phase).
Hours to days later, they may report withdrawal symptoms such as fatigue,
yawning, confusion, indecisiveness, irritability, depression, loss of
motivation, blurred vision, headaches, flulike symptoms, hot or cold spells,
or heaviness in their arms and legs (withdrawal phase).
Similar symptoms occur during caffeine withdrawal among some low-to-moderate
caffeine users in the general population. (18)

Large numbers of chemically sensitive patients and many Gulf War veterans
with unexplained illnesses report that one drink of an alcoholic beverage
causes inebriation and/or a severe hangover. (12,15,19) These augmented
responses suggest that those afflicted have lost their previous natural or
native tolerance for such exposures.

Early in their illnesses, before eliminating caffeine from their diets, many
chemically sensitive patients report having consumed chocolate, coffee, tea,
or cola addictively, often in very large quantities. (15) Some carried
large containers of coffee or tea around wherever they went. Many report
later stopping use of all caffeine and xanthines, generally on the advice of
a friend or physician, and subsequently experiencing several days of intense
withdrawal symptoms. Frequently they report that it was only after
eliminating all xanthines from their diets that they were able to discern
the effects of consuming a single cup of coffee or a chocolate bar. Most
report becoming aware of the unpleasant effects of caffeine only after a
trial of partial or complete caffeine avoidance.

In this regard, chemically sensitive patients resemble certain reformed
smokers or alcoholics who after quitting their addictants report extreme
sensitivity to minute amounts of the addicting agents. Terms like addiction,
withdrawal, and detox pepper the vocabulary of chemically sensitive
patients. One patient described the condition as being "like drug abuse
without any of the fun." These parallels to addiction provide perspective:
they may help explain why the mechanisms that underlie chemical sensitivity
have been difficult to define and why biological markers have proven
elusive.

In summary, drug addiction and TILT share a number of features in common.
TILT also has features reminiscent of toxicity and allergy (Table 1).
However, it is its resemblance to addiction that is perhaps most striking
and that has escaped the attention of many physicians and researchers.

Masking

Suppose that TILT was a mechanism underlying certain cases of chronic
fatigue, migraine, asthma, or depression. It might be reasonable to wonder,
then, why patients experiencing these symptoms do not also report chemical
intolerances.

In fact, some but not all patients do report them. (21,22) Many chemically
sensitive patients with these same diagnoses report that it was not until
they accidentally or intentionally avoided a sufficient number of their
problem incitants that they noticed feeling better.
Then, when they reencountered one of those incitants, robust symptoms
occurred. As they repeated this iterative process of avoidance and
reexposure, they noticed that particular symptoms occurred with particular
exposures.
Most indicate that had they not avoided many chemicals and foods
simultaneously, or unmasked themselves, they might not have determined what
was making them sick.

Masking and unmasking are colorful lay terms for which there is no
scientific equivalent. Nevertheless, investigators' abilities to understand
masking and unmasking and manipulate these variables knowledgeably may
determine the success of studies in this area. When chemically sensitive
patients follow a diet free of their problem foods and live in a relatively
chemical-free home in the hills of central Texas where there are no major
agricultural or industrial operations or air contaminants, they say they are
in an unmasked state. Under these circumstances they claim that if a diesel
truck drove by they could identify specific symptoms due to the diesel
exhaust, for example, irritability, headache, or nausea.

On the other hand, the patients report that when they travel to a large city
like Houston or New York City, stay in a hotel room, and eat in restaurants,
they become masked. In the presence of many concurrent exposures (exhaust,
fragrances, volatiles offgassing from building interiors, various foods) in
New York City many report feeling chronically ill, as if they had flu.

If a diesel truck drove by under these circumstances, most report they would
not be able to attribute any particular symptoms to the exhaust because of
background noise from overlapping symptoms occurring as a consequence of
overlapping or successive exposures. In theory, such background noise or
masking, hides the effects of individual exposures - responses are blurred.

Masking appears to involve at least three interrelated components, any of
which may interfere with the outcome of low-level chemical challenges in
these individuals: acclimatization, apposition, and addiction.

