For decades, both MCAS and CI patients have been misunderstood, marginalized, and often referred for mental health evaluation [6, 42, 43], with practitioners assigning diagnostic labels such as Somatic Symptom Disorder, Multiple Chemical Sensitivity (MCS), or Idiopathic Environmental Intolerances (IEI). Our findings suggest that a vast assortment of chemical exposures may initiate or escalate TILT/CI via chronic, aberrant MC activation.
Similarities between MCAS and TILT
In Figs. 3, 4, 5 and 6, we see that the MCAS and TILT groups had statistically higher scores than did controls on the QEESI scales. We also see that the MCAS and TILT groups share strikingly similar patterns of symptoms and intolerances involving structurally diverse xenobiotics (chemicals, foods, and drugs).
Symptom Severity Scale
For most symptoms, there were significant differences between the MCAS and TILT groups. There was only a slight increase in severity in Affective and Neuromuscular symptoms in the TILT group compared to the MCAS group. Mediators released by MCs in the central nervous system may explain the neuropsychiatric symptoms patients in both groups commonly report.
Chemical Intolerance Scale
The same classes of chemicals appear to trigger symptoms in the MCAS group as in the TILT group, with the TILT group more severely affected. The most problematic triggers for many MCAS patients are fragrances (VOCs at extraordinarily low exposure levels), which also pose major problems for CI individuals .
Other Intolerance Scale
There were no significant differences between the TILT and MCAS groups for most of the items. Only the chlorinated tap water item was scored significantly higher by the TILT group.
Life Impact Scale
The TILT group consistently scored higher than the MCAS group on most of the Life Impact items. Individuals with TILT/CI may have greater difficulty tolerating exposures commonly encountered in social activities.
“Masking” can result from overlapping responses to chemicals as well as from an individual’s tendency to habituate to these substances. Masking obscures the relationship between symptoms and chemical, food or drug triggers, literally hiding the cause-and-effect relationship between them from both patients and clinicians . The control group endorsed more items on the Masking Index than did the TILT and MCAS groups, consistent with our prior studies [38, 46]. People without CI or MCAS may be more apt to use alcohol, tobacco products, and caffeine for their stimulatory effects to offset fatigue and brain fog. The MCAS group reported greater use of drugs/medications which could reflect the fact that MCAS is more commonly treated with medications to prevent MC degranulation and/or to block MC mediator effects. Many individuals with CI have experienced so many adverse drug reactions that they avoid most drugs, favoring alternative therapies such as herbs, homeopathy, or acupuncture .
Connecting MCAS and TILT
Our understanding of the possible role for MCs in TILT is recent. Both patients with MCAS and those with TILT commonly report symptoms in multiple organ systems and often several systems simultaneously. MCs produce and release scores of chemical signals (generically termed “mediators”) that can affect organs, tissues, and systems throughout the body.
TILT encompasses exposures which may have initiated illness, as well as exposures which continue to trigger symptoms. However, until now, TILT has lacked a clear biological mechanism, which MCAS may provide. An understanding of TILT’s two stages, initiation and triggering suggests practical strategies for prevention and intervention, many of which also appear applicable to MCAS. Knowledge of the MCAS mechanism has the potential to inform new medical interventions and treatments for TILT. Failure to eliminate or reduce initiators such as pesticides or mold can result in chronic, even lifelong, illness in susceptible people, suggesting persistent MC activation and degranulation. The symptoms and findings in TILT patients may be best understood in the context of MCs and the mediators they release.
MCAS, TILT, and the nervous system
Our proposal that MCAS could be the biological mechanism for TILT arises out of recent recognition that the spectrum of MC disease extends beyond clinically recognizable allergic phenomena (e.g., allergy, anaphylaxis, urticaria, angioedema, atopic dermatitis or eczema) and differs from the rare MC malignancy called “mastocytosis”. Mastocytosis, first described in cutaneous form in the latter part of the nineteenth century and then in systemic form in the mid-twentieth century, manifests as chronic MCA resulting from neoplastic proliferation of MCs. Only recently, beginning in the 1980s, did researchers hypothesize the existence of MCAS [48, 49]. In 2007, the first case reports of MCAS appeared, describing patients with heightened release of MC mediators, yet without the excessive numbers of MCs which characterize mastocytosis. Many MC mediators have potent but short-lived effects. They are released locally in sensitized tissues and are exquisitely thermolabile, posing major challenges for measurement. MC’s menagerie of mediators produce multi-system inflammation at minimum, and not uncommonly allergic-like phenomena, and sometimes aberrancies in growth and development (typically benign) in virtually any tissue.
