Toxicant-induced Loss Of Tolerance Research Articles

Clinical assessment and patient education of chemical intolerance

Chemical intolerance (CI) is characterized by multi-system symptoms initiated by a one-time high dose or persistent low-dose exposure to environmental toxicants. Symptoms of this “medically unexplained illness” often include fatigue, headache, weakness, rash, mood changes, musculoskeletal pain, gastrointestinal, difficulties with memory, concentration, and respiratory problems. A general disease mechanism called toxicant-induced loss of tolerance (TILT) explains the initiation, symptoms, and intolerances to chemicals, foods, and medicines reported worldwide by individuals with this condition. TILT is a 2-stage disease process initiated by a major chemical exposure, or a series of low-level exposures, followed by multisystem symptoms and onset of new intolerances. Despite its prevalence of up to 20%, most primary care physicians are not aware of this disease process and thus have been unable to recognize patients with CI. This case series describes three family medicine clinic patients who had multisystem symptoms that were triggered by chemical exposures, saw multiple specialists with no improvement, who were eventually diagnosed with CI and went through a behaviorally based avoidance education program. This report describes the impact of a coordinated educational intervention for patients with CI. We offer several educational tools for health practitioners to discuss with their patients. These patient stories highlight the importance for physicians to be knowledgeable about CI in order to facilitate symptom reduction and improve the quality of life for these patients.

What initiates chemical intolerance? Findings from a large population-based survey of U.S. adults

BackgroundWorldwide observations point to a two-stage theory of disease called Toxicant-Induced Loss of Tolerance (TILT): Stage I, Initiation by an acute high-level or repeated lower-level chemical exposures, followed by Stage II, Triggering of multisystem symptoms by previously tolerated, structurally diverse chemical inhalants, foods/food additives and drugs. Until recently, there was no known biological mechanism that could explain these observations. In 2021, we published a plausible and researchable two-stage biomechanism for TILT involving mast cells: Stage I, Initiation via mast cell sensitization; Stage II, Triggering of mast cell degranulation by previously tolerated exposures, resulting in the release of thousands of mediators, including histamine and a host of inflammatory molecules. The objective of this study was to identify common TILT initiators.MethodsA randomized, population-based sample of 10,981 U.S. adults responded to a survey which included items concerning medical diagnoses, personal exposures, antibiotic use, and several possible initiators of Chemical Intolerance (CI). CI was assessed using the internationally validated Quick Environmental Exposure and Sensitivity Inventory (QEESI). Participants identified as chemically intolerant were asked to recall when their intolerances began and what they felt had initiated their condition.ResultsTwenty percent met QEESI criteria for TILT, approximately half of whom identified one or more initiating exposures. Initiators in order of frequency were mold (15.6%), pesticides (11.5%), remodeling/new construction (10.7%), medical/surgical procedures (11.3%), fires/combustion products (6.4%), and implants (1.6%). Protracted antibiotic use for infections involving the prostate, skin, tonsils, gastrointestinal tract, and sinuses were strongly associated with TILT/CI (OR > 2).DiscussionParticipants identified two broad classes of TILT initiators: 1) fossil fuel-derived toxicants (i.e., from coal, oil, natural gas), their combustion products, and/or synthetic organic chemical derivatives, e.g., pesticides, implants, drugs/antibiotics, volatile organic compounds (VOCs); and 2) biogenic toxicants, e.g., particles and VOCs from mold or algal blooms. One in four primary care patients suffers from Medically Unexplained Symptoms (MUS). Doctors in primary care, neurology, psychiatry, psychology, occupational medicine, and allergy/immunology would be well-advised to include TILT in their differential diagnosis of patients with so-called MUS. Because 20% of U.S. adults meet QEESI criteria for CI, the role of contemporary exposures in initiating and exacerbating these conditions via mast cells needs our immediate attention. There is a concomitant need for policies and practices that reduce initiating exposures as well as ubiquitous and often unavoidable triggers such as fragranced personal care, cleaning, and laundry products in multi-occupant housing, workplaces, medical settings, schools, places of worship, and all public buildings—literally anywhere air is shared. Fossil fuels are assaulting humans and other animal species both from within via mast cell sensitization, and from without via climate change.

