United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA/600/8-86/022A
August 1986
External Review Draft
Research and Development
Health Assessment
Document for
Phosgene
Review
Draft
( Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on
its technical accuracy and policy implications.
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EPA/600/8-86/022A
Draft August 1986
Do Not Cite Or Quote External Review Draft
Health Assessment Document
for Phosgene
NOTICE
This document is a preliminary draft. It has not been formally released by the U.S. Environmental
Protection Agency and should not at this stage be construed to represent Agency policy. It is being
circulated for comment on its technical accuracy and policy implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
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DISCLAIMER
This document is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
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1. SUMMARY AND CONCLUSIONS
2. BACKGROUND INFORMATION
CONTENTS
LIST OF TABLES
LIST OF FIGURES V
PREFACE J
ABSTRACT ..
AUTHORS AND REVIEWERS
1-1
1.1 BACKGROUND INFORMATION 1-1
1.2 PHOSGENE METABOLISM 1-3
1.3 PHOSGENE TOXICOLOGY 1-3
1.4 RESEARCH NEEDS i_8
2-1
2.1 PHYSICAL AND CHEMICAL PROPERTIES OF PHOSGENE 2-1
2.2 QUANTITATION AND ANALYSIS 2-1
2.3 PRODUCTION, USE, AND OCCUPATIONAL EXPOSURE OF PHOSGENE .'.'.'.'.'. 2-5
2.3.1 Production 2-5
2.3.1.1 Production Process 2-5
2.3.1.2 Producers and Production Volumes •>. 2-6
2.3.2 Use _ _ 2-6
2.3.3 Occupational Exposure 2-6
2.4 ATMOSPHERIC LEVELS AND FATE OF PHOSGENE '.'.'.'.'.'.'.'.'.'.'.'.'. 2-11
2.4.1 Atmospheric Levels 2-11
2.4.2 Atmospheric Fate 2-13
2.5 REFERENCES FOR CHAPTER 2 '.'.'.'.'.'.'.'.'.'.'.'. 2-15
3. PHOSGENE METABOLISM AND MECHANISMS OF ACTION 3-1
3.1 PHOSGENE METABOLISM 3-1
3.1.1 Chemistry and Biochemistry 3-1
3.1.2 Absorption and Distribution 3-3
3.2 MECHANISMS OF ACTION ...'.'.'.'. 3-4
3.2.1 Hydrolysis Versus Acylation 3-4
3.2.2 Subcellular Biochemical Mechanisms 3-5
3.2.3 Role of the Nervous System 3-7
3.3 SUMMARY 3-9
3.4 REFERENCES FOR CHAPTER 3 '.'.'.'.'.'.'.'.'.'.'.'.'.'. 3-10
4. ACUTE TOXICITY OF PHOSGENE EXPOSURE IN ANIMALS
AND HUMANS 4-!
4.1 ANIMAL STUDIES 4-1
4.1.1 Measurement of Phosgene Exposure 4-1
m
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CONTENTS (continued)
4.1.2 Symptomatic Stages of Acute Phosgene Exposure 4-13
4.1.3 Lung Tissue Analysis After Acute Phosgene Exposure ... 4-17
4.1.4 Measurement of Pulmonary Function 4-18
4.1.5 Site of Lung Injury Following Acute Phosgene
Exposure 4-20
4.1.6 Blood Circulation Disturbances After Acute
Phosgene Exposure 4-23
4.1.7 Recovery After the Development of Acute Symptoms 4-23
4.2 HUMAN STUDIES 4-24
4.2.1 Odor Detection Threshold of Phosgene 4-24
4.2.2 Acute Pathology . i 4-25
4.2.3 Case Studies of Direct Phosgene Exposure 4-26
4.2.4 Indirect Phosgene'Exposure 4-31
4.2.4.1 Butyl Chloroformate Exposure 4-31
4.2.4.2 Carbon Tetrachloride Exposure 4-31
4.2.4.3 Methylene Chloride Exposure 4-32
4.2.4.4 Trichloroethyl ene Exposure 4-32
4.2.5 Late Sequelae of Acute Phosgene Poisoning 4-33
4.2.5.1 Studies of World War I Gassing Victims 4-33
4.2.5.2 Studies of Workplace Exposure 4-34
4.2.6 Secondary Health Effects of Phosgene Poisoning 4-39
4.3 FACTORS AFFECTING PHOSGENE POISONING 4-40
4.4 SUMMARY , 4-41
4.5 REFERENCES FOR CHAPTER 4 4-43
5. SUBCHRONIC AND CHRONIC PHOSGENE EXPOSURE IN ANIMALS 5-1
5.1 LUNG TISSUE ANALYSIS FOLLOWING SUBCHRONIC PHOSGENE
EXPOSURE 5-1
5.2 PREGASSING PROTECTIVE EFFECT OF PHOSGENE EXPOSURE 5-4
5.3 OTHER POSSIBLE EFFECTS OF PHOSGENE EXPOSURE 5-7
5.3.1 Teratogenicity and Reproductive Effects 5-7
5.3.2 Mutagenicity and Carcinogenicity 5-7
5.4 REFERENCES FOR CHAPTER 5 5-9
6. EPIDEMIOLOGY i 6-1
6.1 URANIUM-PROCESSING PLANT, OAK RIDGE, TN 6-1
6.2 EDGEWOOD ARSENAL, MD 6-5
6.3 NIOSH REPORTED STUDIES 6-9
6.4 POISON GAS FACTORY, OKUNOJIMA ISLAND, JAPAN 6-10
6.5 REFERENCES FOR CHAPTER 6; 6-11
IV
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LIST OF TABLES
Number Page
1-1
2-1
2-2
2-3
2-4
2-5
2-6
4-1
4-2
4-3
4-4
4-5
5-1
5-2
6-1
6-2
6-3
Concentration-effect relationships of phosgene exposure in
humans
Physical and chemical properties of phosgene
Comparison of five methods for the detection, quantification,
and moni tori ng of phosgene
Phosgene manufacturers and annual production capacities
Phosgene annual producti on vol ume
Maximum allowable concentration values for phosgene in
several countr i es
Atmospheric levels of phosgene and its precursors at selected
sites in California
Effects of acute and repeated inhalation exposures of animals
to phosgene
Median lethal inhalation dose of phosgene for various species ..
Concentration-effect relationships of phosgene exposure
Severity of poisoning in ten men occupational ly exposed to
phosgene
Summary of clinical findings in six workers after acute
occupational exposures to phosgene
Severity of pulmonary lesions in several animal species
exposed to phosgene
Mortal ity of pregassed rats and mice
Mortality from selected causes among white male chemical
workers exposed to phosgene from 1943 to 1945 and a control
group of white males who worked at the same uranium-processing
plant, Oak Ridge, TN
Selected causes of death among 106 white male workers after
acute exposure to phosgene between 1943 and 1945
Summary of clinical findings in five workers after chronic
occupational exposure to phosgene
1-5
2-2
2-4
2-7
2-8
2-9
2-13
4-2
4-11
4-25
4-35
4-37
5-4
5-6
6-3
6-5
6-7
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LIST OF FIGURES
Number
4-1 Exposure (C x T) of cats to phosgene 4~12
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PREFACE
The Office of Health and Environmental Assessment has prepared this health
assessment to serve as a source document for EPA use. The health assessment
was originally developed for use by the Office of Air Quality Planning and
Standards to support decision making regarding possible regulation of phosgene
as a hazardous air pollutant. However, the scope of this document has since
been expanded to address multimedia aspects.
In the development of the assessment document, the scientific literature
has been inventoried, key studies have been evaluated, and summary/conclusions
have, been prepared so that the chemical's toxicity and related characteristics
are qualitatively identified. Observed effect levels and other measures of
dose-response relationships are discussed, where appropriate, so that the
nature of the adverse health responses is placed in perspective with observed
environmental levels.
The relevant literature for this document has been reviewed through
January 1986. In addition, selected studies of more recent publications (July
1986) have been incorporated in the sections on phosgene toxicology.
Any information regarding sources, emissions, ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air.
While the available information is presented as accurately as possible, it is
acknowledged to be limited and dependent in many instances on assumption rather
than specific data. This information is not intended, nor should it be used,
to support any conclusions regarding risk to public health.
If a review of the health information indicates that the Agency should
consider regulatory action for this substance, a considerable effort will be
undertaken to obtain appropriate information regarding sources, emissions, and
ambient air concentrations. Such data will provide additional information for
drawing regulatory conclusions regarding the extent and significance of public
exposure to this substance.
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ABSTRACT
£
Phosgene (COC12) is primarily manufactured for the synthesis of isocyanate-
based polymers, carbonic acid esters, and acid chlorides. Annual production
volume in the United States is estimated to be above one billion pounds. Ambient
and indoor air concentrations of phosgene are produced by (1) direct emissions
during its manufacture, handling, and use; (2) thermal decomposition of chlori-
nated hydrocarbons; and (3) photochemical oxidation of chloroethylenes in the
air. In the atmosphere, the most important sinks for the removal of phosgene
are heterogeneous decomposition and slow liquid-phase hydrolysis.
Phosgene, an acutely toxic gas, was once used in chemical warfare. The
effects of acute inhalation exposure are primarily respiratory, causing pulmo-
nary emphysema, pulmonary edema, and possibly death due to paralysis of the
respiratory center as a result of anoxia. Persistent effects of.acute phosgene
poisoning may involve organs other than the lungs, principally the brain, though
these effects are thought to be the result of anoxia caused by pulmonary edema.
Limited epidemiology studies indicate no increase in the incidence of
cancers among workers chronically exposed to phosgene. No definitive conclu-
sions can be drawn regarding possible teratogenic, reproductive, carcinogenic,
or mutagenic effects of phosgene exposure because adequate studies have not
been performed.
vm
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AUTHORS AND REVIEWERS
AUTHORS
The following personnel of Dynamac Corporation were involved in the prepa-
ration of this document: Nicolas P. Hajjar, Ph.D. (Project Manager); Charles
E. Rothwell, Ph.D. (Principal Author); Christian Alexander, Louis Borghi, and
Bernard Shacter, Ph.D. (Authors).
REVIEWERS
The following individuals reviewed an earlier draft of this document and
submitted valuable comments:
Dr. Robert Beliles
Carcinogen Assessment Group
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington, DC
Dr. William Currie
Duke University Medical Center
Durham, North Carolina
Dr. Ivan Davidson
Bowman Gray School of Medicine
Winston-Sal em, North Carolina
Dr. Werner Diller
Bayer A. G.
Leverkusen
Federal Republic of Germany
Dr. Gary Hatch
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
Dr. Jerry Ott
Union Carbide Corporation
Danbury, Connecticut
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Project Manager:
Ms. Darcy L. Campbell
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
919-541-4477
Special assistance to the project manager was provided by Dr. Dennis
Kotchmar.
Technical assistance within the Environmental Criteria and Assessment Office
was provided by: Ms. Frances Bradow, Mr. Doug Fennel!, Ms. Ruby Griffin, Ms.
Barbara Kearney, Ms. Emily Lee, Ms. Theresa Harris, Mr. Allen Hoyt, Ms. Diane
Ray, and Ms. Donna Wicker.
Technical assistance also provided by Northrop Services: Mr. John
Bennett, Ms. Kathryn Flynn, Ms. Miriam Gattis, Ms. Lorrie Godley, Ms. Patricia
Tierney, Ms. Varetta Powell, and Ms. Jane Winn-Thompson.
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1. SUMMARY AND CONCLUSIONS
1.1 BACKGROUND INFORMATION
Phosgene (COCK) is a colorless, highly toxic gas at ambient temperature
and pressure. At low concentrations, phosgene has been described as having a
characteristic odor similar to that of moldy hay; at higher concentrations it
has an irritating, pungent smell. Phosgene gas is only slightly soluble in
water, and rapidly decomposes in solution to yield carbon dioxide and hydro-
chloric acid. Synonyms for phosgene include carbonyl chloride, carbonic
dichloride, carbon oxychloride, and chloroformyl chloride.
John Davy first synthesized phosgene in 1812 by the photochemical reaction
of carbon monoxide and chlorine, using activated charcoal as a catalyst. The
name phosgene was given to the gas to indicate the role played by sunlight in
its formation. Originally, the main uses of phosgene were in the manufacture
of aniline dyes and certain pharmaceutical preparations such as creosotal,
hedonal, and aristochin. However, it was not used in major quantities until
1915, when Germany began using it as a chemical warfare agent. Production
dropped off after World War I, but was sharply increased in the early 1940's in
anticipation of a resurgence of chemical warfare in World War II. Industrial •
uses for phosgene began in about 1955, when it was used as an intermediate in
the manufacture of toluene diisocyanate. The U.S. International Trade Commis-
sion (USITC) reported that the volume of phosgene produced in 1957 was five mil-
lion pounds. Phosgene production increased rapidly through the 1970's as the
demand for diisocyanates increased and other uses for phosgene were found.
Presently, phosgene is produced in a manner very similar to that used by
Davy in 1812; equimolar amounts of anhydrous chlorine gas and high-purity
carbon monoxide are reacted in the presence of a carbon catalyst. Production
volumes, as reported to the USITC, have been relatively constant through the
1980's, generally staying slightly above one billion pounds per year. However,
these reported volumes may be lower than actual production volumes because a
large amount of the phosgene produced is used captively in the formation of
August 1986 1-1 DRAFT—DO NOT QUOTE OR CITE
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other end products and therefore not reported to the USITC. Current industrial
uses for phosgene include the synthesis of isocyanate-based polymers, carbonic
acid esters, and acid chlorides. It is also used in the production of dye
intermediates and pesticides and in metallurgy for separating ores.
Workplace exposures to phosgene do not arise solely from the manufacture,
handling, and use of phosgene. Potentially lethal levels of phosgene can be
generated by the decomposition of chlorinated hydrocarbons. Solvents that have
been shown to decompose when in contact with an open flame or a hot metal sur-
face to form phosgene include methylene chloride, chloroform, carbon tetra-
chloride, Freon, trichloroethylene, and perch!oroethylene. Therefore, workers
involved in the use of these solvents near a heat source (e.g., welders, fire-
men, painters) as well as phosgene workers are potentially at risk. In 1976,
the National Institute for Occupational Safety and Health (NIOSH) estimated
that 10,000 workers were potentially exposed to phosgene in the workplace.
However, preliminary data from the National Occupational Exposure Survey,
conducted by NIOSH from 1980 to 1983, indicated that 2358 workers were poten-
tially exposed to phosgene in the workplace in 1980. The current Threshold
Limit Value - Time Weighted Average (TLV - TWA) for phosgene; the time-weighted
average concentration for a normal 8-hour workday and a 40-hour workweek, to
which nearly all workers may be repeatedly exposed daily without adverse effect,
as determined by the American Conference of Governmental Industrial Hygienists,
is 0.1 ppm (0.4 mg/m3). ;
Direct atmospheric emissions of phosgene, as well as the thermal decomposi-
tion of chlorinated hydrocarbons, are generally contained; although they may
pose a significant indoor hazard in industrial and residential settings, they
constitute only a negligible contribution to phosgene levels in the environment.
Of far greater consequence is the photochemical oxidation of the chloroethy-
lenes. The two major chloroethylenes that contribute to the atmospheric pool
of phosgene are perchloroethylene and trichloroethylene. Phosgene levels have
been measured in ambient air using a gas chromatograph equipped with two elec-
tron capture detectors. In rural areas of California, phosgene was present at
an average concentration of 21.7 parts per trillion (ppt), while in California's
urban areas the average was 31.8 ppt. The highest level recorded was measured
over Los Angeles, 61.1 ppt, although it has been suggested that higher levels
may be reached under highly stagnant weather conditions.
August 1986
1-2
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Investigations into the atmospheric fate of phosgene have shown that at
least two tropospheric sinks exist for its elimination. One sink is hetero-
geneous decomposition; phosgene will decompose when in contact with most sur-
faces, especially at elevated temperatures. The second sink is liquid-phase
hydrolysis. In one case, an intermittent rainfall that lasted from 50 to 60
hours reduced the ambient air concentrations of phosgene by 15 to 20 percent.
Other studies indicated that tropospheric loss of phosgene through photolysis,
gas-phase hydrolysis, or gas-phase reactions involving 0- and OH- radicals is
insignificant. Because of the existence of at least two major tropospheric
sinks, it is unlikely that phosgene will have an adverse impact on the
stratosphere.
1.2 PHOSGENE METABOLISM
The low solubility of phosgene in water enhances its acute toxicity by
allowing the inhaled gas to penetrate into the alveolar spaces. The amount of
the gas that does go into solution is rapidly hydrolyzed to form carbon dioxide
and hydrochloric acid. The amount of hydrochloric acid produced after inhala-
tion of lethal doses of phosgene is believed to be toxicologically insignifi-
cant. However, the reaction of phosgene with v/ater is much slower than its
reaction with other chemical groups such as -NHg, -OH, or -SH groups. The
metabolism of phosgene in laboratory animals has not been studied. However,
iji vitro studies and chemical measurements on the reactivity of phosgene with
proteins and various chemicals indicate that the pathology of phosgene toxicity
is a result of its ability to directly acylate tissue components.
1.3 PHOSGENE TOXICOLOGY
Before World War I, essentially nothing was known of the health effects of
phosgene. During the war, artillery shells were filled with liquid phosgene
and fired amid enemy troops. Upon impact, the shells would explode, filling
the air with phosgene gas. Frequently, troops dispensing the chemical would
also be exposed as a result of leaky shells or because enemy artillery fire
hit the stockpile of phosgene-filled shells. This resulted in thousands of men
suffering from acute inhalation exposure to phosgene, with medical personnel
August 1986 ' 1-3 DRAFT-DO NOT QUOTE OR CITE
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having no idea how to treat them. It has been estimated that 80 percent of all
gas deaths during World War I were due to phosgene exposure.
Soon after phosgene's deployment, American, French, Italian, British, and
German scientists began animal studies to investigate its toxicity. Dosing was
carried out to mimic the battlefield situations; concentrations were high
enough to cause frank lesions, or death, and the route of exposure was in-
variably by inhalation. It was reported that, initially, phosgene appeared to
specifically attack the terminal bronchioles of the lung. Other immediate
effects, such as lacrimation, and irritation of the upper airways, were noted,
but were relatively mild when compared to those caused by other warfare gases.
The phenomenon of the "clinical latent phase," a period essentially devoid of
serious symptomatology, was also noted. The duration of the clinical latent
phase was found to .be inversely proportional to the extent of exposure.
Several hours after the animals were exposed to phosgene, pulmonary edema
became evident, sometimes increasing lung weights by as much as fourfold. At
the height of the pulmonary edema, the blood of the animals assumed a sticky,
concentrated consistency, leading to an enlargement of the right side of the
heart. It was believed that phosgene exerted its toxic effect directly on the
lung and that involvement of other tissues was a secondary effect. However,
there was debate over the cause of death. Some scientists believed that death
was due to pulmonary edema, while others believed it was a result of the hema-
tological effects.
During this period, acute inhalation studies were performed on mice, rats,
guinea pigs, rabbits, cats, dogs, goats, and monkeys. The pathological find-
ings among species were essentially alike and agreed with the lesions seen in
the victims exposed to the gas during the war. However, the susceptibility to
the lethal effects of phosgene did vary among species. Cats were most sus-
ceptible, with an L(CT)5Q of ~200 ppm-min, followed by monkeys (-300 ppm-min),
rats (~400 ppm-min), guinea pigs (~500 ppm-min), humans (~500 ppm-min), mice
(-500 ppm-min), dogs (~1000 ppm-min), rabbits (~1500 ppm-min), and goats
(~2000 ppm-min).
The concept of a "death product" was introduced by Fritz Haber to explain
the relationship between the extent of exposure to phosgene and death. Accord-
ing to "Haber1s Law," the biological effect of phosgene is directly propor-
tional to the exposure expressed as: the product of the atmospheric concentra-
tion (C) and the time of exposure (T); CT = K, where K can be death, pulmonary
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edema, or other biological effects of phosgene exposure. Haber's Law has been
shown to be valid within certain limits by subsequent investigations. For man,
phosgene exposures above 30 ppm-min can produce pulmonary damage, whereas an
exposure of at least 150 ppm-min is necessary to produce clinical evidence of
pulmonary edema (Table 1-1). The human L(CT)p L(CT)5Q, and L(CT)100 values,
as shown in Table 1-1, have been estimated to be 300, 500, and 1300 ppm-min,
respectively. It should be noted that in general, the reported exposure is the
dose (CT) offered, not necessarily the biologically effective dose which is
inhaled. For example, by holding the breath or keeping respiration shallow
with reduced breath volume per minute, the inhaled dose may be much smaller
than the dose that is offered.
TABLE 1-1. CONCENTRATION-EFFECT RELATIONSHIPS OF PHOSGENE EXPOSURE
IN HUMANS
Perception of odor >0.4 ppm
Recognition of odor >1.5 ppm
Signs of irritation in eyes, nose,
throat, and bronchi >3 ppm
Beginning lung damage >30 ppm-min
Clinical pulmonary edema >150 ppm-min
L(CT)X ~300ppm-min
L(CT)5o ~500 ppm-min
L(CT)10o ~1300 ppm-min
Post-World War I research elucidated many of the pathological lesions
caused by phosgene inhalation, but very little was learned of its mechanism of
action. In fact, it was not until the World War II era that researchers had
enough evidence to show that phosgene binds directly to tissue macromolecules.
Until that time, it was believed that phosgene was inhaled into the alveolar
spaces where it slowly reacted with water to produce hydrochloric acid. Sup-
posedly, it was the hydrochloric acid that produced the toxic lesions.
Although the exact mechanism of phosgene toxicity has still not been fully
elucidated, many aspects are currently understood. When inhaled in concentra-
tions sufficient to produce pulmonary edema, the course of phosgene poisoning
proceeds through a series of phases that are common to all mammalian species
investigated. Initially, phosgene interacts with sensory receptors within the
bronchial tree to produce a bioprotective vagal reflex syndrome. This syndrome
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Is characterized by the onset of rapid, shallow breathing, leading to reduc-
tions in vital capacity and respiratbry volume. Subsequently, there is a drop
in arterial oxygen partial pressure and blood pH, while arterial carbon dioxide
partial pressure tends to increase. Cardiac symptoms are bradycardia and,
occasionally, sinus arrhythmia. Other cholinergic symptoms such as increased
salivation, nausea, urination, and defecation have been observed in animals.
The intensity of the vagal reflex syndrome is not dose related, especially in
humans where mental and emotional influences are important. The reflex shows a
tendency to regress within hours after the exposure has ended.
Other immediate symptoms of phosgene exposure to concentrations above 3
ppm include irritation of the eyes and upper airways possibly due to the for-
mation of hydrochloric acid. At higher concentrations (>200 ppm), phosgene
produces apnea of several seconds' duration, bronchoconstriction, bronchial
epithelium desquamation, and inflammatory bronchiolar changes.
After entering the lung, studies indicate that phosgene acylates tissue
macromolecules in cells of the lowest extremity of the respiratory tract. The
initial site of injury is still a point of debate, alveoli or bronchioles, and
may depend on the dose. Nonetheless!, animal necropsy observations have indi-
cated damage to the bronchioles involving vacuoles in ciliated cells and Clara
cells, extracellular septal edema, intracellular edema of the walls of the
respiratory bronchioles, spastically constricted bronchioles, and emphysematous
expansion of the distal segments. Alveolar damage has been shown to include
edematous swelling and plicated surfaces of alveolar cells, lamellar inclusions
in type II septal cells, disaggregated basal membranes, and decreased numbers
of mitochondria in endothelial cells. Later anatomical defects include mem-
brane rupture of single endothelial cells at the blood-air barrier.
In addition to the structural damage, numerous enzymes are inhibited by
phosgene, and anoxia and cellular decay lead to the release of histamine and
various enzymes. It has been suggested that enzyme inhibition and consequent
disruption of pulmonary energy metabolism may play a major role in damage to
lung tissue after exposure to phosgene.
The structural damage to the lung allows blood plasma to enter the inter-
stices and alveoli. Depending on the dose, alveolar edema may become apparent
after only a few minutes. The hematocrit value first shows a slight decrease,
followed by a relatively late rise. Lymph drainage from the lung increases
substantially. In animal studies, gas exchange across the blood-air barrier is
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inhibited relatively early; the impairment in diffusion has not yet been ob-
served in humans. Arterial oxygen partial pressure tends to normalize, but
then decreases towards the end of the clinical latent phase. The increasing
acidosis is first of a respiratory type and then of a mixed respiratory and
metabolic type.
Pulmonary edema increases until it becomes clinically evident. Gas ex-
change becomes insufficient, and the mucous membrane of the bronchi becomes
necrotic and is shed. Leukocytes migrate into the bronchiolar walls and into
the alveolar interstices. Pulmonary arterial pressure remains normal up to
shortly before death. Death is usually due to paralysis of the respiratory
center as a result of anoxia. However, if anoxia is treated effectively, thus
prolonging life, death may still ensue due to circulatory shock or infection.
Although the mechanism of toxicity described above for phosgene inhala-
tion is based mainly on animal data, it appears to hold for humans as well.
After acute exposure to phosgene, patients usually experience mild to severe
irritation of the eyes and throat; a dry, unproductive cough; nausea and vom-
iting; and occasionally a weak and dazed feeling. These initial symptoms are
usually short-lived, lasting about 2 to 20 minutes, and are followed by a period
of subjective well-being that can last from 1 to 24 hours, depending on the ex-
posure. A few patients return to work during the clinical latent phase.
