1998 Congressional Hearings
Intelligence and Security



Testimony of Dr. Christine M. Gosden

Before the Senate Judiciary Subcommittee on Technology, Terrorism and
Government and the Senate Select Committee on Intelligence on Chemical
and Biological Weapons Threats to America: Are We Prepared?
Wednesday, April 22, 1998




Introduction



It is a very special honour to testify before this committee. Chemical
and biological weapons are not humane weapons which kill rapidly and
mercifully. I have recently witnessed the long-term effects of the
chemical weapons attack on the large civilian population in Northern
Iraq, in the town of Halabja. I was shocked by the devastating effects
of these weapons which have caused problems such as cancers, blindness
and congenital malformations. My experiences of the devastating power
of these weapons have emphasized the importance of protecting
individuals and nations against chemical and biological weapons
attacks. Having seen and experienced their suffering and heart their
pleas for help, I know I must do everything I can to help the people
of Halabja and enter into a partnership with them to try to find
effective therapies for bodies, minds and spirits which have been
affected by the winds of death and destruction wrought by clouds of
toxic weapons


My trip to Iraq was made on entirely humanitarian grounds, to study
what had happened, learn about the effects and try to help the people
who had been affected. I am the Professor of Medical Genetics in the
University of Liverpool in the United Kingdom and I formerly worked
for the British Medical Research Council (the British equivalent of
NIH). My principal fields of medical research have always been
directed to trying to understand the causes of congenital
malformations and cancer and provide effective therapies for them.
This journey and the horrifying findings have shocked and devastated
me to an extent which I had not believed possible. It is the
deliberate use of weapons of this ferocity, which have the power to
kill or maim in perpetuity, which I find so terrible.


I'd like to share with you today some of what I have learned during my
travels and research. At first glance, it might not appear that Saddam
Hussein's use of poison gas against his own people in 1988 has much
relevance to today's issue of domestic preparedness in the United
States. However, I believe there are at least three "lessons learned"
from Halabja that are directly related to the topic which your
committees are addressing:


-- First, national plans for responding to chemical or biological
weapons incidents in the United States (or the United Kingdom for that
matter) must take into account the possibility that multiple types of
chemical and biological agents may be used in the attack, greatly
complicating an effective response;


-- Second, that treating immediately the victims of chemical attack is
absolutely critical not only for saving lives, but for preventing
long-term radiation-like medical and genetic problems; and


-- Third, and most important, given that technological and other
barriers against chemical weapons use have fallen away, it is vitally
important that each of our nations maintain adequately funded national
medical preparedness programs to treat potential chemical weapons
casualties, both civilian and military.


The Attack on Halabja



Let me begin by describing the poison gas attack on the Iraqi town of
Halabja. This was, let me emphasize, the largest-scale chemical
weapons (CW) attack against a civilian population in modern times.


Halabja was a bustling city in Northern Iraq with a population which
was predominantly Kurdish and had sympathised with Iran during the
Iran-Iraq war in the 1980s. The population at the time of the attack
was about 80,000 people. Troops from the Kurdish Patriotic Union of
Kurdistan (PUK) entered Halabja on 15th March 1988 amidst heavy
resistance from Iraqi security and military forces.


Halabja fell to the PUK troops (accompanied by Iranian revolutionary
guards) four hours later. The Iraqis responded with heavy artillery
fire and an early wave of six aircraft bombarded an area near Halabja
with ordinary high explosives. The civilians had been prevented from
leaving the town by the PUK, hoping that the Iraqis would not attack a
town with civilians in it -- thus providing a human shield.


The CW attack began early in the evening of March 16th, when a group
of eight aircraft began dropping chemical bombs; the chemical
bombardment continued all night. According to Kurdish commanders on
the scene, there were 14 aircraft sorties during the night, with seven
to eight planes in each group, and they concentrated their attack on
the city and all the roads leading out of Halabja. The chemical
attacks continued until the 19th. Iraqi planes would attack for about
45 minutes and then, after they had gone, another group would appear
15 minutes later.


Let me emphasize that this was not the first chemical attack by Saddam
Hussein. Previous attacks had been launched by Iraqi aircraft against
20 small villages in 1987. However, the scale and intensity of the
chemical campaign against Halabja was entirely different -- this was
the first time that chemical weapons had been used on a major civilian
population of this size. The victims of the attack included women,
children and the elderly.


Saddam Hussein's Chemical "Cocktail"



There is something else that sets Halabja apart from other known
chemical weapons attacks -- including the Aum Shinrikyo attack on the
Tokyo subway in 1995. The Halabja attack involved multiple chemical
agents -- including mustard gas, and the nerve agents SARIN, TABUN and
VX. Some sources report that cyanide was also used. It may be that an
impure form of TABUN, which has a cyanide residue, released the
cyanide compound. Most attempts directed to developing strategies
against chemical or biological weapons have been directed towards a
single threat. The attack on Halabja illustrates the importance of
careful tactical planning directed towards more than one agent, and
specific knowledge about the effects of each of the agents.


Exposed civilians are particularly at risk if a war strategy aims to
produce civilian casualties on a large scale. Developing medical
treatment regimes for trained military personnel, who are generally
young, healthy and of approximately the same weight and size, is
challenging enough. But the demands of developing effective treatment
regimes for children, the elderly and infirmed is even more daunting.
And the task is ever more daunting when having to treat a chemical
weapons "cocktail."


Saddam Hussein clearly intended to complicate the task of treating the
Halabja victims. At a minimum, he was using Halabja as part of the
Iraqi CW test program. Handbooks for doctors in Iraqi military show
sophisticated medical knowledge of the effects of CW. The Iraqi
military used mustard gas in the "cocktail," for which there is no
defense or antidote. And it is also worth noting that Saddam did NOT
use the nerve agent SOMAN, but instead used TABUN, SARIN and VX, as I
said above. This is noteworthy because it shows that Hussein's experts
were also well aware that pyridostigmine bromide -- one of the chief
treatments against nerve agent -- is relatively ineffective against
TABUN, SARIN and VX, but highly effective against SOMAN, the only
agent he DID NOT use.


