Identifying potential initiators
The purpose of this paper was to examine eight major exposure events associated with TILT to better understand the often-misunderstood pathology of toxicant induction (the initiation step) followed by loss of tolerance (the second and often only observed step). We found that mixed VOCs/SVOCs, followed by synthetic pesticides and combustion products, were the primary exposures associated with TILT initiation. In many instances, such as exposure to pesticides, mixed VOCs/SVOCs, nerve agents, anti-nerve agent pills, lubricants and additives, and WTC exposures could be housed under the phrase “synthetic organics,” as defined earlier. That such exposures were predominant in several major initiating events suggests that they may play a role in TILT initiation and provides further evidence for TILT as a new, two-step disease mechanism.
As a broader group, synthetic organic chemicals were a primary source in five cases (Gulf War, building remodeling, aircraft oil fumes, casino workers, tunnel workers) and a secondary source in three cases (WTC tragedy, moldy environment, implants). Four of eight initiating events (Gulf War Illness, WTC tragedy, Aerotoxic Syndrome, tunnel workers) involved decomposition of synthetic organics by burning or pyrolysis, producing secondary exposures. Such combustion products consist of variable mixtures of organic and inorganic gases and particles. The fact that these exposures were pervasive in several major events suggests their relevance to TILT initiation.
Although the proportion of exposed and/or ill individuals who later developed TILT fluctuated considerably depending on the exposure event, the proportions across all cases were far from trivial, supporting the potential magnitude of this public health problem on a global level. The largest proportion of exposed individuals to develop TILT occurred in the case involving the family in a moldy home, potentially due to gene-related similarities between individuals with heightened susceptibility. The lowest proportion occurred surrounding the EPA building renovation, still resulting in nearly a dozen cases among just 2000 exposed.
To date, the identification of TILT initiators stems from observational reports and studies of major exposure events, as highlighted in this analysis. Noteworthy, however, is a study undertaken for the European Commission [5, 6] that revealed other initiators including wood-preservative chemicals (pentachlorophenol), organic solvents, anesthetic agents, carpets and glue, and formaldehyde.
The case of the EPA building renovation was the first large-scale event to demonstrate TILT. The fact that numerous employees developed chemical intolerance following this exposure served as early evidence for TILT as a new medical problem that can evolve in some sick building occupants.
Miller and Prihoda , who surveyed Gulf War veterans, chemically intolerant patients, surgical implant patients, and a control group, used the QEESI to identify individuals who reported developing multisystem symptoms and new-onset intolerances for structurally unrelated chemicals, foods, and drugs which they had previously tolerated and are tolerated by most people. This recurrent pattern of illness following major exposure events occurring in unrelated individuals seen by different doctors in different countries supports a shared underlying mechanism.
Exposures and associated symptoms reported by individuals involved in the WTC collapse closely parallel symptoms of the Gulf War veterans, EPA workers, and others reporting TILT following exposures to combustion products and synthetic organics from building and furnishing materials. Dust samples from the WTC wreckage contained complex mixtures including PAHs (combustion products), pesticides, PCBs (building materials), polychlorinated dibenzodioxins, phthalate esters, and brominated diphenyl ethers (used as fire retardants) . It remains unclear which specific chemicals or chemical combinations are responsible for TILT initiation.
Pesticides were implicated in at least two of the initiating events explored in this analysis, namely, the Gulf War and casino workers examples. As early as the 1960s, occupational health practitioners observed that some individuals who “recovered” from acute pesticide poisoning experienced protracted multisystem symptoms . In the same report, 20 of 114 victims stated that even 3 years later they could no longer tolerate pesticides and became symptomatic from merely a “whiff” of pesticides. Among a group of Nicaraguan agricultural workers, Rosenstock et al.  noted decrements in neuropsychological performance that persisted years after accidental organophosphate intoxication. Various studies have similarly shown persistent memory difficulties, cognitive problems, motor impairment, mood alteration, fatigue, and other symptoms following organophosphate pesticide exposure [3, 60, 61].
In a study by Miller and Mitzel (1995) , 112 individuals reported TILT-like symptoms following either a well-documented pesticide exposure or building remodeling. The reason this study was not included in the eight events documented in this paper was because unique initiating exposures were difficult to document, a ubiquitous defect of many studies of exquisitely sensitive persons. Despite having had entirely different exposures, both groups exhibited remarkably similar symptom patterns and subsequently reported near-identical triggers (chemicals and specific foods) for their symptoms. Not unexpectedly, the pesticide-exposed group reported somewhat more severe neuromuscular, affective, airway, gastrointestinal, and cardiac symptoms. This study, coupled with Miller’s detailed evaluations of Gulf War veterans, led to the development of the QEESI (detailed described later).
