The Toxicant Response

Reprinted from the Discovery Magazine, November 2013 issue

Extreme Chemical Sensitivity Makes Sufferers Allergic to Life

Its sufferers were once dismissed as hypochondriacs, but there’s growing biological evidence to explain toxicant-induced loss of tolerance (TILT).

by Jill Neimark

After exposure to certain chemicals, some people may be unable to tolerate ordinary cleaning fluids, perfumes or other substances shown here.

Keith Negley

A Radical Path

Miller did not start her career thinking about low-dose poisons. She was a newly minted industrial hygienist with long, blond hair and wide-set blue eyes when, in 1979, she was hired for the United Steelworkers union in Pittsburgh. The union had 1.2 million mostly male members. “I loved visiting steel mills, smelters and mines,” she recalls. “I found it fascinating to go to coke ovens and see steel being made in the blast furnace and watch parts made by pouring molten metal into molds in foundries.”

Miller sometimes got headaches after a few hours in the same environments the workers had worked in for decades, but she didn’t think much about those headaches at the time. She was just trying to make sure the companies complied with standards set by the Occupational Safety and Health Association (OSHA).

But then the National Institute for Occupational Safety and Health (NIOSH) asked her to examine some female steelworkers diagnosed with psychological and management problems. The women soldered piecework for electronics in two different plants. They worked in rooms without fume vents, and they complained of headaches, fatigue and difficulty concentrating.

In a paper she presented that year at a NIOSH symposium, Miller proposed that toxicants in fumes from the soldering might be responsible for their complaints. “I was the only non-psychiatrist at the meeting,” she recalls, “and by the time I finished my talk, the experts were lined up at the microphone to attack my ideas.”

It was another heretic, controversial Chicago allergist Theron Randolph, who first lent support. Randolph broke with his profession around 1950 and had begun to test and treat individuals for a wide range of sensitivities vastly different from typical allergies, which could be diagnosed through the appearance of elevated immune cells, called immunoglobulins, in the blood. Randolph was convinced that his patients suffered from food and chemical sensitivities that couldn’t be measured in traditional ways. He invited Miller to attend his weekly staff meetings, where cases were discussed.

When Randolph took a patient history, Miller recalls, it lasted hours. He would begin an appointment by saying, “Tell me the last time you felt truly well, and go from there.” He would type out the history directly as the patient talked. Miller remembers details like, “She felt ill in the train station in Chicago. … She felt nauseous on the foam rubber mattress.”

Randolph would “hospitalize” patients for a few weeks in specially constructed units near his Chicago offices. During their confinement, they breathed filtered air, slept on untreated cotton bedding, drank purified water and fasted for days. Their symptoms, from arthritis to headaches to fatigue, would often melt away.

Then he would do blinded challenges on patients — feed a patient an organic apple and a sprayed apple, or expose them to a whiff of copy paper in a glass jar. Symptoms such as migraines or joint pain would recur in response to whatever substances the individual patient was sensitive to. Avoiding those triggers was the inevitable prescription when they left the clinic.

“Many patients were able to get off their medications and get well. These people were reacting to tiny doses of substances, doses that simply should not be causing symptoms. It broke every paradigm of medicine I knew,” explains Miller. “I decided to go to medical school, and then to work as a researcher within a university setting, to establish scientific credibility for this amazing work, which at the time, virtually nobody in academic medicine or science believed.”

Body of Evidence

Two decades and hundreds of peer-review papers later, Miller has amassed a fascinating body of research that suggests a model by which a genetically vulnerable person might succumb to TILT. One major insight draws on the fields of epilepsy and chronic pain syndrome, both of which are associated with abnormal brain activity. In some cases of chronic pain, what begins as an acute, localized injury spreads and becomes a generalized pain syndrome known as reflex sympathetic dystrophy. Pain signals seem to flame across the entire body, and the condition is debilitating and difficult to treat.

Similarly, abnormal brain activity and processing is well known in the field of seizure disorders; temporal lobe epilepsy has been traced to a phenomenon called limbic kindling, in which repeated, intermittent, low-intensity stimulation across the limbic structures of the brain may eventually lead to a seizure.

