TILT - New Theory_Kurzfassung

Toxicology and Industrial Health (1999), 1-11

Are we on the threshold of a new theory of disease? Toxicant-induced loss of tolerance and its relationship to addiction and abdiction

CLAUDIA S. MILLER

Environmental and Occupational Medicine, Department 0! Family Practice' University of Texas Health Science Center at San Antonio' 7703 Floyd Curl Drive, San Antonio, Texas

'Toxicant-induced loss of tolerance (or TILT) describes a two-step disease process in which (1) certain chemical exposures, e.g. indoor air contaminants, chemical spills. or pesticide applications, cause certain susceptible persons to lose their prior natural tolerance for common chemicals, foods' and drugs (initiation); (2) subsequently, previously tolerated exposures trigger symptoms. Responses may manifest as addictive or abdictive (avoidant) behaviors. In some affected individuals, overlapping responses to common chemical, food' and drug exposures, as well as habituation to recurrent exposures, may hide (mask) responses 10 particular triggers. Accumulating evidence suggests that this disease process might underlie a broad array of medical illnesses including chronic fatigue, Fibromyalgia, migraine headaches, depression, asthma, the unexplained illnesses of Gulf War veterans, multiple chemical! sensitivity, and attention deficit disorder.
Keywords: addiction chemical intolerance' chronic fatigue. environmental illness. Gulf War veterans. multiple chemical sensitivity theory of disease.

Introduction

A yet-to-be-proven general mechanism for disease is a theory of disease (e.g., the germ theory or the immune theory). This paper addresses the prerequisites a new theory of disease must fulfill prior to its acceptance by the scientific community-anomaly, causality, generalizability, and novelty-and whether toxicant-induced loss of tolerance (TILT) meets these criteria. Also discussed are the implications of this theory for case definitions, biomarkers, medical diagnosis and treatment, and prevention and public health. As a new theory of disease, TILT unites and gives meaning to observations by investigators from more than a dozen countries, offering a new context for scientific discussion, research, and intervention. TILT is a recently described theory of disease (Miller, 1996a, 1996b, 1997) that is based upon the collective observations of researchers, physicians, and patients in more than a dozen countries over the past half century (Randolph, 1962; Randolph and Moss, 1980; AOEC, 1992; Health Canada, 1992; NRC, 1992; ATSDR, 1994; Ashford and Miller, 1998; Ashford et aL, 1995). The TILT theory of disease (Figure 1) posits that following exposure to a single high level, or repeated lower levels, of a chemical or mixture of chemicals, certain individuals lose specific tolerance for various chemicals, foods, and drugs (initiation phase) (Miller, 1997). Subsequently, everyday exposures to these substances trigger symptoms, thus perpetuating illness (triggering phase). 'Loss of tolerance', as defined by a federally sponsored recent consensus panel (MilIer et al., 1997), i~ "the loss of prior natural or native tolerance", parallel to a diabetic's loss of tolerance for sugar. 'Triggering' was defined as the provocation of symptoms by a chemical, food or drug stimulus (Miller et al., 1997).

1. Abbreviations: EMU, Environmental Medical Unit; TILT, toxicant induced loss of tolerance.

Masking

Figure 1. Phenomenology of TILT. Illness appears to develop in two stages (depicted in the portion of the iceberg below the waterline, not visible to the physician): (1) loss of specific tolerance following acute or chronic exposure to various environmental agents such as pesticides, solvents, or au contaminants in a sick building; followed by (2) triggering of symptoms by very small quantities of previously tolerated chemicals, foods, drugs, and food/drug combinations (alcohol, caffeine). A physician (represented by the ship) sees only the tip of the iceberg-the patient's symptoms- and formulates a diagnosis based upon them. Because of masking (due to habituation and overlapping of multiple responses), both physician and patient may fail to recognize that everyday, low-level exposures are triggering symptoms. Even if such triggers are recognized, an initial exposure event that could have initiated loss of specific tolerance might not be noticed or linked to the patient's illness ~
There is accumulating evidence for this two-step process. Reliable observers have described new-onset intolerances following identifiable exposures in demographically diverse groups. These groups include radiology workers from several countries exposed to X-ray developer solutions (Genton, 1998), EPA employees Washington, DC, exposed to volatile organic chemicals outgassing from new carpet and other of fice materials (Hirzy and Morrison, 1989), home owners in Germany exposed to pentichlorophenol wood preservative used in Iog houses (Ashford et al., 1995),. sheep dippers in Great Britain exposed to organophosphate pesticides (Stephens et al., 1995; Monk, 1996; Ashford and Miller, 1998), hospital workers in Nova Scotia exposed to building air contaminants (Ashford and Miller, 1998), casino card dealers in Lake Tahoe, California, exposed to solvents and pesticides (Cone and Sult, 1992), and Gulf War Veterans exposed to a wide variety of substances during military service (Fiedler et al., 199 ; Miller, 1996b; sor an t er, 1998; Miller and Prihoda:
Despite the demographic diversity of these groups and the heterogeneity of their exposures, all exhibit multi-system symptoms and new-onset intolerances for common chemical exposures, foods, drugs, alcoholic beverages, and caffeine. Symptoms vary from person to person within each exposure group.
These observations conform neither to currently understood mechanisms of toxicity nor to any other generally accepted explanation for disease (Waddell, 1993): symptoms appear to occur in response to structurally diverse substances at exposure concentrations that are orders of magnitude below established thresholds for toxicity.

A theory of disease is a yet-to-be proven general mechanism for a class of diseases, e.g., the germ and immune theories of disease. In the evolution of a new theory of disease, there is invariably an early observational phase during which anecdotal cases are noted and described. As clinical observations accumulate, a corrigible, tentative hypothesis is formulated, e.g., some 'germ' must be transmitted from one organism to another, or the host must form an 'antibody' of some sort directed against an 'antigen'. Armed with this crude theory, scientists next search for biological markers and other evidence that might elucidate the process.

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