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OCR for page 101
4
IRRITANTS ANT) ~JESICANTS
BACKGROU?~O
The compounds discussed in this chapter ( see Table 4-1 ) are
mustard gas (H), chloroacetophenone (CN) ~ dibenz [b ~ f ] [ 1~4] oxazepine
(CR) ~ o-chlorobenzylidene malononitrile (CS)' brombenzyl cyanide
(CA), diphenylaminochlorarsine (DM), chloropicrin (PS), nonanoyl
morpholide (EA 1778), a cycloheptatriene (EA 4923), ant 123 com-
pounds involved in 1 imitet test ing . H is a ves icant, pulmonary irri-
tant, and systemic poison, depending on dose ant route of entry into
the body. The other compounds are irritants. Of the irritants, DM
is a sternutator (a substance that causes sneezing), whereas the
others are lacrimators. All are called gases in warfare use,
although they may be administered as vapors, liquid droplets, smokes,
or mixtures thereof. Mustard gas and irritant chemical agents, the
latter often called harassing agents, were introduced to the battle-
field in World War I to confuse, harass, and disable enemy troops.
Since the 1920s, irritants have been used as riot-control agents by
civil authorities. Of these, CN came into widespread use ant is now
commonly supplied in a formulation under the name Mace. Although CS
was synthesized in 192S, it became known as a riot-control agent only
in the 1960s, when it appeared safer than CN.
For military use, harassing agents are intended to reduce or
destroy the ef feet iveness of enemy troops . For this purpose, rapid
onset of effects is usually, but not always, desired. Rapid
recovery facilitates the handling of prisoners, whereas men injured
by mustard gas require intensive care ant weeks for recovery. There
were no plans for studying long-term effects of World War I-harase-
ing agents.
Riot-control agents are also designed to have a rapid onset of
effects, produce a high degree of immediate disability, and require a
short recovery time as soon as the rioters are dispersed from the
area. With the increasing use of such agents as CN and CA in recent
years, their possible long-term effects have aroused concern.
At the end of World War I, medical thought was turning to the
possibility thee soldiers who had been gassed with mustard, chlorine,
pho~gene, and other agents would develop tuberculosis. In the early
postwar years, publications described efforts to identify cases of
tuberculosis among gas casualties. The expected epidemic failed to
appear, and attention subsided. More extensive studies, such as that
of Beebe, were initiated. 1 Gradually, mustard gas became the
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center of interest; the discovery of its mutagenic properties stimu-
lated further he search . Suf f ic lent ~ ime has now passed for long-term
effects to become clear. Mustard gas has become the subject of a
large body of reports, which have disclosed a multifaceted problem.
On the other agents discussed here, there is no such volume of
informal ion. Their e f fects have generally been regarded as tran-
sient, ant only in the Himsworeh reports on the use of CS in the
Lontonderry riots of 1969 is there even a proposal to study the long-
te.- effects of the riot-control agents . Indeed, on several com-
pounts, practically no useful information is available, except with
regird to chemistry, acute toxicology, and pathology.
Because information on possible long-term ef fects of the other
irritant chemicals used in the Edgewood tests is sparse, this chapter
focuses on the effects of mustard gas and two lacrimators, CS and CN.
Information on the potential long-term adverse effects of these
chemicals is derived from several sources: first, observation of
long-ter~ disabilities in soldiers who were exposed to a single ~ in
most cases) toxic concentration of irritant during World War I and in
persons exposed in peaces ime ace idents or riot-control procedures;
second, studies of morbidity in workers chronically exposed to chemi-
cal irritants during their manufacture; and third, studies in which
experimental laboratory animals were exposed to selected chemicals
by topical application, injection, or aerosol inhalation.
A review of the literature on experiments to assess possible
chronic effects, especially mutagenic activity and carcinogenicity,
of the irritant and vesicant agents reveals that these ef fects have
not been studied systematically by current standards and techniques.
The current view is that a carefully selected battery of tests
involving prokaryotic and eukaryotic organisms can be used to assess
the mutagenic ity or care inogenic ity of a chemical . Mutagenic ity
tests should include asesys for gene mutations and chromosomal aber-
rations. No such systematic investigation has been conducted of any
of the agents reviewed in this chapter, except possibly mustard gas.
In the case of any agent for which a risk assessment is desires with
respect to past human exposure or that continues to be used for riot
control or relates purposes, it seems desirable to use a battery of
tents, such as those recommended in the National Research Council
report on chemical environmental mutagens.4
Under the sponsorship of the National Cancer Institute and the
National T Toxicology Program, two chronic tests of CN and CS adminis-
tered by inhalation are unter way. 5,6 Preliminary data obtained in
the subehronic studies preparatory to the definitive inhalation car-
cinogenicity tests are presented in the sections of this chapter
dealing with CS and CN. One probable adverse effect, to judge from
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observation of the subehronic Bests, is irritation of the upper res-
piratory tract and tunas. A potential consequence of inhalation of
these chemicals by humans is pulmonary damage that might readily
develop into pneumonia. Prediction of any other chronic effecte,
including carcinogenesi~, awaits the generation of appropriate data,
including in vitro and in viva bioassays.
REFERENCE S
1 . Beebe, G. Lung cancer in World War I veterans: Poss ible rela-
tion to mustard-gas injury and 1918 influenza epidemic. J. Natl.
Cancer Ins t . 25: 1231-1252, 1960.
2. Himsworth, H. Chairman. Report of the Enquiry into the Medical
and Toxicological aspects of CS (Orthochlorobenzyl itine Malono-
nitrile) Part I, Enquiry into the Medical Situation Following the
Use of CS in Londonderry on 13th and 14th August, 1969. London :
Her Ha je~ty's Stationery Office. Command 4173. 1969. 13 p.