The end of the latent phase is usually marked by the onset of a cough ac-
companied by expectoration of frothy edema fluid. There is commonly a sensa-
tion of tightness or pain across the chest followed by shortness of breath and
a choking sensation. The patient is usually restless, anxious, or agitated,
and sometimes cyanotic. Clinical findings include hemoconcentration, leuko-
cytosis, low systemic arterial pressure, and bilateral rales. The patient
.usually recovers completely, with typical hospital stays ranging from a few
days to a couple of weeks.
Most victims of severe acute phosgene poisoning complain of symptoms for
some time such as rapid, shallow breathing, shortness of breath on exertion,
and general feelings of lassitude and reduced physical fitness. In general,
though, physical examinations and chest roentgenograms typically indicate no
physical damage; more sophisticated pulmonary function studies reveal abnor-
malities associated with emphysema. Pulmonary emphysema can also occur after
multiple exposures to toxic levels of phosgene. The measurable changes in
pulmonary function that are consistently observed vary in type and severity,
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but cannot be correlated with the severity of phosgene intoxication or with the
chronic symptomatology. In most cases, these symptoms are not disabling and
last from several months to several years, until they completely disappear. In
patients where phosgene poisoning has led to chronic disability, the effects
are more closely related to smoking habits, psychological disorders, or pre-
existing pulmonary abnormalities than to the severity of exposure. Persistent
effects of acute phosgene poisoning have also involved organs other than the
lungs, most notably the brain. Symptoms include neurasthenia, speech incoor-
dination, paralysis, and Raynaud-like effects. These latter abnormalities are
considered to be secondary effects of anoxia caused by pulmonary edema, or due
to preexisting psychological disorders.
Questions exist as to whether ^repeated short-term or more chronic, con-
tinuous low-level exposures to phosgene might be associated with pulmonary or
other effects analogous to those described above as being induced by acute
high-level exposures. Based on the existing scientific literature, however,
no definite conclusions can be drawn regarding pulmonary function effects
associated with chronic exposure levels several orders of magnitude below those
at which acute phosgene exposure effects are known to occur. Researchers have
concluded that no significant human; health effects have been found at phosgene
concentrations below 0.1 ppm. The measured ambient concentrations of phosgene
are much lower, the maximum being 61 ppt. The relationship of product of
concentration and exposure time (CT) for phosgene exposure cannot be used to
draw conclusions regarding chronic, low-level phosgene exposure. In general,
the CT relationship is valid only between 1 and 200 ppm. Data on acute effects
from phosgene exposure cannot be extrapolated to extended chronic exposure;
thus, no clear inferences about chrbnic exposure effects can be drawn from the
data on acute effects. More studies are required in order to evaluate the
effects resulting from possible fenceline exposures.
In addition to the lack of evidence of pulmonary function effects being
associated with chronic exposures, epidemiology studies indicate that there has
been no increase in the incidence of cancers among workers chronically exposed
to phosgene as compared to the population in general. Except for acute phosgene
poisoning, there also appears to be no significant increase in the number of
deaths in phosgene-exposed workers due to asthma, tuberculosis, or pulmonary
disease as compared to the general population. While these studies are nega-
tive, they do not provide an adequate basis, due to study limitations, to draw
August 1986 ; 1-8 DRAFT—DO NOT QUOTE OR CITE
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conclusions regarding the likelihood of phosgene having a carcinogenic or pul-
monary disease potential.
No studies have been performed to investigate the teratogenicity or repro-
ductive effects of phosgene. There are no adequate long-term animal cancer
bioassays for phosgene, and as previously mentioned the available epidemiologic
data are inadequate to assess the carcinogenic potential in humans.
While there is at present no evidence for phosgene's role as a carcino-
gen agent, such a hypothesis exists because of its ability to induce the for-
mation of adducts with cellular macromolecules and because phosgene is a metab-
olite of compounds with known carcinogenic activity. Overall, the carcino-
genic data are inadequate to assess the carcinogenic potential of phosgene for
humans and, according to the Environmental Protection Agency's Carcinogen Risk
Assessment Guidelines, phosgene is a group D compound.
1.4 RESEARCH NEEDS
Essentially the same research needs exist now as when the National Insti-
tute for Occupational Safety and Health (NIOSH) published its criteria document
on phosgene in 1976. Chronic toxicity studies need to be performed in labora-
tory animals with inhalation exposures to phosgene at or near 0.1 ppm. These
studies should also address the issues of carcinogenicity, mutagenicity, tera-
togenicity, and reproductive effects in both male and female animals. Further-
more, additional epidemiologic studies are needed to provide more information
on the human health effects of long-term, low-level exposures to phosgene.
Research is also needed on the reproductive and fetotoxic effects of high doses
of phosgene in animals, and followup studies of humans who have been previously
exposed to high levels of phosgene are needed to better understand the persist-
ence of chronic symptomatology.
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2. BACKGROUND INFORMATION
2.1 PHYSICAL AND CHEMICAL PROPERTIES OF PHOSGENE
Phosgene is also commonly referred to as carbonyl chloride, carbon oxy-
chloride, carbonic dichloride, and chloroformyl chloride. It is a colorless,
highly toxic gas under conditions of ambient temperature and pressure. Phos-
gene is produced by mixing pure chlorine gas with purified carbon monoxide in
the presence of activated charcoal. When in contact with large amounts of air,
phosgene has an odor reminiscent of moldy hay (Windholz, 1983). It is a planar
molecule with interatomic distances of 0.128 and 0.168 nm between C-0 and C-C1,
respectively. It is used in the synthesis of isocyanate-based polymers,
polycarbonates, carbonic acid esters, acid chlorides, dye intermediates, and
pesticides, and in metallurgy for the separation of ores (Beard, 1982). The
physical and chemical properties of phosgene are presented in Table 2-1.
2.2 QUANTITATION AND ANALYSIS
Phosgene inhalation can result in death if prompt, appropriate medical
attention is not provided. The proper medical treatment for an individual
exposed to phosgene depends on the concentration and length of the exposure
(Oilier et al., 1979). It is, therefore, essential to have a means by which to
monitor both exposure time and concentration levels whenever this gas is
present in the work environment. A number of techniques are presently used to
determine phosgene concentrations in air. These include passive dosimetry,
manual colorimetry, automatic colorimetry, gas chromatography, infrared
spectroscopy, and paper tape monitoring.
The passive dosimeter is a popular device with phosgene workers and medi-
cal personnel because it measures the concentration of phosgene gas present in
the breathing zone of each worker (Moore and Matherne, 1981; Diller et al.,
1979). This device consists of a small clip-on badge that contains a piece of
paper tape that has been saturated with 4(4'-nitrobenzyl)pyridine. Phosgene
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TABLE 2-1. PHYSICAL AND CHEMICAL PROPERTIES OF PHOSGENE
Parameter
Value
Reference
CAS number
Molecular formula
Molecular weight
Conversion factor
Solubility
Water
Organic solvents
Melting point
Boiling point
Vapor pressure
20°C
30°C
Vapor density
Density
19
d4
o
d4
75-44-5
COC12
98.92
1 ppm = 4.043 mg/m3
Decomposes in water
Decomposes in alcohol; very
soluble in benzene, toluene,
glacial acetic acid, and most
liquid hydrocarbons
-104°C
-101-127°C
8.3°C
8.2°C
8.1°C
1215 mmHg
1.6 atm
2.2 atm
3.42
1.392
1.432
Hardy (1982)
Windholz (1983)
Windholz (1983)
Windholz (1983)
Beard (1982)
Beard (1982)
Verschueren (1983)
Windholz (1983)
Beard (1982)
Windholz (1983)
Verschueren (1983)
Windholz (1983)
Verschueren (1983)
Verschueren (1983)
Verschueren (1983)
Verschueren (1983)
Windholz (1983)
reacts with the treated tape to produce a deep red color. The sensitivity and
color stability of the dosimeter can be increased by the addition of an acid
acceptor such as N-phenylbenzamine (Noweir and Pfitzer, 1971). The color in-
tensity indicated by the tape is logarithmically proportional to the phosgene
exposure, with a range of 2 to 100 ppm-min (Matherne et al., 1981). The advan-
tages of this monitoring system over the others is that it measures personal
exposures; the badge can be worn anywhere that is convenient for the individual,
provided the tape is exposed to the air; and it provides immediate information
August 1986
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DRAFT—DO NOT QUOTE OR CITE
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on the exposure dose, which can be used to decide what, if any, medical treat-
ment is needed. An extensive review on reagents that react colorimetrically
with phosgene can be found in a report prepared by the Atlantic Research Cor-
poration (Snyder et al., 1983).
Comparisons of the other five detection methods have been made (Tuggle et
al., 1979; Kistner et al., 1978), and the results are presented in Table 2-2.
The authors concluded that three of the techniques, automated colorimetry, gas
chromatography, and infrared spectrophotometry, showed promise of attaining the
sensitivity to detect levels of phosgene below its present threshold limit
value (TLV, 0.1 ppm) and of being adaptable to real-time monitoring. Other
reports (Enviro Control Inc., 1981) also indicate that the paper tape monitor
is an excellent method for monitoring phosgene levels in the workplace. A
brief description of each of these five methods is provided below (Tuggle et
al., 1979).
In the manual colorimetric method, air is drawn through a midget impinger
containing a diethylphthalate (DEP) solution of 4(4'-nitrobenzyl)pyridine (NBP)
and N-benzylaniline (BA). The subsequent color change of the solution is
measured in a spectrophotometer at a wavelength of 475 nm. A 25-minute air
sample drawn at a rate of 1 L/minute into 10 ml of reagent is recommended for a
detection range of 0.05 to 1.0 ppm of phosgene (American Industrial Hygiene
Association, 1969). The method has the advantage of proven dependability
through extended use, and was the recommended method at one time (National
Institute for Occupational Safety and Health, 1976). However, its response
time (see Table 2-2) is much too slow to be useful as a continuous monitoring
device.
In automated colorimetry, sample air is bubbled into a flowing stream of
NBP-BA-DEP reagent. While passing through the machine's mixing coils, any
phosgene in the sample will react with the reagent, causing a color change.
Air bubbles are separated from the liquid, which then flows to a colorimeter
where its absorbance is measured. In this process, air is sampled at 1
L/minute, and the NBP-BA-DEP reagent flow rate is 0.2 mL/minute. The limit of
detection for this method is 0.001 ppm of phosgene. A drawback of this method
is its long response time, allowing phosgene leaks to go undetected for up to
20 minutes.
Of all the methods, gas chromatography equipped with an electron capture
detector has proven to be the most sensitive for phosgene detection. Tuggle et
August 1986 2-3 DRAFT—DO NOT QUOTE OR CITE
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al. (1979) list the limit of detection for this method at 0.0001 ppm (Table
2-2); however, several researchers have used this method to measure ambient air
levels of phosgene in the parts per trillion (ppt) range (Singh et al., 1977).
Another advantage that the gas chromatograph provides is its high specificity
for phosgene. Disadvantages include the need for a trained technician to
operate and maintain the system, occasional down time, and frequent column
degradation due to the corrosiveness of phosgene. This latter problem has been
f*
diminished somewhat by the use of Teflon columns packed with Chromosil 310 .
Infrared spectroscopy has been used to record phosgene levels as low as
0.025 ppm (Esposito et al., 1977). One infrared field machine uses a compact
infrared analyzer in conjunction with a 20-m variable path length cell. Air is
drawn into the machine, and the absorbance at a sample wavelength where phos-
gene absorbs (11.8 urn) is measured directly against the reference wavelength of
11.2 pm, which is a blank region for phosgene. The difference in absorbance
corresponds to the phosgene content of the air (Tuggle et al., 1979).
Paper tape monitors have recently measured phosgene concentrations as low
as 0.005 |jg/L (Hardy, 1982). One commercially available detection system draws
sample air through the top half of a chemically treated tape moving at a con-
stant rate. The bottom half, which is not exposed to the air, serves as the
reference. The degree of color change incurred by the top half of the tape is
proportional to the phosgene concentration. Photometric comparison is made of
both the upper and lower halves of the tape, and an external recorder activates
an alarm if preset phosgene concentrations are exceeded (Tuggle et al., 1979).
Other methods that have been successfully used to measure phosgene in
ambient air include pulsed flow coulometry (Singh et al., 1975) and ultraviolet
spectroscopy (Crummett and McLean, 1965). In liquid form, phosgene can be
assayed iodometrically (Beard, 1982). A review of some of the early methods of
phosgene detection has been reported by the National Institute for Occupational
Safety and Health (1976).
2.3 PRODUCTION, USE, AND OCCUPATIONAL EXPOSURE OF PHOSGENE
2.3.1 Production
2.3.1.1 Production Process. Phosgene is manufactured by the reaction of equi-
molar amounts of anhydrous chlorine and high-purity carbon monoxide in the
presence of a carbon catalyst (SRI International, 1984; Hardy, 1982).
August 1986 . 2-5 DRAFT—DO NOT QUOTE OR CITE
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2.3.1.2 Producers and Production Volumes. Table 2-3 lists the companies which
v/ere listed by SRI International (1985) as domestic manufacturers of phosgene
as of January 1, 1985.
The U.S. International Trade Commission (USITC) reported the production
volumes for phosgene (U.S. International Trade Commission, 1981, 1982, 1983,
1984, 1985) shown in Table 2-4. According to SRI International (1985), the
USITC production volume data are understated. In recent years, as much as 35
to 40 percent of the total phosgene produced has not been reported by some pro-
ducers because all of their production is captively used (SRI International,
1984). i
2.3.2 Use ;
Phosgene is a widely used chemical intermediate. It is usually produced
and used captively at the point of production. In 1981, production of toluene
diisocyanate (TDI) accounted for 51 percent of the phosgene used. The re-
mainder was used in the production of polymethylene polyphenylisocyanate (33
percent), polycarbonate resins (9 percent), and other miscellaneous applica-
tions (7 percent), including use in the synthesis of chloroformate and carbonate
chemical intermediates (SRI International, 1984; Hardy, 1982). Estimates of
phosgene consumption (in millions of pounds) by end product application are
shown below (SRI International, 19&4).
Year
TDI
Polymethylene
polyphenyl-'
isocyanate
Polycarbonate
resins Other Total
1977 758
1981 700
; Occupational
317
465
Exposure
74
125
130
100
1279
1390
Estimates of occupational exposures to phosgene have been reported in in-
dustrial hygiene surveys performed by the National Institute for Occupational
Safety and Health (NIOSH). According to the National Occupational Hazard Sur-
vey (NOHS), conducted by NIOSH from 1972 to 1974, 5752 workers were potentially
exposed to the compound in domestic workplace environments in 1970. In 1976,
NIOSH estimated that as many as 10;,000 workers were potentially exposed to
phosgene (National Institute for Occupational Safety and Health, 1976). Preli-
minary data from the National Occupational Exposure Survey (NOES), conducted by
August 1986
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TABLE 2-3. PHOSGENE MANUFACTURERS AND ANNUAL PRODUCTION CAPACITIES
Manufacturer
Location
Estimated annual
production capacity
(millions of pounds)
BASF Wyandotte Corp.
Polymers Group
Urethanes Chems. Business
Dow Chem. U.S.A.
Geismar, LA
Freeport, TX
200
130
E.I. du Pont de Nemours & Co., Inc.
Polymer Products Dept.
Essex Chem. Corp.
Essex Indust. Chems., Inc., subsid.
Organic Intermediates Dept.
Gen. Electric Co.
Plastics Business Operations
ICI Americas Inc.
Performances Resins Div.
Rubicon Chems., Inc.
Mobay Chem. Corp.
Polyurethane Div.
01 in Corp.
01 in Chems.
PPG Indust., Inc.
Chems. Group
Specialty Products
Stauffer Chem. Co.
Agricultural Chem. Div.
Union Carbide Corp.
Agricultural Products Group
The Upjohn Co.
Polymer Chems. Div.
Van De Mark Chem. Co., Inc.
Deepwater, NJ
Baltimore, MD
Mount Vernon, IN
Geismar, LA
Cedar Bayou, TX
New Martinsville, WV
Lake Charles, LA
Moundsville, WV
Barberton, OH
La Porte, TX
Cold Creek, AL
St. Gabriel, LA
Institute, WV
La Porte, TX
Lockport, NY
<80
8
125
150
450
250
140
110
5
50
24
not available
140
270
8
Total
Source: SRI International (1985).
August 1986
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TABLE 2-4. PHOSGENE ANNUAL PRODUCTION VOLUME
Year
1980
1981
1982
1983
1984
Production volume (billion
1.04
1.12
0.97
1.05
; 1.22
pounds)
Source: U.S. International Trade Commission (1981, 1982, 1983, 1984, 1985).
NIOSH from 1980 to 1983, indicated that 2358 workers, including 282 women, were
potentially exposed to phosgene in the workplace in 1980. Note that the NOES
estimate represents potential exposures to the actual compound only, whereas
the NOHS estimate includes potential exposure to phosgene from its precursors
as well as the parent compound. The National Institute for Occupational Safety
and Health document (1976) did not explain how the estimate of 10,000 poten-
tially exposed workers was derived.
The current TWA-TLV for phosgene exposure in the workplace is 0.1 ppm
(0.4 mg/m3) (American Conference of Governmental Industrial Hygienists, 1985).
This same level, 0.1 ppm, has also bjaen adopted by the Occupational Safety and
Health Administration (OSHA) as an Srhour time-weighted average permissible ex-
posure limit for phosgene (Code of Fjederal Regulations, 1983). The current TWA-
TLV was first adopted by the Americah Conference of Governmental Industrial
Hygienists in 1966 (American Conferehce of Governmental Industrial Hygienists,
1966).
A list of the current standards for phosgene in several countries is pre-
sented in Table 2-5. The Eastern European countries adopted their standards
from the U.S.S.R., while Japan, West Germany, and Great Britain adopted
standards identical to those recommended by ACGIH (National Institute for
Occupational Safety and Health, 1976).
Cucinell (1974) reviewed the literature on the effects of subchronic
exposure of animals to phosgene and suggested that the TWA-TLV for phosgene in
the workplace be 0.02 ppm. This was based mainly on the work of Cameron et al.
(1942) who showed that exposure to pjhosgene at a concentration of 0.2 ppm for 5
hours/day for 5 consecutive days produced evidence of pulmonary edema in 41
percent of the test animals (goats, icats, rabbits, guinea pigs, rats, mice).
Using additional safety factors, Cucinell also suggested that the highest
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TABLE 2-5. MAXIMUM ALLOWABLE CONCENTRATION VALUES
FOR PHOSGENE IN SEVERAL COUNTRIES
Maximum allowable
concentrations
Country
Bulgaria
Czechoslovakia
Czechoslovakia
Egypt
Finland
Germany, East
Germany, West
Great Britain
Hungary
Japan
Poland
Romania
Sweden
United States
U.S.S.R.
Yugoslavia
ppm
0.125
0.5
1.0a
1.0
1.0
0.125
0.1
0.1
0.125
0.1
0.125
0.125
0.05a
0.1
0.125
0.1
mg/m3
0.5
2a
4a
4
4
0.5
0.4
0.4
0.5
0.4
0.5
0.5a
0.2a
0.4
0.5
0.4
aCeiling limit for a short single exposure.
Source: National Institute for Occupational Safety and Health (1976);
Winell (1975).
phosgene level in ambient air that would be safe for all humans to breathe 24
hours a day is 600 ppt. This concentration is ten times higher than the highest
phosgene concentration measured in ambient air (61.1 ppt over Los Angeles;
Singh et al., 1977).
An accidental release of phosgene is not the only potential source of this
gas in the workplace. Various chlorinated hydrocarbons can decompose during
welding or when in contact with a flame or a hot carbon or metal surface to
yield phosgene. Gerritsen and Buschmann (1960) showed that methylene chloride
would decompose to form toxic levels of phosgene under possible working condi-
2
tions. The authors treated a painted wood surface (0.3 m ) with a commercial
chemical paint remover that contained 92 percent of a volatile solvent consist-
ing almost entirely of methylene chloride with small amounts of ethanol and
trichloroethylene. Approximately 50 g of the paint remover was applied to the .
3
surface. The wood was then placed in a large cupboard (6m) that contained a
burning kerosene stove. Phosgene levels were determined at frequent intervals
August 1986 2-9 DRAFT—DO NOT QUOTE OR CITE
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using two different analytical techniques. Potentially lethal levels of
phosgene (up to 128 ppm) were generated after only ten minutes. The authors
also reported two cases of phosgene poisoning, one of which was fatal, under
circumstances similar to their test conditions.
The generation of phosgene duelto the decomposition of chlorinated hydro-
carbons during welding has also beeiji well established. Birgesson (1982) de-
scribed the hazard of exposure to the pyrolysis products of Freon, especially
phosgene, encountered by welders working in cold storage rooms. Rinzema and
Silverstein (1972) and Rinzema (1971) measured the phosgene generated by
various welding techniques in the presence of several individual chlorinated
hydrocarbons. They concluded that chloroform, carbon tetrachloride, ethylene
dichloride, methyl chloroform, and o-dichlorobenzene did not decompose under
common welding conditions to yield toxic levels of phosgene. Trichloroethylene
and perch!oroethylene, however, did;undergo extensive decomposition. The
authors concluded that hazardous levels of phosgene could be generated by
welding in the presence of the latter two solvents. However, the analytical
technique used to quantify phosgene in these studies was susceptible to inter-
ferences from acyl chlorides and acetyl chlorides.
Andersson et al. (1975) and Dahlberg and Myrin (1971) performed similar
experiments to measure the decomposition products of trichloroethylene and
perchloroethylene using various welding techniques. Phosgene levels were
measured by gas chromatography, an analytical method that is not subject to
interferences from other structurally related compounds. It was found that
short-wave (UV) radiation generated by the welding arcs caused both trichloro-
ethylene and perchloroethylene to decompose to form phosgene. However,
dichloroacetyl chloride was formed five times as fast as phosgene when atmos-
pheres containing trichloroethylene!, but not perchl oroethyl ene, were exposed
to welding. The authors concluded that perchloroethylene posed a greater
1
hazard to welders than trichloroethylene. Nonetheless, there are several
published reports of phosgene intoxication in welders working in the presence
of trichloroethylene. •
Noweir et al. (1973b) demonstrated that, under certain conditions, toxic
levels of phosgene can be generated^by the combustion of carbon tetrachloride.
In one experiment, carbon tetrachlofide (10.2 ppm) was combusted in an animal
inhalation chamber and the pyrolysis products were determined to be phosgene,
10.15 ppm; chlorine, 7.2 ppm; chlorine dioxide, 0.6 ppm; other, 5.5 ppm.
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Another source of phosgene generation is via the combustion of polyvinyl-
chloride (PVC). Brown and Birky (1980) measured the generation of phosgene
after the thermal decomposition of PVC by four different methods: (1) thermal
degradation of PVC in a resistively heated furnace, (2) electrical overloading
of a PVC-clad wire, (3) electrical arcing between electrodes partially covered
with PVC, and (4) electric-arc initiated flaming combustion in a cup furnace.
Phosgene levels were analyzed and quantified using gas chromatography, infrared
spectroscopy, and mass spectroscopy. The authors demonstrated that significant
quantities of phosgene were generated from PVC by the electric arc method
(30-50 ppm), and lesser quantities were formed in the other scenarios (0.5-1.3
ppm). Bjerre (1984) also demonstrated that toxic levels of phosgene could be
generated from the thermal decomposition of PVC and summarized the optimal
conditions for its formation: (1) PVC combustion takes place in an inter-
mediate temperature region at a probable lower limit of 500°C and with a
limited excess of oxygen; (2) the gases of combustion keep a temperature
between 330 and 600°C for the longest possible period of time; and (3) the
gases are, at the same time, in contact with hot surfaces, e.g., copper, iron,
activated carbon, that act as catalysts. Phosgene was not detected as a com-
bustion product of several polyurethane-ether foams (Paulson and Moran, 1974).
.2.4 ATMOSPHERIC LEVELS AND FATE OF PHOSGENE
Measurable quantities of phosgene have been found in ambient air, but not
in water, because phosgene decomposes in water immediately after going into
solution.
2.4.1 Atmospheric Levels
Ambient air concentrations of phosgene have been attributed to three main
sources: (1) direct emissions of phosgene during its manufacture, handling, and
use; (2) thermal decomposition of chlorinated hydrocarbons; and (3) photooxida-
tion of chloroethylenes in the air. The first two sources are generally con-
tained, and although they pose a significant indoor hazard, they constitute only
a negligible contribution to the environmental concentrations (Singh, 1976). Of
far greater consequence is the photochemical oxidation of chloroethylenes. The
two major chloroethylenes that contribute to the atmospheric pool of phosgene
are perch!oroethylene and trichloroethylene. In 1975 alone, it was estimated
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that 1.5 x 10 tons of these compounds were released into the world's en-
vironment. At that rate, Singh (1976) estimated that those emissions could
result in the formation of about 3.0 x 10 tons of phosgene per year.
The photooxidation of trichloroethylene and perchloroethylene to phosgene
(and other compounds) was demonstrated experimentally by Gay et al. (1976).
The compounds, at 3.45 to 5.0 ppm, were photooxidized in air with ultraviolet
light (wavelength not reported) in the presence of nitrogen dioxide. Analyses
were performed by long-path infrared spectroscopy and wet chemical and chemi-
luminescent procedures. Under these conditions, 66 percent of the trichloro-
ethylene and 7 percent of the perchloroethylene samples were degraded after 140
minutes of irradiation, yielding phosgene concentrations of 0.47 and 0.12 ppm,
respectively. Of the other compounds studied, 1,1-dichloroethylene was also
photooxidized to phosgene, but ethylene, vinyl chloride, and 1,2-dichloro-
ethylene did not yield phosgene, although these compounds were extensively
photooxidized under the test conditions. The authors proposed a reaction
sequence that involves photolysis of nitrogen dioxide to form ozone, which
reacts with the double bond to form.an unstable epoxide. The epoxide rear-
ranges through chlorine atom movement to yield phosgene and other products.