In real life, these three components probably operate concurrently, although
here they are considered individually.
There is some notation that can be used to help depict these components. In
the addiction literature, responses to addictive drugs are often illustrated
graphically using a biphasic curve or sine wave (Figure 3).
The portion of the sine wave above the horizontal axis represents symptoms
with onset of exposure, often called stimulatory symptoms;
the portion below the horizontal axis represents symptoms with offset or
cessation of exposure, often referred to as withdrawal symptoms.
The height or amplitude of the sine wave in either direction is proportional
to the severity of the response.
For persons not sensitive to a particular substance, the curve would be a
flat line with zero amplitude in either direction.
The length of the biphasic curve represents the duration of symptoms
following an exposure, reportedly ranging from minutes up to several days
depending upon the exposure and the individual.
Of course, the particular nature of the symptoms vary from one sensitive
subject to the next and from substance to substance.

Suppose researchers wished to test a putatively sensitive subject by
exposing him to a low concentration of xylene. Xylene is a common indoor air
contaminant and a component of Molhave's mixture (23) that has been used in
human inhalation challenge studies. How would the researchers ensure that
their subject was unmasked (at true baseline) before challenge?

The following components of masking would need to be considered and
controlled:

Acclimatization.

For most of the population, with continuous or repeated exposure to many
environmental stressors, adaptation occurs. That is, symptoms diminish as
exposure continues. Chemically sensitive patients' symptoms also decrease
with continuing exposure; however, when exposure ceases, these individuals
often report marked withdrawal symptoms. Thus, what they describe is more
akin to habituation than to adaptation. Suppose further that the subject who
is challenged with xylene works in a sick building where he is routinely
exposed to low levels of xylene on a regular basis. Administering a test
exposure of xylene below the odor threshold (0.62 ppm) (24) may produce
little or no effect on the subject if he has been working in that same
building during the preceding week (Figure 4). On the other hand, if he
avoided the building and all other sources of xylene for 4 to 7 days before
testing, a more robust response to the xylene challenge might be
anticipated.

Thus, a sensitive subject's response to a challenge may range widely in
intensity, from none to maximal, depending on how recently that person has
been exposed to the test substance or a chemically related substance. If
insufficient time has elapsed, for example, less than 4 days, the challenge
may yield a false negative response as a result of habituation. If too much
time has elapsed, for example, weeks or months, sensitivity may have waned.

Apposition.

Suppose next that the research subject is sensitive to multiple substances.
On the day he is scheduled for challenge testing, he gets up in the morning,
uses some scented soap or hair spray, cooks breakfast on a gas stove, and
drives his car through heavy traffic to reach the laboratory. Inside the
laboratory building he rides an elevator where he is exposed to people
wearing various colognes. If he were sensitive to several of these
exposures, his responses might overlap in time. Such responses reportedly
can last for hours or days. If this is true, they could persist during a
placebo challenge, resulting in a false positive response. Thus, apposition
or juxtaposition of the effects of closely timed exposures is a second
component of masking that must be controlled prior to and during challenge
studies (Figure 5).

Addiction.

Many of the symptoms reported by chemically sensitive patients mirror those
commonly associated with addiction. Addiction may be a component of masking.
Addicted individuals consciously or subconsciously time their next "hit" so
as to forestall withdrawal symptoms (Figure 6), a phenomenon that occurs in
alcohol, tobacco, and caffeine addictions. However, addiction to foods also
is reported among chemically sensitive patients. Randolph described wheat,
eggs, milk, and corn as the most common addictants in his patients.(14,17)
Frequently these individuals report intense cravings and consume astounding
quantities of foods, for example, a pound of chocolate, several bags of
popcorn, a dozen doughnuts, or 30 cups of coffee in one day. Patients most
often report this kind of addictive consumption in the early stages of their
illness, before they practiced avoiding problem exposures.

Foods may contain bioactive constituents such as tyramine, monosodium
glutamate, and opiates.(13)

Persons who routinely use tobacco, caffeine, alcohol, or foods containing
bioactive substances may need to avoid these substances before testing
because the pharmacologic effects of these agents could override or mask the
effect of an experimental challenge. Failure to eliminate addictants before
testing could result either in false positive challenges due to lingering
symptoms from an addictant used in the hours or days preceding a placebo
challenge or in false negative challenges due to masking by an addictant.