A Primer on the Effects of CW Use Against Humans



Let me spend just a few moments describing the basics of chemical
weapons, their effects, and treatment for exposure to them.
Recognition of the way in which these agents work is the key to
providing effective antidotes and treatment. I realise that in
providing written testimony for such a distinguished body, it is
unusual to delve into scientific detail. However, I hope this will be
of help in trying to provide a clearer understanding of the measures
we can take -- and their limitations -- against the likely impacts of
mass casualty attacks involving chemical weapons. The following table
summarizes the key points.


Mustard Gas



Symptoms, toxicity and short-term effects. Large doses can be
life-threatening, if untreated. Mustard gas produces blisters and
damage to skin, eyes, respiratory, gastrointestinal tracts, There is
usually erythema; vesication; burns; lung damage; Mustard gas also
affects many other systems including haematopoietic and immune
systems. Haematological effects include leucopenia; thrombocytopenia;
decrease in RBCs; and sepsis. Secondary infections of damaged tissue
can occur easily.


Long term effects. The most serious of the long term effects arise
because mustard gas is carcinogenic and mutagenic. In the respiratory
system there are increased risks of chronic lung disease, asthma,
bronchitis. Permanent impairment of vision; may occur and eye damage
may be severe, leading to blindness. Skin lesions and burns may be
severe with persistent changes and hypersensitivity to mechanical
injury. Carcinogenic and mutagenic effects can result in cancers,
Carcinogenic and mutagenic effects can result in cancers, congenital
malformations and infertility. Long term effects (mutagenesis,
carcinogenesis, eye, skin, lung, fertility) etc are dose and route
dependent.


Antidotes. The tragedy of any population exposed to mustard gas is the
fact there is no antidote. Decontamination must be completed within 2
minutes to prevent tissue damage. Furthermore, toxic effects may be
delayed (is there is a latent period), so personnel may not realise
the extent or significance of their exposure and thus not seek
immediate treatment or made efforts to wash off all the mustard gas
and remove contaminated clothing.


Care. The immediate and continuing need for treatment of mustard gas
injuries is extensive. Burn care, eye therapy, pulmonary support are
required. The eye is most sensitive organ; instant removal of agent is
required to prevent damage. Initially irrigate with copious amounts of
water; at treatment medical, facility use saline eyewash.


Decontamination methods. Contaminated clothing must be removed
immediately. Mustard gas can be hydrolysed by bleach (0.5%
hypochlorite solution) or alkali, so these should be used as swiftly
as possible. For effective skin decontamination commercially available
tubes containing Fuller's earth powder should be used. The powder
should be dispersed over exposed areas, left for 1 min and removed
gently with clean gauze or cotton. If powder unavailable, use water
and regular soap to remove chemical agent from skin. Baking soda
solution can also be used for decontamination of skin, avoiding eye
penetration.


Persistence in environment and other features. Mustard gas has low
volatility and thus may be very persistent on earth and solid surfaces
and in contribution to water table. Mustard gas can persist for many
years unless hydrolysed in alkaline soils, or if the soil is treated
with bleach. May persist in acid soils, and thus potentially in the
water table for many years. It is thus important to identify those
conditions after a mustard gas attack when this is the case and treat
the affected areas with bleach or alkali. Hydrolysis is PH and
temperature dependent.


Nerve Agents



General. Nerve agents, SARIN, TABUN and VX have rather complex
mechanisms of action. Nerve gases can affect all the different parts
of the central and peripheral nervous system. Different receptors are
responsible for the kanor classes of response to nerve gases.


Muscarinic effects. The most important of the muscarinic effects are
to the following:


Pupils and ciliary body -- pinpoint pupils, eye pain, blurred vision,
headache


Nasal mucous membranes  --  rhinorrhoea



Bronchial tree -- tightness in chest, bronchoconstriction, cough
Gastrointestinal -- nausea and vomiting


Sweat, salivary, tear glands -- increased sweating, salivation and
tears


Heart  --  bradycardia



Bladder  --  frequency, involuntary micturition



Nicotinic effects.  The principal nicotinic effects are those on:



Striated muscle -- fatigue, muscle weakness, twitching, dyspnea,
flaccid paralysis of muscles (including respiratory system), cyanosis


Sympathetic ganglia -- elevation of blood pressure then hypotension


Central nervous system effects. The principal central nervous system
effects are:


Immediate, acute effects -- generalised weakness, depression of
respiratory and circulatory centres, cyanosis, hypotension,
convulsions, loss of consciousness, coma


Delayed and chronic effects -- giddiness, anxiety, jitteriness,
restlessness, emotional lability, excessive dreaming, insomnia,
nightmares, headaches, tremor, withdrawal, depression, bursts of slow
waves of elevated voltage on EEG, drowsiness, difficulty
concentrating, slowness of recall, confusion, slurred speech, ataxia


So, what do we take away from all this? Let me summarize by making a
few points. Medical chemical countermeasures designed to increase
protection may be unavailable or ineffective. Nothing is effective
against mustard gas -- one of the oldest chemical weapons. Mustard gas
must be removed within 2 minutes to prevent damage. The drug atropine,
the most commonly-used for treatment of nerve agent exposure,
ameliorates muscarinic effects, but has little effect on nicotinic
effects, such as muscle twitching. And oximes, also used to treat
nerve gas exposure are useful in counteracting nicotinic effects, but
won't function without atropine. And, as I indicated before,
pyridostigmine bromide, protects against SOMAN when given as a
preventive, but is not effective as a treatment by itself and is
ineffective against SARIN, TABUN AND VX.


Long Term Effects on the People of Halabja



It is important to remember the basic tenets of humanitarian efforts
and the internationally recognised purposes of medicine and medical
research which are to maintain health, relieve human suffering and
prevent death from disease. In the case of Halabja, all these seem to
have been overlooked or forgotten and we have so far failed to
understand what has happened to these people or helped them
effectively. By learning to help them, we will in turn help ourselves
better understand and prepare for potential chemical weapons use
against our own populations.