Numerous studies have linked chronic multisystem symptoms and new-onset chemical intolerances to organophosphate and carbamate pesticide exposures. Such studies include the case of the casino workers explored in this analysis, as well as farmers, an attorney whose home was exterminated, and others [27, 62, 63]. Ashford et al.’s nine-country European study likewise identified TILT-like cases following various pesticide exposures [5, 6]. Furthermore, in addition to contamination from air bleeding off of the engines, aircraft cabins are often treated with pesticides .
While vehicle exhaust and other combustion products are commonly reported triggers, this analysis also points to these pollutants as potential initiators (e.g., the WTC disaster, Gulf War veterans’ exposures to oil well fire smoke, diesel exhaust, and incineration of human waste, plastics, and other battlefield materials). More recently, soldiers deployed to Iraq and Afghanistan have reported persistent pulmonary and multisystem symptoms attributed to exposure to combustion products from nearby burn pits in which a wide range of trash was burned, including, but not limited to, paint, medical and human waste, metal/aluminum cans, munitions, petroleum and lubricant products, plastics, rubber, wood, electronics, and discarded food [65, 66]. Chronic and acute upper and lower airway disease due to combustion products is well documented. Less widely known are studies linking air pollution with psychiatric emergency room visits, psychiatric hospital admissions, family disturbances, and anxiety [67,68,69,70,71,72,73]. Whether individuals with these exposures develop new-onset chemical, food, and drug intolerances needs to be further studied.
Research has linked indoor air pollution to reduced cognitive performance and productivity [74, 75]. Others have shown an association between air pollution and autism [76, 77]. We (authors Miller and Palmer) have documented a two-to-three-fold risk for autism and for ADHD in offspring of mothers who are chemical intolerant, based on the QEESI .
Thousands of patients report developing multisystem symptoms and chemical, food, and drug intolerances following a wide variety of surgical implants. Common chemical exposures in these cases include silicone and various metals. In addition, processing aids and peroxides such as 2,4-dichlorobenzoyl peroxide are synthetic organics substances that may initiate TILT . Metals leaching from implants may also play a role .
In the U.S., increasing numbers of people report adverse reactions to mold . Molds release not only spores and fragments, but also mold VOCs (mVOCs) that become airborne and have toxic and immunogenic effects. Inamdar et al. [82,83,84] (2012) demonstrated adverse neurological effects on fruit flies (Drosophila melanogaster) of short-chain mVOCs containing as few as eight carbons (e.g., 1-octen-3-ol). With changing climate and increasing major flood events, mold appears to be placing more people at risk for developing TILT. Repairing or refurbishing wet interiors introduces potential exposures to cleaning chemicals, bleach, paints, and other exposures that can exacerbate illness. Unfortunately, many occupants have little choice but to remain in their homes during clean-up.
TILT-related dose and exposure levels
As it relates to the toxicity of various compounds, it has long been understood by toxicologists that the “dose makes the poison.” A more nuanced approach to toxicology, however, is to say that the “dose plus host makes the poison.” This latter concept highlights the important role that person-to-person biological variation plays in determining the toxicity of a given xenobiotic to a particular individual. Polymorphisms in the genes that code for various cytochrome P450 (CYP) enzymes have been shown, for instance, to produce different metabolic phenotypes and in turn play a role in such variation. For example, individuals whose CYP2D6 phenotype renders them poor metabolizers of debrisoquin are at risk of various adverse drug reactions, whereas extensive metabolizers are at greater risk of lung cancer, perhaps due to the production of carcinogenic metabolites .
As it relates to TILT, our analysis demonstrates that important chemical concentration data are often missing from major exposure events, in some cases due to the hazardous nature of the event (e.g., Gulf War combat zone) or its unexpected and episodic occurrence (e.g., WTC disaster). While improved environmental field monitoring would contribute invaluably to understanding TILT, limited measurement data available for our analysis suggest that TILT initiation may occur within the range of chemical exposure levels typically considered hazardous (e.g., the tunnel workers being evacuated due to high benzene concentrations). While measurement data did not exist to characterize the numerous exposures experienced by Gulf War veterans, evidence from other combat zones in the same general geographic region similarly showed extremely high exposure levels (in this case for PM), as noted by an Institute of Medicine report on Joint Base Balad (one of the largest U.S. military bases in Iraq), stating that “the average of the 51 PM10 measurements was 709 µg/m3 (range 104–9576 µg/m3) and [that] the NAAQS [National Ambient Air Quality Standard] was exceeded for 49 of the 51 samples . Similar results were shown for PM2.5.
