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

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Abstract: 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

Clinical observations in North America1-7 and Europe8 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. Some conditions that have been attributed to chemical sensitivity, 88KB .pdf).4

Efforts to formulate a case definition for chemical sensitivity, identify relevant biomarkers, and 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.

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.

Figure 2: Phenomenology of chemical sensitivity

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.

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 caffeine, alcoholic beverages, various drugs, and foods reportedly trigger symptoms in these individuals, after 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 individuals affected 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 viewing chemical sensitivity as a syndrome to viewing 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 addicted behaviors (Latin ad "toward" + dicare "proclaim"), chemically sensitive patients respond as though they were abdicted (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, flu-like 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. However, it is TILT's resemblance to addiction that is perhaps most striking and that has escaped the attention of many physicians and researchers.

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