There had been no systematic and detailed research study carried out
in Halabja in the 10 years since the attack. The novel effects such as
those on reproductive function, congenital malformations, long term
neurological and neuropsychiatric effects, (especially on those who
were very young at the time) and cancers in women and children are of
special importance. There is no knowledge about the ways in which the
serious and long term damage caused by these weapons can be treated.
For example, the eye, respiratory and neuropsychiatric problems do not
appear to respond to conventional therapy. It may be necessary to
develop new methods of research and treatment.


And so, I set about to determine the long-term effects of chemical
weapons attack, using the Halabja attack as a case study. It has been
a collaborative research project with the doctors and people of
Halabja and Souleymania. The results of what we found are being
prepared for publication in a leading medical journal. What we have
found is sobering, if not frightening. They must serve as a wake-up
call to all of us about the need for improving our medical
preparedness and national and international response plans to chemical
weapons attack.


The list of the serious long term effects of these weapons is in
itself evidence of the terrible effects these weapons.


1.  Respiratory Problems



2.  Eye problems



3.  Skin problems



4.  Neuropsychiatric problems



5. Cancers -- Head, neck, respiratory tract, skin, gastrointestinal
tract, leukemias and lymphomas (especially in children), and
reproductive (including breast and ovary)


6.  Congenital abnormalities



7.  Infertility



8.  Miscarriages, stillbirths, neonatal and infant deaths.



Many of the people in Halabja have two or more major problems. Thus
someone may be blind as a result of the attack, still have serious
skin burns and have respiratory problems. Their difficulties may
continue too because of the increased risks of cancers of all types
including leukemias and lymphomas, which are very common. The
occurrences of genetic mutations and carcinogenesis in this population
appear comparable with those who were one to two kilometers from
ground zero in Hiroshima and Nagasaki, and show that the chemicals
used in the attack have a general effect on the body similar to that
of ionizing radiation. I have included as an Annex detailed
descriptions of the major medical problems and treatment needs.


Many people have expressed their astonishment that since the people
were bombarded with this awful cocktail of weapons, they do not all
have identical problems. I think there are several reasons for this.
Some people received different doses; some were drenched in liquid
mustard gas and nerve agents, others breathed in vapour; some people
were outside, others were inside; and some were wrapped in clothing or
wet sheets or washed off the chemicals quickly. It's also important to
note that people vary in their ability to detoxify and this is
genetically determined. Finally, the DNA target for the mutagenesis is
the whole of the human genome. Many different genes may be affected;
in the body, conferring risks of cancer or disease; and, in eggs or
sperm, causing congenital abnormalities or lethality in offspring.


A great deal remains unknown. The long term effects such as those on
fertility and congenital malformations are not well characterised. The
most effective ways of treating the long term problems are not known.
For example, should there be attempts to treat the blindness resulting
from the corneal blistering and scarring with corneal transplants or
would the pain be best treated with medicated contact lenses or
special artificial tears. It is important too for research and therapy
to be undertaken in a concerted and thoughtful way with the patients
being fully involved in the research and as partners in devising
effective methods for treatment.


The Need for Enhanced Medical Preparedness to Treat CW Casualties



In order to provide effective defence against chemical and biological
weapons attacks, there is a need for a good comprehensive working
knowledge of the chemical and biological weapons which all the major
military powers have stockpiled. This has to be couple with an
understanding of the principal ways of deploying each of the different
types of weapons and the likely civilian and military targets against
which they might be deployed. The principal methods of defence against
each of these weapons, such as decontamination methods, antidotes and
methods of treating casualties to prevent long term effects are
extremely important. Some practical steps are detailed in Annex 2.


Political skill and diplomacy to prevent the use of these weapons,
either in terrorist attacks, civil wars or in major or minor conflicts
must be the major target. It is obvious from studies of the effects of
these weapons that there are virtually no humane chemical or
biological weapons. These weapons can kill, maim and produce life-long
damage on the populations they are used against and, if mutagenic and
carcinogenic chemicals are deployed, can damage future generations,
long after the immediate effects of the attack have appeared to
recede. We owe future generations a heritage free from threat, pain,
disfigurement and handicap.


That concludes my remarks. I would be happy to answer any questions
you may have.


Annex 1



Examples of the Major Problems the People Face and the Extent of the
Help Needed


Severe respiratory problems



These require assessments of lung function, trials of drugs which may
be of help and consideration of the possibility of lung transplants
for the most severely affected.


Cancers



The cancer risks in this population are high and the people are dying
very young of large, aggressive, rapidly metastasising tumours. There
is a need for improved diagnosis, surgery, pathology and better
imaging (CT, MR, and bone scans. Methods of chemotherapy and
radiotherapy for these chemical weapons induced cancers may be
different from those of other cancers and require knowledge of the
types of mutations which lead to these cancers. There is of course
need for special and excellent palliative and terminal care, pain
control, expert nursing


Congenital malformations



The types and range of congenital malformation are extremely
extensive, although certain major effects can be seen. These include
congenital heart conditions, mental handicap, neural tube defects and
cleft lip and palate. The is a need for paediatric surgeons to repair
heart defects, cleft palate etc, improved diagnosis and imaging and
many other forms of professional help ( eg speech therapy,
occupational therapy and specialist teaching for the handicapped )


Neurological and psychiatric problems



These are amongst the most alarming of the effects of these weapons
and are also the most difficult to quantify scientifically and
diagnose. They are the problems which make the people feel extremely
desperate. Many try to commit suicide and there are many examples of
failed suicides, the surgeons frequently have to remove bullets from
people who have unsuccessfully tried to shoot themselves. Many people
(especially those who are young have memory problems or poor attention
span. Conventional antidepressant drugs may have severe side effects
on those with nerve gas or organophosphage poisoning, so the
development of new therapeutic regimes for those who have been
poisoned by chemical weapons is important. Professional help and
expertise, drugs and support teams need to be developed and advanced
neuroimaging for those with protracted nerve gas damage may help to
identify the problems


Physiotherapy and rehabilitation therapy are particularly important
for those with irreversible neurological damage.


Skin and eye problems



The effects of mustard gas burns may persist for life and cause much
pain and suffering. Professional help and expertise, research into
long term effects of burn Provision of artificial tears, special skin
cream for burns Radical forms of therapy such as corneal grafting for
eye problems and skin grafting for severe skin burns may be the only
real form of effective treatment, but these treatments may also be
extremely painful, difficult and prone to complications such as
infection making careful research into the balances of benefits of
treatment very important.