Multiple Chemical Sensitivity.

Multiple Chemical Sensitivity (MCS), a condition also known as Chemical Sensitivity (CS), Chemical Intolerance (CI), Idiopathic Environmental Illness (IEI) and Toxicant Induced Loss of Tolerance (TILT), is an acquired multifactorial syndrome characterized by a recurrent set of debilitating symptoms. The symptoms of this controversial disorder are reported to be induced by environmental chemicals at doses far below those usually harmful to most persons. They involve a large spectrum of organ systems and typically disappear when the environmental chemicals are removed. However, no clear link has emerged among self-reported MCS symptoms and widely accepted objective measures of physiological dysfunction, and no clear dose-response relationship between exposure and symptom reactions has been observed. In addition, the underlying etiology and pathogenic processes of the disorder remain unknown and disputed, although biologic and psychologic hypotheses abound. It is currently debated whether MCS should be considered a clinical entity at all. Nevertheless, in the last few decades MCS has received considerable scientific and governmental attention in light of the many persons reporting this illness. In this review, we provide a general overview of the history, definition, demographics, prevalence, and etiologic challenges in defining and understanding MCS.

Mast cell activation may explain many cases of chemical intolerance

BackgroundThis paper explores the relationship between chemical intolerance (CI) and mast cell activation syndrome (MCAS). Worldwide observations provide evidence for a two-stage disease process called toxicant-induced loss of tolerance (TILT) as a mechanism for CI. TILT is initiated by a major exposure event or a series of lower-level exposures. Subsequently, affected individuals report that common chemical inhalants, foods, and drugs (i.e., various xenobiotics) trigger multi-system symptoms.PurposeTo determine whether MCAS provides a plausible biological mechanism for CI/TILT.MethodsUsing the validated Quick Environmental Exposure and Sensitivity Inventory (QEESI), we compared patients diagnosed with MCAS (n = 147) to individuals who reported chemical intolerances (CI/TILT) following various exposures (n = 345) and to healthy controls (n = 76). Using ANOVA, we compared QEESI scores across groups. Clinical scores for the MCAS patient group were used to predict CI status using logistic regression.ResultsMore than half (59%) of the MCAS group met criteria for CI. A logistic regression model illustrates that as the likelihood of patients having MCAS increased, their likelihood of having CI/TILT similarly increased, to a near-perfect correspondence at the high ends of the QEESI and clinical MCAS scores. Symptom and intolerance patterns were nearly identical for the CI and MCAS groups.DiscussionWe present data suggesting that xenobiotic activation of mast cells may underlie CI/TILT. The strikingly similar symptom and intolerance patterns for MCAS and TILT suggest that xenobiotics disrupt mast cells, leading to either or both of these challenging conditions. Faced with patients suffering from complex illness affecting multiple organ systems and fluctuating inflammatory, allergic, and dystrophic symptoms, clinicians can now ask themselves two questions: (1) Could MCAS be at the root of these problems? (2) Could environmental exposures be driving MC activation and mediator release? Increasing our understanding of the connection between TILT and MCs has the potential to expose a new link between environmental exposures and illness, offering new opportunities for improving individual and public health.ConclusionThe close correspondence between QEESI scores and symptom patterns for MCAS and TILT patients supports xenobiotic-driven mast cell activation and mediator release (i.e., MCAS) as a plausible unifying biological mechanism for CI/TILT, with profound implications for medicine, public health, and regulatory toxicology.

Toxicant-induced loss of tolerance for chemicals, foods, and drugs: assessing patterns of exposure behind a global phenomenon