Dilling et al. (1976) also indicated that phosgene, in the presence of nitrous
oxide, increased the degradation rate of trichloroethylene.
Phosgene levels have been measured in ambient air by a group of re-
searchers in California (Brodzinskyiand Singh, 1983; Singh et al., 1977;
Singh, 1976). All monitoring was conducted on a 24-hour basis using a gas
chromatograph equipped with two electron-capture detectors in series. Cali-
brations were performed using a permeation tube and were checked in the
field using absolute pulse flow coulometry. Data on measurements taken at four
different locations in California are presented in Table 2-6. In rural areas,
phosgene was present at an average concentration of 21.7 ppt, while in urban
areas the average was 31.8 ppt. the highest concentration measured by the
researchers was 61.1 ppt in Los Ang4les, although it was suggested that higher
concentrations could occur under highly stagnant weather conditions (Singh et
al., 1977). The authors also stated that the relatively smaller differences in
phosgene concentrations between urban and remote locations (about 30 percent)
as compared to the bigger differences for its precursors (twentyfold) was an
indication of the relative stability of phosgene in the troposphere, and that
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TABLE 2-6. ATMOSPHERIC LEVELS OF PHOSGENE AND ITS PRECURSORS
AT SELECTED SITES IN CALIFORNIA
Location
Badger Pass
Los Angeles
Site charac-
terization
Remote
Urban
Concentrations of compounds detected (ppt)
Perch! oro- Trichloro-
Phosgene ethyl ene ethyl ene
21.7+5.2 30.7±10.5 15.6 2.5
(13.3-28.9) (15.4-92.1) (14.4-21.6)
31.8±8.3 674.4±498.7 312.6 302.3
(21.1-61.1) (60-8-2267.3) (25.5-1772.3)
Menlo Park Urban-suburban 30.3±3.1 201.9±413.9 113.51528.1
(27.8-38.9) (16.0-2490.0) '(10.0-5490.0).
Palm Springs Downwind of 29.3±6.2 278.2±232.6 39.7±83.6
Los Angeles (16.7-44.4) (17.7-1153.1) (12.8-828.8)
Values represent mean concentrations ± S.D. of multiple samplings
(n = 10-257).
Source: Singh et al. (1977).
its precursors are well distributed in the atmosphere before any significant
conversion to phosgene occurs.
Fenceline monitoring with colorimetric indicator badges (sensitive to
about 0.01 ppm) at one phosgene production plant revealed no color changes
(Oilier, 1986).
2.4.2 Atmospheric Fate
Preliminary studies on the atmospheric fate of phosgene suggest that
phosgene is not eliminated through gas-phase hydrolysis as was commonly be-
lieved. When present in a cloud chamber at 10 ppm and 100 percent relative
humidity, phosgene decomposition at various temperatures is only slightly en-
hanced compared to the decomposition of 10 ppm phosgene in dry air (Noweir et
al., 1973a). Gay et al. (1976) and Singh et al. (1975) .confirmed these find-
ings: The known absorption cross-section of phosgene and smog-chamber studies
(where 1-5 ppm phosgene was stable for 15 hours under simulated tropospheric
irradiations in the presence of 10,000 ppm of water vapor) suggested negli-
gible tropospheric loss through photolysis and gas-phase hydrolysis. Butler
and Snelson (1979) calculated a half-life for the homogeneous gas-phase hydroly-
sis of 1 ppb phosgene in the atmosphere to be between 20 and 630 years. Other
gas-phase reactions involving 0- and OH- radicals are also very slow (Singh,
1976).
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The two important sinks for the removal of phosgene from the ambient air
appear to be heterogeneous decomposition and slow liquid-phase hydrolysis. The
importance of heterogeneous decomposition has been confirmed by findings that
showed that low concentrations of phosgene were destroyed shortly after contact
with most surfaces, especially at elevated temperatures, i.e., 200 to 900°C
(Noweir et al., 1973a). At normal atmospheric temperatures, however, liquid-
phase hydrolysis appears to be a more significant sink. At a Palm Springs
site, a 15 to 20 percent decline in the ambient air concentration of phosgene
was measured following intermittent rainfall that lasted from 50 to 60 hours
(Singh et al., 1977). Because of the existence of at least two major tropo-
spheric sinks, Singh et al. (1977) concluded that no possibility exists for any
significant stratospheric impact, i;e., destruction of the ozone layer, due to
phosgene. ;
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2.5 REFERENCES FOR CHAPTER 2
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limit values for 1966: recommended and tentative limits. Cincinnati, OH:
American Conference of Governmental Industrial Hygienists; p. 11.
American Conference of Governmental Industrial Hygienists. (1985) Threshold
limit values and biological exposure indices for 1985-1986. Cincinnati,
OH: American Conference of Governmental Industrial Hygienists; p. 27.
American Industrial Hygiene Association. (1969) Phosgene. In: AIHA analytical
guides. Detroit, MI: American Industrial Hygiene Association.
Andersson, H. F.; Dahlberg, J. A.; Wettstrom, R. (1975) Phosgene formation
during welding in air contaminated with perch!oroethylene. Ann. Occup.
Hyg. 18: 129-132.
Beard, R. R. (1982) Phosgene, COC12. In: Clayton, G. D.; Clayton, F. E., eds.
Patty's industrial hygiene and toxicology: v. 2C, toxicology. 3rd rev. ed.
New York, NY: John Wiley & Sons; pp. 4126-4139.
Birgesson, D. (1982) An unknown working environment hazard for refrigerating
equipment fitters: freon. Arbetsmiljo (6): 48-50.
Bjerre, A. (1984) Health hazard assessment of phosgene formation in gases of
combustion of polyvinyl chloride using a simplified method of mathematical
modelling. Ann. Occup. Hyg. 28: 49-59.
Brodzinsky, R.; Singh, H. B. (1983) Volatile organic chemicals in the
atmosphere: an assessment of available data. Research Triangle Park, NC:
U. S. Environmental Protection Agency, Environmental Sciences Research
Laboratory; pp. 120-121; EPA report no. EPA-600/3-83-027a. Available
from: NTIS, Springfield, VA; PB83-195503.
Brown, J. E.; Birky, M. M. (1980) Phosgene in the thermal decomposition
products of poly(vinyl chloride): generation, detection and measurement.
J. Anal. Toxicol. 4: 166-174.
Butler, R.; Snelson, A. (1979) Kinetics of the homogeneous gas phase hydrolysis
of CC13COC1, CC12HCOC1, CH2C1COC1, and COCL2. J. Air Pollut. Control Assoc.
29: 833-837.
Cameron, G. R.; Courtice, F. C.; Foss, G.. L. (1942) Effect of exposing 3
different animals to low concentrations of phosgene (1: 5,000,000 =0.9 mg/m )
for 5 hours on five consecutive days. Second report. In: First report on
phosgene poisonining: chapter VIII. Washington, DC; British Embassay Defense
Staff; Porton report no. 2349.
Code of Federal Regulations. (1983) Occupational safety and health standards.
29 C. F. R. 1910, subpart Z.
Crummett, W. B.; McLean, J. D. (1965) Ultraviolet spectrophotometric determina-
tion of trace quantities of phosgene in gases. Anal. Chem. 37: 424-425.
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Cucinell, S. A. (1974) Review of the toxicity of long-term phosgene exposure.
Arch. Environ. Health 28: 272-275.
Dahlberg, J. A.; Myrin, L. M. (197i) The formation of dichloroacetyl chloride
and phosgene from trichloroethylene in the atmosphere of welding shops.
Ann. Occup. Hyg. 14: 269-274.
Oilier, W. F. (1986) [Letter to Ms.;Darcy Campbell re chronic phosgene exposure
at production sites]. Leverkusen, West Germany: Institutes Fuer Roentgen-
diagnostik und Nuklearmedizin; September 30.
Oilier, W.; Drope, E.; Reichold, E. (1979) Eine Phosgen-Indikator-Plakette
fuer den Aerztlichen Notfall [A phosgene-indicator badge for medical
emergencies]. In: 6. Internationales Kolloquium fuer die Verhuetung von
Arbeitsunfaellen und Berufskrankheiten in der chemischen Industrie [6th
international symposium on the prevention of occupational risks in the
chemical industry]; June; Frankfurt am Main, West Germany. Heidelberg,
West Germany: Berufsgenossenschaft der Chemischen Industrie; pp. 137-150.
Dilling, W. L.; Bredeweg, C. J.; Tefertiller, N. B. (1976) Organic
photochemistry: simulated ^atmospheric photodecomposichloride,
1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene, and other
compounds. Environ. Sci. Techno!. 10: 351-356.
Enviro Control, Inc. (1981) Assessment of engineering control monitoring
equipment - volume 1. Cincinnati, OH: National Institute for Occupational
Safety and Health; NIOSH report no. 210-79-0011. Available from: NTIS,
Springfield, VA; PB83-152629.
Esposito, G. G.; Lillian, D.; Podolak, G. E.; Tuggle, R. M. (1977)
Determination of phosgene in ;air by gas chromatography and infrared
spectrophotometry. Anal. Chem. 49: 1774-1778.
Gay, B. W., Jr.; Hanst, P. L.; Bufalini, J. J.; Noonan, R. C. (1976)
Atmospheric oxidation of chlorinated ethylenes. Environ. Sci. Techno!.
10: 58-67.
Gerritsen, W. B.; Buschmann, C. H. (1960) Phosgene poisoning caused by the use
of chemical paint removers containing methylene chloride in ill-
ventilated rooms heated by kerosene stoves. Br. J. Ind. Med. 17: 187-189.
Hardy, E. E. (1982) Phosgene. In: Kirk-Othmer encyclopedia of chemical
technology: v. 17. 3rd ed. New York, NY: Wiley & Sons; pp. 416-425.
Kistner, S.; Lillian, D.; Ursillo, J.; Smith, N.; Sexton, K. ; Tuggle, M. ;
Esposito, G.; Podolak, G.; Mallen, S. (1978) A caustic scrubber system
for the control of phosgene emissions: design, testing, and performance.
. J. Air Pollut. Control Assoc. :28: 673-676.
Matherne, R. N.; Lubs, P. L.; Ketrfoot, E. J. (1981) The development of a
passive dosimeter for immediate assessment of phosgene exposures. Am.
Ind. Hyg. Assoc. J. 42: 681-684.
Moore, G.; Matherne, R. N. (1981) .Field experiences with a phosgene dosimeter
system. Ann. Am. Conf. Gov. Ind. Hyg. 1: 253-254.
August 1986 ; 2-16 DRAFT-NOT QUOTE OR CITE
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National Institute for Occupational Safety and Health. (1976) Criteria for a
recommended standard occupational exposure to phosgene. Rockville, MD:
U. S. Department of Health, Education, and Welfare, Public Health
Service, Center for Disease Control; HEW publication no. (NIOSH) 76-137.
Available from: NTIS, Springfield, VA; PB-267514.
NOES, National Occupational Exposure Survey [data base]. (1984) [Data on
phosgene exposures, 1980-1983]. Cincinnati, OH: Department of Health and
Human Services, National Institute for Occupational Safety and Health.
ASCII.
NOHS, National Occupational Hazard Survey (1972-1974) [database]. (1976)
Cincinnati, OH: Department of Health and Human Services, National
Institute for Occupational Safety and Health. ASCII.
Noweir, M. H. ; Pfitzer, E. A. (1971) An improved method for determination of
phosgene in air. Am. Ind. Hyg. Assoc. J. 32: 163-169.
Noweir, M. H.; Pfitzer, E. A.; Hatch, T. F. (1973a) Decomposition of phosgene
in air. Am. Ind. Hyg. Assoc. J. 34: 110-119.
Noweir, M. H.; Pfitzer, E. A.; Hatch, T. F. (1973b) The pulmonary response of
rats exposed to the decomposition products of carbon tetrachloride vapors
at its industrial threshold limit concentration. Am. Ind. Hyg. Assoc. J.
34: 73-77.
Paulson, D. R.; Moran, G. F. (1974) Analysis of some toxic combustion products
of low-density flexible polyurethane-ether foams. Environ. Sci. Technol.
8: 1116-1118.
Rinzema, L. C. (1971) Behavior of chlorohydrocarbon solvents in the welding
environment. Int. Arch. Arbeitsmed. 28: 151-174.
Rinzema, L. C. ; Silverstein, L. G. (1972) Hazards from chlorinated hydrocarbon
decomposition during welding. Am. Ind. Hyg. Assoc. J. 33: 35-40.
Singh, H. B. (1976) Phosgene in the ambient air. Nature (London) 264: 428-429.
Singh, H. B.; Lillian, D. ; Appleby, A. (1975) Absolute determination of
phosgene: pulsed flow coulometry. Anal. Chem. 47: 860-864.
Singh, H. B.; Salas, L. ; Shigeishi, H.; Crawford, A. (1977) Urban-nonurban
relationships of halocarbons, SF6, N20, and other atmospheric trace
constituents. Atmos. Environ. 11: 819-828.
Snyder, R. E.; Schulte, B. E.; Mangoba, L.; McHale, E. T. (1983) Research and
development of hazardous/toxic waste analytical screening procedures:
available field methods for rapid screening of hazardous waste materials
at waste sites(class A poisons), interim report. Fort Detrick, MD: U. S.
Army Medical Research and Development Command; contract no.
DAMD17-78-C-8075. Available from: NTIS, Springfield, VA; ADA-129683.
SRI International. (1984) Chemical economics handbook. Menlo Park, CA: SRI
International. Section 687.1020A-H.
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SRI International. (1985) Phosgene (carbonyl chloride) fchloroforayl
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America. Menlo Park, CA: SRI International; pp. 777-778.
Juggle R M-LEspos1to,6. 6 ; Guinivan T L ; Hess T L ;
sliced Sonfer^etho^s^r^n^aW. Am. Ind, Hyg. Assoc. 0.
40: 387-394.
U S International Trade Commission. (1981) Synthetic organic chemicals:
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Available from: GPO, Washington, DC; S/N 354-128/9122.
U S International Trade Commission. (1982) Synthetic organic chemicals:
U> united Sites production and sales 1981 Washington DC: U. S
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Available from: GPO, Washington, DC; S/N 0-387-604/1286.
GPO, Washington, DC; S/N??? i
U S International Trade Commission. (1984) Synthetic organic chemicals:
United States production and sales 1983 Washington DC: U. S.
International T?ade Commissidn; USTIC publication 1588; pp. 260, 298.
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Tnlernational Trade Commission; ^l^^7c^.^&11^ PP' 259' 29
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chemicals in the work environment. Ambio 4: 34-36.
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3. PHOSGENE METABOLISM AND MECHANISMS OF ACTION
3.1 PHOSGENE METABOLISM
3.1.1 Chemistry and Biochemistry
There are no adequate reports in the literature on the i_n vivo or i_n vitro
metabolism of phosgene. Therefore, our limited knowledge of the interactions
of molecular phosgene once in contact with living organisms comes from chemical
and biochemical studies. Phosgene gas is only slightly soluble in water. Nash
and Pattle (1971) bubbled phosgene (10-20 ppm in dry air) at a flow rate of 0.6
liters per minute through 4 mL of water for 30 seconds. Under these conditions
only 15 to 20 percent of the phosgene was absorbed. Absorption was unchanged
in neutral buffer or acid solutions, but was increased in alkaline, solutions
and increased still more in solutions containing non-ionized amines, phenoxide
ions, or sulfite.
Once dissolved in water, phosgene is rapidly hydrolyzed to form carbon
dioxide and hydrochloric acid (HC1):
-Cl
-Cl
0 = C^ + H20 > C02 + 2HC1
The reaction rate is so fast that early investigators could not measure it
(Rona, 1921). Later, the pseudo-first-order rate constants for the hydrolysis
«. ~\
of phosgene at 35 and 45.5°C were measured to be 26.7 and 75 sec , respectively
(Manogue and Pigford, 1960). From these data, a half-life for the hydrolysis
of phosgene at 37°C can be calculated to be 0.026 seconds.
Despite the rapid rate of reaction with water, it has been demonstrated
that phosgene reacts even more rapidly with other functional groups. Potts et
al. (1949) reacted diphosgene, trichloromethylchloroformate, with aqueous solu-
tions of a number of compounds. Diphosgene was used instead of phosgene because
it was easier to handle and diphosgene has been reported to possess chemical and
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toxicological reactivities indistinguishable from those of phosgene (Potts et
al., 1949; Bruner and Coman, 1945).I After the reaction of diphosgene with the
test solution was complete, the amount of liberated gas was measured. Since
only the reaction with water would yield gas, a reduction in gas production
was considered to indicate that the carbonyl group had reacted with the solute.
Compounds with free amino, hydrazinb, sulfhydryl, and hydroxy groups were found
to be acylated by diphosgene in the; presence of large excesses of water. Hexa-
methylenetetramine, aniline, p-aminbbenzoic acid, and cysteine all bound 80 per-
cent or more of the diphosgene carbonyl groups. The acylation reactions of
phosgene with -NH2, -OH, and -SH grbups are shown below (Gerard, 1948):
; ,NH-R
2 H2N-R »• 0 = (/
1 \H-R
./cl ! /°~R
0 = C<^ + 2 HO-R > 0 = C(^ +2HC1
^Cl I 0-R
2 HS-R
Biochemical studies have also indicated that phosgene can acylate tissue
niacromolecules. Cessi et al. (1966) allowed 20 mg of poly-L-lysine to react
v/ith 10 mg of [14C]phosgene (0.1 mGi) dissolved in a small amount of tetrahydro-
furan. Human serum albumin (100 mg) was also reacted with 0.2 mCi of [" C]phos-
gene in a similar manner. Both reactions yielded highly labeled derivatives.
Enzymatic hydrolysis of the serum albumin derivatives, followed by amino acid
analysis of the resultant labeled peptides, indicated that phosgene bound to
the s-amino groups of proteins.
The acylating properties of phosgene have given rise to some questions of
the potential carcinogenicity of phosgene. When phosgene and cysteine are
chemically reacted, a stable adduct identified as 2-oxothiazolidine-4-carboxylic
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acid (4-carboxy-thiazolidine-2-one) is formed (Mansuy et al., 1977). This same
adduct is also formed when chloroform (Mansuy et al., 1977; Pohl et al., 1977)
or carbon tetrachloride (Shah et al., 1979) is incubated with rat hepatic micro-
somes in the presence of cysteine. Both chloroform and carbon tetrachloride
are demonstrated animal carcinogens (Eschenbrenner and Miller, 1944; Interna-
tional Agency for Research on Cancer, 1971). One current theory is that cyto-
chrome P-450-mediated metabolism of these compounds produces metabolites, one
of which is phosgene, that form stable adducts with cellular macromolecules,
leading to carcinogenesis (U.S. Environmental Protection Agency, 1984, 1985).
However, there are no acceptable studies in the literature that test the poten-
tial carcinogenicity of phosgene in laboratory animals (see Section 5.3.2 for
details).
3.1.2 Absorption and Distribution
It is generally accepted that unreacted phosgene does not get past the
pulmonary circulation. Using the solubility and hydrolysis rate of phosgene in
water as determined by Manogue and Pigford (1960) and Hall (unpublished), a
phosgene exposure concentration of 25 ppm, and published values for the thick-
ness of the blood-air barrier (1 uM), capillary diameter (8 uM), and blood
residence time in the capillaries (1 sec); Nash and Pattle (1971) calculated
that phosgene would mainly diffuse undecomposed through the blood-air barrier
into the blood, but that only a small portion would leave the capillaries
undecomposed. However, the percentage actually entering the capillaries would
probably be much less than implied above because both the solubility and
decomposition of phosgene are increased by the presence of biologically
important chemical groups (Nash and Pattle, 1971). In an abstract by Slade et
al. (1983), a study was described in which mice, rats, hamsters, guinea pigs,
and rabbits were exposed by inhalation to [ CJphosgene at 1.6 ppm for 3
minutes. [ C] was detected at very low levels in blood and liver samples of
14
all animals. However, this study is of limited value because the [ C] labeled
compounds were not identified.
Gerard (1948) presented the findings of several studies that indirectly
demonstrate that significant levels of phosgene do not get past the lung. In
one study, a plug was placed in a main bronchus of a dog and the animal was ex-
posed to phosgene at a level "far exceeding the normal lethal dose." The plug
was then removed from the protected lobe and placed in the other bronchus (to
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keep edema fluid from spilling over}. ' The dog did not die from this exposure
despite extreme pathology in the exposed lung and the loss of large quantities
of plasma fluid. Other studies, in Which one dog was exposed to phosgene and a
second dog received blood from the exposed dog (either by transfusion or crossed
circulation) without adverse effect, also indicate that undecomposed phosgene
does not enter the general circulation.
3.2 MECHANISMS OF ACTION ;
3.2.1 Hydrolysis Versus Acylation
Although the effects of phosgene in animals have been studied extensively
for many years, the exact mechanisms of action remain elusive. It was believed
at one time that phosgene owed its toxicity to the property of being hydrolyzed
in the presence of water to HC1 and C02 (Winternitz et al., 1920). Although it
was understood that the effects of inhalation of HC1 and phosgene are different,
the difference was ascribed to the fact that HC1 strikes first and hardest at
the larynx and trachea, damaging less the distal portion of the respiratory
tract, i.e., the bronchioles and pulmonary alveoli. With phosgene, on the
other hand, little decomposition takes place until the gas reaches the lungs,
where, in the smaller bronchi and in the alveoli, it comes into contact with
sufficient water vapor to bring about the evolution of HC1. This would explain
the severe damage produced by phosgene in the lower air passages rather than in
the trachea and bronchi. '
It is now believed that the pathology observed with phosgene inhalation is
mainly a result of the acylating properties of phosgene, although HC1 production
may play a minor role, especially in high-level exposures (Oilier, 1985). Nash
and Pattle (1971) calculated the maximum concentration (C) of hydrochloric acid
which would be produced in a tissue' if a molar concentration (C-^) of phosgene
were present in the gas in contact vh'th a slab of tissue of thickness (b) in
which phosgene has a diffusion coefficient (D) and was hydrolyzed with a rate
defined by a constant (k) using thei following formula:
C ='
k/D
where (D2) is the diffusion coefficient of acid in the tissue. Using the
solubility (\) and hydrolysis (k) values of Manogue and Pigford (1960), the
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maximum concentration of acid in a blood-air barrier of thickness 1 pm in con-
tact with 25 ppm of phosgene is 7 x 10 M, which is negligible. It was
concluded that HC1 production could not account for the toxicity seen with
exposures to phosgene at 25 ppm.
Additional evidence for acylation over hydrolysis as the major mechanism
of phosgene's toxicity was provided by Potts et al. (1949). Rats and mice were
exposed to ketene (H2C=C=0) at 0.5 mg/L for 1.5 minutes. Seven of eight mice
died within 0.5 to 24 hours (rat mortality not reported), and showed clinical
symptoms similar to those seen in phosgene exposures. Sections of the lungs of
these animals were given to a pathologist as unknowns and were reported by him
as "severe phosgene poisoning." Ketene, like phosgene, can acylate the free
amino groups of protein in solution, but unlike phosgene does not hydrolyze to
form a strong acid. Finally, substances that protect prophylactically against
phosgene poisoning (hexamethylenetetramine, free amines, and thromboplastin) do
not protect against HC1 poisoning (Oilier, 1985).
3.2.2 Subcellular Biochemical Mechanisms
Frosolono and Pawlowski (1977) have extended the studies on phosgene to
obtain information on the biochemical mechanisms of phosgene damage in the lung
at the organelle and enzymatic levels. Because of its pronounced chemical re-
activity, the authors speculated that phosgene might inhibit a broad spectrum
of pulmonary enzyme systems, disrupting the basic metabolism of the lung and
producing profound effects upon the integrity of the tissues (Potts et al.,
1949). Male rats (CFE Carworth) were exposed for the most part to phosgene at
100 ppm for 10 minutes (1000 ppm-min), although exposures as high as 4300
ppm-min were also used. Most exposures were for ten minutes. Groups of animals
were killed at 0, 30, and 60 minutes postexposure, and lungs taken for biochem-
ical determinations. The extent of pulmonary edema was also determined for
comparison purposes. Lungs were fractionated into four major subcellular or-
ganelle fractions: nuclear debris, mitochondrial-lysosomal, microsomal, and
soluble (cytoplasmic). Activities of p-nitrophenyl phosphatase, cytochrome C
oxidase, ATPase, and lactic dehydrogenase within these fractions were found to
be decreased (generally 10-80 percent) at all intervals after exposure. There
was a corresponding increase in protein concentration in all fractions, which
was particularly marked in the soluble fraction. Lactic dehydrogenase levels
in serum rose with time after exposure, with a concomitant fall of the enzyme
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level in the tissue homogenate and soluble fractions. Pulmonary edema, as
indicated by an increased water content in the lung, was not evident at 30
minutes, but there was a 5 percent increase in water content at 60 minutes.
Based on these results, the authors suggested that one possible mechanism play-
ing a role in phosgene damage may be associated with either inhibition or loss
of enzyme activity in the lung.
In a companion paper, Pawlowski and Frosolono (1977) evaluated ultrastruc-
tural alterations in rat lungs by electron microscopy, attempting to correlate
them with their biochemical observations (Frosolono and Pawlowski, 1977).
Exposure conditions were the same as: described for the biochemical studies.
