The Scientific Case for Chemical
Sensitivity
William Meggs, MD, PhD, FACEP, FACMT
Brody Medical School at East Carolina University
Greenville, NC, USA
What is Chemical Sensitivity?
Chemical sensitivity
• Acquired Intolerance of airborne chemicals
• Products of combustion
– Tobacco smoke, vehicle exhaust, furnance fumes, gas
appliances
•
•
•
•
Perfumes and fragrances
Products for Cleaning
Pesticides
Paints and other solvents
– Outgassing of VOCs
How Many people suffer from
chemical Sensitivity?
Epidemiology of Chemical
Sensitivity
State
Prevalence
NC
30%
Seriously
affected
4%
CA
15.9%
7%
NM
15%
GA
12.6%
Sweden
30%
4%
References
• NC: Meggs WJ, Dunn KA, Bloch RM, Goodman PE, and
Davidoff AL. Arch Environ Health 1996;51:275-282.
• CA: Kreutzer R, Neutra RR, Lashuay N. Amer J Epid
150:1-12 (1999).
• NM: Voorhees RM. Memorandum from New Mexico
Deputy State Epidemiologist to Joe Thompson, Special
Council, Office of the Governor. 13 March 1998.
• GA: Caress SM, Steinemann AC, Waddick C. Arch
Environ Health (in press).
• Sweden: Millqvist E. Presentation, 19th International
Symposium on Man and His Environment in Health and
Disease. Dallas, TX. June, 2001.
MCS
• Multiple chemical sensitivity syndrome
• Defined by occupational physician
– Mark Cullen, MD, Yale University
• Onset with a chemical exposure
– No longer considered necessary
• Sensitive to multiple chemicals of multiple classes
• More than one organ system involved
– Respiratory system
– Nervous system
– Cullen M. Occup Med: State of Art Reviews. 1987:2;655-662
RADS
• Reactive airways dysfunction syndrome
• Defined by pulmonologist
• Asthma-like illness
– Bronchial hyper-reactivity
• Onset with a single acute chemical exposure
– Brooks S et al. Chest 985:88;376-384.
RUDS
•
•
•
Reactive upper-airways dysfunction syndrome
Upper airway analogue of RADS
Rhinitis and sinusitis developing in association
with an acute chemical exposure
–
Meggs WJ and Cleveland CH Jr. Rhinolaryngoscopy
findings in patients with the multiple chemical
sensitivity syndrome. Arch of Environ Health
1993;48:14-18.
SBS
• Sick building syndrome
• First described by WHO committee
• Widespread reports of illness among
workers in tightly sealed buildings
• Respiratory & neurological symptoms
dominant
Olfaction in ‘MCS’
•
•
•
•
Controlled study
Odor thresholds
Nasal resistance
Beck depression inventory
– Doty RL et al. Olfactory sensitivity, nasal resistance,
and autonomic function in patients with multiple
chemical sensitivities.
Arch Otolaryngol Head Neck Surg. 1988
Dec;114(12):1422-7.
Olfaction in MCS
• results do not support the hypothesis that
MCS is associated with greater olfactory
threshold sensitivity
• MCS is associated with:
– decreased nasal airway patency
– depression
– increased respiration rate
Challenge Tests
• Controlled study
– Subjective sensitivity versus tolerant
• Exposure to side-stream tobacco smoke
• Significant increase in symptoms
– nasal congestion, headache, chest discomfort or
tightness, and cough
• Significant increase in nasal resistance
Nasal resistance in cm H2O/L/sec
Significant Changes in nasal resistance in subjectively sensitive
But not in non-sensitive
8
7
6
5
East
4
3
2
1
0
pre
post
Is chemical sensitivity a disorder of
the airway mucosa?
•
•
•
•
Airway irritant sensitivity
Neurogenic inflammation
Chemoreceptors on sensory nerve c-fibers
Release of substance P and other
neurokinens
Rhinosinusitis
• Rhinitis and sinusitis are inflammation of
the nasal and sinus passages.
• These membranes are continuous.
• Causes and pathophysiology are the same.
• Rhinitis and sinusitis are regarded as one
disorder by the American Academy of
Otolaryngology.
• Hence, one disorder/one word.
Asthma and Rhinosinusitis:
“One Airway/One Disease”
• The airway is one continuous passage, with a
continuous lining.
• Both disease entities are characterized by airway
inflammation.
• The causes and pathophysiological mechanisms
are similar, though locations in the airway are
different.
• Asthma and rhinosinusitis are closely related
disorders.