In fact, Miller hypothesized that a process similar to kindling may be driving the pain and sensitivities documented in TILT. Toxicants like solvents, pesticides or volatile molecules from oil spills can travel straight into the brain via the olfactory receptors — nasal neurons that number in the many millions, thickly studding the inner lining of the nose. Our brains are exquisitely primed to respond to nasal receptors. Not surprisingly, even healthy individuals show significant changes in brain wave activity during brief exposures to olfactory stimuli that are actually below the sensory threshold and not even consciously perceived.

“The lack of a blood-brain barrier in the olfactory system allows chemicals direct access to the limbic system,” says Miller. “And the olfactory pathways are already known to be particularly susceptible to electrical and chemical kindling. Moreover, most chemical exposures are intermittent, which is the kind of exposure known to potentiate kindling and sensitization.” Intermittent lower-dose exposures can be as toxic as a single higher-dose exposure; Miller cites monkey research showing that either 10 nontoxic weekly doses or one toxic dose of an organophosphate pesticide led to the same increase in brain wave activity as measured by electroencephalogram, or EEG.


Miller hypothesizes that exposure to toxicants permanently decreases the threshold needed to excite the limbic network, setting the stage for a phenomenon much like kindling. “It’s not actual kindling in the strict scientific sense of inducing a seizure,” she notes, but that sensitization could theoretically lead to permanent changes in function — and permanently increased reactivity to chemicals processed through the olfactory neurons.

Supporting her view is research from the Danish Research Centre for Chemical Sensitivities at Copenhagen University Hospital Gentofte, where scientists have demonstrated that individuals with chemical intolerance show greater sensitization in the central nervous system. The center’s research has found that 27 percent of the Danish population has some noticeable sensitivity to chemicals. A much smaller number, 0.5 percent, is so sensitive that lifestyle must dramatically change.

In another study, researchers at the center chose 15 chemically intolerant patients from those who had come to the center asking for help. They also looked at 15 healthy individuals. Then they injected capsaicin, the active molecule in hot pepper, under the skin and lightly tapped the area with a blunt, rigid nylon filament — starting at six centimeters away, and tapping closer and closer to the injection site. When the pricking sensation changed to pain, it was recorded.

Not only is capsaicin odorless, it is known to induce a pain response modulated specifically by the central nervous system. “It was really interesting,” comments dermatologist Jesper Elberling, the lead author on the study. “In chemically intolerant individuals, the area of skin pain was significantly greater, as were the reported levels of pain. Something is going on in the central nervous system — some process of sensitization and heightened response.”

The center is now planning a study to look at genes involved in sensitization in the brain, to see if they are activated in chemically sensitive individuals. “In 2010, we unsuccessfully tried testing genes involved in detoxification and concluded that variants in detoxification genes and pathways are less important than previously thought,” says the center’s director, Sine Skovbjerg Jakobsen. “We don’t find consistent immunological abnormalities, nor do we find an abnormal sense of smell.”

So something else is going on in the brain. Much like Miller, the Danish researchers suspect that sensitization of the brain, probably by some kind of kindling process, could be at the root.

Astoundingly, in 2010, Elberling reported on a single case study where electroshock therapy (ECT) actually put severe chemical intolerances in remission. ECT has been proven effective in severe depression and refractory pain syndromes — its impact is in the brain itself, where it seems to reset thresholds of reactivity.

The 45-year-old male patient had become so chemically intolerant that he had been on sick leave for two years, had moved out of his home and could only see his children outside, not indoors. He was so isolated, he felt “a desperation he feared would lead to severe psychological breakdown,” says Elberling.

Before his illness, the patient worked as a stock manager in an industrial spray paint company. “At pre-ECT baseline,” says Elberling, “his self-rated chemical sensitivity symptom severity was 95 out of 100. After the third ECT treatment, he declined to 30 out of 100, and he gradually resumed ordinary life activities.” He was able to entertain, shop and spend time with family and friends. He was put on standard maintenance therapy (an ECT treatment every two weeks) for four months with only mild residual sensitivities.

“It is likely that ECT triggered the recovery process of brain regions reorganized in this chemically intolerant patient,” Elberling says. Although this example is extreme, it does point to a brain-driven mechanism that could inform future research.