While concentration data did not exist for our case study on mold, measurements from related research has shown mVOC levels to range from non-detect to roughly 1 ppb in homes that experience complaints, suggesting that mVOCs may affect individuals at extremely low levels (if in fact they are responsible for the complaints). While this analysis did not focus on TILT triggers, such exposures appear to elicit symptoms at very low levels (below those described here for initiation). More field research is needed to determine chemical exposure levels and internal doses required to both initiate TILT and trigger symptoms in susceptible individuals to aid our understanding of chemical intolerance and help prevent future illness.
Chemical intolerance has been overlooked in both medicine and public health, despite 15–36% of the U.S. population reporting being “especially” or “unusually” intolerant to certain chemicals, and ~ 5% reporting physician-diagnosed “MCS,” “IEI,” or other environmentally or chemically related impairment .
A nationally representative U.S. population survey conducted in 2016 (n = 1137) found a prevalence of 25.9% self-reported chemical sensitivity and 12.8% reported medically diagnosed “multiple chemical sensitivities” or MCS . Two previous nationally representative U.S. population surveys, conducted in 2002–2003  (n = 1057) and 2005–2006  (n = 1058), found a prevalence (respectively) of 11.1% and 11.6% self-reported chemical sensitivity and 2.5% and 3.9% medically diagnosed MCS. Based on these data, the prevalence of chemical sensitivity may have increased by over 200%, and diagnosed MCS by over 300%, in the past decade.
In a U.S.-based study, 35% of people reported one or more types of adverse health effects attributed to exposure to fragranced consumer products such as cleaning supplies, air fresheners, fabric softeners, and personal care products . Fragranced consumer products are typically composed of tens to hundreds of compounds, many derived from petrochemicals . Fragrances are common symptom triggers for most chemically intolerant patients irrespective of their initiating event. It is not always clear whether exposure to a fragrance initiates TILT, or whether an individual associates their symptoms (e.g., headache, brain fog, breathing difficulties) to a distinctive odor for the first time.
Similarly, in Japan, Hojo et al. (2018)  reported a 10-year increase in CI in Japan from the 1999–2003 period to 2012–2015, based on QEESI scores for Chemical Intolerances, Other Intolerances, and Life Impact. Construction and renovation, which had been the predominant onset/trigger exposures for CI ten years ago, decreased from 69 to 35%, while electromagnetic fields increased significantly from 0 to 26%, perfume from 0 to 21%, and medical treatment from 2 to 7%. These changes may be attributable to greater exposure awareness, increased exposures to synthetic substances, and perhaps the proliferation and use of electronic devices. Notably, most of these reports from the U.S. and Japan involve triggering, the second stage of TILT, but not necessarily initiating exposures.
It is difficult to estimate TILT’s current prevalence and impact for a variety of reasons. First, there is little or no follow-up of exposed workers, families, soldiers or others except in a few countries where detailed, longitudinal data are collected. Even in those countries, few doctors are aware of TILT’s two-step mechanism, Initiation and Triggering. Additionally, there are no consistent biomarkers or unique pathology that clearly links illness to particular initiating exposures. For decades, Gulf War veterans fought for recognition of their illnesses. In 2016, Congress declared that Gulf War veterans with medically unexplained conditions that appeared during Gulf War service should be recognized. The Gulf War veterans had such diverse exposures, triggers, and symptoms, that a unifying mechanism has eluded researchers. Scientists and physicians saw no underlying etiology, just as Civil War doctors could not make sense of the fevers and symptoms of soldiers who fell ill. They did recognize one common denominator, fever, but their observations preceded the germ theory of disease and so they knew nothing of the microscopic invaders that were underlying the health crisis. Similarly, doctors today are likely facing another new disease mechanism [2, 7].
Identifying a physiological mechanism
Possible physiological mechanisms to explain TILT are being explored. Any proposed mechanism needs to address the two stages of TILT—initiation and triggering. We have described how this process often begins, citing examples of initiating exposures including employment in the EPA headquarters during renovation, participation in the Gulf War, pesticide exposure among casino workers, exposure to aircraft oil fumes, the World Trade Center tragedy, surgical implants, and damp and moldy environments. Following initiation, even tiny amounts of structurally diverse chemicals, foods, and drugs trigger symptoms and perpetuate illness. It is evident that both the nervous system and the immune system must participate in this process, although a specific biological mechanism and markers have remained elusive.
