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From the Townsend Letter
November 2006


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

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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.

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.

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 mixture23 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 four to seven 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 four 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.

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.

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).

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.

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.

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).


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 the following: 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 four to seven 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 Environmental Medical Unit (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 food and water that is less chemically contaminated, 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.

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 non-outgassing construction materials and furnishings and point source control (ventilated television enclosure). Click here for a higher quality image. (100 KB .pdf)

The rationale for housing subjects in an environmentally controlled facility for several days before challenges is twofold: 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 hours 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 four to seven 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 while spacing introduction of individual foods four to seven 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 four- to seven-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 xylene29 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 four to seven 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.

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.

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

Reprinted from Environmental Health Perspectives. March 1997; Vol. 105, Supplement 2 and Townsend Letter for Doctors and Patients. 210:76-84 (January 2001).

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. 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.

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