Testing the TILT Theory

After the germ theory of disease was introduced in the late 1800s, many
overly enthusiastic investigators who were careless in their bacteriological
techniques announced they had discovered causative agents for tuberculosis,
yellow fever, and other diseases. These pronouncements and subsequent
retractions became so frequent that in 1884 the President of the New York
Academy of Medicine lamented that a bacteriomania had swept over the medical
profession. (25)

To prevent future such pseudodiscoveries, Robert Koch, who identified the
organisms responsible for tuberculosis, anthrax, and cholera, proposed a set
of rules for etiological verification. His postulates required that:
the microbe must present in every case of the disease;
it must be isolatable in pure culture;
inoculating a healthy animal with the culture must reproduce the disease;
and the microbe must be recoverable from the inoculated animal and be able
to be grown again.

Just as bacteriomania engulfed the medical profession in the 1880s,
chemomania is poised to engulf it now. Chemical sensitivity is in need of a
set of postulates to ensure that future causal determinations are
scientifically based. Below is a set of postulates that, if met, would
confirm (and if not met, refute) that a person's symptoms were caused by a
particular substance:

* When a subject simultaneously avoids all chemical, food and drug
incitants, remission of symptoms occurs (unmasking).

* A specific constellation of symptoms occurs with reintroduction of a
particular incitant.

* Symptoms resolve when the incitant is again avoided.

* With reexposure to the same incitant, the same constellation of symptoms
reoccurs, provided that the challenge is conducted within an appropriate
window of time. Clinical observations suggest that an ideal window is 4 to 7
days after the last exposure to the test incitant.

To apply these postulates (illustrated in Figure 7), the timing of exposures
and the degree of masking should be rigorously controlled. To accomplish
this, a hospital-based clinical research facility, an EMU, is needed to
isolate subjects from background exposures (Figure 8). (4,5,15,16,26) The
EMU would be constructed, furnished, and operated to minimize exposure to
airborne chemicals.

For example, no disinfectants, perfumes, or pesticides would be allowed in
the unit. Ventilation would maximize fresh outside air and provide optimal
particulate and gas filtration. Patients would eat chemically
less-contaminated foods and water, testing one food per meal to determine
the effects of specific foods. If symptoms persisted despite this approach,
fasting for a few days would be attempted before reintroducing single foods.

The rationale for housing subjects in an environmentally controlled facility
for several days before challenges is 2-fold: to prevent extraneous exposure
of patients to inhalants or ingestants so responses to them are not
misinterpreted as positive responses when placebo challenges are
administered (false positives),
and to minimize masking that might blunt or eliminate responses to active
challenges (false negatives).

Although the terms exposure chamber and environmental medical unit appear
similar, conceptually they differ in important ways with regard to patient
safety and control of interfering exposures.

By definition, an EMU is in a hospital where patients can remain 24 hr a day
in a clean environment for up to several weeks. Like an intensive care unit
or coronary care unit, the EMU would be a specialized, dedicated hospital
facility. The EMU must be in a hospital to accommodate very sick patients;
exposure chambers do not offer comparable levels of care. Because chemical
challenges may precipitate bronchoconstriction, mental confusion, severe
headaches, depression, and other disabling symptoms, these patients should
not be tested in an exposure chamber on an outpatient basis.

Conventional exposure chambers do not reduce background chemical exposures
for extended periods (up to several weeks) so the effects of a particular
challenge in a patient can be assessed accurately. This is the central
limitation of exposure chambers and the reason they should not be used to
rule in or rule out chemical sensitivity. If subjects are not kept in a
clean environment for several days before and during challenges, false
positive responses may occur because of interfering exposures and false
negative responses may occur because of masking. In contrast to an exposure
chamber, an EMU would minimize interfering exposures before and during
challenges, thus maximizing the reliability and reproducibility of test
responses.

Availability of an EMU would allow physicians to refer a wide variety of
cases in which environmental sensitivities were suspected to the unit for
definitive evaluation. There physicians could observe first-hand whether a
patient's symptoms improved after several days on a special diet in a clean
environment. If improvement occurred, single chemicals at concentrations
encountered in normal daily living as well as single foods could be
reintroduced one at a time while the effects of each introduction were
observed. Thus, the EMU would be a tool to determine in the most direct and
definitive manner possible whether chemical sensitivities exist.

