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OF PARADIGMS AND PARADOXES: UNRAVELING THE BASIS OF CHLORINE TOXICITY Jeffrey Brent, M.D., Ph.D. Toxicology Associates University of Colorado Health Sciences Center Aurora, CO USA WHAT WOULD YOU EXPECT TO BE THE OUTCOME OF THIS CASE? 32 y/o male was working along the side of a railroad tanker car filled with liquid Cl2 when the hose broke and a cloud of yellowgreen 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? THE CLASSICAL PARADIGM OF THE EFFECTS OF GAS INHALATION 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 Ex. deep pulmonary structures (alveoli) NOX Chlorine has intermittent solubility ACUTE CHLORINE EXPOSURES LIMITATIONS OF OUR DATABASE 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 YPRES, BELGIUM 22 APRIL 1915 Release of 180,000 kg Cl2 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 Cl2/phosgene EXAMPLES OF MAJOR CASE-SERIES OF ACUTE CHLORINE EXPOSURES (POST-WW I) Cite Event N FU LoVecchio, 2005 Poison Center series (mostly household) 298 Days Guloglu, 2002 Chlorine tank release 106 None Agabiti, 2006 Swimming pool accident 236 1 month Moulick, 1992 Acute release 82 1 month Abhyanker, 1989 Acute release 14 6 months Jones, 1986 Train derailment 116 6 yrs Charan Broken hose/railcar 19 2 yrs Barrett, 1984 Acutely exposed workers 129 1 month Hasan, 1983 Leaking storage tank/HVAC 18 5 months Kaufman, 1971 Storage tank release 22 5 yrs Weil, 1969 Railcar puncture 12 7 yrs Kowitz, 1967 Longshoreman 156 2.9 yrs Joyner, 1962 Train derailment 12 7 yrs Chassis, 1947 Subway system 208 16 months CLASSICAL CANINE STUDY – UNDERHILL (1920) 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 CLASSICAL CANINE STUDY – WINTERNITZ (1920) 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 EFFECTS OF CHLORINE INHALATION IN HUMAN VOLUNTEERS (ROTMAN, 1983) 8 healthy non-smokers Exposed for 4 or 8 hours to 0, 0.5, & 1 ppm @ 1 ppm: ↓ FEV1 ↓Peak exp flow rate ↓FEF25 – 75 ↑ Airway resistance WHAT GENERALIZATIONS CAN WE MAKE BASED ON THESE DATA? VERY LARGE EXPOSURES 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 DIFFICULTIES IN INTERPRETING POSTEXPOSURE PFTS Diverse patterns of abnormalities ? Related to exposure Rarely have pre-exposure PFTs Most common pattern is obstructive Typically resolves in weeks to months LARGE EXPOSURES – THE FIRST CHLORINE PARADOX 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 SOLUTION TO THE FIRST CHLORINE PARADOX 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 SOLUTION TO THE FIRST CHLORINE PARADOX Cl2 + H20 OCl- + 2 H+ + 2Cl- HOCl + HCl This reaction completely explains chlorine’s toxicological properties SOLUTION TO THE FIRST CHLORINE PARADOX Cl2 + H20 OCl- + 2 H+ + Cl- HOCl + HCl NO2 Nitrite-chlorine complexes Nitration injury Irritation Chlorination injury: Reacts with – NH2 groups •O Oxidative injury Thus, due to the rapid hydration of Cl2 it theoretically assumes the properties of a highly soluble gas. Fig. 4. Regression of diffusion model to Cl2 distribution data obtained during nasal breathing in 1 subject Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Copyright ©1999 American Physiological Society Fig. 6. Pooled distributions for 10 subjects Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Copyright ©1999 American Physiological Society Fig. 8. Pooled compartmental Cl2 absorption for 10 subjects Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999 Copyright ©1999 American Physiological Society THE SECOND CHLORINE PARADOX Cl2 + H20 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 [Cl2] very low. TREATMENT OF CHLORINE EXPOSURES Stop exposure Don’t forget ocular decontamination General supportive care Bronchospasm ALI/ARDS No reported beneficial effect of corticosteroids LONG-TERM EFFECTS OF INHALATIONAL CHLORINE TOXICITY Almost all reported individuals eventually recover without significant long-term sequelae Recovery may take months, sometimes > 1 year WHAT WOULD YOU EXPECT TO BE THE OUTCOME OF THIS CASE? 32 y/o male was working along the side of a railroad tanker car filled with liquid Cl2 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. CHLORINE RARELY CAUSES RADS 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 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 : [email protected]
