In this presentation, I’m going to offer two research tools: The QEESI and the EMU.
One is expensive, and we don’t have it yet, but when we do it will be worth every penny.
The other you can download for free from my website. I’ll tell you what QEESI and
EMU stand for, but first I need to give you a little background.
Twenty years ago, in 1991, my co-author, Dr. Nicholas Ashford of MIT and I spoke at
the first National Academies meeting on the topic of individual susceptibility. The
National Research Council convened clinicians, toxicologists, immunologists,
epidemiologists, and others interested in the health effects of low-level chemical
exposures.
Recommendations from this meeting included:
- Establishing a case definition for chemical susceptibility
- Developing relevant animal models
- And conducting epidemiological studies to determine prevalence
Participants assigned their highest priority to research using an environmental control
unit, which I will refer to as an EMU or environmental medical unit—a clinical research
unit in which subjects are housed for the control of exposures to foods and chemicals….
Uses of units would include control of exposures and challenging subjects in a welldefined environment.”
Studies suggest that at least 10-15% of people experience adverse reactions to low-level
chemical exposures. 4-6% report that their reactions interfere with their ability to work,
go to school, travel and other activities. Just as reports of adverse drug reactions are
increasing with the increased numbers of pharmaceuticals we all take, the phenomenon of
chemical intolerance has emerged as our environmental chemical exposures have
increased.
Here we see that synthetic organic chemical production has grown exponentially since
World War II. The same is true for pesticide production.
By the way, it’s not that I haven’t updated my slides since 1988. Reporting metrics
changed around that time, and it’s no longer easy get a snapshot picture like this of total
chemical or pesticide production in the U.S.
People often think principally of chemicals in our outdoor environment—in our air, water
and soil—but indoor air pollution has also increased due to things like cleaning
chemicals, fragrances, and outgassing from new furnishings. Because many of these
involve evolutionarily novel substances, it’s reasonable to expect wide variation in the
ability to metabolize and excrete these substances, depending on the chemical and the
individual.
This graph shows fresh air ventilation standards for the U.S. over time. They applied to
schools, office building, not homes. At the turn of the last century, building codes
required lots of fresh air—because the goal was to control body odor in public spaces. It
would be unbearable in a meeting with people like this who had not bathed for some
time. Then came indoor plumbing, and people starting taking more baths, so required
levels of fresh air were able to be decreased. In the 1970s, we reduced fresh air indoors
again because of the oil embargo. Heating and cooling air for buildings consumes
enormous amounts of energy. Recirculating building air that has been heated or cooled
saves money by saving energy.
Why is Indoor Air important? Think about where you spend the majority of your day.
Americans spend, on average, 90% of their day indoors—homes, offices, schools or
vehicles. The factors I just mentioned, increased sources of indoor air contaminants,
coupled with decreased fresh air to dilute them, have made indoor air quality an EPA
public health priority.
This graph shows a representative GCMS analysis of indoor and outdoor air sampled
inside and outside the same office building at the same time. The top graph shows a far
greater variety of volatile organic chemicals or VOCs and at much higher concentrations,
indoors than out-of-doors. Further, the VOCs in these complex indoor mixtures can
interact with each other, ozone, and particles to form new contaminants.
Such a complex mixture is common in “sick buildings” or even newly constructed homes
or schools in which building materials, furnishings, carpeting and other sources
contribute to the mixture. Following the oil embargo and the lowered fresh air standards I
showed you before, we witnessed the first cases of “sick building syndrome” in
government buildings, office buildings and schools.
In the late 1980’s, the EPA had the unwelcome opportunity to study sick building
syndrome in ___ headquarters building in Washington, D.C. I served as a consultant to
the EPA for their sick building outbreak, which followed the installation of 27,000 square
yards of new carpeting, fresh paint, glues and other sources used in offices with variable
amounts of fresh air. We learned that not everyone who works in a sick building gets
sick or stays sick. Hundreds of EPA workers, including many agency scientists reported
symptoms consistent with “sick building” syndrome. A subset of individuals reported
protracted illness. Unfortunately, some of these former EPA employees remain ill and
chemically intolerant to this day.
This subgroup reported multisystem symptoms and new-onset intolerances to everyday
exposures including chemicals, food and drugs—exposures they said never bothered
them before and which don’t bother most people.
The EPA sick building drew national attention and our attention to the fact that there
were other groups of people who shared similar experiences following various exposures.
We saw that chemical intolerance, that is, having symptoms triggered by everyday
chemical exposures, occurred in many different demographic groups: industrial workers,
communities with hazardous exposures, not just sick buildings. These were people of all
ages, white collar, blue collar—men, women, and children.
Here are examples of the wide variety of exposures that trigger symptoms among people
who are chemically intolerant, including cleaning agents, solvents, pesticides, outgassing
from new furnishings, and medical drugs and anesthetics.
I was struck by the fact that people who reported becoming chemically intolerant
following an organophosphate pesticide exposure experienced the same new-onset
intolerances and range of symptoms that were reported by people exposed to chemicals
used during remodeling years. Later, while I was serving as a consultant to the VA, I saw
the same pattern of illnesses among veterans who had become ill following the first Gulf
War.