3. Himsworth, H., Chairman. Report of the Enquiry into the Medical
and Toxicological Aspects of CS (Orthochiorobenzylidene Malono-
nitrile). Part II. Enquiry into Toxicological Aspects of CS and
its Use for Civil Purposes. London: Her Ma jesty' ~ Stationery
Off ice. Command 4775. 1971. 82 p.
4. National Research Council, Committee -on Chemical Environmental
Mutagens. Identifying and Estimating the Genetic Impact of Chem-
ical Mutagens. Washington, D.C.: National Academy Press. 1983.
5. Tracor Jitco, Inc. Subchronic study report on CS2. Rockville,
Md.: Tracor Jitco, Inc., 1982. 286 p.
6. Tracor Jitco, Inc . Study Report on alpha-Chloroacetophenone .
Rock~ille, Md.: Tracor Jieco, Inc., 1982. 177 p.
MUSTARD GAS
CHARACTERI STICS
Mustard gas (H)--also known as yellow cross, yperite, sul fur
mustard, Schwefellost, bis(2-chloroethyl) sulfide, and dichlor-
diethylaul f item-is a chemical-warfare agent with both ~resicant and
systemic effects. H is colorless and almost odorless and is an oily
1 iquid at 14-215°C with a molecular weight of 159.08. Except in
extremely colt weather, the low vapor pressure (0.072 mm Hg at
20°C) and low~olatility of H are sufficient to make contaminated
surfaces a source of danger to anyone nearby. H is slightly soluble
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in water and soluble in oils, fats, and organic solvents. It pene-
trates clothing readily. Moist skin of armpits, groin, and inner
surfaces of thighs is especially vu' nerable. i5 ~ 7 ~ 77
Its garlicky odor, faint at first, is soon imperceptible. E2po-
sure to H does not cause immediate discomfort; rather, the onset of
effects is delayed and -insidious. Troops have been known to remain
in contaminated areas until their eyes, skin, and respiratory organs
were affected. Exposure of skin produces erythema, then blisters
that are painful and slow to heal. Such eye injuries as conjunc-
tivitis, keratitis, and corneal ulcers cause temporary or permanent
blindness. The respiratory effects of H include rhinitis, larya-
gitis, bronchitis, and, in severe cases, destruction of mucous men
branes. The bone marrow and digestive system are affected by sys-
temlc administration of H. The multiple effects of this insidious
agent make it among the most potent used on the battlefield.
TOXICOLOGY
Mutagenicity
Mutations are heritable changes in genes or chromosomes.
Although mutations occur spontaneously as rare events in all
organ ems, their rates of occurrence can be markedly increased by
exposure to mutagenic agents. Geneticists generally agree that the
effects of human exposure to mutagens are deleterious and that such
exposure should be minimized. 54 ~ 53 The basis for concern about
hen exposure to mutagens is that increases in the rates of muta-
tion in human germ cells and somatic cells may lead to art increased
incidence of genetic diseases and cancer, respectively.
After H. J. Mum er showed in 1927 that Tic rays induce sex-linked
recessive lethal mutations in the fruit fly Drosophila me~ano-
gas~cer,5\ efforts were made to determine whether chemicals can also
be mutagenic. Unequivocal evidence of chemical mutagenesis was not
obtained unt i' the 1940~. Among the first demonstrations of chemical
mutagenesis was a report by Auerbach and Robson6 that mustard gas
induces mutations in Drosophila. Over several years, Auerbach and
her colleagues found that mustard gas causes genetic alterations
ranging from gene mutations to chromosomal breaks asked rearrange-
ments. ~
lDhe mechanism of mutagenesis by sulfur mustard (and other mus-
tarda) involves the alkylatlon of DNA. As a bifunctional alkylating
agent, sulfur mustard. causes cross-linkage of DNA strands, as well as
monofunctional alkyla~cion producta.~9 Sulfur mustard and nitrogen
mustard have been used in mutation studies in a variety of organisms,
but data on the relative frequencies of induction of dif fe rent alky-
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ration products in DNA by the two agents are limited. Nevertheless,
sulfur mustard seems to exhibit greater SN1 character50 as an
alkylating agent than does nitrogen mustard.l9 Because agents
involved in SNI reactions attack oxygen sites in DNA more readily
than do agents whose reactions are almost exclusively of the SN2
type, sulfur mustard may differ substantially from nitrogen mustard
in the spectrum of alkylation products formed in UNA. Such dif fe-
rences in mechanisms of alkylat ion and in alkylat ion products can
feat to considerable differences in mutagenicity.30~7t Therefore,
although nitrogen mustard and sul fur mustard are both alkylating
agents, one must be caut ious in assuming they are comparably muea-
genic .
A comprehens ive review of the mutagenic ity of sul fur mustard and
nitrogen mustard has been publishes by Fox and Scoet.l9 The muta-
genicity data base on nitrogen mustard is more extensive than that on
sulfur mustard. Nevertheless, results have been reported regarding
the genetic activity of sulfur mustard in tests for forward mutations
and reversions in bacteria; 12 differential killing of DNA-repair-
deficient strains of microorganisms and their repair-proficient
counterparts; 34 ~ 38 revere ions in fungi; 38, 68 chlorophyl 1
mutations in vascular plants 19 gene mutations and chromosomal
aberrations in Drosophila;5, t9 reversions in cultured L517BY mouse
lymphoma cells ;7Z~st-mediated assays involving bacteria or
mammal fan cells in mice; 12 and dominant lethal mutations in
mice .62 Clastogenic ef fects of sul fur mustard have been studied in
plant root tips and microsporocytesl9 and in cultured mammalian
cells.65
Data from a mouse dominant-lethal test suggest that sulfur
mustard reaches germinal tissue ant induces dominant lethal
mutations.62 However, the data are inadequate for prediction of
genetic risk to human germ cello. Uncertainties stem from the lack
of data on defined genetic events induced by sulfur mustard in mam-
mal fan spermatogonia or oocytes and from the variat ion in mutagenic
potency that has been observed for the mustards in various assay sys-
teme. Nevertheless, the possibility that sulfur mustard is a human
ge.,u cell mutagen cannot be disregarded, part icularly because it is
mutagenic in diverse assays, including tests for germ cell mutations
in Drosophila and dominant lethals in mice; moreover, other direct-
acting alkylating agents are known to induce mutations63 ant chro-
mosomal alterations 1 in mammalian germ cells.