BackgroundDespite 15–36% of the U.S. population reporting Chemical Intolerances (CI) or sensitivity, the condition has been overlooked in medicine and public health. CI is characterized by multisystem symptoms and new-onset intolerances that develop in a subset of individuals following a major chemical exposure event or repeated low-level exposures. While Toxicant-Induced Loss of Tolerance (TILT) is a two-stage disease mechanism proposed to explain CI, less is known about the exposures that initiate the disease, than about the intolerances that have been documented.MethodsWe reviewed eight major exposure events that preceded onset of chemical intolerance in groups of individuals sharing the same exposure. Our goal was to identify the chemicals and/or groups of chemicals that were most pervasive during each exposure event as well as identify the concentrations of key chemicals involved in each exposure event and the proportions of exposed individuals who ultimately developed TILT following exposure. Case studies we selected for review included (1) workers at U.S. Environmental Protection Agency (EPA) headquarters during renovations; (2) Gulf War veterans; (3) pesticide exposure among casino workers; (4) exposure to aircraft oil fumes; (5) the World Trade Center tragedy; (6) surgical implants; (7) moldy environments; and (8) tunnel workers exposed to solvents.ResultsMixed volatile and semi-volatile organic compounds (VOCs and SVOCs), followed by pesticides and combustion products were most prevalent across TILT initiation events. As a broader category, synthetic organic chemicals and their combustion products were the primary exposures associated with chemical intolerance. Such chemicals included pesticides, peroxides, nerve agents, anti-nerve agent drugs, lubricants and additives, xylene, benzene, and acetone.ConclusionA select group of exposures were predominant in several major initiating events, suggesting their potential role in TILT initiation. Such insights are useful to public health scientists, physicians, and policymakers seeking to minimize harmful exposures and prevent future disease.

Toxicant-Induced Loss of Tolerance: A Theory to Account for Multiple Chemical Sensitivity

Toxicant-Induced Loss of Tolerance: A Theory to Account for Multiple Chemical Sensitivity

Could Environmental Exposures Facilitate the Incidence of Addictive Behaviors?

Could Environmental Exposures Facilitate the Incidence of Addictive Behaviors?

INDOOR AIR QUALITY: Scented Products Emit a Bouquet of VOCs

A survey of selected scented consumer goods showed the products emitted more than 100 volatile organic compounds (VOCs), including some that are classified as toxic or hazardous by federal laws.1 Even products advertised as “green,” “natural,” or “organic” emitted as many hazardous chemicals as standard ones. Anne Steinemann, a professor of civil and environmental engineering and public affairs at the University of Washington, Seattle, and colleagues used gas chromatography–mass spectrometry to analyze VOCs given off by the products. They tested 25 air fresheners, laundry detergents, fabric softeners, dryer sheets, disinfectants, dish detergents, all-purpose cleaners, soaps, hand sanitizers, lotions, deodorants, and shampoos. Many of the products tested are top sellers in their category. A single fragrance in a product can contain a mixture of hundreds of chemicals, some of which (e.g., limonene, a citrus scent) react with ozone in ambient air to form dangerous secondary pollutants, including formaldehyde.2 The researchers detected 133 different VOCs. Most commonly detected were limonene, α- and β-pinene (pine scents), and ethanol and acetone (often used as carriers for fragrance chemicals).1 Steinemann and colleagues found the average number of VOCs emitted was 17.1 Each product emitted 1–8 toxic or hazardous chemicals, and close to half (44%) generated at least 1 of 24 carcinogenic hazardous air pollutants, such as acetaldehyde, 1,4-dioxane, formaldehyde, or methylene chloride.1 These hazardous air pollutants have no safe exposure level, according to the U.S. Environmental Protection Agency.3 Of the 133 VOCs detected, only ethanol was listed on any label (for 2 products), and only ethanol and 2-butoxyethanol were listed on any Material Safety Data Sheet (for 5 products and 1 product, respectively).1 The Consumer Product Safety Commission, which regulates cleaning supplies, air fresheners, and laundry products, currently does not require manufacturers to disclose any ingredients on the label, including fragrances in these products.4 The same is true for fragrances in personal care items, which are overseen by the Food and Drug Administration.5 The Household Product Labeling Act, currently under review in the U.S. Senate, would require manufacturers to label consumer products with all ingredients, including fragrance mixtures.6 “Disclosing all ingredients could be a first step to understanding potential toxicity and health effects,” says Steinemann. Although the authors did not seek to assess whether use of any of the products studied would be associated with any risk,1 Steinemann says she receives hundreds of letters, phone calls, and e-mails from people who report a variety of respiratory, dermatological, and neurological problems they attribute to scented products: “Children have seizures after exposure to dryer sheets, and adults pass out around air fresheners,” she says.7 Steinemann and colleague Stanley M. Caress have written elsewhere that 19% of respondents across two U.S. telephone surveys reported health problems they attributed to air fresheners, and nearly 11% reported irritation they attributed to scented laundry products vented outdoors.8 “It’s important to take people’s complaints seriously,” says Steinemann, because “these human experiences are helping to inform science.” One of her next projects will focus on biomarkers of exposure and effect to better understand how fragranced products may cause a range of adverse health effects. “The ultimate goal is to improve public health,” Steinemann says. For now, she recommends cleaning with basic supplies like vinegar and baking soda. Steinemann’s study “strongly suggests that we need to find unscented alternatives for cleaning our homes, laundry, and ourselves,” says Claudia Miller, an allergist and immunologist at the University of Texas Health Science Center at San Antonio. An expert in chemical sensitivity, or toxicant-induced loss of tolerance, Miller created the Quick Environmental Exposure and Sensitivity Inventory,9 a screening tool for chemical intolerance. According to Miller, products intended to keep homes smelling fresh can set people up for a lifetime of chemically induced illness, and repeated exposure to small amounts of household chemicals can trigger symptoms to previously tolerated chemicals.10 “The best smell is no smell,” Miller says.