In succeeding years, Dr. Ashford and I documented this same pattern of illness in
different demographic groups in more than a dozen different countries where people did
not know each other, did not speak the same language, and were not exposed to the same
media.
What these groups did share in common were the following:
A well-documented initial exposure event
Subsequent adverse and amplified responses to previously tolerated and structurally
diverse exposures, including common chemicals, foods, drugs, alcoholic beverages, and
caffeine.
These observations could not be explained by classical allergy or traditional toxicology.
This is what Kuhn called a compelling anomaly—an observation that is not explained by
current paradigms and therefore drives the search for a new explanation.
Dr. Ashford and I asked ourselves, could we be dealing with a new theory of disease?
Here’s how we conceptualized it:
First, an acute or chronic initial exposure event occurs in susceptible individuals, leads to
a loss of specific tolerance. Subsequently, everyday low-level exposures to chemicals
foods and drugs trigger symptoms in these now sensitive individuals. In this drawing, the
physician sees only the tip of the iceberg, the patient’s symptoms, and formulates a
diagnosis based upon the migraines, depression, chronic fatigue, etc. They are not
etiologic diagnoses. The water line represents masking, resulting from overlapping to the
many triggers the now sensitive person encounters, which we will discuss further, but
which hides the relationship between symptoms and their triggers.
So what is the evidence for Toxicant Induced Loss of Tolerance as a new disease
paradigm or theory of disease?
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The similar reports from different groups in different regions and countries.
What are the new intolerances
o People who used to enjoy drinking alcohol find that even one drink of
their favorite beverage—whether beer, wine or a margarita—makes them
ill.
o Exposures to low levels of structurally diverse chemicals that never
bothered them before and don’t bother most people, for example, diesel
exhaust, cleaning chemicals, and fragrances, suddenly trigger symptoms
ranging from mild to disabling. I vividly recall one Gulf War veteran who
loved the smell of WD40. But reported after the war, WD40 and other
exposures at work would make him ill. Or the EPA workers exposed in
EPA’s sick building, who used to look forward to playing poker or bridge
with friends, but could suddenly no longer tolerate their friends’ colognes
or cigarette smoke.
o From our own studies, over 90% of chemically intolerant people report
intolerances to foods, foods they had enjoyed before their exposure. This
was particularly striking. Why would people in such different
demographic groups, with different initiating exposures, so consistently
report new on-set food intolerances?
o Likewise, drug intolerances were also very common. Many patients
reported adverse reactions to multiple drugs. Some had been prescribed
several different classes of antidepressants or antibiotics in attempt to find
one they might tolerate. Some patients might tolerate a quarter or a half
of the usual dose of a drug, e.g., an SSRI or an analgesic.
To me, this was the strongest evidence that we were dealing with a new disease
paradigm. Other evidence that points to TILT as a new theory of disease include its
resemblance to addiction. One of my papers on the reading list for this meeting, is from
the journal Addiction, and addresses the remarkable parallels between chemical
intolerance and addiction. There are a few published, hypotheses regarding the anatomic
locus for chemical intolerance. There are also models involving limbic sensitization and
cholinergic supersensitivity.
So how do we test this new theory? If we want to study chemical intolerance in humans,
we need a case definition for chemical intolerance. But how do you develop a case
definition given all this variation among people in terms of symptoms, the kinds of
exposures that initiated their illness, and the seemingly endless variety of chemical, food,
and drug that trigger symptoms. Research requires that we be able to differentiate cases
from controls, despite the lack of a case definition. If we are dealing with a new class of a
disease there would be no single case definition, e.g. infectious diseases.
To begin, we collected data from 4 different exposure groups who reported becoming ill
with chemical intolerances following an identifiable exposure event. We asked about
their symptoms, chemical and other intolerances, ongoing exposures, and the impact of
their illness on their lives. Using factor analysis, we identified the most common
responses among these affected individuals. We then surveyed unaffected individuals and
developed scoring criteria that predicted chemical intolerance. The result of this work is
the Quick Environmental Exposure and Sensitivity Inventory (QEESI).
The QEESI is used in both clinical practice and research, and it has been translated into
several languages as researchers in other countries have adopted it for their own studies.
The QEESI can be self-administered. There are 5 sections with a total of 50 questions
which take 12 to 15 minutes to answer. It has high sensitivity and specificity for
chemical intolerance.
On the QEESI, individuals rate the severity of their symptoms in 10 different categories
on a 10-point scale—ranging from “not a problem” to “disabling.”
Since the hallmark of TILT is new-onset of intolerances, manifested by multisystem
symptoms, it may be important to consider not just a snapshot of current symptoms, but
the change in symptoms over time, for example, before and after an individual’s initiating
event, whether a pesticide application, remodeling of their home or an exposure at work.
About half of chemically intolerant patients make such attributions. Other don’t recall a
specific initiating event or recall a series of exposures over months or years.