Pathogen IS iS of Skin bee ions
Vogt et al.72 recently studied the pathogenesis of lesions
caused by the appl ices ion of H to the skin of guinea pigs and
rabbi to; their methods inc luded l ight and e lee tron microscopy, h i s to-
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chemistry, ant the use of contrast ing Evans blue dye. Cutaneous
applications of H at 25-250 ~g/cm2 caused severe injury to the skin
of both species and resulted in nonve~icating, necrotic, encrusted
inf lavatory lesions .
Cutaneous response to H had immediate and delayed phases. Within
the first hour of exposure, injury to superficial capillaries and
venules, vascular leakage, and infiltration by granulocytes with a
high percentage of basophile were obeemed. The delayed phase was
evident after ~ h; was manifested by nuclear pyknosis, an increase in
lysosomal enzymes, and autophagic vacuoles in basal epideneal cells;
and was accompanied by diffuse vascular leakage, infiltration by
polymorphonuclear leukocytes, and ulceration. After the peak of
inflammatory reaction at 24-72 h, the superficial, encrusted ulcers
healed in about 10 d. Topical and systemic administrat ion of gluco-
cort icosteroids decreased the extent of edema during the immediate
phase, but d id not af feet the rate of heal ing.
Care inc,~eni~ i tv
Because of the corre let ion between mutagenic ity ant care inogeni-
city, one would expect sulfur mustard to be carcinogenic on the basis
of mutagenicity data alone. This expectation in borne out by carcin-
ogenicity tests in experimental animals and by data from human expo-
sures. The International Agency for Research on Cancer classifies
sulfur mustard a. one of relatively few chemical agents on which the
data are adequate to show an association with the induction of cancer
in humans. 7
H-induced carcinogenic effects have been demonstrated in mammals.
Heston26 reported that in two experiments the intravenous injection
of aqueous H into strain A mice resulted in pulmonary tumors in 93X
and 68Z of the surviving mice. In 1953, Heston27 documented the
appearance of a variety of tumors in strain A, C3H, and C3Hf mice
after the subcutaneous injection of H in olive oil. At the injec-
tion site (middorsal area), there were sarcomas. At other sites,
there were mammary and pulmonary tumors and hepatomss, and one mouse
developed lymphocytic leukemia. Heston28 found significant
increases in tuna eumore of ter inhalat ion exposure of mice .
Heston26~28 reported many separate experiments, some of which were
performed with nitrogen mustard. Heston concluded that both mustard
compounds were mutagenic and care inogenic .
Chrc nic exposure of rats to H ( at 1 or 100 ug/m3, 6.5 in/d, S
d/wk) at Edgewoot produced an increase in epithelial cell tumors, but
no evidence of systemic injury.45
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The investigations discusses above show a clear progression from
the d~isco~rery of a mutagenic action of H in Drosophila' through the
studies of alkylation reactions of H with TUNA, to the experimental
production of tumors in mammals, including humans.
INDUSTRIAL AND MILITARY EXPOSURE S
A few clinical observations may be instructive before discussion
of the major studies of H carcinogenicity in humans.
Jackson and Adamo31 studied 33 cases of extensive basal cell
carcinoma, two of which involved mustard-gas burns sustained during
World War ~ ~ One of those deve loped 35 yr at ter the burn, but 2 yr
after irradiation with cobalt-60. In the other, basal cell carcinoma
developed at the site of three separate burns, 3 yr after exposure.
Some of the mustard burns did not lead to basal eel 1 cancer.
I'lig _ al.35 treated nineteen patients suffering from peo-
riasis vulgaris once or twice with 50 g of 0. 005X H in petrolaeum.
They cone luded that whole-body inunct ion with H presents a low car-
cinogenic risk. That is likely to be erroneous, in view of the low
dose and brie f treatment used .
When examining reports of exposures to chemical agents, one
should note the different conditions involved. After July 1917,
during World War I, H was used often by both Germany and the Allies.
Some areas of French battler ield. became so badly contaminated that
they were abandoned by both ~ides. 13 Thorpe69 estimated atmos-
pheric concentrations of H during gas shelling as averaging 3 ppm,
with a maximum of 5 ppm (about 19 and 32 mg/m ~ respectively).
Prentiss estimated thee exposure at 23 ppm ~ 150 mg/m3) for 10 min.
giving a Ct ~ product of concentration and duration of exposure) of
about 1, 500 ma. minims, would be lethal for an unprotected man. 60
In military and riot-control situations, exposure to agents is
acute, but relatively brief. the clinical cases citedl7.40
involved "Iong-eerm" exposure, meaning a few months to a few years.
Nakamura,53 in a 1956 paper, reported working conditions in a
Japanese mustard-gas factory operated secretly in Hiroshima from 1930
to 1945. Workers alternately worked 1 h in gas product ion and 2 h in
a gas-free env ironment over a 10-h workday. They wore gasmasks and
complete protective clothing, including rubber boots, and were often
rotated. Nevertheless, many workers showed a darkening of skin; some
developed ulcers ~ diarrhea, ant jaundice and later coughed blood and
developed tuberculosis. The concentration of mustard gas78 may
have reached 50-70 mg/m3, as determined by bioassay. The bioassay
involved exposure of unprotected birds in the work areas that resul-
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ted in death in 12-15 he Exposed rabbits refused food, coughed, and
tied within a 3-d period. Some adverse health effects experienced by
workers may have been due to the inadequacy of protective equipment.