What we do know, based on worldwide observations by patients and clinicians, is that any mechanism purported to explain TILT must explain the characteristics most closely associated with this illness: (1) symptoms involving virtually any system in the body or several systems simultaneously; (2) differing symptoms and severity in different individuals, even those sharing the same exposure; (3) induction by a wide range of chemicals; (4) subsequent triggering at lower levels of exposure than those involved in initiation; (5) concomitant food intolerances, estimated to occur in a substantial percentage of those with chemical intolerances; (6) the spreading of intolerances to include other, often chemically dissimilar substances, each of which may trigger a different constellation of symptoms; (7) adaptation (masking), that is, acclimatization to incitants including various chemicals, foods and drugs, with continued exposure; withdrawal symptoms and loss of this tolerance with removal of the incitants; plus augmented response with re-exposure after an appropriate interval (for example, 4–7 days), and (8) an apparent threshold effect referred to by some practitioners as the patient’s “total load.”
When considering the two-stage process involved in TILT, it is useful to recall that multi-stage processes are not absent elsewhere in pathology. For instance, chemically—, or radiometrically—caused cancer proceeds through a mutagenic event, followed by promotion of the mutation to a recognized tumor [91, 92]. Chemicals that initiate mutations can be followed by promotion of the genetic damage by other chemicals that are recognized as promotors. The steps are independent, although some chemicals can be both initiators and promoters. Furthermore, endocrine disruption can cause damage to the reproductive system while not being apparent until puberty when developmental hormone production increases. Hormones are, after all, biochemical catalysts that accelerate somatic processes. TILT can be seen as another example of a multi-step damage mechanism in which the loss of tolerance to certain chemicals (or foods or drugs) is initiated by exposure(s), which later expresses itself as intolerance to specific chemicals—called “triggers.” Often the initiators and triggers can be dissimilar chemicals, foods, or drugs whose effects may express themselves at very low levels of exposure.
One promising potential physiological mechanism to explain TILT involves mast cells. Mast cells are the first line of defense involved in our bodies’ cellular immunity (as opposed to humoral). They consist of white blood cells that originate in the bone marrow and subsequently migrate to every tissue in our bodies during an immune response, in particular the interface between our tissues and the external environment—the nasal mucosa, the olfactory-limbic tract, lungs, skin, blood and lymph vessels, gastrointestinal tract, and urogenital tract. Mast cells are sometimes regarded as our “primitive immunity,” protecting the body against xenobiotics in the form of chemicals, foods, drugs, mold, and viruses. Further details on mast cells as a potential physiological mechanism underlying TILT is the focus of another manuscript currently under preparation by some of the current authors.
Opportunities and challenges in diagnosing TILT
Undoubtedly, personal exposure history, living conditions, nutritional status, and genetic and epigenetic make-up determine TILT susceptibility. Effects of major initiators (e.g., OPs, mold) may persist indefinitely, or even be lifelong. In contrast, symptoms triggered by chemicals, foods, or drugs may be reversible within hours or days. Affected individuals may be unable to link their symptoms to specific exposures if they are heavily "masked." Masking results from overlapping responses to many different chemicals, foods, and drugs, and the normal habituation that occurs with chronic exposures. Until "masked" individuals reduce their overall exposures, it may be impossible to know which if any of their symptoms or health problems may be related to their exposures. For a detailed discussion of masking, see Miller .
The ideal way to determine whether an individual is impacted by TILT and how they might modify their diets and environment to reduce their symptoms is through a specially designed hospital facility called an Environmental Medical Unit (EMU). EMUs employ "takeaway medicine" by controlling diet and insofar as possible eliminating all potential problem exposures in a chemically “clean” room. In an environmentally controlled medical unit, patients can be housed long enough (4–7 days) to achieve a clean baseline, free of symptoms, thus enabling double-blind, placebo-controlled challenges and allowing physicians to observe patients prior to EMU entry, after unmasking, and before and after specific exposure challenges, while employing objective measures such as proteomics, pulmonary function testing, or brain imaging. As microscopes enabled scientists to see the "germs" responsible for infectious diseases in the late 1800s, the EMU today is a tool that can enable physicians to see the effects of patients’ environments. Such facilities are needed for research, diagnosis, and treatment of TILT. Without these tools, the complex illnesses and exposures involved in TILT will continue to elude us. Currently, no EMU exists in the U.S.
To avoid missing or overlooking TILT, doctors must first understand initiation and triggering, and take detailed exposure histories. Overlooking an exposure that initiates TILT may be missing the only opportunity to intervene and prevent worsening health. Too many people remain in a sick building, a moldy home, or continue to use pesticides or other initiating/triggering chemicals, only to have their symptoms and intolerances spread to other triggers including diverse chemicals, foods, and drugs that never bothered them before. Importantly, if initiating exposures continue, TILT becomes frustratingly complex and nearly impossible to reverse.