The investigation was limited to those events that took place in the terminal
bronchoalveolar region. The earliest morphologic result of phosgene damage,
seen immediately after exposure, was: a vesiculation of cells in the terminal
bronchiolar epithelium, and most probably represented the beginning of edema in
these cells. This was followed by septal extracellular edema with minimal in-
tracellular edema. Intracellular edema developed next and led to cellular dis-
ruption and necrosis. Fluid appeared in the alveoli after the intracellular
and extracellular interstitial spaces of the septa became very swollen. Inter-
stitial cells seemed to be very susceptible to the effects of edema. Whether
I
these cells are the specific targets of phosgene chemical reaction remains to
be determined. However, because of the decreases in enzyme activity, the
authors suggested that metabolic depression and disturbances may precede major
ultrastructural changes in the alveolar region.
In a recent biochemical study, Currie et al. (1985) determined the effects
of phosgene on pulmonary energy metabolism. Male Sprague-Dawley rats were ex-
posed to 1 ppm phosgene for 4 hours ;(CT = 240 ppm-min). Lungs were obtained at
the end of the 4-hour exposure and at 24-hour intervals thereafter over a 4-day
period for histological and biochemical assessments to correlate the onset of
pulmonary edema with changes in energy metabolism. Edema was estimated by his-
tologic methods and by measurement of lung wet and dry weights. In parallel
studies, mitochondria! oxygen uptake or respiratory activity was measured using
oxygen electrodes. The respiratory control ratio or State 3/State 4 ratio is
a sensitive measure of mitochondria] structural integrity and was used as an
indicator of damage to the mitochondria! electron transport chain. The investi-
gators observed that the significant reduction in the respiratory control index,
found immediately following phosgene exposure, coincided with the highest level
August 1986 3-6 DRAFT-DO NOT QUOTE OR CITE
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of percent water in the lung. There was a concomitant decrease in ATP concen-
tration, based on mmol ATP/g wet weight of lung, that persisted on the third
day after exposure. The authors concluded that reductions in ATP levels and
in Na-K-ATPase activity may play a major role in damage to lung tissue after
exposure to phosgene.
Frosolono and Currie (1985), reasoning that the maintenance of alveolar
structural integrity, essential for exchange of respiratory gases, is dependent
upon reduction of alveolar surface tension forces by the integrated function of
pulmonary surfactant system constituents, determined the response of the pulmo-
nary surfactant system to phosgene. The animals used and the phosgene exposure
conditions were similar to those described in their energy metabolism studies
(Currie et al., 1985). Immediately upon termination of phosgene exposure,
microsomal protein and palmitoyl transferase activity were reduced roughly 20
percent below normal values, and lung wet weight, used as a measure of edema,
was elevated approximately 20 percent above control levels. From the first
through the third day after exposure, all measured parameters except the
phosphatidylinositol constituent of the surfactant fraction were increased
above control values. In general, maximum levels were observed on the second
day; however, the palmitoyl transferase activity and surfactant concentration
continued to increase on the third day. Based on these results, the authors
suggested that (1) components of the pulmonary surfactant system may be in-
volved in maintenance of pulmonary fluid balance, and (2) the presence of excess
water in the lungs as a result of phosgene exposure may represent a signal for
increased synthesis of antiedematogenic materials (surfactant) to promote
removal of inappropriate fluid.
3.2.3 Role of the Nervous System
Because of the bradycardia, salivation, vomiting, urination, and defeca-
tion regularly occurring in animals exposed to phosgene, all suggestive of
abnormally high parasympathetic tone, Bruner et al. (1948) investigated
neurogenic involvement following phosgene exposure in an electrocardiographic
study. Thirteen healthy dogs were exposed to either 0.5 mg/L (125 ppm) phos-
gene for 30 minutes or 5.0 mg/L (1250 ppm) for 3 minutes. Both exposures are
an L(CT)gg for dogs. Electrocardiography during or shortly after gassing
showed a combination of sinus arrhythmia, sinus bradycardia, and prolonged con-
duction time related to heightened vagal activity. These changes regressed to
August 1986 3-7 DRAFT—DO NOT QUOTE OR CITE
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normal values as the heart rate increased during the second to sixth hour, and
showed no further change despite subsequent development of tachycardia coinci-
dent with development of pulmonary edema, anoxemia, and circulatory shock. No
correlation could be discovered between changes of electrocardiographic mea-
surements and either the rate of development or severity of the effects of
phosgene poisoning. In dogs in which the vagi were cut or blocked before or
after gassing, or in which the end drgans were blocked by the administration of
atropine, the bradycardia was absent, but no change was produced in the pulmo-
nary response to phosgene. The authors concluded that the early bradycardia of
experimental phosgene poisoning'was mediated by efferent vagal fibers, but that
the vagal efferent fiber to the lung and afferents from the lung, trachea, and
larynx have little, if anything, to do with the pulmonary tissue's response to
phosgene.
Ivanhoe and Meyers (1964) put forward the hypothesis that the pulmonary
edema induced by phosgene may be related to hypoactive sympathetic activity.
These investigators exposed 8 adult male and 2 adult female New Zealand rabbits
to phosgene doses ranging from 50 p^m for 14 minutes to 200 ppm for 25 minutes.
Changes in the total electrical activity of the cervical sympathetic nerve
before and after the animals had been gassed were measured. The animals that
survived four hours after exposure ^ere sacrificed at that time, and the lungs
examined. The exposure to overwhelming concentrations of phosgene was followed
by an immediate marked drop in total recorded electrical activity of the cervi-
cal sympathetic nerve in six of the, ten animals, a change that usually occurred
during exposure and never more than, 20 minutes after its termination. On
several occasions, great increases !in urinary bladder and intestinal peristaltic
activity were observed in the gassed animals, coincidental with the drop in
electrical nerve activity. Gross observations of the lungs at the end of the
experiment revealed congestive changes of the patchy hyperemia type, charac-
teristic of neuroparalytic acute pulmonary edema. Assuming'that the abrupt
sharp drop in the electrical activity of the right cervical sympathetic nerves
that followed phosgene gassing in the rabbits reflects a similar and coincident
fall in sympathetic tone everywhere else in the organisms, including the lung,
and considering the fact that the patchy hyperemia was still in its first
stages of development at a time when the neural effects had already occurred, the
authors suggested a cause-and-effeqt relationship between the fall in sympa-
thetic activity and a vascular dynamic disturbance in the lung leading to edema.
August 1986 3-8 DRAFT-DO NOT QUOTE OR CITE
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In this regard, the authors call attention to the observations of other
researchers, which could be interpreted as manifestations of reduced sympa-
thetic activity following exposure to phosgene, such as the bradycardia and
systemic arterial hypotension observed by Patt et al. (1946) and the increased
motor activity of the bladder and intestinal tract observed by Coman et al.
(1947). However, the authors' conclusions should be viewed skeptically because
only 60 percent of the animals showed a drop in electrical activity.
3.3 SUMMARY
Although j_n vivo and in vitro studies on the metabolism of phosgene have
not been performed, chemical and biochemical data, as well as indirect animal
studies, aid in the understanding of several aspects of phosgene metabolism and
its mechanisms of action. Phosgene reacts rapidly with water, but more rapidly
with certain chemical groups found in tissue macromolecules, such as free amines
and sulfhydryls. Because of its high reactivity, it is doubtful that any unre-
acted phosgene will enter the general circulation even after exposure to high
concentrations of the gas. The pathology of phosgene poisoning is mainly due
to its acylating properties and not a result of HC1 generation upon hydrolysis,
although HC1 production may play a minor role. The production of pulmonary
edema following phosgene exposure has been correlated with reductions in pulmo-
nary ATP levels and Na-K-ATPase activity, as well as inhibition of other pulmo-
nary enzymes. The role of the nervous system in the toxicity of phosgene is
considered to be a nonspecific effect of irritant gases (Diller, 1985).
August 1986 3-9 DRAFT—DO NOT QUOTE OR CITE
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3.4 REFERENCES FOR CHAPTER 3
Bruner, H. D.; Coman, D. R. (1945) The pathologic anatomy of phosgene
poisoning in relation to the pathologic physiology. In: Fasciculus on
chemical warfare medicine: v. II, respiratory tract. Washington, DC:
National Research Council, Committee on Treatment of Gas Casualties; pp.
234-330.
Bruner, H. D.; Boche, R. D.; Gibbon, M. H.; McCarthy, M. D. (1948)
Electrocardiographic study of:heart and effect of vagotomy in phosgene
poisoning. Proc. Soc. Exp. Biol. Med. 68: 279-281.
Cessi, C.; Colombini, C.; Mameli, L. (1966) The reaction of liver proteins
with a metabolite of carbon tetrachloride. Biochem. J. 101: 46c-47c.
Chemical Warfare Service. (1920) Collected studies on the pathology of war gas
poisoning. New Haven, CT: Yale University Press.
Coman, D, R.: Bruner, H. D.; Horn,! R. C., Jr.; Friedman, M. D.; Boche, R. D.;
McCarthy, M. D.; Gibbon, M.1 H.; Schultz, J. (1947) Studies on
experimental phosgene poisoning. I. The pathologic anatomy of phosgene
poisoning, with special reference to the early and late phases. Am. J.
Pathol. 23: 1037-1074. j
Currie, W. D.; Pratt, P. C.; Frosplono, M. F. (1985) Response of pulmonary
energy metabolism to phosgene.( Toxicol. Ind. Health 1: 17~27.
Oilier, W. F. (1985) Pathogenesis of phosgene poisoning. Toxicol. Ind. Health
1: 7-15.
Eschenbrenner, A. B.; Miller, E. (1944) Induction of hepatomas in mice by
repeated oral administration of chloroform, with observations on sex
differences. JNCI J. Natl. Cancer Inst. 5: 251-255.
Frosolono, M. F.; Currie, W. D. (1985) Response of the pulmonary surfactant
system to phosgene. Toxicol. Ind. Health 1: 29-35.
i
Frosolono, M. F.; Pawlowski, R. (1977) Effect of phosgene on rat lungs after
single high-level exposure: I. biochemical alterations. Arch. Environ.
Health 32: 271-277.
Gerard, R. W. (1948) Recent research on respiratory irritants. In: Andrus, E.
C.; Bronk, D. W.; Garden, G. JA., Jr.; Keefer, C. S.; Lockwood, J. S.;
Wearn, J. f.; Winternitz, M. ;C., eds. Science in World War II: v. II,
advances in military medicine;. Boston, MA: Little, Brown and Company; pp.
565-587. ;
International Agency for Research ion Cancer. (1971) Carbon tetrachloride. In:
IARC monographs on the evaluation of carcinogenic risk of chemicals to
man: v. 1, some inorganic substances, chlorinated hydrocarbons, aromatic
amines, N-nitroso compounds and natural products. Lyon, France: World
Health Organization; pp. 53-60.
August 1986
3-10
DRAFT—DO NOT QUOTE OR CITE
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Ivanhoe, F.; Meyers, F. H. (1964) Phosgene poisoning as an example of
neuroparalytic acute pulmonary edema: the sympathetic vasomotor reflex
involved. Dis. Chest 46: 211-218.
Manogue, W. H.; Pigford, R. L. (1960) The kinetics of the absorption of
phosgene into water and aqueous solutions. AIChE J. 6: 494-500.
Mansuy, D.; Beaune, P.; Cresteil, T.; Lange, M.; Leroux, J.-P. (1977) Evidence
for phosgene formation during liver microsomal oxidation of chloroform.
Biochem. Biophys. Res. Commun. 79: 513-517.
Nash, T.; Pattle, R. E. (1971) The absorption of phosgene by aqueous solutions
and its relation to toxicity. Ann. Occup. Hyg. 14: 227-233.
Patt, H. M.; Tobias, J. M.; Swift, M. N.; Ppstel, S.; Gerard, R. W. (1946)
Hemodynamics in pulmonary irritant poisoning. Am. J. Physiol. 147:
329-339.
Pawlowski, R.; Frosolono, M. F. (1977) Effect of phosgene on rat lungs after
single high-level exposure: II. ultrastructural alterations. Arch.
Environ. Health 32: 278-283.
Pohl, L. R.; Bhooshan, B.; Whittaker, N. F.; Krishna, G. (1977) Phosgene: a
metabolite of chloroform. Biochem. Biophys. Res. Commun. 79: 684-691.
Potts, A. M.; Simon, F. P.; Gerard, R. W. (1949) The mechanism of action of
phosgene and diphosgene. Arch. Biochem. 24: 329-337.
Rona, P. (1921) Ueber Kampfgasvergiftungen. II. Ueber Zersetzung der
Kampfstoffe durch Wasser [Combat gas poisoning. II. The decomposition of
combat material by water]. Z. Gesamte Exp. Med. 13: 16-30.
Shah, H.; Hartman, S. P.; Weinhouse, S.v(1979) Formation of carbonyl chloride
in carbon tetrachloride metabolism by rat liver jjn vitro. Cancer Res. 39:
3942-3947.
Slade, R.; Graham, J. A.; Hatch, G. E. (1983) Inhaled 14C-phosgene: species
comparison and biochemical fate. Toxicologist 3: 110.
U. S. Environmental Protection Agency. (1984) Health assessment document for
carbon tetrachloride. Cincinnati, OH: Environmental Criteria and
Assessment Office; p. 8-44; EPA report no. EPA-600/8-82-001F. Available
from: NTIS, Springfield, VA; PB85-124196.
U. S. Environmental Protection Agency. (1985) Health assessment document for
chloroform. Research Triangle Park, NC: Environmental Criteria and
Assessment Office; p. 4-35; EPA report no. EPA/600/8-84/004F. Available
from: NTIS, Springfield, VA; PB86-105004.
August 1986 3-11 DRAFT-DO NOT QUOTE OR CITE
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4. ACUTE TOXICITY OF PHOSGENE EXPOSURE IN ANIMALS AND HUMANS
4.1 ANIMAL STUDIES
Animal studies on phosgene were initially undertaken because of its use as
a chemical warfare agent in World War I. As used during the war, phosgene
produced its noxious effects in humans through inhalation. Consequently,
animal studies were also conducted using the inhalation route of administra-
tion, and essentially all studies on the effects of phosgene in animals have
been carried out via this route.
The effects of acute exposure of animals to phosgene, summarized in Table
:-4-l, are based largely on the data presented by Diller and Zante (1982).
Extrapolating from the data in their tables, Diller and Zante proposed an
approximate L(CT),-n for a number of species and ranked them according to their
susceptibility to acute phosgene toxicity as shown in Table 4-2.
4.1.1 Measurement of Phosgene Exposure
The magnitude of exposure to a toxic gas or .vapor is determined by the
concentration of the toxic component (C) and the duration of exposure (time,
T). In comparing the lethalities of potential war gases, Haber (1924) intro-
duced the concept of a "death product," expressed as the product of the concen-
tration and exposure time. This was later postulated as "Haber1s Law," which
in its general form states that the product of the concentration and time of
exposure required to produce a specific physiologic effect is equal to a
constant, or CT = K. Although this law generally applies to physiological
effects, the effect observed by early investigators was death.
The validity of the CT = K relationship for phosgene poisoning was tested
by Flury (1921). Twenty cats were exposed to phosgene concentrations ranging
from 5 to 500 mg/m3 for 0.5 to 120 minutes (CT values ranged from 37.5 to 562
ppm-min). When K (death or survival) was plotted as a function of C (ordinate)
and T (abscissa), the curve that best fit the data was a hyperbola, as
August 1986 4-1 DRAFT—DO NOT QUOTE OR CITE
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TABLE 4-2. MEDIAN LETHAL INHALATION DOSE OF PHOSGENE FOR VARIOUS SPECIES
(ppm-min)
Species L(CT>50
Cat ~ 200
Ape ~ 300
Rat - 400
Guinea pig - 500
Man - 500
Mouse ~ 500
Dog -1000
Rabbit -1500
Goat -2000
Source: Oilier and Zante (1982)
predicted by the CT = K equation (Figure 4-1). Although Flury's work supported
the concept of Haber's Law, questions were raised by other investigators about
its validity.
Bruner and Coman (1945) reviewed the available literature and concluded
that "for practical purposes the CT product for .a species may be regarded as a
constant within the middle ranges of concentrations and duration of exposure."
However, they also stated that at the extremes of concentration the relation-
ship completely breaks down. From the available data it appears that the
CT = K relationship for lethality is valid for phosgene concentrations between
1 and 200 ppm and for exposure times long enough to negate the effects of an
animal holding its breath.
More recently, Atherley (1985) reviewed the uses and limitations of
Haber's Law as an index of exposure. Atherley cautioned that confusion
between the use of dose and exposure, and insufficient consideration of time
as a factor call into question the validity of its usage for many substances.
Whereas Haber's Law does not hold for some other noxious gases, it appears to
apply, within limits, to toxic endpoints of phosgene exposure. :
Rinehart and Hatch (1964) studied the responses of 118 Wistar rats exposed
to phosgene concentrations ranging from 0.5 to 4 ppm over time periods ranging
from 5 minutes to 8 hours. The exposures were varied to give CT products
between 12 and 360 ppm-min. Response was expressed in terms of impaired
pulmonary gas exchange capacity as measured by the decreased rate of uptake of
carbon monoxide (Long and Hatch, 1961) and ether. The authors concluded that
the product of phosgene concentration and exposure time (CT) appears to be a
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LETHAL POISONING
ANIMAL SURVIVED
300
250
"I
H200
o
g
oc
150
ui
o
100
30
60 90
INHALATION TIME (T), min
120
Figure 4-1. Exposure^ (C x T) of cats to phosgene.
Source: Adapted fropi Flury (1921).
4-12
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suitable way to express the magnitude of phosgene dosage, since equal degrees
of respiratory response were observed from exposures to various combinations of
C and T that gave the same CT product.
4.1.2 Symptomatic Stages of Acute Phosgene Exposure
The lung appears to be the principal target organ for phosgene inhalation,
and the characteristic pathologic feature is the delayed development of
pulmonary edema. This was demonstrated in some of the earliest studies on
phosgene poisoning carried out at the time of World War I. Underbill (1919,
1920), in his studies on the toxicity of phosgene, exposed over 500 dogs for 30
minutes to phosgene concentrations ranging from 44 to 120 ppm. He pointed out
that phosgene acted chiefly as a respiratory irritant but was also a lacrimator.
Very small doses (concentration not reported) scattered in the air caused
coughing, watering of the eyes, and intense dyspnea. The influence of small
doses was limited mainly to the terminal bronchioles and alveoli of the lungs.
This effect produced edema of the lungs accompanied by an interference of
pulmonary gas exchange and consequent cyanosis on exertion. It usually took
several hours for the serious symptoms to develop. In the dogs exposed to high
concentrations, there was slight lacrimation and uneasiness, and the pupils
became clouded. Subsequently, the dogs developed a hard cough, respiration
became more and more difficult (usually there was rattling in the throat), and
death followed 3 to 12 hours after exposure. The heart action grew weaker as
death approached, but persisted after all attempts at breathing had ceased.
Changes in hematocrit were not prominent in the early stages of phosgene
poisoning; however, as time passed, the blood assumed a sticky, concentrated
consistency, probably reacting in time to impede heart action and to interfere
with the proper blood supply to the tissues, and thereby altering metabolism.
Pointing out that pulmonary edema is a very prominent feature of phosgene
poisoning, Underbill (1919, 1920) suggested that the edema may be an apparent
attempt toward repair or alteration of injury. However, at sufficiently high
exposure levels, the whole mechanism governing the exudation of tissue fluid
was thrown out of control so that the response became overwhelming. Under
these conditions, a reaction that initially may be regarded as beneficial even-
tually becomes a direct menace to continued existence by creating mechanical
difficulties for respiration and circulation. Considering the changes in the
blood and lungs at intervals following phosgene exposure, Underbill concluded
that the development of edema is associated with well-defined changes in the
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fluid and electrolyte content of the blood and tissues, without an apparent
increase in the permeability of the blood vessels. Fluid and electrolytes
probably pass from the tissues to the blood in an attempt to compensate the
latter for its loss as pulmonary edema fluid.
On the basis of alterations in hematocrit, Underbill (1919, 1920) con-
ceived three stages in phosgene poisoning. In the first few hours (5-8) after
phosgene poisoning, there was a slight, temporary dilution of the blood.
Oxygen-carrying capacity, erythrocyte count, and total hemoglobin followed a
curve parallel with that of changes in hematocrit throughout all stages of
phosgene poisoning. In the second stage, the period of blood dilution was
followed by an interval during which the hematocrit increased to a point far
beyond the normal value and remained near this level for several hours. Edema
reached its maximum development during this stage. After the period of in-
creased hematocrit, the blood gradually became more dilute until it was slightly
under the normal value, which was eventually regained and the animal recovered.
Underbill ascribed the immediate ca:use of death in phosgene poisoning to blood
concentration, with its attendant decrease in circulation, oxygen starvation of
the tissues, fall in temperature, and, finally, suspension of vital activities.
Winternitz et al. (1920) carried out necropsy studies on the same dogs
used by Underbill (1919, 1920). The changes found at necropsy after gassing
varied greatly with the time the :animals had survived; consequently, the
animals were divided into three groups: animals dying or killed within 48
hours after gassing ("acute period?), those killed or dying after 3 to 10 days
("subacute period"), and those killed or dying after 11 to 129 days ("chronic
period"). Gross findings on 260 dogs dying during the acute period showed
frothy fluid oozing from the mouth;, with some loss of weight, probably due to
loss of fluid by mouth. There was engorgement of the great vessels in the
abdomen and congestion of the visc'era. The liver was enlarged and was a dark
purplish color. The spleen was only slightly enlarged, but like the other
abdominal organs, had the general appearance of acute congestion. The heart
was generally enlarged, being more' marked on the right than on the left side.
The lungs were very voluminous and heavy. In animals dying in the first 12
hours, the edematous condition was! not quite so marked, whereas in those dying
between 24 and 48 hours it was often the most prominent feature, overshadowing
the congestion and emphysema. ThMs, in the first few hours before the edema
became well developed, congestion I/as clearly responsible for the larger share
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of the increased pulmonary weight. Lung tissue increased rapidly in weight,
reaching a maximum 18 to 24 hours after gassing when it often was, in fatal
cases, more than four times the normal weight. The esophagus, stomach, intes-
tines, pancreas, adrenals, thyroid, and brain showed no gross abnormalities.
For 66 dogs dying in the subacute phase, infection of the respiratory tract
was the main finding. If death was delayed more than four days, initial signs
of repair, including organization of the exudate in the alveoli and bronchi,
were generally seen. Congestion, edema, and emphysema were still present to
a moderate degree. Edema was still marked, but less so than in animals in the
acute group. The right side of the heart was still dilated in the subacute
phase animals. The pathology of the 177 dogs dying after 11 to 129 days dif-
fered little from that observed in the animals which were killed or died in
the subacute period. The healthier looking dogs in the third group, which
were killed rather than dying spontaneously, showed moderately collapsed lungs.
There was evidence of obi iterative bronchiolitis and an associated atelectasis
and emphysema. The presence of pathogenic organisms in many "recovered"
animals was assumed to be an explanation for the fatal pneumonia that may
develop even months after gassing.
The authors drew the following conclusions based on their studies. Phos-
gene inhalation in dogs found its chief anatomical expression in the respiratory
tract. The lesions seen at autopsy varied according to the length of time the
animal survived after gassing. At first there was severe pulmonary edema asso-
ciated with extreme congestion, which reached a maximum toward the end of the
first 24 hours and disappeared gradually in animals surviving 10 days or longer.
The edema was associated with an inflammatory exudation of fibrin and leukocytes,
which was most marked in and around the finer bronchioles and spread to a vari-
able extent throughout the lung tissue. A typical lobular or pseudolobular
pneumonia resulted. The character of the phosgene lesion was explained by the
localization of the action of the gas upon the air tubes. The epithelium of the
trachea and larger bronchi was not damaged, while that of the smaller bronchi
and bronchioles was seriously injured, the more distal portion suffering most.
In addition to the changes in the mucosa, the bronchi also showed pathological
contractions and distortions, which resulted in more or less complete oblitera-
tion of their lumina. These, in turn, lead to mechanical disturbances in the
air sacs, resulting in atelectasis or emphysema (Winternitz et al., 1920).
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In a note on the comparative! pathology of acute phosgene poisoning,
Winternitz et al. (1920) concluded!that the pathology of phosgene poisoning in
the goat, dog, monkey, rabbit, guinea pig, rat, and mouse was similar. The
important lesions were confined to the lower respiratory tract. These consisted
essentially of an edema filling many of the alveoli, associated with inflamma-
tory changes that began in the bronjchioles and extended into the alveoli. There
was a well-marked variation in spepies toward phosgene lethality, which found
its chief expression in the pathological picture as a difference in the amount
of edema. Although edema developed more rapidly in the more susceptible spe-
cies, it did not attain the degree bommonly found in those animals that survived
the same dose for a longer interval. This not only emphasizes the time factor
in its production, Winternitz stated, but also clearly indicates that edema
itself is not the cause of death. \
The studies of Underbill (1919, 1920) and Winternitz et al. (1920) were
carried out at Yale University. Meek and Eyster (1920) carried out a concur-
rent study on the pathological physiology of acute phosgene poisoning in dogs
at the University of Wisconsin, wi[th results comparable to those of Underbill
i
and Winternitz et al. The animals' were subjected for 30 minutes to phosgene
at a concentration of 80 to 100 ppmj, a level sufficient to produce death within
24 hours in most instances. A wellrmarked succession of events ensued, finally
resulting in typical pulmonary edema. In the first stage, prior to edema devel-
opment, there was early injury to the linings of the deep respiratory passages.