As immunologic "first responders", activated MCs can initiate, amplify, and prolong wide-ranging neuroimmune responses . Several investigators have pointed to neurogenic inflammation as a mechanism for CI [10, 51,52,53]. Rather than being the mechanism for CI, neuroinflammation may be the consequence of MCA and mediator release initiated by xenobiotic/chemical exposures. MCs affect neural function via their released mediators which bind with specific neuronal receptors [18, 54]. Also, MCs physically abut neurons in many tissues. Wherever such dyads are present, there is constant mediator “cross-talk” between the two cell types. Thus, MCA can provoke nearby neurons, inducing their associated symptoms; similarly, neurons can provoke nearby MCs, inducing their associated symptoms.
Correspondingly, quieting of MCs can help reduce neuronal activation, and, again, vice versa. . Additional file 1: Table S1 lists selected MC mediators involved in neuroinflammation (after Theoharides et al. [56,57,58,59]. Many investigators have documented neuroinflammation and inflammatory mediators in CI [53, 60,61,62].
Both MCAS and TILT have prominent neurological features. For example, organophosphate pesticides, which bind irreversibly to cholinergic receptors in the parasympathetic nervous system, appear to be among the most severe and permanently damaging TILT initiators. Correspondingly, organophosphates have been shown to trigger degranulation in human and animal MCs . The parasympathetic nervous system also modulates MC activity via a cholinergic pathway . MCs play pivotal roles in regulating cerebral blood flow , directly affecting brain function. Notably, both MCAS and TILT patients commonly report cognitive difficulties which may be the result of reduced cerebral blood flow due to chemical exposures, such as vehicle exhaust or pesticides . Brain MCs lie close to cerebral blood vessels, nerves, and the meninges, and inhabit the area postrema, choroid plexus, thalamus, hypothalamus, and limbic system, thus affecting memory, mood, and concentration. MCs can migrate between nerve tissue and lymphatics and appear to contribute to neuroinflammation in many disorders [67,68,69].
Notably, during stress, corticotropin-releasing factor is secreted by the hypothalamus, and, together with neurotensin, triggers MCs to release inflammatory and neurotoxic mediators, thereby disrupting the blood–brain barrier leading to neuroinflammation . Referring to ADHD, Song et al.  cite increasing evidence that MCs are involved in brain inflammation and neuropsychiatric disorders. Selective release of inflammatory mediators by MCs, interacting with glial cells and neurons, may activate the hypothalamic–pituitary–adrenal axis and disrupt blood–brain barrier integrity.
This physiology of MCAS mirrors the two stages of TILT—initiation and triggering, that is, initiation by a single intense exposure, or repeated lower-level exposures (pesticides, implants, drugs, etc.), which immunologically sensitize MCs in the brain and/or other key sites. Thereafter, chemicals structurally related to the initiating event, as well as unrelated xenobiotic exposures, trigger mediator release by these pathologically “twitchy” MCs. Cognitive and mood effects can include sudden rage (e.g., “road rage”); impulsive, violent, or abusive behaviors; addictive tendencies; mental confusion/fatigue; and/or a sense of depersonalization. MC “twitchiness” renders these cells vulnerable to a host of unrelated exposures that never bothered the person before and do not bother most people. Therefore, it seems plausible that MC sensitization and triggering can explain both stages of TILT—initiation and triggering.
Assessing and treating TILT/CI
Trigger identification and avoidance, rather than medications, are mainstays for treating CI. Likewise, these are the first steps for managing MCAS. Medications or desensitization procedures benefit many MCAS patients .
Identifying and assessing TILT
A systematic two-step evaluation works well for identifying patients with CI. First, administer the three-item Brief Environmental Exposure and Sensitivity Inventory (BREESI) screener [39, 71] to help identify individuals with significant intolerances for chemicals, foods, and drugs. If one or more BREESI items are endorsed, the full QEESI is administered (http://tiltresearch.org/wp-content/uploads/sites/30/2017/05/qeesi.pdf). These instruments help identify initiators and triggers of CI. A detailed exposure/symptom history and timeline coupled with the QEESI can help identify environments needing specific assessment. Removing initiating exposures appears to be essential for sustained improvement among both TILT and MCAS patients. For both conditions, the QEESI Symptom Star, graphed based upon serial administrations of the QEESI over time, illustrates the dynamics of symptom severity as chronologically related to exposures [72,73,74] (see Additional file 1: S2).