Studying patients with complicated conditions like chronic fatigue syndrome
or Gulf War syndrome in a conventional exposure chamber would not provide
the same information, since chambers allow only short-term residence, do not
control the entire range of background contaminants, and provide inadequate
separation from background exposures prior to challenges.

An analogy may help illustrate the importance of controlling exposures for
extended periods before challenge. If one wished to determine whether a
coffee drinker's headaches were due to caffeine, it would not be adequate
simply to give the person a cup of coffee and ask him how he felt. It is
obvious that the individual would have to stop using caffeine for a period
before a meaningful test of caffeine sensitivity could be performed. In this
instance, a false negative challenge likely would be the result of failure
to avoid coffee before challenge. Similarly, placing a putatively sensitive
person in a conventional exposure chamber and exposing him to a low
concentration of a chemical might not produce any noticeable effect. On the
other hand, if this same person remained in a clean environment such as an
EMU for a few days before being tested and his condition improved, one could
then perform meaningful challenges.

Placing patients in an EMU would simultaneously control all three components
of masking: stopping all exposures several days before challenge testing and
spacing test exposures 4 to 7 days apart would preclude acclimatization or
habituation;
eliminating background chemical noise and allowing the effects
of each challenge to subside before introducing the next one would control
apposition;
and excluding drugs, alcohol, nicotine, and caffeine and spacing
introduction of individual foods 4 to 7 days apart would interrupt any
addiction.
Individual sensitivity could then be evaluated in the EMU following the
postulates in Figure 7 for etiological verification.

For research purposes, challenges must be performed in a double-blind,
placebo-controlled manner. Patients with chronic fatigue syndrome, migraine
headaches, seizures, depression, asthma, or unexplained illnesses such as
Persian Gulf illness could also be tested for sensitivities in an EMU using
these postulates. Thus, the EMU could be used to determine whether
particular patients with these diagnoses had a masked form of this illness.

What evidence is there that unmasking patients in an EMU and conducting
challenges within a 4- to 7-day window of time is either useful or
necessary? Thousands of credible patients and dozens of physicians have
attempted this approach. They report that patients' symptoms resolve within
a few days after they enter such a facility and that robust symptoms occur
when challenges are conducted after several days of avoidance.

Other evidence corroborates these observations:
Withdrawal symptoms of several days' to a week's duration are known to occur
in some persons following cessation of exposure to nitroglycerine (dynamite
workers' headaches), (27) caffeine, (18,28) nicotine, and alcohol. Note
that these substances are chemically unrelated.

In individuals chronically exposed to xylene (29) or ozone, (30) reexposure
after several days' avoidance results in robust symptoms. Foods may require
one to several days to navigate the digestive tract before they are
eliminated. Taken together, these observations suggest that individuals with
sensitivities to multiple incitants might experience effects that linger as
long as several days following initial avoidance. Thus, it may be argued
that patients should be removed from their entire background of food and
chemical exposures for 4 to 7 days before challenges, as Randolph first
proposed. (14,17)

While it is conceivable that synergistic or additive chemical combinations
may be necessary to reproduce certain symptoms, this is a limitation of any
form of challenge testing. Wherever possible within the bounds of safety and
feasibility, chemical combinations believed to precipitate the most robust
and measurable responses should be explored. However, 40 years of clinical
observations, although anecdotal, suggest that single test substances may
suffice for most sensitive subjects.

Confirmation or refutation of these claims seems a logical first step that
should precede testing of complex mixtures.

Finally, because isolating patients in a hospital environment like the EMU
may have unanticipated psychological consequences, early studies in this
area should examine the responses of control subjects in the same
environment.

Conclusion

Good pathological and physiological theories provide "a unified, clear, and
entirely intelligible meaning for a whole series of anatomical and clinical
facts, and for the relevant experiences and discoveries of reliable
observers..." (31)
Theories and experiments that overlook salient observations or do not
control experimental conditions adequately may lead to erroneous
conclusions.
During the late 19th century, researchers collected sputum from patients
with tuberculosis but were unsuccessful in culturing any organism.
Some concluded that tuberculosis was not an infectious disease.
These early investigators did not know that the tuberculin bacillus was
fastidious and would grow out only after many weeks on a specialized culture
medium.

Correspondingly, scientists' abilities to observe and understand chemical
sensitivity may depend on optimizing experimental conditions, that is,
appropriate timing of challenges and use of an EMU for unmasking patients.