Yamada et al.79 found 97 deaths during the period 1946-1957
among worker. exposed to H in a Japanese factory before and after the
war. Of the 97 deaths, 20 were from malignant tumors, 13 of them in
the respiratory system. In 1963, Yamada78 further reported 172
deaths, extending the survey to 1933-1962. Yamada gave no figure on
the total number of men, but Wade et al .73 seated that there were
495. Forty-eight deaths (2BX) were caused by cancer, including 28
(161 of the 172) involving the respiratory tract. Among 5,030 deaths
in the nonexposed general population, 406 (81) were from cancer,
including 25 (0.5X of the S,030) involving the respiratory tract
(Table 4-21.
Wad a et al. extended Yamata' ~ observations on the same men, 73
f inding 33 deaths from respiratory tract cancers for 1952-1967, com-
pared with an expected 0.9, a relative risk of nearly 37. For 960
employees not exposed to H. Wada et al. found only three deaths from
respiratory tract cancer, compared with 1. ~ expected. These data
point to a connection between long, low-dose exposure to H and later
cancer, especially in the respiratory tract.
Weiss ant Weiss75 found a statistically signif Leant increase in
malignant tumors, especially bronchial and bladder carcinomas and
leukemia, among 245 German workmen employed in the manufacture of H
ant nitrogen mustard (HN) in the period 1935-1945. The 245 men,
studied over 20 ye, all had verified case histories. By 1974, 114 of
these men hat died, 40 of malignant tumors ant 38 of chronic respira-
tory ailments. From 1951 to 1972, there were 32 deaths from various
cancers among the exposed workmen, more than expected in a comparable
nonexposed population; only bronchial carcinoma showed a statis-
tically significant difference:- 11 observed vet 5 expected, a
re let ive risk of more than 2 .
Hellmann25 studied German munitions workers and reported 20
deaths from cancer among 157 former workmen. It is not clear whether
these were included in the 245 of Weiss and Weiss.
Morgenstern et al.48 reported on over 200 workmen in an
American chemical plant making H during World War II, focusing on 10
case histories that illustrated the immediate and delayed ef fects of
daily exposure to small quantities of H vapor. Exposure for 3 wk.to
6 ma 'ed these men to the tispeneary for treatment of respiratory
distress . Typically, a man developed some or all of the following
symptoms: ret eyes, photophobia, lacrimation, impaired vision,
blepharospasm, loss of taste ant smell, nosebleed, sore throat, chest
pain, wheezing, and dyspnea. After several such occurrences, a
worker was removed from further contact with H.
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TABLE 4-2
Characteristics of Male Mustard-Gas Workers Who Died
from Cancer (1955-1967)a
Case
___
Interval
f ram
Exposure Employment Age at
Durat ion, to Death, Death, Site of
yr ma ~ ma yr Neoplasm Histolo~ Type
3 7 2 22 4 62 Pharynx Undif ferent iated
4 5 3 22 0 40 Pharynx Squamou ~ ce 1 ~
5 8 0 24 5 57 Paranasal ~ inus Squamous ce 11
6 4 11 23 2 44 Paranasal sinus Squamous cell
7 7 5 28 1 65 Paranasal ~ inus Squamous ce 11
10 ~ 0 16 10 62 Larynx Squamous cell
11 10 0 19 2 52 Larynx Squamous cell
12 12 10 22 11 58 Larynx Squamous cell
13 7 11 20 10 58 Larynx Squamous ce 11
15 8 0 25 5 48 Larynx Squamous cell
16 7 0 23 4 59 Trachea Squamous ce 11
18 1 4 10 1 1 30 Bronchu ~ Squamou ~ c e 11
21 6 1 23 1 62 Bronchus Squamous ce 11
22 ~ 1 17 4 62 Lung Squamous cell
23 2 0 33 0 54 Bronchus Undifferentiated
24 17 0 27 0 54 Bronchus Undifferentiated
26 16 4 27 10 61 Bronchus Undifferentiated
27 4 10 17 9 61 Bronchus Squamous cell
29 2 2 19 3 58 Bronchus Undifferentiated
30 ~ 5 22 5 63 Bronchus Undif ferent fated
32 5 ~ 20 ~ 50 Bronchus Undifferentiated
38 7 11 27 7 74 Lung Squamous cell
40 2 0 27 6 55 Bronchus Squamous ce 11
43 0 3 26 1 47 Lung Undif ferent iated
44 7 3 29 0 63 Bronchus Squamous ce 11
__ —^
a Data from Wada _ alms
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Buscher,ll MorgensterD et al.~48 and others emphasized the
lingering bronchitis, bronchial asthma, hoarseness, aphonia, and
hypersensitivity to "oke ~ dust, and fumes that develop especially
in men working in ludustri~ situations tat expose them to mustard
at constant low concentrations. Even after discontinuing such work,
they may be subject to continuing respiratory and systemic disablli-
ties with a general deterioration of health that leaves them partial
or complete invalids . These men recovered partially af ter leaving
the mustard plant, but were sub ject to bronchitis, were susceptible
to respiratory infections, and were like By to develop bronchlectasis.
Many men were partially or completely disabled by 1945, when these
observations ended. The implication of the observed disabilities is
that complete recovery would probably not occur. It should be empha-
sized that the sequelae outlined here resulted from the chronic,
long-term exposure to H in the working environment. Most important,
these long-ter~ sequel ae ~ except the malignancies ~ generally const i-
tuted extensions or continuations of acute probe ems experienced
during exposure to H; they did not sudden1 y appear years af ter
exposure.
MEDICAL EFFECTS
Immediate Ef fects
An unprotected person exposed to H vapor will suffer simultane-
ously from skin burns, eye injury, and irritation of the respiratory
tract. 20 The acute effects of H depend on the concentration of the
gas, the duration of exposure, the ambient temperature, the extent of
protection, and the susceptibi~ ity of the person. 23 Clothing will
be contaminated and become a secondary source of poisoning even af ter
a gas cloud has blown away.
