1. Jeffrey Brent, M.D., Ph.D. Toxicology Associates University of Colorado Health Sciences Center Aurora, CO USA

2. 32 y/o male was working along the side of a railroad tanker car filled with liquid Cl 2 when the hose broke and a cloud of yellow- green gas was released. He immediately developed shortness of breath and intense eye and throat irritation. On presentation to the hospital he was in moderate respiratory distress, 119/62, 28,110, 100% on 2 L by mask. His eyes were red and tearing and he had diffuse rales, expiratory wheeze, ↑ E/I ratio. How would you treat him? What is his prognoses?

3.  Generally effects of gases depend on their aqueous solubility  Highly soluble gases:  Affect mostly eyes and oro/naso pharynx  Ex.: Ammonia  Low solubility gases  Mostly deep pulmonary structures (alveoli)  Ex. NO X  Chlorine has intermittent solubility

4.  Many descriptions published  All are uncontrolled case series  No pre-exposure PFTs  When PFTs are done they have varying degrees of quality control  Dose assessments rare

5.  Release of 180,000 kg Cl 2 over 5 minutes  15,000 French troops exposed  800 fatalities  2,500 -3,000 incapacitated  Majority were able to return to duty  Reports of long-term disability confounded by:  Smoking  TB  Later releases were mixed Cl 2 /phosgene

6. CiteEventNFU LoVecchio, 2005Poison Center series (mostly household) 298Days Guloglu, 2002Chlorine tank release106None Agabiti, 2006Swimming pool accident2361 month Moulick, 1992Acute release821 month Abhyanker, 1989Acute release146 months Jones, 1986Train derailment1166 yrs CharanBroken hose/railcar192 yrs Barrett, 1984Acutely exposed workers1291 month Hasan, 1983Leaking storage tank/HVAC 185 months Kaufman, 1971Storage tank release225 yrs Weil, 1969Railcar puncture127 yrs Kowitz, 1967Longshoreman1562.9 yrs Joyner, 1962Train derailment127 yrs Chassis, 1947Subway system20816 months

7.  50 – 2,000 ppm X 30 min → labored breathing  At highest doses → severe muc memb injury & bronchospasm  If lived 3-5 days: acute pul inflammation, lobar pneumonia, abscesses & necrosis  Autopsies of survivors  @ 5-15 days: organizing pneumonia & bronchiolitis  @ 6 months: emphysema, patchy BO

8.  Massive exposures (similar to Underhill high dose)  Early deaths mostly due to upper airway injury  Later deaths due to pneumonia  Even later deaths due to bronchiolitis

9.  8 healthy non-smokers  Exposed for 4 or 8 hours to 0, 0.5, & 1 ppm  @ 1 ppm:  ↓ FEV 1  ↓Peak exp flow rate  ↓FEF 25 – 75  ↑ Airway resistance

11.  Rapidly fatal acute necrotic pulmonary edema and tracheobronchitis (human experience)  This tends to occur at > 1,000 ppm  Most pts who survive exposure initially have abnormal PFTs

12. Diverse patterns of abnormalities  ? Related to exposure  Rarely have pre-exposure PFTs Most common pattern is obstructive Typically resolves in weeks to months

13.  Not a highly soluble gas  But, affects eyes, nasopharynx, and upper respiratory tract  Requires > 50 ppm to show significant lower airway effects  Thus tends to act like a high solubility gas

14.  Solution lies chlorine’s chemical properties dictating its toxicokinetic/dynamic profile  Early theories of toxicity 1. Hydration of chlorine →HCl → acid injury  However, chlorine 35X more toxic than HCl fumes in mice (Barrow 1977) 2. “Oxidative injury” – nonspecfic re chemical/mechanism

15. Cl 2 + H 2 0 OCl - + 2 H + + 2Cl - HOCl + HCl This reaction completely explains chlorine’s toxicological properties

16. Cl 2 + H 2 0 OCl - + 2 H + + Cl - HOCl + HCl NO 2 Nitrite-chlorine complexes Nitration injury Chlorination injury: Reacts with – NH 2 groups Thus, due to the rapid hydration of Cl 2 it theoretically assumes the properties of a highly soluble gas. O Oxidative injury Irritation

17. Copyright ©1999 American Physiological Society Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Fig. 4. Regression of diffusion model to Cl2 distribution data obtained during nasal breathing in 1 subject

18. Copyright ©1999 American Physiological Society Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Fig. 6. Pooled distributions for 10 subjects

19. Copyright ©1999 American Physiological Society Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Fig. 8. Pooled compartmental Cl2 absorption for 10 subjects

20. Cl 2 + H 2 0 OCl - + 2 H + + Cl - HOCl + HCl Why is it that if hypochlorite is mixed with an acid chlorine gas is liberated? Answer: Because the release of chlorine gas formed keeps the [Cl 2 ] very low.

21.  Stop exposure  Don’t forget ocular decontamination  General supportive care  Bronchospasm  ALI/ARDS  No reported beneficial effect of corticosteroids

22.  Almost all reported individuals eventually recover without significant long-term sequelae  Recovery may take months, sometimes > 1 year

23. 32 y/o male was working along the side of a railroad tanker car filled with liquid Cl 2 when the hose broke and a cloud of yellow-green gas was released. He immediately developed shortness of breath and intense eye and throat irritation. On presentation to the hospital he was in moderate respiratory distress, 119/62, 28,110, 100% on 2 L by mask. His eyes were red and tearing and he had diffuse rales, expiratory wheeze, ↑ E/I ratio.

24.  RADS = reactive airway dysfunction syndrome  Caused by an acute exposure to a pulmonary irritant  < 12 cases of chlorine induced RADS, almost all in smokers, ex-smokers, or subjects c atopic disease

25. Thank you very much for your attention … I hope it was interesting If you have any questions or would like a copy of these slides please contact me at : Jeffrey.Brent@uchsc.edu