Irritation from this resulted in a!certain amount of reflex cardiac inhibition
and vasoconstriction. Coincident wjith these changes, there was a direct action
of the gas on the red blood cells, which caused them to agglomerate and obstruct
the pulmonary capillaries. This in turn put a strain on the right side of the
heart, with a right-sided cardiac dilatation being apparent. Even during this
stage, the injury to the alveolar ;membranes and the increased pressure initi-
ated the transfusion of fluid from the blood into the tissue spaces and later
into the air passages of the lungs. The rapid development of this edema was
the major characteristic of the s;econd stage. It resulted in hemoglobin
concentration, reduction in blood volume, and decreases in heart size, all of
which proceeded to extreme degrees. Death under such conditions was either due
to the edematous condition of the!lungs, interfering sufficiently with ex-
change so that the animal asphyxiated, or the blood volume was so reduced that
even though the hemoglobin was oxygenated there was not enough fluid to secure
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its proper distribution to, and circulation in, the tissues. In either case,
the tissues died of oxygen starvation. The authors concluded that death was
due to a combination of the two causes.
4.1.3 Lung Tissue Analysis After Acute Phosgene Exposure
Cameron et al. (1942b) exposed a group of animals to phosgene at an
average concentration of 3.47 mg/m (0.86 ppm) for a single 5-hour exposure.
The exposed animals consisted of 20 mice, 10 rats, 10 guinea pigs, 10 rabbits,
2 cats, 2 monkeys, and 2 goats. On the morning following exposure, 10 percent
of the rats (1/10) and 60 percent of the mice (12/20) were dead. There were
no other mortalities, although one cat and one monkey were very ill and
exhibited labored breathing. All survivors of the experiment were killed on
the morning following exposure. All animals were necropsied, and one lung
from each animal was fixed in formalin for sectioning. Upon examination, 54 of
56 animals (96.4 percent) showed microscopic evidence of pulmonary involvement
that was severe in 29 animals (39 percent), mild in 17 (31 percent), and slight
in 16 (30 percent). The most frequent effect noted in the lungs was edema.
Cameron and Courtice (1946) studied the production and removal of edema
fluid in lungs after exposing rabbits, dogs, and goats to 440 mg/m3 (110 ppm)
of phosgene. Edema fluid was collected by inverting the animal immediately
after death or when the animal was killed. In 24 rabbits exposed to phosgene
for 15 to 30 minutes, increased time of exposure caused edema of greater severity.
Rabbits exposed for 30 minutes usually died quickly with massive pulmonary
edema. Yet all groups, regardless of extent of edema, showed little or no
hemoconcentration, indicating that withdrawal of fluid from undamaged tissues
into the blood was also rapid. The edema fluid had the same protein concen-
tration as the plasma, suggesting an increase in capillary permeability. In
studies on 12 dogs and 2 goats exposed to phosgene for 10 to 30 minutes, consid-
erable hemoconcentration occurred as fluid was lost into the lungs. As edema
developed, lymphatic flow increased rapidly in dogs exposed to phosgene,
reaching levels many times higher than normal. However, the lymphatics removed
only about 10 percent of the pulmonary edema fluid formed, when death occurred
from 6 to 12 hours after exposure. After 24 hours, the production of edema
fluid seemed to lessen and the animal recovered. Nonetheless, for dogs killed
several days later, when hemoconcentration had disappeared, the lungs were
often still edematous. Based on these studies, the authors concluded that
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anoxia due to pulmonary edema was a more important factor in causing death
than hemoconcentration and a decreased blood volume.
A systematic analysis of the sequence of tissue changes in lungs of
animals following exposure to phosgejne was carried out by Coman et al. (1947).
The dogs, cats, rabbits, and guinea pigs employed in the studies were adults of
mongrel origin; the rats were of the Wistar strain. The animals were exposed
to potentially lethal doses of phosgene which varied according to species sus-
ceptibility. Exposure times varied :from 3 to 30 minutes for dogs, from 3.5 to
57 minutes for rats, and were 13, 35, and 9 minutes for the cats, rabbits, and
guinea pigs, respectively. The course of phosgene poisoning was divided into
three phases: (1) the incipient phase, which extended from gassing up to two to
six hours; (2) the critical phase in which the majority of deaths occurred (in
survivors, this phase ended about thjree days after exposure); and (3) the regres-
sive and reparative phase, which extended from the fourth day onward. Exten-
sive emphysema was the earliest prominent lesion in animals exposed to poten-
tially lethal doses of phosgene. Sloughing of the bronchiolar mucosa and
questionable bronchial restriction were also found at once after gassing.
Peribronchial edema, pulmonary congestion, and alveolar edema developed
subsequently and in that order. The rapidity of development and extensiveness
of these lesions were roughly proportional to the severity of the exposure.
Recovery from the massively edematogs lung was found to be primarily a process
of resorption of edema fluid and scarring. A moderate cellular inflammatory
reaction accompanied this process, 'sometimes so excessive as to resemble
bronchopneumonia. The late effects; of phosgene poisoning consisted of pulmo-
nary scarring, lobular emphysema, arid small, irregular areas of atelectasis and
bronchitis. Apart from effects on lungs, dogs poisoned by doses of phosgene,
which killed 70 to 99 percent of the group, immediately showed bradycardia, a
general lassitude, motor activity |>f the colon and bladder, and a rapid,
shallow type of restricted breathin:g. There was no relationship between the
severity of these signs and survival The authors concluded that there was no
asymptomatic interval between exposure and onset of overt damage. Rather, the
anatomic pulmonary damage, begun during gassing, steadily progressed. The
results of Coman et al. (1947) parallel those of Winternitz et al. (1920).
4.1.4 Measurement of Pulmonary Function
Gibbon et al. (1948) investigated the possibility that elevated pulmonary
pressures might be a factor in the [pulmonary edema produced by phosgene. This
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was done by direct measurement of the pulmonary arterial pressure and by
evaluation of the pulmonary pressure gradient in cats. In studies using 5
cats exposed to highly lethal doses of phosgene at concentrations of 0.29 mg/L
(72 ppm) for time periods ranging from 8.5 to 13 minutes, no abnormal eleva-
tions of pressure were found in the pulmonary artery up to 30 hours after
gassing. These results seem to make untenable the hypothesis that the pulmo-
nary edema of phosgene poisoning is of purely hydrostatic origin.
Long and Hatch (1961) described a sensitive means for measuring early and
minimal degrees of functional pulmonary impairment in rats following exposure
to phosgene, based on a reduction in the rate of respiratory uptake of carbon
monoxide (CO). At least 8 unanesthetized rats were exposed to each of the
following concentration ranges of phosgene for 30 minutes: 0.5 to 1, 1 to 2, 2
to 3, 3 to 4, and 4 to 5 ppm. Postexposure tests on CO retention, oxygen
consumption and breathing frequency were run at intervals from 1 to 72 hours
after exposure. There was a progressive loss of capacity to absorb CO over the
first six to eight hours after exposure, followed by a prolonged period of re-
covery. Moreover, there was a direct correlation between the systematic de-
crease in the magnitude of the effect and the lowering of the phosgene concentra-
tion. Measurable changes in CO uptake were found even with the lowest level of
exposure, below 1 ppm, and in the absence of microscopic changes at necropsy.
In a study designed to determine the increase in permeability of the
respiratory membrane of rabbits after exposure to phosgene, Boyd and Perry
(1960) exposed 62 male rabbits to 0.27 mg/L (67 ppm) of phosgene for 30
minutes. The animals were then divided into two groups and anesthetized with
urethane, either immediately or 16 hours after gassing. Fluid was collected
from the respiratory tract at hourly intervals after anesthetization. In preli-
minary experiments, this exposure killed 80 to 100 percent of the rabbits. The
response to phosgene during the first six or seven hours after exposure con-
sisted of a mild edema of the trachea, bronchioles, and alveolar tissues. Also,
there was some congestion, emphysema, and contraction of pulmonary capillaries.
In 19 of 31 animals anesthetized 16 hours after gassing for fluid collection,
the pulmonary edema had markedly increased, there was more emphysema and some
hemorrhage, the pulmonary capillaries were less contracted, and there was less
edema in the bronchioles and trachea. In the other 12 animals, there was a
premortal gush of respiratory tract fluid (60 times normal) similar in composi-
tion to blood plasma, and pulmonary edema was maximal. The animals also
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displayed intense hemoconcentratiojn. The authors concluded that the clinical
course of phosgene poisoning is characterized by a latent period of several
hours following exposure, during which many pathological changes occur.
Results comparable to those found in rabbits were also obtained in cats
and dogs (Boyd and Perry, 1963). 'Fifty-seven cats and 12 dogs were exposed to
an estimated ID™ of phosgene, the concentration of phosgene varying between
0.10 and 0.30 mg/L (25-75 ppm) fon 30 minutes of exposure. During the hour or
two before death, the volume outppt of respiratory tract fluid increased some
thirtyfold in half the animals (cats, -35 ml/kg/24 hr; dogs, -15 ml/kg/24 hr),
and its lipid and sodium chloride contents were similar to those of blood
plasma. The ability of the animals to excrete such large volumes of respira-
tory tract fluid appeared to be due to a marked reserve capacity of the ciliary
drainage mechanism, which was evidently not affected by the dose of phosgene
given to these animals. !
4.1.5 Site of Lung Injury Following Acute Phosgene Exposure
The first changes occurring in lungs of dogs after inhalation of phosgene
for a short time were examined by Oilier et al. (1969) utilizing comparative
radiographic studies as well as light and electron microscopy. Forty-two dogs
(30 beagles and 12 mongrels) were exposed to either 94.5 or 107.5 ppm phosgene
for 10 minutes. Examinations were carried out at various intervals after
exposure. The first changes were found in the alveolar wall 1.5 hours after
inhalation, with the alveolar epithelium appearing intensely folded. The
alveolar wall was edematous, and the alveoli contained a cell-free exudate.
The peripheral parts of the lung were emphysematous. The edema increased
during the first hours. After rupture of the alveolar walls, the exudate
contained fibrin and cellular debris. A severe bronchiolitis with some necro-
sis developed six to eight hours after phosgene inhalation. Lymphostasis occur-
red in the peribronchial interstijtium. Roentgenograms at four hours revealed
only acute emphysema, and six hours after inhalation, a lung edema was recogniz-
able. These results would appear:to support the conclusions of Boyd and Perry
(1963, 1960) regarding the time sequence of pathological changes induced by
phosgene.
Rinehart and Hatch (1964) studied the responses of 118 Wistar rats to
phosgene exposure. Exposure concentrations were between 0.5 and 4 ppm for
intervals ranging from 5 minutes; up to 8 hours (CT values ranged between
12 and 360 ppm-min). Beginning qhanges in pulmonary performance were noted
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following exposures to CT values as low as 30 ppm-min. Deaths occurred at
doses greater than 180 ppm-min, with associated reduction in CO uptake to less
than 50 percent of the normal value. Survival from exposures exceeding 300
ppm-min was less than 40 percent. Low-level exposures to phosgene, below 100
ppm-min, appeared mainly to affect the ventilatory process through increased
resistance to breathing and poorer distribution of the ventilating air in the
lungs. Above 100 ppm-min, loss of diffusing capacity became relatively impor-
tant. The authors surmised that these differences in nature of response
reflect differences in the major site of action, with the respiratory bronchi-
oles being the site in the first case and the alveoli in the second.
In an extension of the studies of Rinehart and Hatch (1964) on the depen-
dence of the site of lung injury on the level of phosgene administered, Gross
et al. (1965) also exposed 117 male Wistar rats to phosgene at concentrations
between 0.5 and 4 ppm for periods ranging from 5 minutes to 8 hours. The CT
values ranged from 13 to 360 ppm-min. The animals were killed four days after
phosgene exposure and the lungs examined. A second series of 15 rats was
exposed to 1.7 ppm phosgene for 120 minutes and then killed in groups of 3
at 4, 8, 24, and 48 hours and 1 week after exposure. In addition, a third
group of rats was exposed to 2.2 ppm phosgene for 80 minutes and killed 3
months after exposure. The authors found that at the doses administered,
there was development of a chronic pneumonitis, with the severity of response
depending on the dose level. At the lower concentrations, relatively small
amounts of the alveolar surface epithelium, involving only adjacent alveoli,
were affected. At higher concentrations, little unaffected alveolar tissue was
present and the pneumonitis was considered severe. The authors attributed this
difference to the two target sites involved, i.e., the alveolar surface epithe-
lium and the alveolar capillary. A reversible chronic pneumonitis resulted
when the phosgene dose was low and when the alveolar epithelium was merely
irritated. In contrast, when high concentrations of phosgene were adminis-
tered, much of the surface epithelium was destroyed, rendering it incapable of
reacting to injury. The unprotected capillary was then severely injured and
responded with the profuse exudation of pulmonary edema.
Gross et al. (1967) elaborated on their view regarding the nature of the
response of respiratory tissue to irritants, pointing out that the alveolar
wall is composed of two embryo!ogically different tissues. The network of
alveolar capillaries is of mesodermal origin, whereas the alveolar membrane is
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of entodermal origin. These twq tissues respond differently to injury. A
respiratory irritant in dosages Sufficient to penetrate the alveolar membrane
and injure the subjacent capillary will cause the classical reaction of all
capillaries—namely, the loss of semi permeability and leakage of fluid or
cells or both into the air spaces, resulting in pulmonary edema or pneumonia.
If the dosage of the irritant is not sufficient to injure the capillaries,
only the alveolar membrane may respond to the injury. This is characterized by
a proliferation of cohesive, alveolar cells and the elaboration of an argyro-
philic supporting stroma. j
Hatch et al. (1986) investigated the concentration-response of inhaled
phosgene in rabbits, guinea pigs,, rats, hamsters, and mice. Lavage fluid pro-
tein accumulation 18 to 20 hr aftier 4 hr exposures to 0.1, 0.2, 0.5 and 1.0 ppm
phosgene was used as the indicator of pulmonary edema. All species had similar
basal levels of lavage fluid prqtein. Phosgene significantly affected mice,
hamsters, and rats at 0.2 ppm and above, while guinea pigs and rabbits were
significantly affected only at 0.5 ppm and above. No significant effects were
observed at the 0.1 ppm exposure I level.
Diller et al. (1985) carried out studies on 155 male albino Wistar rats to
establish the minimal inhalationjdoses of phosgene necessary for the production
of changes within the lung blood-air barrier. Groups of 10 to 15 animals were
exposed to a total dose of 50 ppm-min of phosgene at 5, 2.5, 1, 0.15, or 0.1
ppm for 10, 20, 50, 300, or 500 minutes, respectively. The animals were
sacrificed 48 hours after exposure for either morphological examination by
light and electron microscopy ajone, or in combination with bronchoalveolar
lavage. Another group of 14 rats was exposed to 0.1 ppm x 250 minutes (CT = 25
ppm-min) phosgene and sacrificed at 48 hours, and a final group was exposed to
0.1 ppm for 60 minutes. The authors found that at least 50 ppm-min (5 ppm x 10
minutes) was necessary for the production of alveolar edema, the minimal effec-
tive concentration of phosgene being 5 ppm. The smallest phosgene exposure to
produce an increase in pulmonary lavage protein content was also 50 ppm-min,
and the smallest phosgene exposure to produce widening of pulmonary interstices
was 25 ppm-min. There was no phosgene threshold concentration for these latter
two parameters, which was assumed to be indicative of physiological compensato-
ry mechanisms within the blood-air barrier. The authors concluded that the
primary localization of pulmonary damage by phosgene depends on the concentra-
tion of gas used. At very low 'concentrations of phosgene (0.1-2.5 ppm), the
i
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changes are primarily located at the transition from terminal bronchioles to
alveolar ducts; at higher concentrations of phosgene (5 ppm), it is primarily
the alveolar region that exhibits alterations (Type I pneumocytes) associated
with the initiation of edema. The authors suggested that these results would
appear to confirm a concentration dependence of the primary localization of
phosgene damage, as had been suggested earlier by Gross et al. (1965).
4.1-6 Blood Circulation Disturbances After Acute Phosgene Exposure
Although the characteristic pathologic feature of phosgene poisoning is
pulmonary edema, disturbances in blood circulation are also evident (Underbill,
1919, 1920). Hemodynamics in phosgene poisoning and the possible mechanisms
contributing to circulatory disturbance were investigated by Patt et al.
(1946). Circulatory measurements were made on both anesthetized and
unanesthetized dogs before and after exposure to phosgene at concentrations of
0.4 to 0.7 mg/L (100-175 ppm) for 30 minutes. Circulatory changes were fol-
lowed at various intervals for 13 hours after gassing. Heart rate fell precip-
itously with gassing, then slowly rose to above the initial value. Arterial
pressure fell distinctly and progressively with time after gassing. The fall
in arterial pressure was sharper in the short-survival groups. Venous pressure
did not change significantly or consistently. Pulmonary circulation time was
increased on the average by two-thirds at 8 to 12 hours after gassing, often
accompanied by a rising arteriovenous oxygen difference in the systemic cir-
cuit. The hematocrit rose sharply in relation to the increase in circulation
.time with a concomitant increase in blood viscosity. The authors concluded
that the circulatory disturbances observed may contribute to the final physio-
logic breakdown by exaggerating the tissue anoxia already present because of
the low arterial oxygen saturation. They believed, however, that death is due
primarily to an interference with oxygen uptake through edematous lungs. If
the animal survives the acute stage of pulmonary edema with its attendant
anoxia, circulatory failure may become a more important factor in the ultimate
outcome.
4.1.7 Recovery After the Development of Acute Symptoms
Koontz (1925) attempted to determine whether pathologic lesions persist in
the lungs of dogs that have been gassed with phosgene but have recovered from
all symptoms. Dogs of an unspecified breed were gassed with the minimum lethal
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dose (concentration not reported)!of phosgene. Ninety-five dogs that recovered
from the gassing, as determined ; after temperature, pulse, and respiration
became normal, and all symptoms such as coughing, depression, and general lack
of well-being had disappeared, were studied. Of these, 34 died or were killed
in the kennels by other dogs, and the other 61 were sacrificed at intervals
ranging from 2 weeks to 15 months after recovery. The lungs of 68 of the dogs
appeared normal by gross examination. Of the remaining 27, 3 showed emphysema
and 2 showed pneumonia. The others had lesions such as congestion, hemor-
rhage, edema, and emphysema in varying degrees of intensity. Most of these
gross lesions were found in dogs; that died. Microscopically, of the 95 dogs
studied, the lungs were normal in 21 and almost normal in another 24, showing
only small areas in which there Were lesions of minor degree. Lesions in the
lungs of other dogs consisted primarily of bronchi plugged with cellular debris,
and atelectasis in adjacent lung tissue in the early stages of recovery, pro-
gressing to obliterative bronchiolitis and patches of organization. The lungs
took on a more normal appearance as the time from date of recovery increased.
Durlacher and Bunting (1947) exposed 31 dogs of both sexes (breed not
specified) to phosgene at 0.29 mti/L (72 ppm) for 30 minutes. The animals were
then divided into several groups- and given a variety of treatments, including
60 percent oxygen therapy during the pulmonary edema phase. Consolidation of
one or more lobes of the lung wa<5 found in the animals four to nine days after
phosgene exposure. Organization of the pulmonary exudate occurred as the
initial edema subsided, resulting in severe late anoxemia and mortality in
spite of oxygen therapy during this period. Two dogs that survived the stage
of pulmonary organization showed only focal scars in the pulmonary parenchyma
and bronchioles 27 and 59 days after gassing.
4.2 HUMAN STUDIES
4.2.1 Odor Detection Threshold of Phosgene
The National Institute of Occupational Safety and Health (1976) reported the
results of two studies that investigated the odor detection threshold for phos-
gene. In one report, 56 "technically trained" military personnel were exposed
to increasing concentrations of phosgene until all the subjects could detect the
gas by odor. The lowest concentration that could be detected by some of the
subjects was 0.4 ppm. At concentrations of 1.2 and 1.5 ppm, 39 and 50 percent
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of the subjects reported detecting phosgene, respectively. In the second study,
a group of four volunteers were asked to identify the lowest concentration at
which they all could recognize the distinctive "hay-like" odor of phosgene. The
authors of this second study distinguished this value, 1.0 ppm, from the "detec-
tion threshold," described above which they felt was neither reliable nor repro-
ducible.
4.2.2 Acute Pathology
Within certain limits, the acute toxicity of phosgene to humans is depen-
dent upon the concentration of the gas and the length of time that an individu-
al is exposed. An extensive review of the literature on the health effects of
phosgene (both animal and human) led Diller and Zante (1982) to construct a
table to describe the concentration-effect relationships of phosgene exposure
in humans (Table 4-3).
TABLE 4-3. CONCENTRATION-EFFECT RELATIONSHIPS OF PHOSGENE EXPOSURE
Perception of odor >0.4 ppm
Recognition of odor >1.5 ppm
Signs of irritation in eyes, nose,
throat, and bronchi >3 ppm
Beginning lung damage >30 ppm-min
Clinical pulmonary edema >150 ppm-min
L(CT)i -300 ppm-min'
L(CT)50 -500 ppm-min
L(CT)10o -1300 ppm-min
Source: Oilier and Zante (1982).
At very high levels (>200 ppm), phosgene crosses the blood-air barrier,
reaches the pulmonary capillaries, and reacts with blood constituents (Diller,
1985a). Death occurs rapidly from acute overdistension of the right heart,
"acute cor pulmonale." The pathology associated with this severe poisoning
includes hemolysis in the pulmonary capillaries with hematin formation, conges-
tion by erythrocyte fragments, and stoppage of capillary circulation. Death due
to such massive exposure is relatively rare. More commonly, individuals are
exposed to small or moderate quantities of phosgene; the pathology resulting
from these lower exposures is quite different than that described above.
The pathogenesis following acute exposure to small or moderate concentra-
tions of phosgene (about 30-300 ppm-min) shows three distinct phases: initial
reflex syndrome, clinical latent phase, and clinical edema phase (Oilier,
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1985a). Immediately after exposure, the victim usually feels an irritation of
the eyes and throat and pain or tightness in the chest. He may also complain
of shortness of breath on exertion, an irritating cough, and nausea and vomit-
ing. These .initial symptoms abate rapidly and are followed by the clinical
latent phase, which is relatively free of symptomatology. A few patients
return to work during this period; of subjective well-being. The duration of
the latent phase is inversely proportional to the inhaled dose: after rela-
tively large doses, it may be 1 to; 4 hours and after small doses, 8 to 24 hours
(Oilier, 1985a).
The latent period ends when t|he amount of edema fluid in the lungs becomes
sufficient to interfere with respjiration. At the onset of the clinical edema
phase, the patient experiences a| definite shortness of breath. He also
presents a productive cough, expectorating large amounts of frothy, often
bloody, sputum. The mucous membrane of the bronchi becomes necrotic and is
shed. Leukocytes migrate into the bronchiole walls and into the alveolar
interstices. The patient becomes1 anoxic and cyanotic. If the patient is not
treated properly, death usually occurs as a result of paralysis of the respira-
tory center due to anoxemia. Eve'n with effective treatment of the anoxemia,
death may result from circulatory ishock. In the absence of adequate antibiotic
therapy, death may occur from superinfectious pneumonia because of increased
susceptibility to infection. j
Ardran (1964) reported that the development of pulmonary edema in both
humans and dogs after exposure to phosgene could be predicted by viewing
radiographs taken on inspiration and expiration. If the film taken on expira-
tion shows an increase in lung vqlume, this is an indication that edema may
develop. The lung volume returns!to normal as the edema resolves. The author
stated that these changes can be Observed within minutes of exposure and that,
in 20 years of using this technique in both clinical and experimental situa-
tions, it has been a reliable indicator. However, this technique of predicting
the onset of pulmonary edema by evaluating an initial overdistension of the
lungs is in contrast to the findings of Oilier (1976).
4.2.3 Case Studies of Direct Phosgene Exposure
The following case studies ekpand on the generalities mentioned above and
also present the diverse ways in[which phosgene intoxication may be encoun-
tered. Delepine (1922) presented! a detailed description of the symptomatology
he experienced after acute exposure to phosgene. While conducting experiments
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on phosgene in 1917, the author was required to enter a room containing the gas
(concentration not reported) at "frequent intervals over the course of three-
quarters of an hour." He first noticed some mild irritation of his eyes and
throat that was not severe enough to cause him to stop his experiments. At one
point, however, the gas escaped the room and he was forced to breathe it
freely. This brought about a violent fit of coughing. Delepine ran away, but
during his flight he was required to stop frequently because of the violence of
his cough. The cough lasted for about 15 to 20 minutes after he had left the
building. He felt weak and dazed, and the open air seemed to smell of phos-
gene. His condition improved for the next three to four hours (clinical latency
period); then he began to experience a choking sensation, giving him the
sensation of impending death from lack of air. Recovery of normal breathing
took several days, but a marked lassitude continued for an additional few days.
No mention of any late sequelae of the poisoning was made; recovery seemed
complete.
Two case histories of men exposed to phosgene gas were reported by
Stavrakis (1971). In the first case, a 30-year-old male was accidentally
exposed to an unknown quantity of phosgene while at work. The only reported
initial effect was a short-lived cough. The patient finished his shift and
went home. An hour later (4 hours postexposure) the cough recurred, this time
accompanied by expectoration of some mucus. A short time later, he arrived at
the hospital in serious condition with evidence of severe dyspnea, restless-
ness, chest pain, and a persistent, productive cough. A roentgenogram of the
lungs showed the presence of pulmonary edema. The patient improved rapidly and
was discharged from the hospital on the fifth day, free of symptoms. The
condition of the patient after discharge was not followed up.
In the second case, a male, age 31, was exposed to phosgene when a pipe
conducting the gas accidentally ruptured. That evening, he reported to the
hospital with signs of acute progressive pulmonary edema and extreme hemocon-
centration and leukocytosis. Despite aggressive therapy, the patient died 3.5
hours after admission.
