jeffrey brent, m.d., ph.d. toxicology associates university of colorado health sciences center...

Jeffrey Brent, M.D., Ph.D.Toxicology Associates

University of Colorado Health Sciences CenterAurora, CO

USA

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.

How would you treat him? What is his prognoses?

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. NOX

Chlorine has intermittent solubility

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

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

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

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

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

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

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

Diverse patterns of abnormalities ? Related to exposure Rarely have pre-exposure PFTs

Most common pattern is obstructiveTypically resolves in weeks to months

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 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

Cl2 + H20 OCl- + 2 H+ + 2Cl- HOCl + HCl

This reaction completely explains chlorine’s toxicological properties

Cl2 + H20 OCl- + 2 H+ + Cl- HOCl + HCl

NO2

Nitrite-chlorine complexes

Nitration injury

Chlorination injury:Reacts with –NH2 groups

Thus, due to the rapid hydration of Cl2 it theoretically assumes the properties of a highly soluble gas.

•O

Oxidative injury

Irritation

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

Copyright ©1999 American Physiological Society

Nodelman, V. et al. J Appl Physiol 86: 1984-1993 1999

Fig. 6. Pooled distributions for 10 subjects

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

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.

Stop exposure Don’t forget ocular decontamination

General supportive care Bronchospasm ALI/ARDS No reported beneficial effect of

corticosteroids

Almost all reported individuals eventually recover without significant long-term sequelae

Recovery may take months, sometimes > 1 year

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.

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 : Jeffrey.Brent@uchsc.edu