Annex 2



Practical Guidelines for Civilian Defense Against Chemical Warfare
Agents


Shelter -- Stay indoors. Shut all windows and doors. Move towards
inner spaces, closets, etc. Seal openings with adhesive tapes. If
possible, prepare ahead of time food and drinking water supply in
sealed plastic containers. Cover the containers with plastic bags and
seal tightly.


Protection -- Avoid contact with the chemical agent. Roll down
sleeves. Use impermeable material such as plastic overgarments, gowns,
blankets, etc., to cover exposed skin areas. Protect hands with gloves
or plastic bags. If a protective chemical warfare mask is not
available, use regular towels soaked with sodium bicarbonate (baking
soda) solution (25g for each 1000 ml water). Breathe through the
towel, shifting it from time to time to breathe through wet areas.


Decon -- Remove all droplets of chemical agent from the skin using
clean gauze or cotton wool. Do not rub the skin. For effective skin
decontamination use commercially available tubes containing Fuller's
earth powder. Disperse powder over exposed skin areas. Leave powder
for 1 min and remove gently with a clean gauze or cotton. Do not rub
powder into the skin. If a powder is not available, use water and
regular soap to remove the chemical agent from the skin. Baking soda
solution can also be used for decontamination of skin including the
facial area (avoid eye penetration).


Post Attack -- When the area is declared clean, remove all protective
equipment cautiously. Use rubber gloves to protect your hands while
removing contaminated material or use tweezers or similar devices. Put
all contaminated material in plastic containers. Seal the containers
and label them appropriately. When leaving the house or shelter (after
the area is declared clean), move opposite to wind direction.


Annex 3



Sources and Bibliography



1.  Textbooks of toxicology



Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human
Poisoning. Matthew J Ellenhorn. 2nd Edition 1997 Williams and Wilkins,
Baltimore and London


Principals and Methods of Toxicology, Ed A Wallace Hayes. 3rd Edition,
1994. Raven Press New York


2.  Databases, Electronic Sources and other media.



Medline searches (including NIH medical publications database,



National Environmental Protection Agencies Databases,



US Military Information Sources,



Pesticides databases,



UN



Weapons monitoring agencies (SIPRI)



Instructions Issued to Iraqi military doctors.



Chemical warfare texts



Film archives and photographs of the Halabjan attack



3.  Important references with abstracts



Azizi, F., Keshavarz, A., Roshanzamir, F., and Nafarabadi, M. (1995).
Reproductive function in men following exposure to chemical warfare
with sulphur mustard Med War 11, 34-44. To investigate the acute and
chronic effects in young men of exposure to chemical warfare
containing mustards, the time course of changes in serum
concentrations of total and free testosterone, dehydroepiandrosterone
(DS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and
prolactin was evaluated in 16 men in the first three months and
testicular function in 42 men one to three years after injury. Serum
total and free testosterone and DS were markedly decreased in the
first five weeks after exposure. The lowest values were: total
testosterone 237 +/- 165, free testosterone 22.5 +/- 9.7, DS 39 +/-
25; as compared to controls: total testosterone 773 +/- 245 ng/d1,
free testosterone 35.5 +/- 11.2 pg/ml and DS 207 +/- 37 micrograms/d1.
FSH, LH, prolactin and 17 alpha-OH progesterone were normal in the
first week. The response to GnRH was subnormal in four of five
subjects. LH increased by the third and FSH and prolactin by the fifth
week. All hormone levels had returned to normal by twelfth week after
exposure. In 28 of 42 men seen one to three years following injury,
sperm count was below 30 million cells/ml, and FSH was increased as
compared to men with sperm above 60 million cells/ml. Testicular
biopsy showed complete or relative arrest of spermatogenesis. This
study demonstrates that the exposure to sulphur mustard results in
very low androgen levels and hypo-responsiveness to GnRH in the first
five weeks and normalization by the twelfth week after injury.
However, side effects of mustard on sperm cells persist and may cause
defective spermatogenesis years after exposure


Benschop, H., van, d., Schans,GP, Noort, D., Fidder, A.,
Mars-Groenendijk, R., and de, J., LP (1997). Verification of exposure
to sulfur mustard in two casualties of the Iran-Iraq conflict J Anal
Toxicol 21, 249-51. The exposure of two Iranian victims of the
Iran-Iraq conflict (1980- 1988) to sulfur mustard was established by
immunochemical and mass spectrometric analysis of blood samples taken
22 and 26 days after alleged exposure. One victim suffered from skin
injuries compatible with sulfur mustard intoxication but did not have
lung injuries; the symptoms of the other victim were only vaguely
compatible with sulfur mustard intoxication. Both patients recovered.
Immunochemical analysis was based on detection of the N7-guanine
adduct of the agent in DNA from lymphocytes and granulocytes, whereas
the N-terminal valine adduct in globin was determined by gas
chromatography-mass spectrometry after a modified Edman degradation.
The valine adduct levels correspond with those found in human blood
after in vitro treatment with 0.9 microM sulfur mustard


Betts-Symonds, G. (1994). Major disaster management in chemical
warfare Accid Emerg Nurs 2, 122-9. A disaster is internationally
defined as: 'a catastrophic event which, relative to the manpower and
resources available, overwhelms a healthcare facility and usually
occurs in a short period of time'. War produces such events following
every major engagement, resulting in continuous streams of casualties
with injuries reflecting the type of campaign being fought and weapons
used. Chemical weapons are designed more to injure than to kill, as
has been demonstrated in conflicts that have involved the use of such
weapons where mortality has been 3-5%. However, the use of such
weapons when overlaid on conventional injury cause added medical
problems along with a massive tactical contamination problem. It is
therefore essential that disaster planning and training takes account
of these hazards in areas where such a threat exists, in order to save
the maximum number of lives and prevent secondary casualties among
hospital and rescue staff. The principles outlined in this paper apply
equally well to civilian disasters involving the many hazardous
materials of industry being transported daily on roads, railways and
in the air. This paper will give an overview of the nature of chemical
weapons and of some of the medical/tactical problems when disaster
involves chemical warfare agents