Everett and Overholt (1968) described a case report of a 40-year-old male
who received a "massive" exposure to phosgene. His medical history showed that
he had been a cigarette smoker for many years, but had quit about a year before
the accident and was in excellent health at that time. The initial effects of
the exposure consisted of a cough, severe burning of the eyes, and an inability
to "get his breath." These initial symptoms abated within two to five minutes,
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and the patient felt fine for the -next two hours. A mild, hacking cough began
two hours after exposure, and at three hours, mild dyspnea began. Six hours
after exposure, he was severely dyspneic and moist rales were noted throughout
both lung fields. The patient was!admitted to intensive care about eight hours
postexposure. He was anxious, agitated, cyanotic, complained of thirst, and
had a constant cough that yielded copious amounts of yellow-brown, watery,
frothy sputum. A roentgenogram disclosed severe pulmonary edema. Pulmonary
function studies revealed acute emphysema. CO diffusion capacity was normal,
and the patient was not hypotensi^/e at any time. By the fifth day in the
hospital, the patient was asymptomatic; and by the seventh hospital day,
studies of pulmonary function showed no abnormalities and a chest X-ray was
normal. His health was followed| up for two years after the accident; no
abnormalities were reported. ;
Case studies of two victims of phosgene inhalation were reported by Regan
(1985). On December 9, 1977, a major phosgene emission occurred in a toluene
diisocyanate production unit. On? man, age 31, was admitted to the hospital
eight hours later with clinicallyj apparent pulmonary edema. He had rales in
both lungs and left chest pain. [His arterial blood gases were normal. The
patient recovered quickly and retbrned to work six days after the accident.
His followup (time not specified) iwas completely normal.
A second man, age 47, was admitted to the hospital 11 hours after the
phosgene emission. He was dyspneic, had bilateral rales, and an X-ray indicat-
ed pulmonary edema. During treatment, the patient's condition deteriorated,
with worsening blood gases (PaO£ j= 60). With intubation, the patient produced
a large amount of pulmonary edema fluid. The patient remained in critical
condition for the next three dayis. Clinical signs included low right-side
heart pressure, low arterial pressure, hemoconcentration, and leukocytosis.
Twelve days after the accident, ihe patient was completely asymptomatic. A
pulmonary function study performed about four weeks after the accident revealed
a mild degree of pulmonary obstruction that the author attributed to the
patient's smoking. \
The following case report (Bradley and Unger, 1982) illustrates that
effective therapy that is sufficient to prevent death due to anoxemia in cases
of severe phosgene poisoning mayjnot prevent a later death from circulatory
shock. The patient was a 23-yeaf-old male, a nonsmoker who had been in good
health. He was exposed to the concentrated gas for five to ten seconds, which
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produced an Immediate cough, but no nausea or vomiting. Approximately one-half
hour later, he experienced secondary symptoms such as dyspnea and tightness in
the chest. By the time the patient reached the hospital, he was cyanotic,
hypotensive, and had a rapid heartbeat and rapid, shallow breathing. A chest
roentgenogram showed pulmonary edema. Four hours after exposure, he was
intubated because of progressive respiratory distress and hypoxia. More than
300 ml of blood-tinged, frothy fluid were suctioned initially, and copious
secretions were suctioned for the next 24 hours.
The patient was transferred to intensive care, and a complete laboratory
workup was done. Pertinent findings included severe pulmonary edema (without
cardiomegaly), leukocytosis, hemoconcentration, and abnormal coagulation
values, indicating disseminated intravascular coagulation. Protein content of
the pulmonary edema fluid was also high (4.8 g/dL). Aggressive therapy,
including mechanically assisted breathing, was used to combat the hypoxia, but
the patient developed ventricular fibrillation and died after six days in the
hospital. No autopsy was performed.
Of historical significance is an accident that occurred in Hamburg,
Germany, in 1928. On May 20 of that year, 11 metric tons (24*640 pounds) of
"pure phosgene" escaped from a storage tank. The weather was warm and dry and
there was a light northeasterly wind. Within a few hours after the leak began,
people started reporting to area hospitals, some having been affected by the
phosgene gas as far as six miles from the site of release. A total of 300
people reported ill within a few days, including 5 firemen and 8 security
officers who were attempting to rescue affected civilians. One particular
hospital admitted 195 victims on the evening of May 20. Of those, 17 were very
ill, 15 were moderately ill, and the rest were only slightly affected. The
history of the disaster as well as case reports of seven of the ten people who
died as a result were reported by Hegler (1928).
With few exceptions, the symptomatology exhibited by the victims of the
Hamburg disaster was identical to that reported above for victims of accidental
workplace exposures to phosgene. One exception was a 52-year-old Hamburg man
who died 11.5 days after exposure. At the time of the accident he was sitting
in a park near the phosgene release area. His initial symptoms were typical
and included headache, dizziness, nausea and vomiting, an irritant cough, and a
sickening-sweet taste in his mouth. These initial symptoms abated and he felt
better until a marked feeling of tightness in his chest began. He reported to
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the hospital 11 hours after exposure showing signs of pulmonary edema. He was
cyanotic, had a very difficult time breathing, and rales could be heard
throughout his lungs. He also exhibited other symptoms common to phosgene
poisoning including pain in his ch|est, elevated pulse rate and temperature, and
an irritant cough that produced bilood-tinged, frothy sputum. On the following
day he felt a little better, but was still dyspneic and showed unusual signs of
brain dysfunction including an intermittent dimming of consciousness, or
confusion as occurs with delirium tremens. Seven days after exposure, the
patient developed a clot in his left calf, which cut off circulation to the
limb, and eventually lead to gangrene. His lungs were clearer and he produced
less sputum. The dyspnea was still present, but was greatly diminished by a
medicine used to treat asthma. He died 11.5 days after his exposure to phos-
gene, apparently from a blood clot lodged in his lung (Hegler, 1928).
Autopsies on six of the fatalities of the Hamburg accident, including the
one described above, were performed by Wohlwill (1928). In general, abnormal-
ities were found only in the luncj. Fatty degeneration of the kidneys, liver,
and heart that was present in a few cases was felt to be secondary to the
pulmonary lesions. However, in tf)e case described above, there were additional
processes noted in the gray matter of the brain and spinal cord as well as
hyperemia and signs of bleeding in the white matter of the brain. Wohlwill
suggested that the cause of these lesions of the brain was of a chemical
nature, and not due solely to ano!xia or reduced circulation. However, he also
stated that all of the extrapulmonary abnormalities observed were secondary to
pulmonary damage.
A third report on the Hamburg disaster was published by Mayer (1928).
This report discussed hematological findings on several victims of the disas-
ter, but does not add significantly to an understanding of the consequences of
such a disaster. i
The only reference to the prognosis of the exposed victims was a statement
by Hegler that there were no late damages two months after the accident.
Followup studies to determine the long-term health effects of phosgene exposure
on the survivors were not reported. Also, other adverse effects of phosgene
exposure were not reported. No other reports in the scientific literature
regarding the Hamburg disaster were found.
Numerous other case studies !of phosgene poisoning have been reported that
support the symptomatology presented above (e.g., Mahlich et al., 1974;
Cordasco and Stone, 1973; Steel, 1942).
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4.2.4 Indirect Phosgene Exposure
Numerous incidences of phosgene poisoning have been reported where the
victim was working with substances other than phosgene.
4.2.4.1 Butyl Chloroformate Exposure. Fabre et al. (1983) reported an inci-
dent where a man, age 48, was exposed to butyl chloroformate (phosgene + butyl
alcohol) when a canister containing the liquid exploded. The explosion
splashed the liquid into his eyes and face, producing a complete blindness that
lasted about 15 minutes and burning sensations on his face and lips. The
patient arrived at the hospital an hour after the accident, presenting signs of
bronchial and facial irritation. Pulmonary and cardiovascular examinations
showed no serious problems at that time. However, a roentgenogram taken the
following day showed signs of pulmonary edema and the patient was also hypoxic.
Symptomatic treatment was initiated, and by the seventh day after the accident
the hypoxia had regressed and a chest X-ray was normal. The patient was
reexamined 12 days later and all findings were normal.
4-2.4.2 Carbon Tetrachloride Exposure. One case has been reported in the
literature of probable phosgene toxicity through the use of a carbon tetra-
chloride fire extinguisher (Seidelin, 1961). A 16-year-old woman was
admitted to the hospital about ten hours after attempting to put out a fire
with a carbon tetrachloride (CC14) fire extinguisher. She apparently had not
been exposed to great heat, but had inhaled smoke and fumes that made her cough
at the time. She felt well for the next six hours and then began to experience
a cough and some difficulty in breathing. When seen at the hospital, her
condition had worsened; she had a persistent, unproductive cough, was extremely
breathless, and was deeply cyanosed. She also presented a rapid heartbeat and
rate of breathing, and a moderate leukocytosis. Her blood pressure and temper-
ature were normal. A chest examination disclosed indications of acute emphyse-
ma, and a roentgenogram revealed severe bilateral pulmonary edema. She was
placed immediately on oxygen therapy, but continued to worsen, losing con-
sciousness and remaining cyanosed. She began to improve eight hours later with
expectoration of small quantities of frothy, very slightly blood-stained
sputum. Her condition was greatly improved the next day, though her cough
persisted and she required oxygen therapy to prevent anoxemia. She was dis-
charged from the hospital on the 13th day, apparently fully recovered. When
last seen six months later, her perfect health had continued and her chest
radiograph was normal. The author indicated that this patient had suffered
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from phosgene poisoning because her clinical signs matched those of people
exposed to phosgene gas and because CCl^ decomposes to phosgene when in contact
with hot surfaces (Yant et al., 1936).
4.2.4.3 Methylene Chloride Exposure. Gerritsen and Buschmann (1960) reported
two cases of phosgene poisoning caused by the use of chemical paint removers
containing methylene chloride in poorly ventilated rooms heated by kerosene
stoves. In the first case, a 52-year-old painter used a chemical paint remover
in the presence of a kerosene stove for several hours, noticing only a burning
sensation in his throat. At lunch, the painter became aware of a feeling of
tightness in his chest and visited;his physician, who made an incorrect diagno-
sis of influenza! bronchiolitis. The patient later returned to his physician
and was found to be dyspneic and ,cyanotic. He was sent to the hospital, but
died despite efforts to save him.' An autopsy revealed extensive degenerative
changes in the epithelium pf the tjrachea, bronchi, and bronchioli together with
hemorrhagic edematous focal pneumonia.
By attempting to simulate the exact conditions that the painter was
exposed to, the authors calculated that the atmosphere the patient breathed
could have contained as much as !16 ppm phosgene after only 3 minutes and
may have reached a maximum of 128tppm after 12 minutes. The particular chemi-
cal paint remover used by the painter contained 92 percent volatile solvent
consisting almost entirely of meth'ylene chloride with small amounts of ethanol
and trichloroethylene. j
The second case reported by Gerritsen and Buschmann is noteworthy because
it involved a 38-year-old woman in her seventh month of pregnancy. She worked
for about three hours in a closed cellar using a chemical paint remover (con-
taining methylene chloride) in th£ presence of a kerosene stove. Some hours
later she felt some tightness in (ier chest and expectorated some blood-stained
sputum. She went to her physiciah, who also misdiagnosed the problem. The
next morning she felt much worse,j was dyspneic, and cyanotic. A chest X-ray
indicated pulmonary edema. Recovery was fairly rapid, and two months later she
gave birth to a healthy child. Another case of probable phosgene poisoning
I
because of the breakdown of methylene chloride in a chemical paint remover was
i
reported by English (1964). ;
4.2.4.4 Trichloroethylene Exposure. Several reports also indicate probable
phosgene poisoning due to the breakdown of trichloroethylene (Glass, 1972;
Glass et al., 1971; Nicholson, 196:4; Spolyar et al., 1951; Derrick and Johnson,
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1943). Only one representative case study will be detailed. Glass et al.
(1971) reported an example of probable phosgene poisoning that occurred when a
welder began welding metal studs that were soaked with trichloroethylene. The
welder, age 45, had been a pack-a-day smoker since the age of 16, and had
developed chronic bronchitis before this incident. He welded the wet studs all
morning, and by 12:30 p.m., he experienced tightness in his chest and some
difficulty in breathing. He generally did not feel well, and deep inspiration
caused him to cough violently. That afternoon he welded only dry studs and
felt much better. He woke up late the next morning after a comfortable night's
sleep, again feeling tightness in his chest and some difficulty in breathing.
On his way to work, he experienced a general lassitude and shortness of breath
on exertion. He was seen by a doctor that morning and was diagnosed as having
acute bronchitis induced by phosgene poisoning and chronic emphysema from his
smoking. A chest roentgenogram showed the lungs to be clear throughout. A
reexamination performed 3.5 months later showed the continued presence of
pulmonary emphysema.
4.2.5 Late Sequelae of Acute Phosgene Poisoning
Oilier (1985b) reviewed the literature on the late sequelae after phosgene
poisoning. The weight of the evidence suggests that the vast majority of
phosgene intoxications have a good prognosis. However, most of the victims of
heavy acute poisonings complain of chronic symptoms such as shortness of breath
on exertion or reduced physical fitness for several months to several years
.after the accident. While simple spirometry findings are usually normal,
sophisticated pulmonary function studies often reveal abnormalities that may
also require years to resolve. The length and severity of these chronic
effects appear to be a function of smoking habits,, previous pulmonary abnormal-
ities, and psychological disorders, rather than the severity of the exposure.
Preexisting chronic bronchitis may undergo severe and progressive deterioration
after toxic pulmonary edema due to phosgene poisoning (Oilier, 1985b).
However, the historical data also indicate that acute exposure to phosgene
neither activates preexisting, quiescent tuberculosis nor increases suscepti-
bility to tuberculosis (Sandal!, 1922; Berghoff, 1919).
4.2.5.1 Studies of World War I Gassing Victims. Thousands of cases of acute
exposure to phosgene occurred during World War I, yet there are only limited
data on the long-term effects on the victims. Berghoff (1919) examined 186
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American soldiers who had been gjassed with phosgene, but made only three
conclusions regarding the long-Win effects: (1) These men showed no marked
predisposition toward active pulmonary tuberculosis, or toward the reactivation
of healed or quiescent pulmonary liesions; (2) they presented little evidence of
material destruction of lung tissue; and (3) victims diagnosed as having
emphysema had a more protracted convalescence than those diagnosed as having
bronchitis. I
Sandal! (1922) investigated ;83 men who were awarded pensions by the
British Army for war gas injuries; The gas that these men were exposed to was
not specified, but exposure to ph'osgene was implied. The most common com-
plaints three years after exposure were shortness of breath on exertion (70
percent of the men); cough and expectoration (54 percent); pain, or a feeling
of tightness across the chest (25 percent); palpitation and occasional giddi-
ness (14 percent); and nausea (12;percent). Seven percent of the men reported
symptoms of neurasthenia. There w'ere no positive cases of tuberculosis. In 53
percent of the men, no physical abnormalities of the lungs were noted.
4.2.5.2 Studies of Workplace Exposure. A followup pulmonary function study on
ten men was performed by Diller et al. (1979) three to nine years after they
had experienced acute phosgene poisoning in the workplace. The severity of
intoxication ranged from "severest pulmonary edema" to slight respiratory
effects (Table 4-4). The men had missed from 2 to 290 days of work due to the
exposure. The reexamination included spirometry, total body plethysmography,
blood-gas analysis at rest and during exercise, argon washout curves, helium
mixing time, and CO diffusion rat|e. Special attention was paid to the smoking
habits of the men. All ten patients stated that they had experienced afteref-
fects of the intoxications for one to three years postexposure. These chronic
sequelae included shortness of bjeath on exertion, palpitation, feelings of
pain or tightness in the chest, and increased perspiration, cough, and expecto-
ration. At the time of reexamination, one of the five men who had developed
pulmonary edema (case 1) had developed emphysema with obstruction and impaired
CO diffusion rate. Of the five men with only minor phosgene intoxications, one
also developed emphysema (case 10). The other men had normal spirometric
values, though some abnormalities!were found for some of the more sophisticated
pulmonary function parameters. Stepwise multiple regression analyses of the
whole group (n = 10) showed that; the extent of pulmonary function impairment
appears to be more dependent on Brooking habits than on the severity or the
elapsed time from the original intoxication.
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TABLE 4-4. SEVERITY OF POISONING IN TEN MEN OCCUPATIONALLY EXPOSED
TO PHOSGENE
Case
1
2
3
4
5
6
7
8
9
10
Agea
40
32
37
35
39
44
43
41
28
39
Smoking
habits8
++
(0)
0
0
(0)
(0)
++
+
No. of
Years
after
exposure
3
9
3
6
3
3
3
3
3
3
Clinical diagnosis
Severest pulmonary edema
Severe pulmonary edema
Marked pulmonary edema
Moderate pulmonary edema
Slight pulmonary edema
Bronchitis
Bronchitis
Dyspnea without rales
Slight interference of respi
gas exchange
Slight effects
Days missed
from work
290
30
• 14
21
14
17
3
3
ratory 2
2
aPatients' ages at the time of examination.
Nonsmoker, 0; ex-smoker >5 years, (0); ex-smoker <5 years, (+); <10
cigarettes per day, +; 10-20 cigarettes per day, ++; rankings reflect
smoking habits at the time of evaluation.
Source: Adapted from Diller et al. (1979).
Diller et al. (1979) also followed the case history of a man for 25 years
after phosgene intoxication. The subject was a light smoker who had suffered
from mild chronic bronchitis since childhood. At the age of 35, he was exposed
to phosgene and developed severe pulmonary edema. He was hospitalized for
seven weeks. During the following months, a reduction in general physical
fitness and a deterioration of his bronchitis were observed. After two years,
vital capacity (VC) and forced expiratory volume (FEV) measurements were
reduced to 70 percent of the normal range. Ten years postgassing, frank
pulmonary emphysema was diagnosed, with VC and FEV about 50 percent of the
normal range. The subject had to take a premature retirement at the age of 52,
17 years after phosgene exposure. This case history illustrates that severe
phosgene intoxication can produce a chronic deterioration of a preexisting
pulmonary lesion (Diller, 1985b).
The late effects of phosgene poisoning in six workers who had suffered
symptoms of acute exposure were discussed by Galdston et al. (1947). Special
attention was paid to psychiatric evaluations and pulmonary function studies.
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The latter included comprehensivejventilatory function tests and respiratory
function tests. The results of thjsse tests are presented in Table 4-5.
Case 1: A female, age 38, was accidentally sprayed in the face with
liquid phosgene. Within a few hours she developed signs of bilateral pulmonary
edema and acute emphysema. By day 12 after the accident, physical and X-ray
examinations indicated that the lungs had returned to normal. When she was
reexamined 14 months after the accident, ventilatory and respiratory function
of the lungs were normal. However,, a relative decrease in vital capacity and a
relative increase in residual air: were found, suggestive of early pulmonary
emphysema. Nineteen months after'the accident, she was still unable to return
to work, complaining of tiredness, weakness, marked breathing difficulty on
exertion and palpitations, sensations of a tight band around the lower part of
the chest, weakness of the left side of the body with pain on exertion, ner-
vousness when among people, and nightmares.
Case 2: A 39-year-old woman accidentally inhaled phosgene. There were no
immediate disabling symptoms, and the patient worked the remainder of the
shift. However, 41 hours after exposure she was admitted to the hospital and
diagnosed as having severe pulmonary edema, acute emphysema, partial collapse
of the left lower lobe, marked anoxemia, fever, and leukocytosis. The patient
was discharged from the hospital 111 days after admission, experiencing only
slight shortness of breath and no undue fatigue after moderately severe exer-
cise. She returned to work one month after discharge. Exertional dyspnea was
no longer a problem at that time. ! ,
When examined six months after the accident, pulmonary function studies
indicated slight abnormalities in ventilatory and respiratory functions. When
last seen 17 months after the inhalation of phosgene, the patient was working,
had no complaints, and did not '. exhibit any abnormalities on physical
examination. ,
Case 3: A male, age 30, took at least two full breaths of phosgene while
filling shells with phosgene. He promptly experienced marked tightness in the
chest, became nauseated, and vomited. After oxygen therapy, he returned to
work and completed his shift. During the night, he experienced increasing
respiratory distress, tightness in the chest, cough with expectoration of thick
yellow sputum, and dizziness. He iwas admitted to the hospital the next day and
was diagnosed as having pulmonary! edema, acute emphysema, and marked anoxemia.
The patient recovered quickly, wab discharged from the hospital on day 13, and
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TABLE 4-5. SUMMARY OF CLINICAL FINDINGS IN SIX WORKERS AFTER ACUTE
OCCUPATIONAL EXPOSURES TO PHOSGENE
Clinical Parameter
Case Number0
2
3
Age
Sex .
Months after accident
Months worked with phosgene
Chronic symptoms
Physical signs
Acute
Chronic
Roentgenogram of chest
Lung volume
(Vital capacity
+ % residual air) =
Total capacity
Intrapulmonary mixing of gases
Pulmonary emptying
Resting pattern of breathing
High rate
High tidal air
High minute volume
Low oxygen extraction
Exercise pattern of breathing
High rate
Low tidal air
Low oxygen extraction
Arterial blood gases
At rest
After exercise
After oxygen administration
Breath holding
Voluntary breathing capacity
Postural tests
Cardiac output
38
F
14
6
A
A
N
N
N
B
N
N
N
N
N
B
N
B
N
N
N
-
N
N
N
N
39
F
6
12
N
A
N
N
N
N
N
N
A
N
A
A
B
N
N
A
A
N
N
A
N
A
30
M
6
18
N
A
N
N
N
N
B
N
A
A
A
A
B
B
N
N
N
-
N
A
N
N
48
M
3
24
A
A
B
N
A
B
A
A
A
B
A
B
B
B
B
N
N
N
A
N
N
N
43
F
5
2
A
N
N
N
N
N
N
N
A
A
A
A
A
N
A
A'
N
A
A
A
N
49
F
5
1
A
N
N
N
N
N
B
B
A
A
A
A
A
A
A
N
-
-
N
N
N
N
Listed in order of severity of exposure; A = definitely abnormal; N = normal;
B = borderline abnormal; - = not done.
Indicates period at which all special studies were performed, except for
arterial blood oxygen, alveolar air oxygen, and carbon dioxide tensions and
cardiac output, which were performed 4-8 months later. Symptoms and physical
and roentgenographic findings were unchanged on reexamination of all available
patients (except No. 5) at that time.
Source: Adapted from Galdston et al. (1947).
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DRAFT-'-DO NOT QUOTE OR CITE
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returned to work three weeks after discharge. At that time he did not experi-
ence any limitation of physical ability. Six months after the accident, pul-
monary function studies revealed a
disturbance in pulmonary ventilation, but
the respiratory function of the lungs was normal. When last examined about a
year after his phosgene exposure, he was in good health and did not exhibit
any new physical findings.
Case 4: A 48-year-old male was accidentally exposed to phosgene. He
experienced a choking sensation, coughed frequently, expectorated tenacious
white phlegm, became nauseated, vomited, and felt dizzy. He was admitted to
the hospital the next morning and was diagnosed as having acute pulmonary
emphysema, edema at the base of each lung, and edema of the pharynx. His
medical history revealed previous exposures to both phosgene and chlorine, as
well as an inconstant pain in the ileft side of his chest. The patient had
complained of this pain prior to exposure, but his private physician was not
able to find its cause. ;
The patient was discharged from the hospital 19 days after admission. A
roentgenogram of the lungs was normal, and he was able to perform moderately
heavy work without respiratory distress or fatigue. However, he was able to
perform only light work on the job; due to pain over the left chest similar to
what he had been experiencing for the past six years. Followup examinations
three and six months after the accident revealed hyperventilation and abnormal-
ities in pulmonary ventilation consistent with emphysema.
Case 5: A female, age 43, inhaled a "low concentration" of phosgene for
about 10 minutes. She experienced sneezing, watering of the eyes, substernal
distress, and nausea and vomiting.I She was promptly admitted to the hospital
where her lungs were found to be clear. Congestion in the conjunctivae and
pharynx cleared within a few days; pulmonary edema did not develop. A teleo-
roentgenogram was interpreted as exhibiting old obliteration of the right
costophrenic sulcus, chronic diffuse emphysema, and a partially calcified
nodule in the right upper lobe. S;he was released from the hospital 16 days
postexposure, still complaining of cough, weakness, shortness of breath on
moderate exertion, and pain over thie heart. She was readmitted to the hospital
several times in the subsequent months for the same complaints. Pulmonary
function studies performed almost six months after the accident showed normal
total lung volume; however, other functional abnormalities not related primari-
ly to the rapid, shallow breathing generally recognized as a chronic effect of
acute phosgene exposure were seen. [
August 1986 ! 4-38 DRAFT—DO NOT QUOTE OR CITE
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Case 6: A female, age 49, was admitted to the hospital 1.5 hours after
inhaling several breaths of phosgene. She was coughing violently, was nauseat-
ed and vomiting, and had a nasal and lacrimal discharge. Roentgenograms of the
lungs on admission and on the following day appeared normal. There was no
leukocytosis, but there was a moderate degree of normocytic anemia. There was
no cyanosis or dyspnea, and her lungs were clear throughout. The patient was
discharged from the hospital after five days, complaining of pain in the left
side of the chest, slight shortness of breath after moderate exertion, and a
nonproductive cough. Her past medical history included several minor exposures
to phosgene and a fairly serious exposure to chlorine. The patient returned to
work, but was unable to work steadily even at light clerical work because of
exertional dyspnea, nausea and vomiting after meals, cough, and precordial pain
not necessarily associated with effort. At the time of followup, about five
months after the accident, X-rays of the gastrointestinal tract, electrocardio-
grams, and urinalyses were all normal, and the anemia had improved. Pulmonary
function studies showed shallow breathing (a typical chronic effect of acute
phosgene intoxication) accompanied by moderately impaired intrapulmonary mixing
of gases. Mixing was not impaired when respirations were deepened. Respira-
tory function of the lungs was normal.
