What initiates chemical intolerance? Findings from a large population-based survey of U.S. adults
Authors: Miller Claudia S. , Palmer Raymond F. , Kattari David , Masri Shahir , Ashford Nicholas A. , Rincon Rodolfo , Perales Roger B. , Grimes Carl , Sundblad Dana R. 
Published: August 2023

Abstract
Background
Worldwide 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.

Methods
A 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.

Results
Twenty 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).

Discussion
Participants 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.