Transcript PATHOPHYSIOLOGY AND CLINICAL SEQUELAE OF CHLORINE

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
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