From their experience with these phosgene victims, Galdston et al. (1947)
were able to draw several conclusions. The chronic symptoms these patients
described were similar to those described by gas victims of World War I. A
common problem was rapid, shallow breathing that was not severe enough to lead
to anoxemia. Breathing oxygen did not alter the pattern of respiration and did
not afford consistent relief of symptoms. The measurable changes in pulmonary
function that were consistently observed varied in type and severity, but could
not be correlated with the severity of phosgene intoxication or with the
chronic symptomatology. The severity of this chronic symptomatology and the
disability associated with it were closely related to the patients' psychologi-
cal reactions. Unfortunately, the authors did not address the smoking habits
of these patients, and long-term followup studies were not performed.
4.2.6 Secondary Health Effects of Phosgene Poisoning
Most of the published information on phosgene inhalation indicates that it
acts solely on the lungs. However, there have been a few reports dating back
to World War I indicating effects on other organs, most notably the heart and
August 1986 4-39 DRAFT—DO NOT QUOTE OR CITE
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i
brain. The most common phosgene-related health effect associated with the
brain appears to be neurasthenia.! Others include a condition that might be
called psychomotor epilepsy, which leads to "drop attacks"; loss of speech
coordination; a peripheral Raynaud-like syndrome; and a condition characterized
by paralysis of all four limbs with persistent paralysis of the peroneal nerve
(Oilier, 1985b). Asthma has also been suggested to result from phosgene
exposure (Oilier, 1985b). Oilier attributes these abnormalities to anoxia
resulting from pulmonary edema rather than from the direct action of phosgene.
4.3 FACTORS AFFECTING PHOSGENE POISONING
A number of studies have examined the ability of various physical and
chemical agents and treatments to jalter the severity of phosgene poisoning.
Based on observations made during World War I that eating a large meal
shortly after exposure to phosgene increased the severity of poisoning, Cameron
(1942) investigated this possibility using laboratory animals. Twenty rats and
10 guinea pigs (strain and sex not specified) were exposed to phosgene at
200 mg/m3 (50 ppm) for 5 minutes: Ten rats and five guinea pigs were given
unlimited food (actual consumption not determined) and the other animals were
not allowed to eat, although water was available for all. Twenty-four hours
after exposure, there was no significant difference in mortality between fed
and unfed animals, but histological evaluation of the lungs of all animals
indicated that in rats, the severity of pulmonary edema was greatest in the fed
group. No difference was observed in guinea pigs. It was concluded that there
was some merit to the observations made during World War I.
Another experiment on the effect of diet on the severity of phosgene
intoxication was performed by Catder (1942). One group of 10 rabbits was fed
a dry bran diet for 3 days during which their mean body weights decreased
by 12.3 percent (206 g). A second group of ten rabbits was fed a normal diet
over the same three-day period. These animals showed no significant weight
loss. All animals were then exposed to phosgene at 430 mg/m (108 ppm) for 30
minutes. Eighty percent of the rabbits on the normal diet died, whereas only
30 percent of the animals fed the:dry bran diet died. The protective effect of
the dry bran diet was ascribed to the dehydration it caused with a concomitant
reduction in pulmonary edema fluid.
August 1986 ; 4-40 DRAFT-DO NOT QUOTE OR CITE
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The effect of exercise on the severity of'phosgene intoxication has also
been investigated. Freeman et al. (1945b) reviewed the literature on the
subject and concluded that there is considerable experimental evidence using
mice, rats, rabbits, and dogs which uniformly supports the view that moderate
exercise during the first few hours after exposure to phosgene does not
adversely affect the survival of exposed animals. However, heavy exercise
appeared to have an adverse effect.
Boyd (1969) compared death rates in rabbits, cats, and albino rats allowed
to inhale the phosgene through the nose (while in an inhalation chamber) to the
animals exposed by introducing the gas directly into the trachea by tracheal
cannulation. In studies with 18 rabbits exposed to an unspecified dose of
phosgene, the mortality rate in trachea!"cannulated rabbits was 88 percent,
versus 25 percent in rabbits inhaling phosgene through the nose. The corre-
sponding mortality rates in 14 cats were 100 and 50 percent, and in 80 rats, 90
and 40 percent, respectively. The combined mortality rate in the three species
(91 and 39 percent) showed a highly significant difference. The author sug-
gested that since phosgene is fairly labile, the lower toxicity from breathing
through the nose may be due to destruction of the gas in the nasobuccopharynx.
Slade et al. (1985) reported that a reduction of lung nonprotein
sulfhydryl groups through administration of buthionine sulfexamine led to an
increased edemagenic effect in the lungs of mice, rats, hamsters, guinea pigs,
and rabbits exposed to 0.2 ppm phosgene for 4 hours. The authors suggested
that nonprotein sulfhydryl may be important in the normal defense of the lung
against the toxic effects of phosgene.
4.4 SUMMARY
Animal studies indicate that the severity of a toxic endpoint (e.g.,
death) following a single inhalation exposure to phosgene is a function of the
concentration and length of exposure; CT = K for concentrations ranging from 1
to 200 ppm. However, this relationship does not hold for exposures to very
high or very Tow concentrations of phosgene or when exposure times are not long
enough to negate the effects of an animal holding its breath.
Animal studies also indicate that there are very few differences between
species in the pathogenesis following acute exposure to phosgene and that the
pathogenesis in man is essentially identical to that seen in experimental
• - . .
August 1986 4-41 DRAFT—DO NOT QUOTE OR CITE
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animals (Bruner and Coman, 1945). In man, exposure to phosgene at concentra-
tions between 3 and 200 ppm causeb an immediate irritation of the eyes and
throat, and pain or tightness in ;the chest. The victim may also complain of
shortness of breath on exertion, an irritating cough, and nausea and vomiting.
These initial symptoms abate rapidly and are followed by the clinical latent
phase, which is relatively free of symptomatology. The latent period ends when
the amount of edema fluid in the lungs becomes sufficient to interfere with
respiration. At this point the patient experiences a definite shortness of
breath, a productive cough, and may become anoxic and cyanotic. Death, al-
though rare, usually occurs as a result of paralysis of the respiratory center
due to anoxia.
Recovery from acute phosgene intoxication is usually complete, however,
most victims of severe poisonings;complain of chronic symptoms such as short-
ness of breath on exertion or reduced physical fitness for several months to
several years after the accident. |In patients where phosgene poisoning has led
I
to chronic disability, the effects are more closely related to smoking habits,
psychological disorders, or preexisting pulmonary abnormalities than to the
severity of exposure. Pathological effects to organs other than the lung are
rare and are considered to be caused by anoxia, not by a direct action of
phosgene.
August 1986 4-42 DRAFT—DO NOT QUOTE OR CITE
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Rothlin. E. (1941) Pathogenic et therapeutique de I1intoxication par le
Phosgene [Pathogenesis and treatment for phosgene intoxication]. Schweiz.
Med. Wochenschr. 71: 1526-1535.
Sandall, T. E. (1922) The later effects of gas poisoning. Lancet (203):
857-859. ;
SchUltz, J. (1945) The prophylactic action of hexamethylenetetramine in
phosgene poisoning. In: Fasciculus on chemical warfare medicine: v. II,
respiratory tract. Washington, DC: National Research Council, Committee
on Treatment of Gas Casualties; pp. 691-712.
Seidelin, R. (1961) The inhalation of phosgene in a fire extinguisher accident.
Thorax 16: 91-93. |
Slade, R.; Graham, J. A.; Hatch, G. E. (1985) Role of lung non-protein SH and
ascorbic acid in ozone, nitrogen dioxide and phosgene toxicity. Fed.
Proc. Fed. Am. Soc. Exp. Bioil. 44: 515.
Spector, W. S., ed. (1956) Handbook of toxicology: volume I, acute toxicities
of solids, liquids and gases to laboratory animals. Philadelphia, PA: W.
B. Saunders Company; pp. 348f349.
Spolyar, L. W.; Harger, R. N.; Keppler, J. F.; Bumsted, H. E. (1951) Generation
of phosgene during operation of trichloroethylene degreaser. Arch. Ind.
Hyg. Occup. Med. 4: 156-160.
Stavrakis, P. (1971) The use of hexamethylenetetramine (HMT) in treatment of
acute phosgene poisoning. Ind. Med. 40: 30-31.
Steel, J. P. (1942) Phosgene poispning: report on two cases. Lancet (242):
316-317.
Swift, M.; Postel, S. (1945) Body fluid distribution in phosgene poisoning.
In: Fasciculus on chemical warfare medicine: v. II, respiratory tract.
Washington, DC: National Research Council, Committee on Treatment of Gas
Casualties; pp. 440-483. !
Tem'll, J. B. (1976) Ten-day inhalation subacute study [unpublished
material]. Wilmington, DE: E|. I. du Pont de Nemours and Company, Haskell
Laboratory for Toxicology and Industrial Medicine; report no. 223-76.
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Tobias, J. M. (1945) The pathological physiology of the lung after phosgene.
In: Fasciculus on chemical warfare medicine: v. II, respiratory tract.
Washington, DC: National Research Council, Committee on Treatment of Gas
Casualties; pp. 331-391.
Underhill, F. P. (1919) The physiology and experimental treatment of poisoning
with the lethal war gases. Arch. Intern. Med. 23: 753-770.
Underhill, F. P. (1920) The lethal war gases: physiology and experimental
treatment. New Haven, CT: Yale University Press; pp. 3-10, 40-41, 85-87,
105, 119-120, 133-137.
Weston, R. E.; Karel, L. (1947) An adaptation of the dosimetric method for use
in smaller animals: the retained median lethal dose and the respiratory
response in normal, unanesthetized, Rhesus monkeys (Macaca mulatta)
exposed to phosgene. J. Ind. Hyg. Toxicol. 29: 29-33.
Winternitz, M. C.; Lambert, R. A.; Jackson, L. (1920) The pathology of
phosgene poisoning. In: Collected studies on the pathology of war gas
poisoning. New Haven, CT: Yale University Press; pp. 35-66.
Wirth, W. (1936) Ueber die Wirkung kleinster Phosgenmengen [The effects of
very small amounts of phosgene]. Arch. Exp. Pathol. Pharmakol. 181:
198-206.
Wohlwill, F. (1928) II. Zur pathologischen Anatomie der Phosgenvergiftung [II.
Pathological findings of phosgene poisoning]. Dtsch. Med. Wochenschr. 54:
1553-1557.
Yant W. P.; Olsen, J. C.; Storch, H. H.; Littlefield, J. B.; Scheflan, L.
(1936) Determination of phosgene in gases from experimental fires
extinguished with carbon tetrachloride fire-extinguisher liquid Ind
Eng. Chem. Anal. Ed. 8: 20-25.
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5. SUBCHRONIC AND CHRONIC PHOSGENE EXPOSURE IN ANIMALS
The effects of phosgene have been studied for the most part following
acute exposure. Some animal studies are available, however, on the effects of
phosgene following repeated exposure over a period of time ranging from a few
days to several months. The studies of chronic, low-level phosgene exposure in
humans are reviewed in Chapter 6, epidemiology.
5.1 LUNG TISSUE ANALYSIS FOLLOWING SUBCHRONIC PHOSGENE EXPOSURE
Rossing (1964) carried out one of the relatively few studies on subchronic
exposure of animals to phosgene. Fourteen mongrel dogs were periodically
exposed to 24 to 40 pom of phosgene for 30 minutes (CT dosages of 720-1200
ppm-min), but remained in the exposure chamber for an additional 30 minutes
while all of the phosgene was evacuated. Based on the size of the chamber
(1300 L) and the flow rate (600 L/min), it was calculated that about 11 minutes
should be required for the gas concentration in the chamber to reach 99 percent
of peak. The total amount of phosgene the animals were actually exposed to was
measured by drawing gas from the top of the chamber at 1 L/min for the entire
exposure period. This sample was bubbled through 0.1N NaOH and the contents
of the bubbler subsequently titrated for chloride. It was reported that the
actual CT agreed satisfactorily with the calculated value (720-1200 ppm-min),
however, the data were not reported.
The animals were exposed in this way three times a week until a definite
rise was seen in their airway resistance, at which time the frequency of expo-
sure was reduced to once or twice a week. Animals dying or sacrificed during
the exposure period were autopsied and.the lungs examined. Of the 14 dogs, 7
died during the first 3 weeks of exposure and 3 were sacrificed at the end'of
3 weeks; of the remaining 4 dogs, 1 died during the llth week and the other 3
completed 12 weeks of exposure, 2 of these being allowed to survive without fur-
ther exposure. With the exception of these two, all physiologic studies were
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performed 48 hours after the last |exposure to phosgene. Rossing's findings in-
dicated that in the .early acute phase there was a sharp rise in dynamic ela-
stance, associated pathologically with extensive edema and inflammation reaction,
and coupled with widespread bronch'iolar obi iterative changes. He suggested that
the early change in elastic behavtor was largely accounted for by the reduction
in the total amount of lung tissue available for ventilation at this time.
After the disappearance of the acute inflammatory reaction, there was a pro-
gressive resolving bronchiolitis, demonstrated physiologically by a definite
increase in lower airway resistance that persists throughout the period of ex-
posure. Microscopic changes suggestive of early, peri bronchiolar emphysema were
seen. In the two animals allowed to survive beyond the exposure period, ela-
stance dropped rapidly to normal and remained so during the period of observa-
tion, but resistance was still elevated in the animals when sacrificed 6 and 11
weeks following exposure.
In another study, Clay and Rossing (1964) exposed adult mongrel dogs (sex
not specified) to doses of phosgene ranging from 24 to 40 ppm for 30 minutes, at
a rate of 1 to 3 exposures per week to induce experimental emphysema, and stu-
died the changes produced histopathologically. There were four experimental
groups of dogs. In Group 1, 7 dogs were exposed 1 or 2 times and sacrificed
within 1 or 2 days after the last exposure. In Group 2, 7 animals were exposed
4 to 10 times and sacrificed at various intervals up to 7 days after the last
exposure. The 5 dogs in Group 3 were exposed from 15 to 25 times and sacrificed
immediately or up to 2 weeks following the last exposure. The 4 animals in
Group 4 were exposed 30 to 40 times and sacrificed immediately or as late as
12 weeks after the last exposure. :
The authors found that repeated exposure to phosgene produced histologic
changes of pulmonary emphysema in dogs. Severe acute or chronic bronchiolitis
was produced in all animals exposed one or more times. Acute bronchiolitis
involving primarily the bronchioles Was consistently found in those animals
sacrificed soon after the last exposure. In the chronic cases, the acute
changes gave way to chronic obi iterative bronchiolitis, and in the cases with
the longest exposure, many bronchioles appeared to have disappeared completely
or to have been converted into small!, inconspicuous fibrous scars.
Cameron and Foss (1941) exposed a group of animals to phosgene at an
average concentration of 4.38 mg/m (1.1 ppm) for 5 hours daily for 5 days.
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The exposed group consisted of 20 mice, 10 rats, 10 rabbits, 2 cats, and 2
goats. Twenty-four hours after the start of dosing, 50 percent of the mice
were dead (10/20); after 48 hours, another 8 died, resulting in a mortality
rate of 90 percent in 48 hours (18/20). All mice showed marked mottling of
the lungs with congestion, edema, and what was described as emphysema. Two
rabbits died after 48 hours (2/10). On examination, one showed large areas of
collapse in the lung with congestion and edema. The other rabbit showed some
edema and congestion. The remaining animals survived and were killed at the
end of the five days of exposure. Microscopic examination of lung tissue from
37 of the animals showed that 22 (59 percent) had lung changes graded as severe,
and 15 (41 percent) had mild lung changes. Severe lesions were found in the
cats, rabbits, guinea pigs, and mice. The goats and rats were much less af-
fected. Edema was present in 35 of the 37 animals examined (95 percent), with
severe edema in 12 animals, moderate edema in 13, and slight edema in 10. All
species showed some degree of edema.
In another study by Cameron et al. (1942), the results of exposing several
species of animals to phosgene at an average concentration of 0.2 ppm for 5
hours daily for 5 consecutive days were reported. The experimental group con-
sisted of 20 mice, 10 rats, 10 guinea pigs, 10 rabbits, 2 cats, and 2 goats.
No deaths occurred during the exposures. Except for some labored breathing
noted in the cats and in one goat, the animals showed little evidence of dis-
tress. At necropsy, pulmonary lesions were seen in 67 percent of the animals.
It was reported that the great majority of such lesions were slight and of little
significance. Discounting the more susceptible animals (guinea pigs) and cor-
recting for the normal incidence of disease in laboratory animals, the authors
estimated that probably between five and ten percent of the animals showed mo-
derately severe lesions. Pulmonary edema was noted in 41 percent of the animals
but was considered to be slight in most cases. In six animals (1 mouse, 1 rat,
3 guinea pigs, and 1 rabbit), it was extensive. Acute bronchitis was noted in
22 percent of the animals, and bronchial regeneration was noted in 20 percent.
The results are summarized in Table 5-1.
Concentrations of phosgene as low as 0.125 ppm 4 hr/day, 5 days/week for
a total of 17 exposure days produced significantly elevated activity of pulmo-
nary glucose-6-phosphate dehydrogenase and non-protein sulfhydryl (glutathione)
concentrations in male Sprague-Dawley rats. Small increases were also seen in
lung weight at the end of the exposure. These changes appeared to return to
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TABLE 5-1 SEVERITY OF PULMONARY LESIONS IN SEVERAL ANIMAL SPECIES
EXPOSED TO PHOSGENE (0.2 ppm, 5 hours/day
for 5 consecutive days)
Total no. of
animals
Severe lesions
Mild lesions
Very slight lesions
No lesions
Mice R
20
0
1
13
6
G.
ats pigs
10 10
1 1
1 3
3 6
5 0
Rab-
bits
10
0
1
5
4
Cats
2
0
0
1
1
Goats
2
0
0
0
2
Total
54
2
6
28
18
4
11
52
33
Incidence of pulmonary
edema
Incidence of severe
bronchitis
Incidence of
bronchial regeneration
Incidence of broncho-
pneumonia
7(1) |2(1) 7(3) 5(1) 1
0
0
0
22
12
11
41
22
20
lumbers in parentheses indicate the number of animals showing fairly severe
Source: Adapted from Cameron et al. (1942).
I
normal by two days postexposure. JThese effects were enhanced at 0.25 ppm expo-
sure levels, however, no consistent increase in hydroxyproline (an indicator
of collagen accumulation) was seep in the lungs of these animals (Franch and
Hatch, 1986).
5.2 PREGASSING PROTECTIVE EFFECT OF PHOSGENE EXPOSURE
Box and Cullumbine (1947) carried out studies in rats and mice to deter-
mine whether an initial nonlethal idose of phosgene would diminish the lethality
of subsequent exposures to phosgene. In preliminary experiments, it was estab-
lished that exposure of rats and mice to CT dosages of 600 and 800 mg/m -min
(150 and 200 ppm-min), respectively, with a 10-minute exposure time, did not
normally produce any deaths, although the animals showed all the symptoms of
severe phosgene poisoning. Ninety-six rats (of unidentified sex and strain)
were divided into 4 groups of 24 ieach. Twelve rats in each group were exposed
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to a dosage of 200 ppm-nrin phosgene, with the other 12 rats in each group serv-
ing as controls. Five days later, each group of 24 was exposed for 10 minutes
to concentrations of phosgene in the lethal range. The mortalities at the end
of 48 hours are shown in Table 5-2.
Statistical analysis demonstrated that there was a lower mortality in the
pregassed than in the control animals (Box and Cullumbine, 1947).
In a study to determine the duration of the pregassing protective effect,
70 mice were divided into 7 groups of 10 each. One group was kept as a con-
trol, and the other groups were exposed to a phosgene dose of 150 ppm-min at 1,
2, 3, 5, 7, and 10 days before the second gassing. The 70 mice were then ex-
posed to a dosage of 1460 ppm-min, about 3 times the L(CT)5Q. Results indi-
cated that animals in the group pregassed 1 day before died significantly
faster, while those pregassed 3, 5, and 7 days before died significantly slower
than the control animals. Further studies demonstrated the following: in
order to produce the apparent increase of resistance to phosgene, it is neces-
sary to produce lung damage; repeated exposures do not produce a cumulative
effect; and rats that have been exposed to a pregassing dose breathe in phos-
gene more rapidly but take longer to die. The authors concluded that the
resistance of pregassed animals can be explained by their more rapid and
shallower breathing (determined visually), caused by lung damage in the first
exposure (Box and Cullumbine, 1947).
The protective effect of pregassing was also investigated by Henschler and
Laux (1960). Twenty Wistar rats (120-150g) were exposed to phosgene at 1 ppm
for 6 hours. Four days later, the rats were exposed to phosgene at 18.2 ppm
for 30 minutes. The animals that were pregassed with phosgene showed an
increase in mean survival time over control animals that were not pregassed.
The authors suggested that the protective effect observed could have been due
to an enlargement of the alveolar wall caused by the first low-level exposure.
Similar results were demonstrated by Gildemeister in 1921 (as reported in
Laqueur and Magnus, 1921). Gildemeister found that cats surviving a phosgene
poisoning could be challenged for a second time with a lethal dose of phosgene
and still survive. When serum of a previously exposed animal was injected into
cats prior to phosgene exposure, mortality was reduced from 64 to 17 percent.
Ong (1972) also showed that guinea pigs or mice exposed to increasing doses of
phosgene could resist a lethal dose. The same result was obtained after one
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TABLE 5-2. MORTALITY OF PREGASSED RATS AND MICE
Exposure dosage (ppm-min) £75 625 785 1100 Total
Mortality in controls 8/12 7/11 9/12 11/12 35/47
Mortality in pregassed animals &/12 2/12 3/12 8/12 16/48
Source: Adapted from Box and Culluinbine (1947).
exposure to a sublethal dose. Thus, 28 of 33 (85 percent) pregassed animals
survived the lethal dose, whereas all of the 15 nontreated control animals died
within 24 hours with typical lung edema. In the pregassed animals, a dose that
was normally lethal or an even higher dose was administered several times with-
i
out lethal effect. The tolerance was established within 24 hours and lasted
for 3 or 4 months.
Ong (1972) investigated the rble of the immune system in the pregassing
protective effect. Minced lung frbm guinea pigs was exposed to a continuous
flow of phosgene for two to three hours, and then an extract was made of the
phosgene-exposed lung tissue. An antiserum was then prepared by four to five
intravenous injections of the extract into rabbits, followed by bleeding the
rabbits nine days after the last injection. Four male guinea pigs were then
injected intravenously with 2 or 3; mL of antiserum, and 2 to 24 hours later
o
exposed for 20 minutes to phosgenei at 41 to 55 mg/m (10-14 ppm),, about 1.5
times greater than the previously Determined lethal concentration of 31 mg/m
(7.6 ppm). Three of four animals survived, the only symptom being a slight
anaphylactic shock in one of the surviving animals.
In a second experiment, antiserum was administered to animals exposed to
twice the lethal dose of phosgene [immediately after gassing. Three of four
experimental animals survived, while all four control animals died. Based on
statistical evaluation, it was concluded that the antiserum had a definite
effect in reducing the mortality of phosgene gassed animals. Further studies
indicated that an anaphylactic shpck may be produced when antiserum is
injected either before or after phosgene poisoning. A high dose of serum,
however, tends to reduce the incidence of anaphylactic shock. In order to
test the possibility of active immunization against phosgene poisoning, guinea
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pigs were injected with extract of guinea pig lung exposed to phosgene, and
were then exposed to doses of phosgene almost twice the lethal dose at various
intervals after injection. It was found that an immunity, lasting for about
60 days, could be induced (Ong, 1972).
Cordier and Cordier (1953) determined the effect of repeated doses of
phosgene on cats. In one study, 15 cats were exposed to 20 to 25 mg/m (5-6.2
ppm) for 10 minutes, on a daily basis, for a total of 2 to 41 exposures. No
differences were found in animal weights or in histology of lungs of animals
exposed to phosgene for a few or many days, even though the animals exposed for
the longer periods received several lethal doses of phosgene. It would appear,
therefore, that for cats there is no additive effect of phosgene when admini-
stered in low daily doses for short periods of time. The authors concluded
that there must be either a process of detoxification or of tissue repair
going on between each exposure. A second study in six cats demonstrated that
o
10 to 15 mg/m (2.5-3.7 ppm) of phosgene administered for 10 minutes daily
for periods up to 12 days was the lowest dose that induced lung edema.
5.3 OTHER POSSIBLE EFFECTS OF PHOSGENE EXPOSURE
5.3.1 Teratogenicity and Reproductive Effects
No data were found in the literature on teratogenic or reproductive
effects of phosgene in humans or animals.
5.3.2 Mutagenicity and Carcinogenicity
No adequate carcinogenicity studies with phosgene have been published.
Limited epidemiology studies do not reveal increased incidences in pulmonary
or any other tumors in men occupationally exposed to phosgene. However, these
epidemiology studies dealt with workers at a single plant and involved rela-
tively small numbers of subjects (see Chapter 6 for details).