Onset of action may occur within several hours of exposure or
after a ~ atent period of up to 24 h. The immediate effects of H
within 0.5-3 h of espo sure include sneezing, acute conjunctivitis,
lacrimation, rhinorrhea or nasal bleeding, soreness and burning of
the the throat, hoarseness and dry, hacking cough, and erythema of
exposed skin. Within 4-16 h of exposure, the effects of H include
eye pain with acute conjunctivitis, corneal edema, lacri~tion,
photophobia, blepharospasm, and edematous erythema of the eyelids;
nausea, vomiting, diarrhea, and epigastric pain; and erythema and
vesication of the skin with coalescence of vesicles to form bul-
lee. 2~47~77 Between 24 and 48 h, effects on the eyes and skin pro-
gress and are manifested by eyelid pain and edema with blepharospasm,
lacrimati=, photophobia, and blludness; erythema, vesication, and
edema of the skin; persistent cough and hoarseness or aphonia due to
membranous laryagotracheobronchi~cis; increased temperature, pulse,
and respiratory rate, as well as granulocytosis resulting from sec-
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T4BLE 4-44
P ~ r c n t e r ~ 1 Tox i c i t y 0 f
CHT in Rat, Mouse, and Rabb it
Spec ies Roueeb LD,o, mg/kg
.
Mou Oral 78 (412-555)
M o u I n t r ~ p e r i e o n e a l ~ 3 ~ ~ 2 - 1 5 ~
Rae Intreperitoneal 21 ~16-27)
Re: Intrevenous 13 ( 11-15)
Rabb i t Intrevenous ~ ~ 1-9
~ Data from Biskup et ·~. 1
b Administered in polyethylene glycol 200.
TABLE 4-4 5
Toxicity of CHT Atministeret Cutaneoualy to Doge~
Amount Appt ied, b Time, Acutc Acute
mI/kg h _ Signs Mortality
1.0 (O) I 1/8 (neurologic) 0/8
0.5 (O) 16 or 24 Noe recorded 8/8
0.5 (O) 2 No to%ic signeC --
0.5 (O) 4-6 Toxic signeC ~~
0.5 (O) 1 ever, 4 d 1/3 (neurologic) 0/3
for 4 doses
0.25 (O) 1 every 4 d 0/3 --
for 4 doses
0.125 (0) 1 ever~r 4 d 0/3 --
for 4 doses
0.5 (N) 24 0/4 0/4
~ Dats froa Dilley ee a1. 3
b 0 ~ occluded, ~ ~ nonoccluded.
c Number of aniaele not stated.
—245-
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REFERE:tJCES
l
1. Blskup, R.K. ~ Loire, S.C. ~ Jr. ~ and Snodgrass, H.L. ~ Jr.
Parenteral toxicity of riot control agents in mice ~ rats ~ and
rabbits. U.S. Army Medical Research Laboratory, Edgewood
Arsenal, Md. EATM 100-22. 1971. 11 p.
8.
Brown , ~ . K. H ., Ferrigan, L . W., and S te~renson , D . E . The acute
toxicity and skin irritant properties of tropilidene ~ cyclo-
hepta-1, 3, 5-triene ~ . Ann. Occup . Hyg. 10: 123-126, 1967 .
3. Dilley, J. V., Newell , G.W., and Sasmore , D . P. The pharmacologic
and toxicologic properties of CHT in dogs and monkeys. Flaal
report, Contract No. 03-4772. Stanford Research Institute, Metro
Park, Ca. January 17, 1977. 79 p.
Dll fey, J.V., Newell, G.W., and Sasmore, D.P. The pharmacologic
and toxicologic properties of CHT in dogs and monkeys. Final
report, Contract No. 03-4771. Stanford Research Instltute,
'enio Park, Ca. May 1978. 35 p.
Heddle , J.A., Hite, M., KIrkhart, B., Mavournin, K., MacGregor ~
J.T., Newell, G.W., and Salamone, M.~. The induction of micro-
nuclei as a measure of genotosicity: A Report of the U.S. Envi-
ronmental Protection Agency Gene-Tos Program. Mutat. Res.
123: 61-~8, 1983.
6. Jorgenson, T.A., and Rushbrook, C.~. Study of the mutagenic
ef fects of CHT by the dominant lethal tent in rats. Final
report, Contract No. DAAK-~-77~-0029. Stanford Research
Institute, Menio Park, Ca. April 1978. 22 p.
McNamara , B. . P ., Weimer , J . T ., Biskup , R . IC., Thomas , W . IJ .,
Hopcus, M.W., Stude, H., Jr., Merkey, R.P., and Clark de Wal, A.,
Jr. Status report of the toxicity of EA 4923. U. S. Army Bio~
medical Laboratory, Aberdeen Proving Ground, Md. EAIR 4697.
1973. 55 p.
Na~clonal Academy of Sciences-National Research Council.
Identifying and Estimating the Genetic Impact of Chemical Muta-
gens. Washington, D.C.: National Academy Press. 1983. 316 p.
9 . S inmost , T . C ., S inger , A ., Koviak , T . A., Shuely , W. ~ ., Sultan ,
W. E., and -King, J.W. Studies of potential irritant agents . I .
A comprehensive investigation of EA 4923. U.S. Army Chemical
Laboratory, Aberdeen Proving Ground, Md. EC-TR-76018. 1976.
139 p.
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10. Stanford Research Institute. Excerpts from Monthly Progress
Reports, #15 (dated 1 Sept. 1978), #14 (dated 1 Aug. 1978), SRI
Project t6465, Contract DAAR-11-77-C-0029. Menlo Park, Ca.
And. ] 11 p.
11. U. S. Army Biomedical Laboratory. Evaluation of EA 4923 for
mutagenicity and chromosome damaging potential. IN EA 4923 - A
volat ile Sensory Irritant , Part 2 - Source Documents . Edgewood
Arsenal, Md. November 8, 1977. p. 217-223.
