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 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.

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. 1987:2;655-662

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 985:88;376-384.

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 1993;48:14-18.

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 Dec;114(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 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.

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 1999;104:1183-1188

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

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

39. Induction Mechanism • Positive feed back loop • Induction exposure produces neurogenic inflammation

43. End Organ Sensitization

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 May;161(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. 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 Induce Airway Inflammation

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