Toxicant-Induced Loss of Tolerance — An Emerging Theory of Disease?

Townsend Letter for Doctors and Patients,  Jan, 2001  by Claudia S. Miller

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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 compone nts: 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)

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 quantifies 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.

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 patients illness.