Abdiction/Addiction Connection

Sometimes in science, as in politics, connections arise that may at first glance appear to be strange bedfellows. That might be the natural first impression of a potential association between chemical intolerance and addiction. But although the conditions are manifested by behaviors that appear to be polar opposites—substance avoidance (or abdiction, as some are beginning to call it) by the chemically intolerant, and compulsive substance use by the addicted—there is evidence to suggest that, biologically, they may actually have much in common. That was the concept behind “Addiction and Chemical Intolerance: A Shared Etiology?” This conference, held 19–20 September 2005 in Research Triangle Park, North Carolina, was the first scientific meeting to be cosponsored by the NIEHS and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). It was also the first time researchers from the fields of environmental health and addiction convened to explore common ground and potential collaborations. “The idea of hosting a conference on chemical intolerance and addiction stems from a long history of individual physicians’ reporting observations on patients that looked like addiction to chemicals, foods, caffeine, or alcoholic beverages,” explained conference chair Claudia Miller, a professor and researcher in environmental medicine at The University of Texas Health Science Center at San Antonio. “There is a striking resemblance between the symptoms and responses to substances reported by chemically intolerant patients and individuals addicted to drugs or alcohol.” Firm numbers on addiction and chemical intolerance are hard to come by, in part because both conditions often go undiagnosed. Approximately 67% of all Americans drink alcohol, yet 90% of the alcohol is consumed by only 30% of the population, said NIAAA director Ting-Kai Li in his keynote address. In the latter half of 2003 (the most recent year for which figures are available), there were 627,923 drug-related emergency room visits in the United States, according to the Drug Abuse Warning Network of the U.S. Substance Abuse and Mental Health Services Administration. As for chemical intolerance, epidemiologic figures compiled and reported at the meeting by William Meggs, a professor of emergency medicine at East Carolina University, suggest the prevalence of the condition (self-reported) to be approximately 12% of the U.S. population, with approximately 4% self-reporting as “seriously affected.” Miller contends that addiction and chemical intolerance represent divergent physiologic responses to a shared underlying disease mechanism she calls toxicant-induced loss of tolerance (TILT). In TILT, a chemical exposure—either acute or chronic and low-level—initiates sensitization to even small amounts of structurally diverse chemicals found in foods, drugs, alcoholic and caffeinated beverages, pesticides, mold toxins and other elements of indoor air, implanted devices, solvents, cleaning chemicals, and more. Thereafter, when affected individuals are exposed to everyday “triggering” substances such as foods, traffic exhaust, or fragrances, they report multisystem symptoms including headache, nausea, difficulty breathing, muscle spasms, and rashes. The fact that different people exhibit different constellations of symptoms has made it difficult to conduct epidemiologic studies or arrive at a case definition, Miller says. In the past, these difficulties have led some observers to speculate that chemical intolerance is psychogenic in origin. As she outlined in her presentation to the approximately 120 attendees, Miller postulates that the TILT mechanism can lead to either abdiction or addiction, with both behaviors intended to avoid unpleasant withdrawal symptoms. She further proposes that TILT may underlie a wide variety of chronic diseases that are increasing in prevalence worldwide, such as asthma, autism, chronic fatigue syndrome, fibromyalgia, and depression. (She described these proposals in depth in an article in the January 2001 issue of Addiction.)