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EFFECTS OF ~ ~S~S
IRRITANT CHEMICALS AT
. . .
EDGEWOOD IN l-WO-MAN TESTS
RL SOP No. 70-3, dated June I, 1967, describes methods used at
Edgewood for searching for and selecting toxic chemicals. Some of
the details in connection with exposure of hen volunteere to
experimental irritant chemicals are described. Human volunteers were
exposed to compounds after review of animal screening data and appro-
val by committees based on a conclusion that the experimental chemi-
c~s were safe for human use. Generally, two volunteers were esposed
to each substance. Subjects were exposed in a wind tunnel at an alr-
speed of 5 mph and were asked to resist leaving the test atmosphere
(up to ~ mind until exposure was unbearable.
During 1962-1972, 123 irritant chemicals were tested. Further
details on the chemicals are available from the MRC repository of
Edgewood data. The substances were classified as irritants on the
basis of the preliminary animal studies. Except where noted below,
exposures were for ~ min or less in an aerosol chamber; each subject
was exposed to a chemi Cal on' y once.
AGENTS THAT CAUSED SLIGHT: OR NO EFFECI S
Of the 123 irritant chemicals, 64 caused might or no effects on
the exposed subjects. Two subjects were exposed to each of the 64
chemicals, except CS 40806, to which only one subject was exposed.
The following 64 irritant chemicals caused slight or no
effects:
301021
CS1086
CS4659
CS15442
CS20409
CS23653
CS27474
CS29780
CS30800
CS36650
CS36667
CS36722
CS3.~149
CS37200
CS38355
CS38731
CS39241
CS39242
CS39666
CS39715
CS40320
CS40325
CS40332
CS40679
CS40683
CS40686
CS40781
CS40785
CS40804
CS40805
CS40806
CS40841
CS40850
CS41462
CS41468
CS41592
CS41623
CS41725
CS42055
CS42057
CS42213
CS42216
CS42740
CS42824
CS43000
CS43001
CS43013
CS43014
CS43166
CS43168
CS43169
CS43945
CS43974
CS43988
CS43989
CS44854
CS45514
CS45659
CS46345
CS47137
CS47148
CS47563
CS48418
CS61804
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CS38731 might have been contaminated with doodle. Despite a
lack of complete toxicity data, it 8eem8 unlikely that the short,
single exposures to the 64 irritant chemicals that caused slight or
no acute effects on the exposed subjects will cause long-term health
effects.
LACRIMATORY AGENTS
The predomloant ef facts of 42 of the 123 irritant chemicals were
ocular, including eye irritation, eye closing, lacrimation, and con-
junctivitis .
Of the 42 lacrimatory agents, 34 caused very mild effected
generally eye irritation, sometimes associated with dermal and upper
respiratory passage irritation. The 34 mild lacrimatory agent o were
tested on two subjects each, except ll 9135 (four subjects), CS46398
(one subject), EA 2542 (17 subjected, EA 3365 (17 subjects), EN 4922
(sis subjecta), and CSS15799 (ylidinea~ine, 21 subjects). The mild
lacrim~eory agents include:
118055 CS30749
119135 CS30785
302049 CS30799
CS2127 CS31979
CS5146 CS37270
CS5616 CS38756
CS18692 CS40331
CS30747 CS40849
CS30748
CS41377 EA 2305
CS41722 EA 2329
CS43331 EA 2413
CS43981 EA 2433
CS46398 EA 2542
CS48861 EA 3176
EA 2284 EA 3365
EA 2302 EA 4922
CS815799
CS38756 and CS40849 might have been contaminated with dioxin.
Addltional details are available on EA 2542 and CS815799. In
1963, two subjects underwent one espo sure each to EA 2542 at Ct's of
39 and 57 mg min/m3. No effects were described. In 1969, EA 2542
was tested further on 15 subjects who had one exposure each. Ct's
ranged from 29.S to 65.S mg.D~in/~5, but no exposure durations are
available. The subjects experienced irritation of eyes, nose,
throat, and periorbital sites. Results of postesposure laboratory
analyses were normal.
In 1972, 21 subjects underwent exposure to CS815799. Seven subj-
ec~cs had aerosol exposures at a Ct of 50 mg min/m3; one was exposed
twice. CSSI5799 exposure caused mild ocular and respiratory irrita-
tion. 'aboratory analyses 7 ~ after exposure retreated increased SCOT
(43.8 and 42.7 lU) in two subjects, both of whom had normal pre-espo-
sure SOOT. One of these two subjects also had 6-10 white cells in
urinary sediment--a finding not seen in preexposure urlaalysis.
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Fourteen CS815799 subjects were exposed cutaneously with 1: solu-
tion, which caused mild irritation. One subject was exposed talcs.
Glared the absence of followup data, it is not possible to pre-
dict whether short exposures to the 34 mild lacrimatory agents will
have long-term health effects among the esposed subjects. The
increase in SCOT in CS815799-exposed subjects might have represented
hepatic reactions to the chemical, but recovery was probably
complet e.
Eight of the 42 t acrimatory agents caused more severe ef facts
than the other 34, namely more prolonged incapacitation in asso-
ciation with lacrimation asked eye closing: llB539, 123175, 126312,
CS encapsulated in gelatin, CS36579, FOGOlLCS, EA 2366, and CS-DM
mixtures .
The CS-~H mixtures were tested on 88 subjects. The CS:DM ratio
in the mixture was ~ :10. Thirty-eight CS-DM exposures occurred in
195B, and half the 1958 subjects had two exposures each. Fifty of
the CS-DM exposures occurred in 1966. Ct's were 0.5-40 me min/~3.
Exposure durations, when recorded-, were 16 s to 2 min. The principal
effects were ocular irritation, lacrimation, and conjunctivitis,
sometimes associated with upper respiratory tract irritation and
cough. One Subject required analgesic therapy after exposure
because of severe discomfort. Results of laboratory analyses 7 ~
after exposure, were available for all the 1966 CS-DM sub Sects, as
weU as some of the earlier subjects. One subject had an increase
in SCOT (to 60 IU) in postesposure laboratory analysis, but his
pre-esposure SCOT had also been slightly high ~ 33. 6 IU) .