The QEESI and BREESI diagnostic tools
The QEESI is a validated diagnostic tool developed by one of the current authors (Miller), which is used internationally by clinicians and researchers to evaluate patients, and to identify research subjects and controls in lieu of a case definition. It is an easy-to-complete and readily accessible questionnaire now used in over a dozen countries to help patients and their caregivers understand this condition and avoid key exposures. The QEESI can also be used to track the emergence of TILT following a major exposure event, to compare patient groups for research, and to document changes in symptoms and intolerances over time with treatment or avoidance [58, 93].
Of note, the QEESI was not the basis for TILT diagnosis or the inclusion of cases in the current analysis for two main reasons. First, the QEESI is a diagnostic tool that must be completed by patients. QEESI reveals triggers, not initiators. In the current analysis, we did not have access to the symptomatic populations who suffered from the described exposure events. Additionally, despite the growing use of the QEESI among medical professionals, it was not deployed to evaluate chemical intolerance by the initial scientists and medical doctors who first documented the exposure events examined in this analysis. In some cases, the exposure events even predated the development of the QEESI tool.
For future research, in addition to helping better understand the more widely documented exposure–TILT relationships, less understood areas such as those involving the intersection between ambient air pollution and psychiatric symptoms as well as the role of surgical implants in initiating TILT could be elucidated (e.g., pre/post-exposure) using the QEESI. Additionally, in the hands of epidemiologists, and perhaps workers or community groups, the QEESI can serve as a tool to facilitate studies of TILT in the wake of exposures such as:
Agricultural application of pesticides or herbicides such as glyphosate (now the most widely applied chemical for weed control on farms, lawns, roadways, and golf courses) that may expose workers, nearby residents, or consumers .
A large oil spill such as the Exxon Valdez in Alaska or the Deepwater Horizon spill in the Gulf of Mexico and the accompanied spraying of dispersant [95, 96].
Fracking, with below-ground injection and release of chemicals that have the potential to contaminate the local environment or pollute groundwater .
First responders, fire fighters, rescue workers, and others in the path of a major fire or explosion such as the destruction of the World Trade Center or the major wildfire that destroyed the city of Paradise, CA, in 2018 .
Military exposures such as combustion products from burn pits (e.g., Afghanistan) or the application of herbicides (e.g., Agent Orange used in Vietnam) [16, 99, 100].
Implanted devices, [36, 37, 41] procedures, materials, or drugs adopted on a broad scale such as various chemotherapies. Also, dental implants, sealants, intraocular lenses, stents, and other medical devices and procedures .
Adoption of new chemical practices or processes such as automated X-ray developing or cleaning of medical equipment, both of which have exposed hospital personnel to glutaraldehyde . Another emerging concern is ethylene oxide, which is used to sterilize plastics that cannot be autoclaved .
The QEESI is a useful tool for patients, researchers, and physicians alike, and is available online where it can be downloaded for free . Additional file 1: Figure S1 presents the so-called “Symptom Star,” which is an illustrative example of the type of visual results that the QEESI, once completed, can offer to help patients and physicians understand and diagnose TILT. In addition to the QEESI, the Brief Environmental Exposure and Sensitivity Inventory (BREESI) has been developed as a much shorter 3-item screener for chemical intolerance with excellent predictive validity . The purpose of the BREESI is to serve as a more useful tool for a quick assessment for TILT—ideal for personal or doctor office assessments and epidemiological studies.
Before there were microscopes, doctors could diagnose bacterial diseases only by signs and/or symptoms and patterns of spread. As with infectious diseases, we will need to apply new tools such as the QEESI and BREESI to better understand the exposure-symptom dynamics of TILT as well as the pathophysiology, genetics and epigenetics of TILT. During and following the Civil War, fever was the “hallmark symptom.” Today, TILT’s hallmark symptom is new-onset intolerances for chemicals, foods, and drugs that never bothered the individual previously and do not bother most people. Frequently, symptoms, and intolerances follow on the heels of recognizable environmental exposure, described herein as TILT initiators. A sick building may initiate TILT gradually over a period of weeks or months. In contrast, an organophosphate exposure may initiate TILT in as little as 2 weeks.
In the present paper, we examined a variety of important exposure events to help identify key exposures that may underlie TILT initiation. While results demonstrated several noteworthy associations, it is important to clarify that this study cannot confirm causation between the initiating exposures and TILT. Future research on exposure events and the underlying mechanism of TILT is needed to demonstrate causality.