The Symptom Star, which appears on the front of the QEESI questionnaire, provides a
way to graph changes in symptoms over time. Especially in clinical practice, it is a very
useful, visual way for patients to communicate changes in their symptoms – both before
and after their “initiating event,” and in response to any therapeutic interventions. The
Symptom Star provides a “gestalt” so you know immediately whether you may be
dealing with one of these complex individuals.
We call this scale Chemical Exposures, because that is how most patients think of them.
These are primarily chemical inhalants—common exposures that are structurally diverse,
for example diesel, fragrances, and pesticides. Patients rate the severity of their
responses to these exposures, again from 0-10, as for all the scales on the QEESI.
The Other Exposures Scale includes diverse items that patients commonly make them ill.
It includes foods, food additives, and other ingestants including caffeine and alcohol, and
asks about patterns that might suggest an addictive component. Chemically intolerant
individuals commonly report pronounced food cravings and withdrawal symptoms.
Adverse reactions to alcohol, caffeine, foods, drugs or medications are extremely
common across all of the groups we have studied. This raises an important research
question: We know that people with chemical intolerances report more problems with
drugs and medications. However, we don’t know whether the reverse is true—are people
who experience adverse reactions to drugs or medications also more chemically
intolerant?
Finally, even though chemical intolerance does not appear to involve IgE, individuals
often report greatly heightened allergic responses—as in reactions to bee stings or
seasonal allergies to pollen—following onset of their chemical intolerances.
The Masking Index asks, whether or not—yes or no—an individual is routinely exposed
to certain everyday exposures. These exposures are ubiquitous. For QEESI©
interpretation, individuals endorsing 4 or more of the items in this index are considered
“masked.” Practices such as the use of a gas stove in the home or routine use of fragrance
may result in overlapping symptoms and make it more difficult for the individual to relate
their symptoms back to specific exposures.
The Life Impact Scale has been a useful way to gauge the impact of chemical intolerance
on many aspects of daily life, such as family relationships, diet, work, and travel.
To develop a surrogate case definition of chemical intolerance, we used a combination of
scores from these 3 sections: the Symptoms scale, the Chemical Intolerances scale, and
the Masking Index. As we’ve said, masking hides the cause-and-effect relationship
between specific symptoms and their triggers.
Here is the scoring system for the QEESI. As an example, an individual reporting high
symptom severity who has a high chemical intolerance score would likely be chemically
intolerant regardless of their masking score. On the other hand a highly masked
individual, e.g., a person exposed to tobacco smoke, fragrances, alcoholic beverage more
than once a week, etc. would likely be less able to identify their chemical intolerances, so
a low score for chemical intolerance in the presence of a high score for symptoms and a
high score for masking would not rule out chemical intolerance.
Clinically, a physician should use the QEESI score in combination with a good
comprehensive medical and exposure history. Therefore, the interpretation chart for the
QEESI uses terms like “suggestive” or “not suggestive” for chemical intolerance. For
research purposes, the numerical scores from the QEESI scales can be used in the
absence of a clinical assessment, and I’m happy to work with other researchers to
determine how to best use the QEESI in their studies.
So I’ve described the QEESI, a validated screening tool for differentiating chemically
intolerant cases from controls.
The second research tool I’d like to present to you is the EMU or the Environmental
Medical Unit. The EMU is a pristine, environmentally-controlled hospital or medical unit
in which patients can be housed long enough, about 4-7 days, to achieve a clean baseline,
free of environmentally-triggered symptoms. The EMU will facilitate double-blind,
placebo-controlled challenges with even very low levels of exposures. It will allow
researchers to observe patients’ symptoms prior to entry into the EMU and after
unmasking and before and after specific challenges, while at the same time employing
objective measure such as proteomics, pulmonary function testing, and brain imaging.
The EMU, constructed, furnished and operated so as to minimize exposure to airborne
chemicals. It is made from non-outgassing materials. No disinfectants, fragrances, or
pesticides would be allowed. Ventilation would maximize fresh air and provide optimal
particulate (HEPA) and gas activated charcoal and other solvents filtration. Foods and
water would also be carefully selected, and in some cases, fasting may be an efficient
approach for achieving a clean baseline.
What happens in the EMU? We see sine waves which represent the overlapping, waxing
and waning of symptoms that occur in a chemically intolerant individual who is
responding to multiple exposures. When all exposures are eliminated concurrently in the
EMU, environmentally-induced symptoms will resolve, generally within 4 to 7 days.
Once the individual has reached a clean baseline, researchers can perform challenges
with single exposures one-at-a-time and observe responses in the absence of background
noise. Challenges could be repeated at an appropriate interval to confirm initial
observations.
Twenty years ago, the top recommendation from the National Research Council’s
conference on chemical intolerance was to conduct exposure challenge studies using an
EMU. Advancements in brain imaging, genomics, proteomics and other areas over the
last 20 years have only heightened the enormous potential of such a facility to help us
understand the biological effects of chemical exposures and the subtleties of individual
susceptibility.
Over the remainder of this meeting, I invite you to consider this question: Where could
we be 20 years from now?