In 1963, two subjects underwent short, single exposures to
118539, which caused lacrimation and severe conjunctivitis, sali-
vation, nasal irritation, chest constriction, and cough. In 1965
eight sub] ecus underwent single exposures to 123175, which caused
lacrimatlon and eye closing for several minutes after cessation of
exposure. Ir1 1966, 12 subjects underwent single exposures to
CS36579, which caused eye pain, profuse lacrimatlon, eye closing and
incapacitation that lasted several minutes after cessation of espo-
sllre, nasal irritation, and. dyspnea. In 1963, two subjects underwent
short, single exposures to EA 2366, which caused lacrimation and con-
junctivitis, respiratory tract irritation and dyspnea, and nausea.
Given the available information on subjects exposed to 118539,
123175, 126312, CS36579, and EA 2366 and their short, low~dose
exposures, one carrot predict long-term health effects of these
agent'. The discomfort associated with the exposures was marked,
but exposures were short and recovery appeared complete.
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RESPIRATORY IRRITANTS
Seventeen of the 123 irritant chemicals caused predominantly
respiratory effects, which were generally mild and transient. Ten
caused nasal and throat irritation, including cough. These upper
respiratory irritants were tested on two subjects each, except
CS5635, CS42818, and EA 2129, which were tested on four subjects
each. Other upper respiratory irritants were CS24302, CS41458,
CS42822, CS42984, CS43010, CS43109, ant
EA 3437.
Seven respiratory irritants caused primarily a sensation of chest
constriction and dyspnea. EA 2097 (CS14632) was tested on 19 sub-
jects, 15 of whom had two exposures each, and EA 2214 was tested on
four subjects. Other lower respiratory irritants were tested on two
subjects each: IlB609, 119400, CS36273, CS42985, and CS43329.
Giver the lack of followup information on the primary respira-
tory irritant chemicals, it is not possible to predict whether they
will have long-term health effects. Because these were short, low-
dos~ exposures in which the acute effects were generally mild, with
complete recovery, the Committee believes that Iong-term health
ef fects are unlike ~ y.
CONCLUST ONS
The Committee analyzed published studies describing the in vitro
and in vitro properties of the agents used and reviewed short-term
data collected by the U.S. Army on volunteers. The ability to pro-
vide definitive answers to the questions raised by ache charge to the
Committee was limited by the absence of long-term followup studies
of the sold iers and by the sparsene ss of chronic studies of these
compounds in animals or in humans after industrial exposure.
In general, the Committee found insufficient evidence deco eYal-
ua~ce these chemicals, except mustard gas. Mustard gas is an esperi-
mental mutagen asps human carcinogen at high doses. Data on the other
irritants are insufficient to evaluate their mutagenicity, carcino-
geniclty, or other long-te~ effects. Tests of all scheme chemicals
involved few exposures and low doses.
MUSTARD GAS (H)
.
Mustard gas is highly reactive and has vesicant and systemic
toxic effects. It is an alkylating agent that is mutagenic in
various laboratory test systems, including mammalian germ cells, but
data are inadequate to predict the extent of its genetic risk in
human. Mustard gas is also carcinogenic in experimental animals
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and hours . Other possible long-tem ef fee to of mustard gas are
related to its systemic toxicity; 8peclfically, it can cause blind-
11e88, permanent scarring of the skin. (which may lead deco skin tumors),
and chronic bronchitis. Reported instances of long-term injury such
as carcinogenesis in workers in a Japanese mustard production plant,
were associated with exposure at high, long-term dosages. Infor-
mation is insufficient to project risks associated with smaller
exposures to mustard gas; however, serious long-term adverse effects
in the small number of soldiers who received one or a few low-dose
exposures at Edgewood seem unlikely (except for some cases of perma-
nent scarring). Some of those exposed at Edgewood suffered skin
injuries that took several weeks to resolve. However, in view of the
small number of persons tested (about 150 healthy men) and the very
low dosages involved, it is unlikely that a statistically significant
increase in the risk of cancer or other chronic disease can be
detected in those exposed to mustard gas at Edgewood. When exposed,
the Edgewood subjects were wearing gasmasks and impregnated
clothing--an ensemble being tested for efficacy against toxic
contamination.
o-CHLOROBENZ TRIDENT MALONONITRIr~ (CS)
Results of experimental studies in microorganisms and short-term
experiments in laboratory animals suggest that long-ter~ medical
abnormalities in soldiers exposed to CS are unlikely. Acute tissue
changes produced in animals and humans seem re~reraible and not likely
to become chroni c in the absence of recurrent exposures. Follownp
information on the long-term state of health of exposed soldiers is
not yet available, but no reports have indicated that Edgewood sub-
jects have experienced any long-term sequelae.
CHLOROACETOPHENONE (CN)
ON, a moderately toxic irritant, h88 immediate effects on the
eyes, skin, and respiratory tract. ON is a strong skin-sensitizlug
agent, but is rarely lethal. The Committee found no evidence of
lasting ocular or respiratory effects in 99 volunteers esposed
experimentally at Edgewood between 1958 and 1972 when subjects
evaluated 2 wk after cutaneous administration or inhalation of
sol. Alleraic contact dermatitis or hypersensitivity in these
were
aero-
vo lun—
, .
-
teers on re-exposure to CN is possible. There ha8 been no systematic
study of the possible mutagenic and neoplasm-promoting ef facts of CN
with current scientific methods.
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DIBENZ[b f] [1 4]0"ZEPINE (CR)
. .