Black, R., Clarke, R., Harrison, J., and Read, R. (1997). Biological
fate of sulphur mustard: identification of valine and histidine
adducts in haemoglobin from casualties of sulphur mustard poisoning
Xenobiotica 27, 499-512. 1. Analytical methods were developed for the
detection of N-terminal valine and histidine adducts in haemoglobin
alkylated with sulphur mustard. 2.
N-(2-hydroxyethylthioethyl)-N-terminal valine was selectively cleaved
from globin with the Edman reagent pentafluorophenyl isothiocyanate.
The resulting thiohydantoin derivative was analysed by high resolution
gc-ms using negative ion chemical ionization. An alternative
procedure, involving acid hydrolysis of globin to its constituent
amino acids and conversion of the adduct to its di-TBDMS derivative,
was less sensitive. 3. N-(2-hydroxyethylthioethyl)histidine was
analysed, after acid hydrolysis of globin, as its
fluorenylmethyloxycarbonyl derivative by 1c-ms-ms using electrospray
ionisation and selected reaction monitoring. 4.
N-(2-hydroxyethylthioethyl)valine and
(2-hydroxyethylthioethyl)histidine were detected in globin isolated
from a rat treated percutaneously with sulphur mustard, and in globin
from five blood samples collected from human casualties of sulphur
mustard poisoning. The adducts are proposed as biological markers of
sulphur mustard poisoning, in addition to urinary metabolites and DNA
adducts


Borak, J., and Sidell, F. (1992). Agents of chemical warfare: sulfur
mustard Ann Emerg Med 21, 303-8. Sulfur mustard is a chemical warfare
agent of historical and current interest. Favored militarily because
of its ability to incapacitate rather than its ability to kill, its
use results in large numbers of casualties requiring prolonged,
intensive care. In light of recent threats of chemical warfare and the
possibilities of chemical acts of terrorism, North American physicians
should be knowledgeable of its effects and the care of its victims


Dacre, J., and Goldman, M. ( 1996). Toxicology and pharmacology of the
chemical warfare agent sulfur mustard Pharmacol Rev 48, 289-326. There
have been reports of chemical attacks in which sulfur mustard might
have been used (a) on Iranian soldiers and civilians during the Gulf
War in 1984 and 1985 and (b) in an Iraqi chemical attack on the
Iranian-occupied village of Halbja in 1988, resulting in many civilian
casualties. Heavy use of chemical warfare in Afghanistan by the Soviet
military is a recent innovation in military tactics that has been
highly successful and may ensure further use of chemical agents in
future military conflicts and terrorist attacks as a profitable
adjunct to conventional military arms. Mustard is a poisonous chemical
agent that exerts a local action on the eyes, skin, and respiratory
tissue, with subsequent systemic action on the nervous, cardiac, and
digestive systems in humans and laboratory animals, causing
lacrimation, malaise, anorexia, salivation, respiratory distress,
vomiting, hyperexcitability, and cardiac distress. Under extreme
circumstances, dependent upon the dose and length of exposure to the
agent, necrosis of the skin and mucous membranes of the respiratory
system, bronchitis, bronchopneumonia, intestinal lesions,
hemoconcentration, leucopenia, convulsions with systemic distress, and
death occur. Severe mustard poisoning in humans is associated with
systemic injury: which is manifested as headache, epigastric
distresses, anorexia, diarrhea, and cachexia and is usually observed
at mustard doses of 1000 mg/min/m3 with damage to hematopoietic
tissues and progressive leucopenia. Sulfur mustard is a cell poison
that causes disruption and impairment of a variety of cellular
activities that are dependent upon a very specific integral
relationship. These cytotoxic effects are manifested in widespread
metabolic disturbances whose variable characteristics are observed in
enzymatic deficiencies, vesicant action, abnormal mitotic activity and
cell division, bone marrow disruption, disturbances in hematopoietic
activity, and systemic poisoning.


Davies, H., Richter, R., Keifer, M., Broomfield, C., Sowalla, J., and
Furlong, C. (1996). The effect of the human serum paraoxonase
polymorphism is reversed with diazoxon, soman and sarin Nat Genet 14,
334-6. Many organophosphorus compounds (OPs) are potent cholinesterase
inhibitors, accounting for their use as insecticides and,
unfortunately, also as nerve agents. Each year there are approximately
3 million pesticide poisonings world-wide resulting in 220,00 deaths.
In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg
of diazinon and 1.23 million kg of ethyl parathion manufactured in the
USA (data supplied by the USEPA). In addition to exposure risks during
pesticide manufacturing, distribution and use, there are risks
associated with the major international effort aimed at destroying the
arsenals of nerve agents, including soman and sarin. The United States
has pledged to destroy approximately 25,000 tons of chemical agents by
the end of the decade. The high density lipoprotein (HDL)-associated
enzyme paraoxonase (PON1) contributes significantly to the
detoxication of several OPs (Fig. 1). The insecticides parathion,
chlorpyrifos and diazinon are bioactivated to potent cholinesterase
inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms
can be hydrolysed by PON1, which also hydrolyses the nerve agents
soman and sarin (Fig. 1). PON1 is polymorphic in human populations and
different individuals also express widely different levels of this
enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly,
while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both
isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at
approximately the same rate. The role of PON1 in OP detoxication is
physiologically significant. Injected PON1 protects against OP
poisoning in rodent model systems and interspecies differences in PON1
activity correlate well with observed median lethal dose (LD50)
values. We report here a simple enzyme analysis that provides a clear
resolution of PON1 genotypes and phenotypes allowing for a reasonable
assessment of an individual's probable susceptibility or resistance to
a given OP, extending earlier studies on this system. We also show
that the effect of the PON1 polymorphism is reversed for the
hydrolysis of diazoxon, soman and especially sarin, thus changing the
view of which PON1 isoform is considered to be protective


