Veterinary Medicine Morphometric Assessment of Concentration and TimeDependent Injury in the Nasal Airways of Rats Exposed to Chlorine Gas 1 Anthony W atkins 2 A nnie J arabek 1 ID: 798581
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Slide1
My Presentation
Slide2Who I Am:
Veterinary Medicine
Slide3Morphometric Assessment of Concentration- and Time-Dependent Injury in the Nasal Airways of Rats Exposed to Chlorine Gas
1
Anthony
W
atkins,
2
A
nnie
Jarabek, 1Jack Harkema1Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824.2U.S. Environmental Protection Agency, Research Triangle Park, NC.
Slide4Chlorine: The Oxidizing Halogen
High Reactivity with Other Elements & Versatility in Reactions
Toxic Effects in its Gaseous State
Morphometric Assessment of Toxicity in Nasal Airway
Slide5High 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.
Slide6Toxic Effects in its Gaseous State
Cl
2
(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.
Slide7Kinetics of Nasal Epithelial Tissue Responses to Inhaled Chlorine
Cl
2
Cl
2
Cl
2
Cl
2
Cl2Cl2Cl2Cl2Cl2Cl2Cl2 Necrosis – Inflammation – Hyperplasia – Mucous Cell Metaplasia
Slide8Assessing the Degree of Toxicity
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)
Time [Duration] (days)xHaber’s LawZwart and Wouterson, 1988; Hoyle et. al., 2010
Slide9Purpose 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.
Slide10Rat 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.
Slide11Female F344 Rats
0.5 ppm x 10 Days; 6h/day
1.0 ppm x 5 Days; 6h/day
Exposure Regimen
(c x t)
Morphometric Analysis of Mucous Cell
Metaplasia
(Volume Density)
MT = Maxilloturbinate
The Experimental Design
Slide12Results of Study
Slide13Nasal Histopathology: Concentration- and Time-Dependent Responses to Cl
2
Slide14Nasal Histopathology: Persistence of Cl
2
-Induced Nasal Toxicity
Slide15Dose-Dependent Responses to 5-Day Cl
2
Exposure: Intraepithelial Mucus in Maxilloturbinates
Slide16Dose-Dependent Responses to 10-Day Cl
2
Exposure: Intraepithelial Mucus in Maxilloturbinates
Slide17Time-Dependent Responses to Cl
2
Exposure: Intraepithelial Mucus
Slide18Summary
5- and 10-day Cl
2
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.
Slide19The 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).
Conclusions & Need of Future Studies (Summer 2012)
Slide20Current Study (Fall 2012)
Continuation of investigating different parameters to support hypothesis (the
exposure regimen
versus the
total dose).
First inflammatory response and parameters (
neutrophils
)
Slide21Final 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
)
Slide22Acknowledgements
Dr. Jack
Harkema
(PI)Annie Jarabek (EPA)Experimental Pathology & Toxicology Lab
U.S. Environmental Protection AgencyCVM (College of Veterinary Medicine) Summer Research ProgramNIH Grant R25 HL103156
Slide23References
Gori
, G. B. (1994). Chapter 2: Chlorine. Regulatory Toxicology and Pharmacology
20: 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 A 85: 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.