Lower Airway Abnormalities in
Rhinosinusitis
• Antigen challenge in the nose leads to
inflammation in the lung.
• Rhinosinusitis is a major risk factor for
developing asthma.
• PFT abnormalities in patients with
rhinosinusitis.
Etiology of Airway Inflammation
•
•
•
•
Infection
Autoimmunity
Allergy
Irritants
Older Concept
• Extrinsic Airway Inflammation
– Allergic in origin
• Intrinsic Airway Inflammation
–
–
–
–
Allergy testing is negative
No extrinsic cause, intrinsic to the system
Non-allergic or Intrinsic asthma
Non-allergic rhinitis
Contemporary Concept
• Allergic Airway Inflammation
– Inflammation initiated by airborne proteins on
pollen grains, mold spores, dust mite feces,
coach roach debri, airborne mammalian
proteins
• Irritant Airway Inflammation
– Inflammation initiated by non-protein, lower
molecular weight chemicals such as solvents,
fumes, products of combustion, VOCs
Mechanisms
• Allergic Inflammation
– Proteins cross link IgE molecules on Mast Cell
surfaces, leading to the release of histamine and
other allergic mediators
• Neurogenic Inflammation
– Chemicals bind to chemoreceptors on sensory
nerve C-fibers, leading to the release of
Substance P, Calcitonin Gene Related Peptide,
and other neurogenic mediators
Crossover Network
• Nerve fibers have histamine receptors
• (some) Mast cells have substance P receptors
Chemical Irritant
Allergen
Sensory
Nerve
Sensory
Nerve
C-Fiber
C-Fiber
Substance P and
Other Mediators of
Neurogenic Inflammation
Mast Cell
Histamine and other
Mediators of Immediate
Hypersensitivity
Effector Cell (vasodilation, bronchospasm, bronchorrhea, chemotaxis … )
Role of Irritants in Allergic
Diseases
• Environmental Adjuvants
– Co-exposure to irritants and allergens leads to
allergic sensitization
– Humans exposed to Diesel Exhaust particles
with KLH develop KLH allergy
• Induction of end-organ sensitivity
– Hay fever patients who develop RADS develop
allergic asthma during pollen seasons
Diesel exhaust prompts sensitization to
new asthma-associated allergens
• Diesel exhaust particles administered by
aerosol 24 hours before antigen (KLH)
exposure
– IgE production to the antigen
• Exposure to antigen without diesel exhaust
particle exposure
– No IgE production to the antigen
– J Allergy Clin Immunol 1999;104:1183-1188
What about extra-airway manifestations
of chemical sensitivity?
Organ system involvement in
chemical sensitivity
Respiratory
Musculoskeletal
Gastrointestinal
Dermatological
Asthma, Rhinitis,
Sinusitis, Pneumonitis
Myositis, Arthritis,
Collagen Vascular
diseases
Irritable Bowel
Syndrome, Inflammatory
Bowel Disease
Dermatitis, Rosacea,
Cutaneous Vasculitis
Organ system involvement in
chemical sensitivity
Cardiovascular
Neurological
Psychiatric
hypertension,
Arrhythmias, Vasculitis,
Recurrent Anaphylaxis
Migraine, Fatigue,
Cognitive dysfunction,
Seizures, Coma
Bipolar disorder,
Depression, Psychosis
Neurogenic Switching
• The site of
inflammation can be
switched from the site
of stimulation
• Occurs in both allergic
and irritant airway
inflammation
• May play a role in
many disease
processes
Central
Nervous
System
Ne
rv
e
rve
e
N
Chemical
Irritants
Allergens
Mast
Cell
Mast
Cell
Effector Cell
Effector Cell
Generalized Adaptation Syndrome
Stage I. Preadaptation
(Nonadapted)
Stage II. Addicted
(Adapted)
IIa. Adapted
IIb Maladapted
Stage III. Postadapted
(Nonadapted)
Shock Reaction (Acute
reactivity to chemicals)
Tolerance
Chronic Illness
Exhaustion
Specific Adaptation Syndrome
• Mal-adaptation to a single substance
• Substance is tolerated without acute
reactions but there is chronic disease
• Elimination of one substance leads to
withdrawal symptoms then resolution of
chronic disease
• Re-exposure to that substance leads to acute
reactions
Chemical Stress Syndrome.
Stage 0. Normalcy
Tolerance of chemical exposures,
wellness without symptoms
Stage 1. –algia
Stage
Sensory Hyper-reactivity.