The only data available in the literature were in a review on the potential
carcinogenicity of 266 chemical substances associated with industrial inhala-
tion exposures (Schepers, 1971). Twenty guinea pigs and 20 rats were dosed
with phosgene by inhalation for 24 and 18 months, respectively. Additional
information on the study design, including the administered dose or sex and
strain of the animals, was not reported. No animals developed pulmonary
neoplasms. An additional group of 20 guinea pigs that were found to have a
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mycobacterial infection also showed no tumors after inhalation exposure to
i
phosgene for 24 months. Helmes et al. (1982) reviewed the literature for
information concerning the carcindgenicity and/or mutagenicity of 671 organic
chemicals, including phosgene, that were listed as air pollutants by Dorigan et
al. (1976). Tables were constructed listing all pollutants considered to be
i
known carcinogens, suspected carcinogens, cocarcinogens, known mutagens,
suspected mutagens, or potential carcinogens or mutagens. Phosgene was not
listed in any of these categories.; Reichert et al. (1983) attempted to deter-
mine the mutagenicity of phosgene [in a Salmonella typhimurium test system, but
found it nonmutagenic under the conditions of the assay because it reacted
rapidly in the test medium. They detected unchanged phosgene in the solution
i
only above a gaseous concentration of 10,000 ppm.
Although the possibility indeed exists that phosgene may be involved in
the hepatocarcinogenicity of chloroform or carbon tetrachloride as a metabolite
of these agents during the long-term administration of phosgene, there is no
direct evidence that phosgene ever gets past the lungs in unchanged form when
animals are exposed to the agent by inhalation. Since essentially all studies
on phosgene have been relatively short term, it remains to be seen whether
phosgene may be carcinogenic in chronic studies when administered by a route that
will permit it to reach susceptible internal organs in unchanged form. However,
because of its relatively high toxicity, special considerations are required
in designing and performing carcipogenicity studies, including the use of a
large number of animals in the experiments. Because there are no adequate
animal data on the carcinogenicity of phosgene, and the existing epidemiology
studies (see chapter 6) suffer from a lack of exposure data and small numbers
of subjects, the available data are judged to be inadequate to assess the
human carcinogenic potential for phosgene. According to the Environmental Pro-
tection Agency's guidelines for carcinogen risk assessment, phosgene should be
considered a group D chemical.
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5.4 REFERENCES FOR CHAPTER 5
Box, G. E. .P.; Cullumbine, H. (1947) The effect of exposure to sub-lethal
doses of phosgene on the subsequent L(Ct)50 for rats and mice Br J
Pharmacol. 2: 38-55.
Cameron, G. R.; Foss, G. L. (1941) Effect of low concentrations of phosgene
for 5 hours on 5 consecutive days in groups of different animals.
Washington, DC: British Embassy Defense Staff; Porton report no. 2316,
serial no. 63.
Cameron, G. R.; Courtice, F. C.; Foss, G. L. (1942) Effect of exposing differ-
ent animals to a low concentration of phosgene 1:1,000,000 (4 mg/m3) for 5
hours. Chapter IX in first report on phosgene poisoning. Washington, DC:
British Embassy Defense Staff; Porton report no. 2349.
Chemical Warfare Service. (1920) Collected studies on the pathology of war gas
poisoning. New Haven, CT: Yale University Press.
Clay, J. R. ; Rossing, R. G. (1964) Histopathology of exposure to phosgene: an
attempt to produce pulmonary emphysema experimentally. Arch. Pathol. 78:
544-551.
Cordier, D.; Cordier, G. (1953) Toxicite des faibles concentrations de phosgene
en inhalations repetees [The toxicity of weak phosgene concentrations in
repeated inhalations]. J. Physio!. (Paris) 45: 421-428.
Docks, E. L. ; Krishna, G. (1976) The role of glutathione in chloroform-induced
hepatotoxicity. Exp. Mol. Pathol. 24: 13-22.
Dorigan, J. ; Fuller, B. ; Duffy, R. (1976) Preliminary scoring of selected
organic air pollutants: appendix IV - chemistry, production, and toxicity
of chemicals 0 through Z. Research Triangle Park, NC: U. S. Environmental
Protection Agency, Office of Air Quality Planning and Standards; EPA
report no. EPA-450/3-77-008e. Available from: NTIS, Springfield, VA-
PB-264446.
Franch, S.; Hatch, G. E. (1986) Pulmonary biochemical effects of inhaled
phosgene in rats. J. Toxicol. Environ. Health: in press.
Helmes, C. T.; Atkinson, D. L.; Jaffer, J.; Sigman, C. C.; Thompson, K. L.;
Kelsey, M. I.; Kraybill, H. F.; Munn, J. I. (1982) Evaluation and classi-
fication of the potential carcinogenicity of organic air pollutants J
Environ. Sci. Health A17: 321-389.
Henschler, D.; Laux, W. (1960) Zur Spezifitaet einer Toleranzsteigerung bei
wiederholter Einatmung von Lungenoedem erzeugenden Gasen [On the
specificity of a tolerance increase by repeated inhalation of pulmonary
edema-producing gases]. Naunyn-Schmiedebergs Arch. Exp. Pathol.
Pharmakol. 239: 433-441.
August 1986 5-9 DRAFT—DO NOT QUOTE OR CITE
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International Agency for Research |on Cancer. (1982) Carbon tetrachloride (group
2B).^In: IARC monographs on the evaluation of the carcinogenic risk of
chemicals to humans: suppl. 4, chemicals, industrial processes and
industries associated with cancer in humans, IARC monographs, volumes
1 to 29. Lyon, France: World iHealth Organization; pp. 74-75.
Laqueur, E.; Magnus, R. (1921) Ueber Kampfgasvergiftungen. V. Experimented
und theoretische Grundlagen izur Therapie der Phosgenerkrankung [Combat
gas poisoning. V. Experimental and theoretical basis for the therapy of
phosgene sickness], Z, Gesamte Exp. Med. 13: 200-290.
Ong, S. G. (1972) Treatment of phosgene poisoning with antiserum: anaphylactic
shock by phosgene. Arch. Toxikol. 29: 267-278.
Reichert, D.; Neudecker, T.; Spengler, U.; Henschler, D. (1983) Mutagenicity
of dichloroacetylene and its degradation products trichloroacetyl
chloride, trichloroacryloyl chloride and hexachlorobutadiene. Mutat. Res.
117: 21-29.
Rossing, R. G. (1964) Physiologic effects of chronic exposure to phosgene in
dogs. Am. J. Physiol. 207: 265-272.
Schepers, G. W. H. (1971) Lung tumors of primates and rodents: part II. Ind.
Med. 40: 23-31.
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6. EPIDEMIOLOGY
Relatively few studies have been performed to determine the health effects
of chronic low-level phosgene exposure in humans. Those that have been reported
indicate that chronic exposure to phosgene at or near the present TLV, often
involving some exposures to higher concentrations, does not result in increases
in mortality or incidence of cancer. As with the animal studies, there are no
reports regarding possible teratogenic or reproductive effects after acute or
chronic phosgene exposure.
6.1 URANIUM-PROCESSING PLANT, OAK RIDGE, TN
Polednak (1980) performed an epidemiological study of workers exposed to
phosgene from 1943 to 1945 at a uranium-processing plant in Oak Ridge, TN.
Phosgene was produced in the "alpha" chemical departments where uranium tri-
oxide was combined with carbon tetrachloride to produce uranium tetrachloride.
Phosgene was released into the work environment due to leaks in the reactor and
to failures in the scrubber systems that were used to remove the gas. The man-
agement attempted to continuously monitor the phosgene levels in the plant; but
aside from accidental releases,, the concentrations were too low for detection.
However, reports from the medical department indicated that exposures to concen-
trations above 1 ppm occurred 4 or 5 times per day in the "alpha" chemical
department. The author therefore assumed that all workers employed in those
departments for at least two days during the period 1943 to 1945 had been ex-
posed to phosgene.
Using the records of the Social Security Administration (SSA), Polednak
ascertained the vital status (as of 1974) of 699 white males who had worked in
the "alpha" department of the plant, as well as a second group of 106 white
males who had been involved in accidents which resulted in acute exposures to
phosgene at levels reported to be greater than 50 ppm (based on clinical symp-
toms). The mortality of 9352 white males who worked at the same plant but were
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not exposed to phosgene was also investigated. Most of controls were employed
in various offices, in cafeterias,|or in service departments. Cause of death
was coded according to the 8th revision of the International Classification of
Diseases by a trained nosologist. |Expected numbers of deaths were obtained by
multiplying death rates for U.S. w^ite males, specific for age (5-year inter-
vals) and calendar year (5-year annual averages) by person-years of followup,
which was from the year of first employment at the plant until death, or the
end of 1973. Cause-specific standardized mortality ratios (SMR's) were ob-
tained, and 95 percent confidence limits were'calculated. These same three co-
horts were followed up by Polednakland Hollis (1985) using SSA records for 1979.
The results of both the major1and followup studies for the group of chemi-
cal workers exposed to low levels are presented in Table 6-1. The discrepancy
between the number of subjects per|group for the two time periods is due to
problems with the SSA records. Approximately 34 percent of the subjects worked
less than 2 months in the department of interest; 52 percent worked between
9 and 51 weeks and only 14 percent worked a year or longer.
The SMR's for all causes and for selected cause categories were similar in
the chemical worker and control groups, and few SMR's were greater than 100.
The relatively low SMR's for all causes, cancers of the digestive organs, and
diseases of the nervous, circulatory, genitourinary, and digestive systems were
interpreted as being a result of the rather rigid selection of healthy workers
at the plant, the "healthy worker"ieffect, and lower incidence of these ail-
ments for residents of Tennessee as compared to the general U.S. population.
The relatively high SMR's for the ''senility, ill-defined causes" category is a
result of the practice by the State of Tennessee to group deaths from unknown
causes into this category. The deaths in the mental, psychoneurotic category
of the 699 chemical workers were dijie to alcoholism.
For the chemical workers (N=699), the SMR's for lung cancer, 127 (95% con-
fidence limit: 66-222) at the end of 1973 and 122 (95% confidence limit: 72-
193), at the end of 1978, were slightly elevated but were not significantly
higher (p >0.05) than those of the;controls (113 and 118) or of the United
States population in general (100).; The authors did not present data on the
smoking habits of the workers or the controls. Increased incidence of death
due to diseases of the respiratory[system was not seen in the chemical workers
exposed to phosgene. Concern was expressed about the 4 observed deaths due to
tuberculosis as compared to the 2.8 expected because of reports in the earlier
August 1986 : 6-2 DRAFT—DO NOT QUOTE OR CITE
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literature that phosgene exposure i;n World War I led to the activation of qui-
escent tuberculosis. However, these observed deaths were not statistically
different from the expected values.;
A second "acute-exposed" group| of white males who worked during the same
period at the uranium processing plant were also studied. The 106 men all re-
ported smelling phosgene, and were treated for phosgene poisoning. Symptoms
that were commonly reported were irritation of the eyes, nose, or throat; nau-
sea and vomiting; and pain in the chest, dyspnea, and rales. Pneuraonitis was
found, based on X-rays, in 25 of the patients. One subject died from pulmonary
edema due to phosgene poisoning. Ajs of 1974 and 1979, approximately 30 and 35
years after exposure, respectively,; 29 and 41 of these men had died, respective-
ly (Table 6-2). j
There were no statistically significant differences in any of the cause of
death categories between observed and expected deaths. However, due to the
small number of individuals in the study, only large increases in mortality
would have been detected. None of [the subjects died of lung cancer, and only
one man died of tuberculosis, at 74! years of age and 32 years after exposure.
Deaths due to respiratory diseases were higher in the acute-exposed group, 7
observed versus 3.5 expected as of tl979. One of these men died of "massive
lobar pneumonia" in 1959. A second died of "massive chronic bronchiectasis" in
1955. According to company recordsj, neither of these men was diagnosed as hav-
ing acute respiratory disease afterj exposure to phosgene. A third man died in
1970 of "chronic bronchitis and emphysema." This individual used tobacco (in
1945) and, after phosgene exposure,! had been diagnosed as having "bronchitis"
by an examining physician; the bronchitis was attributed to that exposure. The
two additional deaths occurred in Ij976, 31 years after exposure. One man died
of emphysema. He reported using tobacco in 1945 and had a "negative" preemploy-
ment chest X-ray and an X-ray diagnosis of chronic bronchitis after phosgene
exposure. The second, who died of "chronic obstructive pulmonary disease," had
a calcified Ghon tubercle (i.e., eviidence of tuberculosis) at preemployment
examination but no evidence of pulmonary disease after phosgene exposure; his
smoking habits were not recorded. !
Polednak and Hollis (1985) have also begun studying 91 female employees at
the same plant who had experienced Jacute accidental exposures to phosgene be-
tween 1943 and 1945. However, the data obtained so far are not sufficient to
make any conclusions, so further followup is necessary.
August 1986 6-4 DRAFT—DO NOT QUOTE OR CITE
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TABLE 6-2. SELECTED CAUJES OF DEATH AMQNG 106 WHITE MALE WORKERS AFTER ACUTE
EXPOSURE TO,PHOSGENE BETWEEN ^9^3-AND 194.5
Observed/expected
no. of deaths
oeieuuea causes or aeath
All causes
Tuberculosis
All cancers
Lung cancer
Diabetes mellitus
Mental, psVchoneuro^ic disorder
Diseases of the circulatory system
Diseases of the respiratory system
Pneumonia
Emphysema
Asthma
Diseases of the digestive system
Diseases of the genitourinary system
External causes of death
Accidents
Suicide
Other causes
Unknown causes (death certificates not
obtained)
P^oce.r Qf the £tad|ler and Pcincreas in 1974
h ' , .
Includes one death from pulmonary edema as
19/4 "' " '
29/27 -
0/0.4
2a/5
0/1. 5
1/0,4
2/0.1
12/13
3/1.4
1/0.5
0/0.4
0/0.1
3/1.5
0/0.4
. 5b/3,l
4b/2.2
1/0.7
I/-
l/-
, and .cancer, .of the large
1979
41/34
1/0.4
3a/6 8
0/2.2
1/0.5
2/0.2
18/17
5/1.9
1/0.7
1/0.5
0/0.1
3/1.8
0/0.5
7b/3.5
4b/2.4
2/0.8
i /-
i/
intestine.
a result of phosgene inhalation.
Source: Adapted from Polednak and Hoi 1 is (1985); Polednak (1980).
Whereas the execution ofthe study designs (original study and update) was
adequate, the study characteristics severely limit the chronic disease conclu-
sions that can be drawn from these studies. The studies are negative, but be-
cause of limiting factors they provide an inadequate basis to assess the car-
cinog^nic and pulmonary disease potential pf phosgene. This is particularly
true for lung cancer due to the small sample size of the study, and for pulmo-
nary disease due to weaknesses in using the underlying cause of death as a mea-
sure of pulmonary system effects.
6.2 EDGEWOOD ARSENAL, MD
Galdston et al. (1947b) followed the case histories of five male employees
of the Edgewood Arsenal, Maryland who had repeated exposures to small amounts of
August 1986 6-5 DRAFT—DO NOT QUOTE OR CITE
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phosgene during the course of 1.5 to 3.5 years. Particular emphasis was placed
on pulmonary,function-and on cardiovascular and psychiatric status. The authors
presented no data on the frequency or level of exposure to phosgene. The clin-
ical findings on the pulmonary function and cardiovascular status of these
patients are presented in Table 6-3.
Case 1: A phosgene worker, age 32, voluntarily entered the Johns Hopkins
Hospital on June 26, 1944, for pulmpnary function studies. He had experienced
conjunctivitis and laryngitis after: two exposures to mustard gas in 1941 and
1943. From March 6 through March 9,, 1941, he inhaled small amounts of phosgene,
which caused a sense of constriction in the chest, dizziness, mental confusion,
i
blurred vision, and severe headaches. He was also exposed to chlorine on July
15, 1941. Additional exposures to phosgene occurred in January 1944, leading
to a sensation of tightness in the phest, slight shortness of breath on exer-
tion, and nervous twitchings in different muscles. Clinical examinations in
June 1944 revealed a normal red blopd count, level of hemoglobin, total and dif-
ferential white blood counts, and urinalysis. A roentgenogram of the heart and
lungs and an electrocardiogram were also normal. However, pulmonary function
studies revealed a decrease in vital capacity, impaired intrapulmonary gas
mixing, and other changes consistent with pulmonary emphysema. The patient
returned to the phosgene plant and jvas reexamined six months later. There had
been no progression of symptoms and! there were no new complaints or physical
findings. I
Case 2: A machinist, age 50, who had worked in the phosgene plant since
May 1941, voluntarily entered the JJDhns Hopkins Hospital on July 9, 1944, for
pulmonary function studies. His pajst history included numerous minor exposures
to phosgene that were usually followed by a sense of constriction in the throat,
breath!essness, cough, nausea, and {vomiting lasting several minutes or hours.
He also reported to be suffering frbm chronic effects of phosgene exposure such
as shortness of breath on moderate exertion (for 3.5 years) and a productive
cough with sputum that occasionally! tasted of phosgene (for the past year).
Physical, hematologic, and urinary analyses showed normal results. However,
chest roentgenograms and pulmonary function studies showed the presence of pul-
monary emphysema. The patient was Examined six months later, and there were
no new complaints or progression of| the symptoms previously noted; physical and
laboratory findings were unchanged.
August 1986 j 6-6 DRAFT—DO NOT QUOTE OR CITE
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TABLE 6-3. SUMMARY OF CLINICAL FINDINGS IN FIVE WORKERS AFTER
CHRONIC OCCUPATIONAL EXPOSURE TO PHOSGENE
Clinical Parameter
Age
Months worked with phosgene
Chronic symptoms
Physical signs
Acute
Chronic
Roentgenogram of chest
Lung volume
(Vital capacity
+ % residual air) =
Total capacity
Intrapulmonary mixing of gases
Pulmonary emptying
Resting pattern of breathing
High rate
High tidal air
High minute volume
Low oxygen extraction
Exercise pattern of breathing
High rate
Low tidal air
Low oxygen extraction
Arterial blood gases
At rest
After exercise
After oxygen administration
Breath holding
Voluntary breathing capacity
Postural tests
Cardiac output
1
32
42
A
N
N
N
A
A
A
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
2
50
36
A
N
B
A
N
B
A
B
A
A
A
N
B
N
N
A
N
A
A
A
Case
3
24
30
A
N
A
A
B
A
A
A
A
A
A
B
B
B
A
N
A
_
A
N
Number3
4
31
16
A
N
N
N
N
B
A
A
A
' B
A
A
B
B
A
N
A
N
N
N
5
26
30
A
N
N
I "(
N
N
N
A
N
N
N
N
N
N
N
N
_
_
_
N
A
-
Listed in order studied; A = definitely abnormal; N = normal;
B = borderline abnormal; - = not done.
Applies to all special studies except arterial blood oxygen, alveolar air
oxygen, and carbon dioxide tension studies performed at rest and after
exercise, which were done 4-8 months later. Symptoms and physical and
roentgenographic findings were unchanged on reexamination of all available
patients (except one) at that time.
Source: Adapted from Galdston et al. (1947b).
August 1986
6-7
DRAFT—DO NOT QUOTE OR CITE
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Case 3: The patient, age 24, voluntarily entered the Johns Hopkins Hospi-
tal on July 16, 1944,- for pulmonary function studies. His past history includ-
ed asthma and several minor exposures to chlorine during the winter of 1941.
Since early 1942, he had inhaled phosgene at least six times. Acute symptoms
were described as immediate coughing, a choking sensation, sweating, nausea
and vomiting, and headache. He was usually fully recovered by the next day.
He last inhaled phosgene in June 1944, about one month prior to admission to the
hospital. Since 1942, the patient had complained of shortness of breath after
moderate exertion. Upon examination, urinalysis, hematology, and physical
status were all normal except for thoracic kyphosis and bilateral sonorous
rales. Roentgenograms and pulmonary function studies indicated the presence of
pulmonary emphysema. At a followup examination six months later, the patient
was still working in the phosgene plant. There were no new complaints or phys-
ical findings, and the symptoms presented on the first admission were still
present. j
Case 4: The patient, age 31,| worked for the Edgewood Arsenal since 1940.
His past history included minor exposures to chlorine in 1942 and an exposure
to mustard gas in 1943. He began work in the phosgene plant in the fall of
1943 and had at least three exposures to phosgene that caused shortness of
breath on moderate exertion and a sticking pain in the chest. Upon voluntary
admission to the hospital in August 1944, physical examination revealed a per-
forated right eardrum and a few so(norous rales at the base of each lung.
Roentgenograms of the lungs exhibited only an old obliteration of the left
costophrenic angle. Pulmonary function studies revealed abnormalities consis-
tent with pulmonary emphysema. In January 1945, a followup examination showed
no new complaints or physical findings; the symptoms previously noted were
still present.
Case 5: The patient, age 26,| worked in the phosgene plant from January
1942 to February 1943; in the chlo[rine plant from February 1943 to November
1943; and again in the phosgene plant from November 1943 through August 1944.
He reported having a few minor exposures to phosgene that caused burning and
watering of the eyes, cough, tightness in the chest, and headache. Since the
fall of 1943, the patient had noticed chronic symptoms such as shortness of
breath on exertion, tightness in the chest, and occasional attacks of coughing.
Upon voluntary admission to the hospital for pulmonary function tests on August
20, 1944, hematology examinations,; urinalysis, and physical examination were
August 1986 ; 6-8 DRAFT—DO NOT QUOTE OR CITE
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performed and all indicated normal conditions. A roentgenogram of the heart
and lungs was also normal. Results of the pulmonary function studies were
normal except for a reduction in voluntary breathing capacity. The patient
entered the Navy shortly after the tests; followup and psychiatric examina-
tions were not performed.
Galdston et al. (1947b) have drawn three major conclusions from these five
cases: (1) emphysema of the lungs may develop after chronic exposure to
phosgene; (2) the measurable disturbances of the lungs are more striking after
chronic exposure to phosgene than after recovery from a serious acute poison-
ing; and (3) the symptoms of chronic exposure to phosgene have not been dis-
abling, in contrast to the frequently prolonged disability seen after acute
exposure (Galdston et al., 1947a). Unfortunately, these patients were not sub-
sequently examined, and therefore, no information is available on the fate of
the symptomatology after phosgene exposure had been discontinued.
6.3 NIOSH REPORTED STUDIES
The National Institute of Occupational Safety and Health (1976) described
three epidemiologic studies in which workers were exposed to phosgene. Two of
the studies were translated from Russian and were poorly described by the origi-
nal authors. Phosgene concentrations were reported to be approximately 0.125 to
0.5 ppm at the work sites, but no increase in pulmonary effects were described.
The third study (a written personal communication from A. F. Myers to NIOSH in
1974) compared the medical records of 326 exposed workers at a phosgene plant
with those of 6288 nonexposed workers. Pulmonary function, "lung problems," and
deaths attributable to respiratory diseases were tabulated for both groups. The
author concluded that there were no chronic lung problems associated with work-
ing in this phosgene plant and that the exposed workers showed no increased mor-
tality due to respiratory diseases compared to unexposed individuals (Myers,
1974). Phosgene measurements at this plant were made on 15 personal air samples
(20-minute collection period) and showed concentrations ranging from nondetected
to 0.02 ppm, with an average of 0.003 ppm. Fixed-position air samples (2-hour
or 20-minute collection periods) were also taken at the plant; phosgene concen-
trations in 51/56 samples ranged from nondetected to 0.13 ppm. The remaining
five samples showed "off-scale" phosgene concentrations (greater than 0.14 ppm)
reportedly due to leaks.
August 1986 6-9 DRAFT—DO NOT QUOTE OR CITE
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6.4 POISON GAS FACTORY, OKUNOJIMA^ ISLAND, JAPAN
Nishimoto et al. (1983) investigated the causes of mortality of 2068 male
workers employed in a poison gas factory in Japan. The factory produced several
poisonous gasses from 1927 to 1945. Phosgene was a relatively minor product;
mustard gas and lewisite were produced in the greatest quantity. The authors
did not separate the workers according to the gas that they were exposed to;
therefore, no conclusions on the Ibng-term health effects of phosgene exposure
can be made from this study.
August 1986 j 6-10 DRAFT—DO NOT QUOTE OR CITE
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6.5 -REFERENCES FOR CHAPTER 6
,-M.; Luetscher, J. A., Jr.; Longcope, .W. T. ; Ballich, -N. L. ; Kremer,
V L; Filley, G. L. ; Hopson, J. L. (1947a) A study of theVesidual
effects of phosgene poisoning in human subjects. I. After acute exposure
J. Clin. Invest. 26: 145-168.
Galdston M.; Luetscher, J. A., Jr.; Longcope, W. T. ; Ballich, N. L. ; Kremer,
V. L ; Filley, G. L. ; Hopson, J. L, (1947b) A study of the residual
effects of phosgene poisoning in human subjects. II. "After chronic expo-
sure. J. Clin. Invest. 26: 169-181.
National Institute for Occupational Safety and Health. (1976) Criteria for a
recommended standard ---- occupational exposure to phosgene Rockville MD-
U. S. Department of Health, Education, and Welfare, Public Health Service
Center for Disease Control; HEW publication no. (NIOSH) 76-137. Available
from: NTIS, Springfield, VA; PB-267514. •
Nishimoto, Y. ; Yamakido, M. ; Shigenobu, T. ; Onari, K. ; Yukutake, M. =(1983)
Long-term observation of poison gas workers with special reference to
respiratory cancers. J. UOEH 5 (suppl): 89-94.
Polednak A P (1980) Mortality among.men occupational ly exposed to phosgene
in 1943-1945. Environ. Res. 22: 357-367.
Polednak 'A. P.; Hollis, D. R. (1985) Mortality and causes of death among
workers exposed to phosgene in 1943-45. Toxicol. Ind. Health 1: 137-151.
September 1986 6-11 DRAFT-DO NOT QUOTE OR CITE
tV U.S. GOVERNMENT PRINTING OFFICE: 1986 - 748-003/40032
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