To date, studies in this area have failed to unmask patients before
challenge. When false positive and false negative responses occurred,
investigators concluded that chemical sensitivity was psychogenic in origin.
(32,33)

In summary, features of TILT overlap those of allergy, addiction, and
classical toxicity, yet TILT may be distinct from each of these.

TILT appears to involve a two-step process (resembling allergic
sensitization) in which persons lose specific tolerance (resembling
addiction) for a wide range of common substances following a chemical
exposure event (resembling toxicity).

Just as the germ theory describes a class of diseases sharing the general
mechanism of infection, the TILT theory of disease posits a class of
chemically-induced disorders characterized by loss of tolerance to
chemicals, foods, drugs, and food and drug combinations.

In the same way that fever is a symptom commonly associated with infectious
diseases, chemical sensitivity may be a symptom associated with the TILT
family of diseases.

Although clinical case definitions have been developed that describe
particular infectious diseases, no clinical case definition can be applied
to the entire class of infectious diseases. The same may be true for TILT
disorders.

The fact that this phenomenon does not fit already accepted mechanisms for
disease is often offered as evidence that the condition does not exist.
However, the same criticism would have applied to the germ and immune
theories of disease when they first were proposed. What is plausible depends
on the biological knowledge of the time. (34)

Looking to the future, carefully conducted epidemiological studies and
animal models likely will play important roles in characterizing the
initiation stage of TILT during which tolerance is lost.

In the meantime, rigorous testing of the second stage of TILT, that is, the
triggering of symptoms by tiny doses of chemicals, foods, drugs, caffeine,
or alcohol, is needed if progress in this area is to occur.

Adopting a set of relevant testable hypotheses for etiological verification
will ensure the credibility of those endeavors.

This paper is based on a presentation at the Conference on Experimental
Approaches to Chemical Sensitivity held 20-22 September 1995 in Princeton,
New Jersey. Manuscript received at EHP 6 March 1996; manuscript accepted 9
September 1996.

Research for this paper was supported in part by an appointment to the
Agency for Toxic Substances and Disease Registry (ATSDR) Clinical Fellowship
Program in Environmental Medicine, administered by Oak Ridge Associated
Universities through an interagency agreement between the US Department of
Energy and ATSDR.

Abbreviations used:
EMU, environmental medical unit; TILT, toxicant-induced loss of tolerance

Correspondence:
Claudia S. Miller, MD, MS Associate Professor
Environmental and Occupational Medicine
Department of Family Practice
The University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive San Antonio, Texas 78229-3900 USA
210-567-7760 Fax 210-567-7764 Email: millercs@...
Website: www.uthscsa.edu

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2. Bascom R. Chemical Hypersensitivity Syndrome Study: Options for Action, a
Literature Review, and a Needs Assessment. A Report to the State of Maryland
Department of Environment. Baltimore, Maryland 1989.

3. Ashford NA, Miller CS. Chemical Sensitivity. A Report to the New Jersey
State Department of Health. Trenton, NJ, 1989.

4. Ashford NA, Miller CS. Chemical Exposures: Low Levels and High Stakes.
New York: Van Nostrand Reinhold, 1991.

5. National Research Council. Multiple Chemical Sensitivities: Addendum to
Biologic Markers in Immunotoxicology. Washington: National Academy Press,
1992.

6. Association of Occupational and Environmental Clinics. Advancing the
understanding of multiple chemical sensitivity.
Toxicol Ind Health 8(4): 1-257 (1992).

7. Thomson G. Report of the Ad Hoc Committee on Environmental
Hypersensitivity Disorders. Ontario, Canada, 1985.

8. Ashford N, Heinzow B, Lütjen K, Marouli C, Molhave L, Mönch B,
Papadopoulos S, Rest K, Rosdahl D, Siskos P, Velonakis E. Chemical
Sensitivity in Selected European Countries: An Exploratory Study. Athens:
Ergonomia, 1994.

9. Cone JE, Sult TA. Acquired intolerance to solvents following
pesticide/solvent exposure in a building: a new group of workers at risk for
multiple chemical sensitivities? Toxicol Ind Health 8(4): 29-39 (1992).