Drasch, G., Kretschmer, E., Kauert, G., and von, M., L (1987).
Concentrations of mustard gas (bis(2-chloroethyl)sulfidel in the
tissues of a victim of a vesicant exposure J Forensic Sci 32, 1788-93.
An Iranian soldier died at a toxicological intensive care unit at
Munich seven days after a vesicant exposure. At the autopsy the
typical symptoms of mustard gas intoxication were found. The vesicant
was detected qualitatively by gas chromatographymass spectrometry
(GC-MS) in the abdominal fat and quantified in the tissues and in the
body fluids by the following method: (1) extraction by
dichloromethane, (2) cleanup of the extracts by thin-layer
chromatography (TLC) on silica plates, (3) extractive derivatization
with gold-chloride, and (4) quantitative determination by
electrothermal atomic absorption spectrometry (ET-AAS). The equal
extracts, after heating, served for blanks. The following
concentrations were found (milligrams of mustard gas/kilograms of
tissue wet weight): brain 10.7, cerebrospinal fluid 1.9, liver 2.4,
kidney 5.6; spleen 1.5, lung 0.8, muscle 3.9, fat 15.1, skin 8.4, skin
with subcutaneous fatty tissue 11.8, liquid from a skin blister: below
detection limit, blood 1.1, and urine: below detection limit


Easton, D., Peto, J., and Doll, R. (1988). Cancers of the respiratory
tract in mustard gas workers Br J Ind Med 45, 652-9. In a study of a
cohort of 2498 men and 1032 women employed in the manufacture of
mustard gas in Cheshire during the second world war 3354 (95%)
individuals were successfully traced for mortality to the end of 1984.
Large and highly significant excesses were observed as compared with
national death rates for deaths from cancer of the larynx (11 deaths
observed, 4.04 expected, p = 0.003), pharynx (15 observed, 2.73
expected, p less than 0.001), and all other buccal cavity and upper
respiratory sites combined (lip, tongue, salivary gland, mouth, nose)
(12 observed, 4.29 expected, p = 0.002). For lung cancer, a highly
significant but more moderate excess was observed (200 observed,
138.39 expected, p less than 0.001). Significant excesses were also
observed for deaths from acute and chronic non-malignant respiratory
disease (131 observed, 91.87 expected and 185 observed, 116.31
expected, respectively). The risks for cancers of the pharynx and lung
were significantly related to duration of employment. None of these
results is substantially altered when expected numbers are calculated
from Cheshire urban areas rather than national rates, although the
relative risks for lung cancer and non-malignant respiratory disease
are substantially reduced if rates for Merseyside, the nearest large
conurbation, are used. The results provide strong evidence that
exposure to mustard gas can cause cancers of the upper respiratory
tract and some evidence that it can cause lung cancer and
non-malignant respiratory disease. (ABSTRACT TRUNCATED AT 250 WORDS)


Glasby, G. (1997).Disposal of chemical weapons in the Baltic Sea Sci
Total Environ 206, 267-73. Large quantities of chemical warfare agents
were dumped in the Baltic Sea after World War II (WWII). This included
32,000 t of chemical munitions containing approximately 11,000 t of
chemical warfare agents which were dumped into the Bornholm Basin and
2000 t of chemical munitions containing approximately 1000 t in the
Gotland Basin. Because this material was contained in wooden crates,
it was distributed throughout the Baltic. The long-term environmental
impact of these agents is unknown


Gupta, R., Patterson, G., and Dettbarn, W. (1987). Acute tabun
toxicity; biochemical and histochemical consequences in brain and
skeletal muscles of rat Toxicology 46, 329-41. Male Sprague-Dawley
rats injected s.c. with an acute non-lethal dose (200 micrograms/kg)
of ethyl N,N-dimethylphosphoramidocyanidate (tabun) showed onset of
hypercholinergic activity within 10-15 min. The maximal severity of
toxicity signs was evident within 0.5-1 h and persisted for 6 h.
Except for mild tremors no overt toxicity signs were evident after 24
h. Within 1 h a dramatic decline of acetylcholinesterase (AChE)
activity occurred in all the brain structures (less than 3%) and
skeletal muscles (less than 10% in soleus and hemi-diaphragm; and 32%
in extensor digitorum longus (EDL)). No significant recovery was seen
up to 48-72 h. Within 7 days rats became free of toxicity signs and
AChE activity had recovered to about 40% in brain structures (except
cortex, 14%) and 65-70% in skeletal muscles. Within 1 h the 16 S
molecular form of AChE located at the neuromuscular junction was most
severely inhibited in soleus, followed by hemidiaphragm and least in
the EDL, and had fully recovered in all the muscles when examined
after day 7. Muscle fiber necrosis developed within 1-3 h in soleus
and hemi-diaphragm and after a delay of 24 h in EDL. The highest
number of necrotic lesions in all muscles was seen at 72 h with the
hemi-diaphragm maximally affected and EDL the least. To determine
detoxification of tabun by non-specific binding, the activity of
butyrylcholinesterase (BuChE) and carboxylesterase (CarbE) was
measured. The inhibition and recovery pattern of BuChE activity was
quite similar to that of AChE, except that the rate of recovery was
more rapid. Within 1 h the remaining activity of CarbE was 10% in
plasma, about 30% in brain structures, and 79% in liver; recovery was
complete within 7 days. The inhibition of BuChE and CarbE can serve as
a protective mechanism against tabun toxicity by reducing the amount
available for AChE inhibition. The prolonged AChE inhibition in muscle
and brain may indicate storage of tabun and delayed release from
non-enzymic sites. Since tabun is a cyanophosphorus compound, the
toxic effects from the released cyanide (CN) could be another reason
for the delayed recovery after tabun


Husain, K., Vijayaraghavan, R., Pant, S., Raza, S., and Pandey, K.
(1993). Delayed neurotoxic effect of sarin in mice after repeated
inhalation exposure J Appl Toxicol 13, 143-5. Delayed neurotoxicity of
sarin in mice after repeated inhalation exposure has been studied.
Female mice exposed to atmospheric sarin (5 mg m-3 for 20 min) daily
for 10 days developed muscular weakness of the limbs and slight ataxia
on the 14th day after the start of the exposure. These changes were
accompanied by significant inhibition of neurotoxic esterase (NTE)
activity in the brain, spinal cord and platelets. Histopathology of
the spinal cord of exposed animals showed focal axonal degeneration.
These changes were comparatively less than in animals treated with the
neurotoxic organophosphate, mipafox. Results from this study indicate
that sarin may induce delayed neurotoxic effects in mice following
repeated inhalation exposure