Subjective symptoms associate with
chemical exposures. (arthralgias,
myalgias, etc.)
Inflammatory reactions to chemicals
(arthritis, myositis, etc.)
Stage 2. –itis Stage
Stage 3. –osis Stage Fibrosis. Tissue destruction
(arthritic deformities, muscle
atrophy and necrosis,etc.)
Chemical Stress Syndrome
• Dynamic
• Patients move back and forth through the stages
• Exposures drive patients between the stages
– Eliminating inflammatory chemicals moves patients to
lower stages
– Exposure to inflammatory chemicals move patients to
higher stages
• Stage 3 – Fibrosis and scarring – is permanent
Irritant Rhinosinusitis
• Acquired disorder with onset related to
irritant exposures.
• Persistent airway inflammation.
• Exacerbations by irritant exposures that
were previously tolerated.
• Burning rather than itching sensation with
irritant exposures
Irritant Rhinosinusitis: Physical
Findings
• Edema and hypertrophy of the airways
• Abnormal mucous
– Thick, white to yellow, crusty exudates
• Nodular hyperplasia
• Hemorrhage
• Injection
– Posterior pharynx, uvula, soft pallet
• Discoloration
– Pale yellow to white patches of mucosa with prominent
blood vessels
Irritant Rhinosinusitis:
Pathological Features
• Chronic inflammation with lymphocytic
infiltrates
• Glandular hyperplasia
• Basement membrane thickening
• Nerve fiber proliferation
• Desquamation of the respiratory epithelium
• Defects in tight junctions
Induction Mechanism
• Positive feed back
loop
• Induction exposure
produces neurogenic
inflammation
High Dose Exposure
Airway Inflammation
Lose dose exposures
End Organ Sensitization
Millqvist Capsaicin inhalation cough test in patients
with “Sensory Hyperreactivity”
Millqvist Capsaicin inhalation cough test in patients
with “Sensory Hyperreactivity”
Patients
Controls
Sanico et al.
Am J Respir Crit Care Med. 2000 May;161(5):1631-5.
Toxicity vs. Sensitivity
100%
% exposed who
get poisoned
• Induction of chronic
airway inflammation
is a toxic effect.
• Dose Response Curve
of toxicity applies.
• Induction of allergic
sensitization by coexposure to irritants is
also a toxic effect.
ED50
dose
Examples of Irritants Reported to
Induce Airway Inflammation
•
•
•
•
•
Hydrochloric acid
Hydrogen sulfide
Acetic Acid
House Fire Smoke
Complex Mixtures Of
Airborne Volatile
Organic Chemicals
•
•
•
•
•
•
•
Chromium dioxide
Ammonia
Chlorine
Chlorine dioxide
Pesticides
Mycotoxins
Solvents
Examples of Irritants Reported to
Exacerbate Airway Inflammation
• Products of Combustion
– Environmental Tobacco Smoke, wood smoke,
furnace fumes, gas appliances
•
•
•
•
Cleaning products
Perfumes and Fragrances
Organic Solvents
Pesticides
Irritant Airway Inflammation and
Ill-conceived, Controversial
So-Called Syndromes
• Multiple Chemical Sensitivity Syndrome
• Sick Building Syndrome
• Gulf War Syndrome
Closing Comments
• Induction of Irritant Airway Inflammation is
a toxic effect with a classical dose response
curve.
• Pathophysiology is understood at cellular
level –on-going irritant exposures produce
ongoing pathological changes and
propagate the inflammation and
hyperresponsiveness.
• The epidemics of airway inflammation and
allergy may be preventable.
• Prediction: Neurogenic inflammation,
neurogenic switching, and irritant
sensitivity will have a broadening impact on
medicine in the coming decades.
References
• Randolph TG, Moss R. An Alternative Approach
to Allergies. Perennial, 1990.
• Dickey LD. Clinical Ecology. Thomas 1976.
• Rea WR. Chemical Sensitivity. Vol 1-4. CRC.
1992-1996.
• Randolph TG. Human ecology and susceptibility
to the chemical enviornment. Thomas, 1962.
• Ashford NA, Miller CS. Chemical exposures, Low
levels and high stakes. Van Nostrand Rheinhold.
1991. 2nd edition 1998.
References
• Meggs WJ. The
Inflammation Cure.
McGraw-Hill, 2003
• “In addition to explaining
inflammations causes &
its role in various diseases,
the atuhors offers advice
on how to maintain
‘inflammation balance’
and feel better.” NYTimes.