Chemically intolerant individuals also show dysfunction in brain imaging on a SPECT scan, which tracks blood flow through tissue. That work was done at the University of Hebron in Barcelona, where researchers followed 10 chemically intolerant patients over a two-year period. Patients’ symptoms were chronic and reliably triggered by exposure levels that previously did not bother them.

To do their study, the Hebron scientists evaluated intolerant patients by SPECT scan. Then, a week later, each of those patients entered a chamber with a healthy individual. For varying periods of time, both were exposed to ordinary fumes from paint, perfume, gasoline and an aldehyde substance of the sort often used to manufacture perfumes or drugs. After exposure, there was a significantly greater decrease in blood flow in specific brain areas, particularly those involved in odor processing, in the chemically intolerant patients.

Miller, meanwhile, has found decreased blood flow through the central artery in the brains of Gulf War veterans suffering from TILT. Eight male veterans complaining of Gulf War illness and eight healthy veterans participated in her study. The veterans were stationed in front of a computer and given routine short-term memory tasks while being exposed to clean, filtered air or air with imperceptible amounts of acetone. Miller and the team told the subjects the air contained acetone whether it did or not. The content of the air had no impact on healthy subjects, but for sick Gulf War veterans, it was a different story. When the air contained trace amounts of acetone, the blood flow through their large middle cerebral artery was significantly slowed.

“I didn’t think TILT was real until we completed this study,” says physiologist Leonid Bunegin, a colleague of Miller’s at the University of Texas, who helped design and carry out the research. “It was the first hard-core study to show a definitive correlation between brain function and low-level chemical exposure.”

Controversy Reigns

Of course, skeptics remain. Not everybody is convinced the new model is valid. As recently as 2008, an Italian case study by University of Padova psychologist Gesualdo Zucco concluded that a chemically intolerant individual had “a debilitating psychological disorder in need of treatment.” After a car accident in 1992, the 36-year-old patient complained of chemical sensitivities so severe she sometimes vomited or fainted.

In a laboratory setting, she was exposed to a “blank stimulus” (no odor at all), odors she’d earlier rated as pleasant (coconut, banana) and odors she said caused symptoms (turpentine, paint). Symptoms she reported were directly related to the information she was given about the safety of the odors. If she was told that a blank stimulus or a pleasant odor was actually harmful, she reacted badly; if she was told it was an odor she’d rated as pleasant, she did not react badly. “There was remarkable consistency across trials,” says Zucco, “and it is noteworthy that at first the patient truly believed her disease was biological in origin.” This is an attitude very common among TILT patients, since they label themselves as afflicted by a physical disease.

After the study, the patient accepted Zucco’s conclusion that the symptoms were psychological. Cognitive psychotherapy, he says “allowed her to manage most of her symptoms, and for several years she sent me Christmas cards letting me know she remained improved.”

But even Zucco doesn’t insist that all cases are psychological. Some may “have a biological or organic origin,” he says. “The point of this study was that it was able to distinguish the difference.”

Miller has a different point of view. TILT, she says, emerges from a more sensitive, highly excitable limbic system. Asthma, depression and panic disorder run in families of sufferers. Shyness, which can be an avoidance behavior to control stimuli, is more prevalent, too.

In other words, she says, personality constructs emerging from the basic biology of the brain can be yet another marker that the individual is at risk for TILT, and easier to sensitize to the disease.

Someday, Miller hopes, you will walk into a physician’s office for a consultation, and along with the typical sheaf of papers about your health history, you’ll be given a different set of questions: the QEESI. You’ll checkmark, on a scale of one to 10, if you feel sick after breathing diesel exhaust or paint thinner, have unusual food cravings, use a gas stove or fabric softener at home, seem oddly sensitive to medications, or suffer inexplicable complaints such as dizziness, rashes, difficulty concentrating, headaches and mood swings. You will be given your QEESI score. And if you’re one in every five who appears to be at risk for TILT, you will be counseled on lifestyle and dietary changes.

You will be like the psychologist that Miller spoke to after presenting findings at a conference.

“The woman took the QEESI, and found she was at greater risk for TILT. She had just ordered new, synthetic carpet for her entire house, and she said to me, ‘I’m not sick, and I don’t want to get sick. I’m canceling the carpet order and installing ceramic tile instead.’”

[This article originally appeared in print as “Allergic to Life.”] 

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