Kadar, T., Shapira, S., Cohen, G., Sahar, R., Alkalay, D., and Raveh,
L. (1995). Sarin-induced neuropathology in rats Hum Exp Toxicol 14,
252-9. Sarin, a highly toxic cholinesterase (ChE) inhibitor,
administered at near 1 LD50 dose causes severe signs of toxic
cholinergic hyperactivity in both the peripheral and central nervous
systems (CNS). The present study evaluated acute and long-term
neuropathology following exposure to a single LD50 dose of sarin and
compared it to lesions caused by equipotent doses of soman described
previously. Rats surviving 1 LD50 dose of sarin (95 micrograms/kg;
IM), were sacrificed at different time intervals post exposure (4 h-90
days) and their brains were taken for histological and morphometric
study. Lesions of varying degrees of severity were found in about 70%
of the animals, mainly in the hippocampus, piriform cortex, and
thalamus. The damage was exacerbated with time and at three months
post exposure, it extended to regions which were not initially
affected. Morphometric analysis revealed a significant decline in the
area of CA1 and CA3 hippocampal cells as well as in the number of CA1
cells. The neuropathological findings, although generally similar to
those described following 1 LD50 soman, differed in some features,
unique to each compound, for example, frontal cortex damage was
specific to soman poisoning. It is concluded that sarin has a potent
acute and long-term central neurotoxicity, which must be considered in
the design of therapeutic regimes


Lee, E. (1997). Pharmacology and toxicology of chemical warfare agents
Ann Acad Med Singapore 26, 104-7. Toxic chemicals have been used as
weapons of war and also as means of terrorist attacks on civilian
populations. The main classes of chemical weapons are: a) nerve
agents, b) vesicant agents and c) blood agents. If an exposure to
nerve agents is anticipated, prophylactic pyridostigmine may be used.
Once exposure has occurred, the management strategy is to reduce
cholinergic activity through the use of atropine as well as to attempt
to regenerate acetylcholinesterase with pralidoxime. Convulsions may
be managed using diazepam. Exposure to vesicant agents may be reduced
through the use of protective gear, but once exposure has occurred, no
specific treatment is available. Treatment remains symptomatic and
supportive. Lethal atmospheric concentrations of hydrogen cyanide gas,
a blood agent, is seldom achieved except in enclosed spaces.
Sub-lethal exposure to hydrogen cyanide may be managed using sodium
nitrite, sodium thiosulphate and VitB12


Ludlum, D., Austin-Ritchie, P., Hagopian, M., Niu, T., and Yu, D.
(1994). Detection of sulfur mustard-induced DNA modifications Chem
Biol Interact 91, 39-49. Sulfur mustard is acutely toxic to the skin,
eyes, and respiratory tract, and is considered carcinogenic to humans
by the IARC. Since all of these toxicities are thought to be initiated
by DNA alkylation, the level of DNA damage should serve as a biomarker
for exposure. To develop methods of detecting this damage, DNA was
modified by (14C)-labeled sulfur mustard and DNA adducts were released
by mild acid hydrolysis. Radioactivity co-eluted on 14PLC analysis
with marker 7-(2- hydroxyethylthioethyl) guanine and
3-(2-hydroxyethylthio-ethyl) adenine synthesized from 2-chloroethyl
2-hydroxy-ethyl sulfide. Unambiguous identification of the major
adduct, 7-(2-hydroxy-ethylthioethyl) guanine, was provided by gas
chromatography combined with mass spectrometric detection. The most
abundant adduct, 7-(2-hydroxyethyl-thioethyl) guanine, accounted for
61% of the total alkylation and could be detected as a fluorescent
HPLC peak with a detection limit of 10 pmol. To demonstrate the
applicability of this method to biological samples, DNA was extracted
from the white blood cells of human blood exposed to 131 microM sulfur
mustard in vitro and shown to contain 470 pmol of
7-(2-hydroxyethylthio-ethyl) guanine per mg of DNA


McDonough, J., Jr, and Shih, T. (1997). Neuropharmacological
mechanisms of nerve agent-induced seizure and neuropathology Neurosci
Biobehav Rev 21, 559-79. This paper proposes a three phase "model" of
the neuropharmacological processes responsible for the seizures and
neuropathology produced by nerve agent intoxication. Initiation and
early expression of the seizures are cholinergic phenomenon;
anticholinergics readily terminate seizures at this stage and no
neuropathology is evident. However, if not checked, a transition phase
occurs during which the neuronal excitation of the seizure per se
perturbs other neurotransmitter systems: excitatory amino acid (EAA)
levels increase reinforcing the seizure activity; control with
anticholinergics becomes less effective; mild neuropathology is
occasionally observed. With prolonged epileptiform activity the
seizure enters a predominantly non-cholinergic phase: it becomes
refractory to some anticholinergics; benzodiazepines and
N-methyl-D-aspartate (NMDA) antagonists remain effective as
anticonvulsants, but require anticholinergic co-administration; mild
neuropathology is evident in multiple brain regions. Excessive influx
of calcium due to repeated seizure-induced depolarization and
prolonged stimulation of NMDA receptors is proposed as the ultimate
cause of neuropathology. The model and data indicate that rapid and
aggressive management of seizures is essential to prevent
neuropathology from nerve agent exposure


Nishimoto, Y., Yamakido, M., Shigenobu, T., Yukutake, M., and
Matsusaka, S. (1986). (Cancer of the respiratory tract observed in
workers having retired from a poison gas factory) Gan To Kagaku Ryoho
13, 1144-8. Okunojima, a small island in the Inland Sea of Japan, off
the shore of Takehara city was notorious for the production of poison
gases from 1927 to 1945. Of the gases produced there, yperite and
lewisite were the most poisonous and caused severe residual damage. It
has been ascertained by studies conducted to date that the retired
workers of this poison gas factory have a high risk of various types
of malignant tumors including cancers of the respiratory tract. Such
cancers observed in the retired workers from the poison gas factory
are characterized by the following clinical features. Cancers are
mainly centraltype tumors with the site of development distributed
from the airway to the hilar region and histologically, squamous and
undifferentiated cell carcinoma predominate. Recently, the occurrence
of malignant tumors has been discussed in relation to suppressed
immune competence. Such disturbance of the immunological surveillance
system seems to induce malignant changes of normal cells. On the other
hand, we have demonstrated that the retired workers often showed
impaired immunity. Therefore we considered that potentiation of
immunity might possibly prevent the occurrence of malignant tumors and
we took steps to enhance the immune competence of the retired workers
with N-CWS. Its effect in preventing carcinogenesis will be shown in
the near future