Interestingly, the MCAS group reported greater use of gas stoves than did the TILT group (58% vs 25%, respectively), perhaps suggesting an important source and intervention for MCAS patients who use gas stoves. Historically, as early as the 1960s, removing gas appliances has been a principal recommendation for CI individuals .
Both TILT and MCAS patients report adverse reactions to foods. Most of these adverse food reactions are food intolerances, as opposed to immunoglobulin-mediated food allergies, e.g., to peanuts, discoverable through skin or blood testing. The gold standard for identifying food intolerances involves the rigorous elimination of suspect foods for 4 to 7 days, followed by judicious reintroduction of single foods, one-at-a-time, under close medical and dietary supervision. We recommend assistance from dieticians who understand food intolerances, food addiction, and elimination diets. Note that foods themselves may be triggers, but food additives and chemical residues on foods also are frequent triggers. Many CI patients opt for organic foods where available and affordable.
After trigger identification and avoidance strategies are implemented, potential medical interventions for CI may include many of those used to treat MCAS, including agents that prevent MC degranulation like cromolyn and/or reduce tissue inflammation caused by MC mediators, such as H1 and H2 antihistamines administered simultaneously [31, 32, 76, 77]. Patients who respond adversely to excipients in commercially available medications may require compounded formulations. Interestingly, low-dose benzodiazepines help some MCAS patients due to the presence of benzodiazepine receptors on not only neurons, but also MCs [78, 79]. Pharmacotherapy for TILT/CI is by no means simple and requires minimizing exposures to chemicals known to precipitate adverse reactions and monitoring for inadvertent introduction of known triggers into the patient’s regimen, such as when a different formulation is provided as a refill. These same challenges exist for MCAS patients.
Other implications for clinical practice
MC degranulation and mediator release offer an elegant explanation for TILT’s numerous “unexplained” symptoms as well as for a host of so-called “idiopathic” illnesses sharing features of TILT. These include Gulf War Syndrome, breast implant illness, some mold-related illnesses, and various other exposure-induced conditions. Likewise, researchers and clinicians who wish to understand TILT-related or -overlapping conditions including fibromyalgia, chronic fatigue syndrome, depression, irritable bowel syndrome, asthma, eczema, attention deficit/hyperactivity disorder, or autism spectrum disorders [80, 81] need to take exposure histories which include asking when the illness began or was exacerbated, whether an initiating event occurred, and whether other people (or animals) were exposed or affected. Domestic cats for example are particularly sensitive to organophosphate pesticides 
To the best of our knowledge, this is the first investigation of the similarities between MCAS and TILT, suggesting MCAS as a plausible mechanism for TILT/CI. However, symptomatic overlap between two study populations is not necessarily proof of a shared pathophysiology. Although an important strength of this study is that the QEESI (the reference standard for identifying CI) was used for all respondents, the MCAS and TILT/CI samples were approximately 20 years apart in data collection. This may introduce unknown historical biases. Additionally, the number of study participants was relatively small and unequal between the groups. Further, only gender and age were assessed and adjusted in the analysis. Other factors, such as medical history (e.g., asthma, obesity, other comorbidities), socioeconomic status, and other lifestyle variables could potentially bias the analysis. As such, these results should be considered preliminary until further studies can be conducted.
Directions for future research and regulation
With this new understanding of the possible role of MCs in TILT, important questions arise concerning individual susceptibility differences that may be influenced by prior exposures, genetics, epigenetics, and nutrition.
Given the close parallels between TILT and MCAS, and the fact that MC activation and mediator release could explain much about TILT, future research should address the following questions: (1) What proportion of the TILT population manifests detectable MC activation as determined by a rigorous diagnostic MCAS work-up? (2) Do patients with TILT have somatic MC regulatory gene mutations as already found in many MCAS patients? (3) If so, are there recurrent mutations reflecting differing clonality patterns (e.g., in KIT)  characterizing differing subsets of TILT patients, perhaps even “fingerprinting” particular initiating exposures? and (4) Would specific treatments targeting MCs, or their mediators prove helpful for the TILT population as a whole or for certain subsets? As more research clarifies the role of MCs in TILT, targeted reduction of exposures can be implemented.