The Scientific Case for Chemical Sensitivity

1
The Scientific Case for Chemical Sensitivity

• William Meggs, MD, PhD, FACEP, FACMT
• Brody Medical School at East Carolina University
• Greenville, NC, USA

2
What is Chemical Sensitivity?
3
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

4
How Many people suffer from chemical Sensitivity?
5
Epidemiology of Chemical Sensitivity
6
References

• NC Meggs WJ, Dunn KA, Bloch RM, Goodman PE, and
  Davidoff AL. Arch Environ Health 199651275-282.
• CA Kreutzer R, Neutra RR, Lashuay N. Amer J Epid
  1501-12 (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.

7
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.
  19872655-662

8
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 98588376-384.

9
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
  19934814-18.

10
SBS

• Sick building syndrome
• First described by WHO committee
• Widespread reports of illness among workers in
  tightly sealed buildings
• Respiratory neurological symptoms dominant

11
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
  Dec114(12)1422-7.

12
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

13
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

14
Significant Changes in nasal resistance in
subjectively sensitive But not in non-sensitive
Nasal resistance in cm H2O/L/sec
15
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

16
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.

17
Asthma and RhinosinusitisOne 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.

18
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.

19
Etiology of Airway Inflammation

• Infection
• Autoimmunity
• Allergy
• Irritants

20
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

21
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

22
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

23
Crossover Network

• Nerve fibers have histamine receptors
• (some) Mast cells have substance P receptors

24
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

25
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 19991041183-1188

26
What about extra-airway manifestations of
chemical sensitivity?
27
Organ system involvement in chemical sensitivity
28
Organ system involvement in chemical sensitivity
29
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

30
Generalized Adaptation Syndrome
31
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

32
Chemical Stress Syndrome.
33
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

34
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

35
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

36
(No Transcript)
37
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

38
(No Transcript)
39
Induction Mechanism

• Positive feed back loop
• Induction exposure produces neurogenic
  inflammation

40
(No Transcript)
41
(No Transcript)
42
(No Transcript)
43
End Organ Sensitization
44
(No Transcript)
45
Millqvist Capsaicin inhalation cough test in
patients with Sensory Hyperreactivity
46
Millqvist Capsaicin inhalation cough test in
patients with Sensory Hyperreactivity
Patients Controls
47
Sanico et al. Am J Respir Crit Care Med. 2000
May161(5)1631-5.
48
Toxicity vs. Sensitivity

• Induction of chronic airway inflammation is a
  toxic effect.
• Dose Response Curve of toxicity applies.
• Induction of allergic sensitization by
  co-exposure to irritants is also a toxic effect.

49
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

50
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

51
Irritant Airway Inflammation and Ill-conceived,
Controversial So-Called Syndromes

• Multiple Chemical Sensitivity Syndrome
• Sick Building Syndrome
• Gulf War Syndrome

52
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.

53

• 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.

54
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.

55
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.