CR, a alla lacrisetory irritant, manifests less acute toxicity
than EN and CS. At low doses, it causes transient effects. There
are a few studies on long-tene health effects, including potential
mutagenicity and teratogenicity. The available data are insuffi-
cient to predict long-tem health effects. The small number of espo-
sures and the small number of subjects exposed to CR at low doses at
Edgewood make the occurrence of demonstrable ef facts in these sub-
jec to unlikely.
CHLOROPICRIN ~ PS ~
PS is acutely toxic and has a variety of sensory ef facts tn
animal. It has not been evaluated thoroughly for mutagenicity or
carcinogenicity. Like those exposed to mustard gas, the subjects
exposed to PS were wearlog gasmasks, and small numbers of soldiers
were e Spored to small doses. PS is urn ikely to have produced detect-
able long-term health ef fects in volunteers exposed at Edgewood.
BROMBENZYL CYANIDE ( CA), DIPHENY~NOCHLORARSINE ( DM), and
1-METHOXY-1, 3, 5-CYCLOHEPTATRIENE ( CHT )
CA, DM, and CHT are unlikely to have produced measurable long-
term health effects in volunteers exposed at Edgewood. But there
are no specific toxicologic data on the mutagenicity and carcino-
genicity of these compounds. CHT is less toxic than CN or DM when
admini stered acutely.
NONAbJOYL MORPHOLIDE
The Committee does not expect long-term health effects in volun-
teers tested with nonanoyl morpholide at the dosages used at Edge-
wood. As with C&, DM, and CHT, specific~tosicologic data regarding
its potential in this regard are not avaliable.
123 IRRITANT CHEMICALS
A total of 123 irritant chemicals were generally tested on only
two subjects each. There are no data on their mutagenicity, carcino-
genicit,r, or other loDg-term health effects. However, because the
exposures were small, detectable adverse effects seem unlikely.
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APPENDIX A
Part 1 ~ Reproduced from Volume I, Anticholinesterases and
Ant icholinergics
HISTORY OF THE EDGEWOOD TESTING PROGRAM
INTRODUCTION
Human experimentation appears to have been an integral part of
the history of the U.S. Army chemical warfare (COO) research efforts
until its suspension in 1975. On June 2B, 1918, the President
directed the establishment of the Chemical Warfare Service (CWS).
Four years ~ ater, in October 1922, the CWS created a Medical Research
Division to conduct research directed at providing a defense against
chemical agents. No matter how exhaustively an agent was tested in
snimaiS, it was felt that its efficacy in humane alto had to be
Studied.
In early 1941, the threat of war increased the urgency of the
development of protection against CW agents and, consequently,
engendered a need for a larger source of volunteers. Formal autho-
rity to recruit and use volunteer subjects in CW experiments was
initiated in 1942. The Secretary of War was asked to rule on the
permissibility of using enlisted men for testing agents of the mus-
tard-gas type. In Jul y 1943, the CWS was assigned responsibility for
all medical research related to CW. This extension of the CWS mission
included toxicological research and the study of hazards to the health
of personnel in the COOS.
The issue of the use of human volunteers was considered by the
Armed Forces Medical Policy Council during the early 1950's. The
Council concluded that es sent ial data could not be obtained unless
Huron volunteers were used, and the use of hears ire medical research
was authorized. By 1954, the Chemical Corps (formerly COOS) had estab-
lished a framework within which to conduct human experimentation, but
it lacked an adequate pool of vol''r~teers. In t955, it was decided
that the most practical source of volunteers would be enlisted men
stationed at Army installations in the vicinity of Edgewood Arsenal.
It was emphasized that voluntary consent of each human subject was
absolutely essential. It was also stated that, in all experiments
involving volunteer subjects, the subjects would be thoroughly
informed of all procedures and of what might be expected as a result
of each test. Furthermore, each volunteer would be free to determine
whether he desired to participate in a given experiment. In October
1959, approval was granted for the conduct of research on volunteers
to investigate defense against incapacitating CW agents.
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The search for incapacitating agents intensified when the Kennedy
administration took office. The involvement with incapacitating
agents represented a departure from an earlier period, begun in 1946,
when interest in highly toxic (acute) anticholinesterase chemicals
resulted from their development in Germany during World War II. The
basic purpose of a military incapacitating agent is to produce tem-
porary ineffectiveness without permanent injury or death. Incapaci-
tating agents (anticholinergic chemicala) and highly toxic (acute)
anticholinesterase chemicals produce functional and at Nctura'
effects on the nervous system which cause rapid or delayed effects
on an individual's performance and behavior.
PROCEDURES USED AT THE EDGEWOOD CHEMICAL TESTING PROGRAM
_ ~
A fairly extensive discussion of the procedures used is provided
in the Inspector General's report, Use of Volunteers in Chemical
Agent Research, prepared by Colonel James R. Taylor and Major William
H. Johnson and dated March 1976 (listed in Appendixes C,D).
RECRUITMENT OF VOLUNTEERS
Recruiting teams (initially administrative officers, but later
often including military physicians from the Edgewood laboratory)
visited Army installations where a briefing, usually with a film and
handouts, was presented to a large number of enlisted men. Gener-
ally 10 to 20 percent of the audience expressed interest and these
men were asked to complete a personal history, which included medical
and psychologic items and the Minnesota Multiphasic Personality
Inventory (MMPI). It was not unusual for 400-600 men to request
assignment in the course of a tour of seven to ten installations. Of
these, no more than 100 were selected and eventually assigned for a
1-to 2-month period of temporary duty at Edgewood Arsenal.
The "incentives" for volunteering consisted of a small monetary
allowance (approximately $lO50 a day for temporary duty), the assign-
ment of only light duties while at Edgewood, and a ~ oat every weekend
free. Some volunteers were genuinely interested in the scientific
and experimental aspects; however, if curiosity or the desire to
"test one ' a self " seemed too strong, the applicant was usually not
accepted.
As a group, the volunteers were above average in physical and
mental qualifications, with a mean IQ near 110, good behavior
records, deviations of the population mean on all scales.
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Representative terms from entire chapter:
riot control