10. Rosenthal N, Cameron CL. Exaggerated sensitivity to an organophosphate
pesticide (letter). Am J Psychiatry 148(2): 270 (1991).

11. Ziem GE. Multiple chemical sensitivity: treatment and followup with
avoidance and control of chemical exposures. Advancing the understanding of
multiple chemical sensitivity. Toxicol Ind Health 8(4): 181-202 (1992).

12. Miller CS, Mitzel HC. Chemical sensitivity attributed to pesticide
exposure versus remodeling. Arch Environ Health 50(2): 119-129 (1995).

13. Bell IR, Miller CS, Schwartz GE. An olfactory-limbic model of multiple
chemical sensitivity syndrome: possible relationships to kindling and
affective spectrum disorders. Biol Psychiatry 32: 218-242 (1992).

14. Randolph TG, Moss RW. An Alternative Approach to Allergies. New York:
Lippincott and Crowell, 1980.

15. Miller CS (1992). Possible models for multiple chemical sensitivity:
conceptual issues and role of the limbic system. Advancing the understanding
of multiple chemical sensitivity. Toxicol Ind Health 8(4): 181-202 (1992).

16. Miller CS. Chemical sensitivity: symptom, syndrome or mechanism for
disease? Toxicology 11: 69-86 (1996).

17. Randolph TG. Human Ecology and Susceptibility to the Chemical
Environment. Springfield, IL: Charles C Thomas, 1962.

18. Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome
after the double-blind cessation of caffeine consumption.
N Engl J Med 327(16): 1109-1114 (1992).

19. Miller CS. Multiple chemical sensitivity and the Gulf War veterans.
Paper presented at The Persian Gulf Experience and Health, NIH Technology
Assessment Workshop, Bethesda, Maryland, 27-29 April 1994.

20. Waddell WJ. The science of toxicology and its relevance to MCS.
Reg Toxicol Pharmacol 18: 13-22 (1993).

21. Fiedler N, Kipen HM, DeLuca J, Kelly-McNeil K, Natelson B. A controlled
comparison of multiple chemical sensitivities and chronic fatigue syndrome.
Psychosom Med 58: 38-49 (1996).

22. Buchwald D, Garrity D. Comparison of patients with chronic fatigue
syndrome, fibromyalgia, and multiple chemical sensitivities.
Arch Intern Med 154: 2049-2053 (1994).

23. Mølhave L, Bach B, Pederson OF. Human reactions to low concentrations of
volatile organic compounds.
Environ Int 12: 167-175 (1986).

24. AIHA. Odor Thresholds for Chemicals with Established Occupational Health
Standards. Fairfax, VA: American Industrial Hygiene Association, 1989.

25. Warner M. Hunting the yellow fever germ: the principle and practice of
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Bull Hist Med 59: 361-382 (1985).

26. Miller CS. White paper: Chemical sensitivity: history and phenomenology.
Toxicol Ind Health 10(4/5): 253-276 (1994).

27. Daum S. Nitroglycerin and alkyl nitrates. In: Environmental and
Occupational Medicine (Rom W, ed). Boston: Little Brown and Co, 1992;
1013-1019.

28. Griffiths RR, Woodson PP. Caffeine physical dependence: a review of
human and laboratory animal studies.
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Proc Royal Soc Med 58: 295-300 (1965).

Table 1. Features of toxicant-induced loss of tolerance compared with
features of addiction, allergy, and toxicity.

Toxicant-induced
Feature loss of tolerance a Addiction a Allergy a Toxicity a
Chemical/drug intolerance + + + +
Ambient air incitants + + +
Food intolerance + +
Alcohol intolerance + +
Caffeine intolerance + +
Withdrawal symptoms + +
Craving, binging + (foods) + (drugs)
Sensitization + +
Induction by chemicals + + b +
Induction by biologicals +
Multisystem symptoms + + + +
Frequent CNS symptomatology + + +
Well-defined mechanism(s) + +
Genetic susceptibility + + + +
Dose-response relationship + c + c +

a Categories are not pure and may overlap in a given host, e.g., haptenation
of a chemical toxin may initiate an immunologic response; brain and liver
toxicity may accompany alcohol addiction.
b Low molecular weight chemicals may combine with tissue proteins producing
haptens that evoke immune responses.
c Dose response does occur for allergens. With the first sensitizing
exposure in a susceptible individual, there is a dose-response relationship;
with subsequent exposures, the sensitized person also responds in proportion
to dose but at a much lower dose level. (20) The same kind of dose-response
relationship may hold true for TILT but this has not been tested. Chemically
sensitive individuals generally report increasingly severe symptoms the
longer they remain in exposure situations, an observation that suggests a
dose-response relationship.