Toxicant-induced Loss of Tolerance

Drug addiction and multiple chemical intolerance (abdiction) appear to be polar opposites--the former characterized by craving and dependency, the latter by aversion. However, when the two are viewed in juxtaposition similarities emerge, revealing a common underlying dynamic, one which appears to be a new paradigm of disease. TILT, or toxicant-induced loss of tolerance, bridges the gap between addiction and abdiction and has the potential to explain a variety of illnesses, including certain cases of asthma, migraine headaches and depression, as well as chronic fatigue syndrome, fibromyalgia and Gulf War syndrome. This paper argues that both addiction and chemical intolerance involve a fundamental breakdown in innate tolerance, resulting in the amplification of various biological effects, particularly withdrawal symptoms. While addicts seek further exposures so as to avoid unpleasant withdrawal symptoms, chemically intolerant individuals shun their problem exposures, but for the same reason - to avoid unpl...

Toxicant-induced loss of tolerance.

Drug addiction and multiple chemical intolerance (abdiction) appear to be polar opposites--the former characterized by craving and dependency, the latter by aversion. However, when the two are viewed in juxtaposition similarities emerge, revealing a common underlying dynamic, one which appears to be a new paradigm of disease. TILT, or toxicant-induced loss of tolerance, bridges the gap between addiction and abduction and has the potential to explain a variety of illnesses, including certain cases of asthma, migraine headaches and depression, as well as chronic fatigue syndrome, fibromyalgia and "Gulf War syndrome". This paper argues that both addiction and chemical intolerance involve a fundamental breakdown in innate tolerance, resulting in an amplification of various biological effects, particularly withdrawal symptoms. While addicts seek further exposures so as to avoid unpleasant withdrawal symptoms, chemically intolerant individuals shun their problem exposures, but for the same reason--to avoid unpleasant withdrawal symptoms. These observations raise critical questions: do addictive drugs and environmental pollutants initiate an identical disease process? Once this process begins, can both addictants and pollutants trigger symptoms and cravings? TILT opens a new window between the fields of addiction and environmental medicine, one that has the potential to transform neighboring realms of medicine, psychology, psychiatry and toxicology.

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

'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 to 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.

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

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

Toxicant-induced loss of tolerance--an emerging theory of disease?

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 withdrawallike 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.

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

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

Chemical sensitivity: symptom, syndrome or mechanism for disease?

Several different meanings have been attached to the term “chemical sensitivity” by those who use it. Feeling ill from odors is a symptom reported by approximately one-third of the population. The syndrome of chemical sensitivity, frequently called “Multiple Chemical Sensitivity” or “MCS” has been the subject of three federallysponsored workshops; at least five different case definitions for research on MCS have been proposed. In contrast, the hypothesis that chemical sensitivity may be a mechanism for disease posits that a broad spectrum of “recognized” chronic illnesses, ranging from asthma and migraine to depression and chronic fatigue, may be the consequence of environmental chemical exposures. According to this theory, a two-step process occurs: (1) an initial salient exposure event(s) (for example, a one-time, intermittent, or continuous exposure to pesticides, solvents, or air contaminants in a sick building) interacts with a susceptible individual, causing loss of tolerance for everyday, low level chemical inhalants (car exhaust, fragrances, cleaning agents), as well as for foods, drugs, alcohol, and caffeine; (2) thereafter, such common, formerly well-tolerated substances trigger symptoms, thus perpetuating illness. “Masking” (acclimatization, apposition, and addiction) may hide these exposure-symptom relationships, thus obfuscating the environmental etiology of the illness. Accumulating clinical observations lend credence to a view of chemical sensitivity as an emerging theory of disease causation and underscore the need for its testing in a rational, scientific manner. While chemical sensitivity may be the consequence of chemical exposure, the term “toxicant-induced loss of tolerance” more fully describes the two-step process under scrutiny.