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My Presentation. Who I Am: Veterinary Medicine. Morphometric Assessment of Concentration- and Time-Dependent Injury in the Nasal Airways of Rats Exposed to Chlorine Gas. 1 Anthony W atkins, 2 A nnie J arabek, 1 Jack Harkema

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  1. My Presentation

  2. Who I Am: Veterinary Medicine

  3. Morphometric Assessment of Concentration- and Time-Dependent Injury in the Nasal Airways of Rats Exposed to Chlorine Gas 1AnthonyWatkins, 2Annie Jarabek, 1Jack Harkema • 1Department of Pathobiology and Diagnostic Investigation,Michigan State University, East Lansing, MI 48824. 2U.S. Environmental Protection Agency, Research Triangle Park, NC.

  4. Chlorine: The Oxidizing Halogen • High Reactivity with Other Elements & Versatility in Reactions • Toxic Effects in its Gaseous State • Morphometric Assessment of Toxicity in Nasal Airway

  5. High Reactivity & Reaction Versatility • High solubility in water: Production of Chloride Acids. • Reactions with numerous elements: Hydrogen, oxygen, organic compounds, alkali and transition metals, etc. • Participates in an array of reactions: chlorination, hydrochlorination, etc., to create chemical intermediates. • Intermediates used to create end-products: disinfectants, aerosols, pesticides, textiles, paint removers, and bleaches. • Used as an effective chemical warfare agent in War World I and the Iraqi War due to its high solubility property. • Gori, 1994.

  6. Toxic Effects in its Gaseous State Cl2(g) + H20(l) HOCl(aq) + HCl(aq) Reaction Mimicked in Nasal Airway (Chlorine and Moist Lining) Cl2(g) + H20(l) HOCl(aq) + HCl(aq) Mucosal Water *Subsequent Ionization follows after this reaction.* • Winder, 2001.

  7. Kinetics of Nasal Epithelial Tissue Responses to Inhaled Chlorine • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 • Cl2 Necrosis – Inflammation – Hyperplasia – Mucous Cell Metaplasia

  8. Assessing the Degree of Toxicity Haber’s Law • Chlorine toxicity in the nasal airways is measured by morphometry: examining the amount of mucous-cell metaplasia that has occurred in the proximal airway (accumulation of mucosubstances). • Haber’s Law is used as the primary relationship to determine the degree of toxicity present in the body. C x T = Total Dose Concentration (ppm) x Time [Duration] (days) Zwart and Wouterson, 1988;Hoyle et. al., 2010

  9. Purpose and Hypothesis • Purpose: To determine the severity of nasal injury in rats exposed to various exposure regimens to evaluate the contribution of concentration (c) and time (t; duration) of exposure. • Hypothesis: The exposure regimen, rather than the total dose, determines the manifestation and magnitude of chlorine-induced nasal pathology.

  10. Rat Nasal Anatomy and Histology • Sagittal view of the rat nose (without septum). • S = squamous, I = incisor, T/R = transitional / respiratory epithelium, HP = hard palate, O = olfactory epithelium, OB = olfactory bulb, and NPD = nasopharyngeal duct. • Dashed blue line demarcates region of T/R epithelium.

  11. The Experimental Design Female F344 Rats Exposure Regimen (c x t) 1.0 ppm x 5 Days; 6h/day 0.5 ppm x 10 Days; 6h/day Morphometric Analysis of Mucous Cell Metaplasia (Volume Density) MT = Maxilloturbinate

  12. Results of Study

  13. Nasal Histopathology: Concentration- and Time-Dependent Responses to Cl2

  14. Nasal Histopathology: Persistence of Cl2-Induced Nasal Toxicity

  15. Dose-Dependent Responses to 5-Day Cl2 Exposure: Intraepithelial Mucus in Maxilloturbinates

  16. Dose-Dependent Responses to 10-Day Cl2 Exposure: Intraepithelial Mucus in Maxilloturbinates

  17. Time-Dependent Responses to Cl2 Exposure: Intraepithelial Mucus

  18. Summary • 5- and 10-day Cl2 exposure caused mucous cell metaplasia in nasal epithelium. • Amount of mucous cell metaplasia was both time (t)- and concentration (c)-dependent. • Rats exposed to the higher c for the shorter t had significantly less intraepithelial mucus compared to rats exposed to the lower c for the longer t.

  19. Conclusions & Need of Future Studies (Summer 2012) • The exposure regimen, rather than total dose (c x t), should be used to estimate chlorine-induced mucous cell metaplasia. • Future studies are needed to determine how other Cl2-induced nasal lesions are dependent on (c x t).

  20. Current Study (Fall 2012) • Continuation of investigating different parameters to support hypothesis (the exposure regimen versus the total dose). • First inflammatory response and parameters (neutrophils)

  21. Final Study (Fall 2012 / Spring 2013) • Final study of investigating different parameters to support hypothesis (the exposure regimen versus the total dose). • Second inflammatory response and parameters (eosinophils)

  22. Acknowledgements • Dr. Jack Harkema (PI) • Annie Jarabek (EPA) • Experimental Pathology & Toxicology Lab • U.S. Environmental Protection Agency • CVM (College of Veterinary Medicine) Summer Research Program • NIH Grant R25 HL103156

  23. References • Gori, G. B. (1994). Chapter 2: Chlorine. Regulatory Toxicology and Pharmacology20: S69-S125. • Hoyle, G. W., W. Chang, J. Chen, C. F. Schlueter, and R. J. Rando. (2010). Deviations from Haber’s Law for Multiple Measures of Acute Lung Injury in Chlorine-Exposed Mice. Toxicological Sciences 118:696-703. • Winder, C. (2001). The Toxicology of Chlorine. Environmental Research Section A85: 105-114. • Zwart, A. and R. A. Woutersen. (1988). Acute inhalation toxicity of chlorine in rats and mice: time-concentration-mortality relationships and effects on respiration. Journal of Hazardous Materials 19: 195-208.

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