Figure 1. Some conditions that have been attributed to chemical sensitivity.

Figure 2. Phenomenology of chemical sensitivity. Chemical sensitivity
appears to develop in two stages:
Stage 1 - loss of specific tolerance following acute or chronic exposure to
various environmental agents such as pesticides, solvents, or contaminated
air in a sick building;
and Stage 2 - subsequent triggering of symptoms by extremely small
quantities of previously tolerated chemicals, drugs, foods, and food and
drug combinations (e.g., traffic exhaust, fragrances, caffeine, alcohol).
Physicians formulate a diagnosis based on symptoms reported to them by their
patients. Because of masking, both physicians and patients may fail to
observe that everyday low-level exposures are triggering symptoms. Sometimes
even when such triggers are recognized, an initial exposure event that
initiated loss of specific tolerance may go unnoticed or may not be linked
by the physician or the patient to the patient's illness.

Figure 3. Graphic representation of symptom progression following exposure
to a single substance in a person sensitive to that substance (e.g.,
caffeine, a solvent, alcohol, nicotine).
The portion of the biphasic curve above the line represents symptoms with
onset of exposure (stimulatory symptoms) and the portion of the curve below
the line represents symptoms with offset of exposure (withdrawal symptoms).
Amplitude is proportional to symptom severity.
The length of the curve (duration of symptoms) may range from minutes to
days.

Figure 4. Graphic representation of acclimatization. Symptom severity
decreases with repeated closely timed exposures (inhalant or ingestant) to
the same substance. Acclimatization is not equivalent to adaptation, since
patients report withdrawal symptoms after exposures cease; conceptually,
acclimatization more closely resembles habituation in this case.

Figure 5. Graphic representation of apposition. If an individual is
sensitive to many different substances, the effects of everyday exposures to
chemicals, foods, or drugs may overlap in time. This apposition of effects
might lead to an individual who feels ill most of the time; however, neither
the individual nor his physician notices the effect of any single exposure.
Apposition tends to mask the effect of interest (solid lines) in much the
same way that background noise masks a sound of interest.

Figure 6. Graphic representation of addiction. A sensitive person who is
addicted to caffeine, alcohol, nicotine, or another substance may
deliberately take that substance at frequent, carefully spaced intervals to
avoid unpleasant withdrawal symptoms. Such exposures may also mask the
effect of interest (e.g., a challenge test using xylene).

Figure 7. Graphic representation depicting the testing of the
toxicant-induced loss of tolerance postulates using an environmental medical
unit.
In the left-hand portion of the figure, a chemically sensitive individual is
experiencing symptoms in response to multiple exposures (chemicals, foods,
drugs) before entering the environmental medical unit. Effects overlap in
time. The effect of any particular exposure cannot be distinguished from the
effects of other exposures, and the person's symptoms may appear to wax and
wane unpredictably over time.

Postulate 1 - When all chemical, food,and drug incitants are avoided
concurrently, remission of symptoms occurs. Anecdotally, patients report
going through withdrawal or detox for the first several days during which
they experience symptoms such as increased irritability, headaches, and
depression. After 4 to 7 days, most report feeling well and theoretically
are at a clean baseline.

Postulate 2 - A specific constellation of symptoms occurs with
reintroduction of an incitant.

Postulate 3 - Symptoms resolve when the incitant is again avoided.

Postulate 4 - Reexposure to the same incitant within an appropriate window
of time (estimated to be about 4-7 days) produces the same symptoms. For
research purposes, challenges should be conducted in a double-blind,
placebo-controlled manner.

Figure 8. Preliminary design sketch of a patient room in an environmental
medical unit. Note use of the nonoutgassing construction materials and
furnishings and point source control (ventilated television enclosure).
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disposition: Bouchard M et al, full plain text, 2001: substantial sources
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EPA Preliminary Remedial Goals, PRGs, 2003 Oct, air and tap water --
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eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
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