Ohbu, S., Yamashina, A., Takasu, N., Yamaguchi, T., Murai, T., Nakano,
K., Matsui, Y., Mikami, R., Sakurai, K., and Hinohara, S. (1997).
Sarin poisoning on Tokyo subway South Med J 90, 587-93. On the day of
the disaster, 641 victims were seen at St. Luke's International
Hospital. Among those, five victims arrived with cardiopulmonary or
respiratory arrest with marked miosis and extremely low serum
cholinesterase values; two died and three recovered completely. In
addition to these five critical patients, 106 patients, including four
pregnant women, were hospitalized with symptoms of mild to moderate
exposure. Other victims had only mild symptoms and were released after
6 hours of observation. Major signs and symptoms in victims were
miosis, headache, dyspnea, nausea, ocular pain, blurred vision,
vomiting, coughing, muscle weakness, and agitation. Almost all
patients showed miosis and related symptoms such as headache, blurred
vision, or visual darkness. Although these physical signs and symptoms
disappeared within a few weeks, psychologic problems associated with
posttraurnatic stress disorder persisted longer. Also, secondary
contamination of the house staff occurred, with some sort of physical
abnormality in more than 20% Pour-Jafari, H. (1994). Congenital
malformations in the progenies of Iranian chemical victims Vet Hum
Toxicol 36, 562-3. The incidence of congenital malformations among the
progenies of the Iranian chemical victims were studied. A higher
incidence of abnormalities were found among survivors' offspring of
Iranian gas victims. Parental exposure to chemical weapons may be
associated with an increased risk for some congenital malformations


Sasser, L., Cushing, J., and Dacre, J. (1993). Dominant lethal study
of sulfur mustard in male and female rats J Appl Toxicol 13, 359-68.
Sulfur mustard (HD) (bis(2-chloroethyl)sulfide) is a strong alkylating
agent with known mutagenic and suspected carcinogenic properties, but
occupational health standards have not been established. The purpose
of this study was to determine the dominant lethal effect in male and
female rats dosed orally with HD, for which currently available data
are ambiguous. Sprague-Dawley rats of each sex, 6-7 weeks old, were
orally administered 0, 0.08, 0.20 or 0.50 mg kg-1 HD 5 days a week for
10 weeks, after which dominant lethal studies were conducted during
the post-exposure period. The studies were conducted in two phases: a
female dominant lethal phase in which treated or untreated males were
mated with treated females and their fetuses were evaluated 14 days
after copulation; and a male dominant lethal phase in which treated
males cohabited with untreated females for 5 days and fetuses were
evaluated 14 days after the mid-point of the week of cohabitation, for
each of 10 weeks. In addition, motility, population size and
morphology were measured in sperm obtained from the cauda epididymis.
Parental growth rates were reduced in both sexes treated with the high
level of HD. Female dominant lethal effects were not observed,
although significant male dominant lethal effects were observed in
HD-exposed male rats mated to untreated females at 2 and 3 weeks'
post-exposure. These effects, which included increases of early fetal
resorptions and preimplantation losses and decrease in total live
embryo implants, were most consistently observed at a dose of 0.50 mg
kg-1. A significant P(P < < 0.05) increase in the percentage of abnormal
sperm was detected in males exposed to 0.50 mg kg-1 HD. The timing of
dominant lethal effects is consistent with an effect during the
post-meiotic stages of spermatogenesis, possibly involving the
generally sensitive spermatids


Solberg, Y., Alcalay, M., and Belkin, M. (1997). Ocular injury by
mustard gas Surv Ophthalmol 41, 461-6. Sulfur mustard is a chemical
warfare agent which was widely used during World War I and more
recently in conflicts in the Middle East. This highly toxic compound
causes severe dermal, gastrointestinal, respiratory and ocular
injuries. It acts as an alkylating agent that induces structural
changes and, hence, destruction of nucleic acids and proteins,
impairing the cell's normal homeostasis and eventually causing its
death. Sulfur mustard reacts rapidly with ocular tissues, and after a
latent period of a few hours the patient starts suffering from severe
eye pain, photophobia, excessive lacrimation and blindness. The
injury, which is restricted to the anterior segment of the eye, may
cause long-lasting incapacity in large numbers of casualties.
Approximately 0.5% of the severely wounded victims may develop late
complications which require prolonged ophthalmologic observation and
therapy. In light of the ever-present threat of mustard chemical
warfare against military and civilians, physicians worldwide should be
aware of its grave effects and know how to care for its victims


Somani, S., and Babu, S. (1989).Toxicodynamics of sulfur mustard Int J
Clin Pharmacol Ther Toxicol 27, 419-35. Mustards have become an
important topic of global discussion in recent years. The latest
extensive reports and conference of 145 nations in Paris (January 13,
1989) reveal that several countries have stockpiled large quantities
of mustard gas. This situation creates an imminent danger to
accidental or intentional exposure of this gas to civil populations
throughout the world. In view of the sparse literature on the toxic
nature of mustard gas, we have tried to present an integrated panorama
of this compound and its derivatives. In this article, efforts were
made to review mustard gas -- its chemical nature, mode of action,
methods available for its analysis in biological fluids and target
organs, absorption, distribution, metabolism and excretion and its
toxicity to various organs. The effects of mustard poisoning may be
local, systemic, or both, depending on environmental conditions,
exposed organs, and the extent and duration of exposure. The toxic
effects of mustard include inhibition of mitosis, NAD depletion,
decreased tissue respiration and finally cell death. Most of the toxic
effects are related to alkylation of DNA. Mustards are also selective
in their accumulation in fat tissue. The immediate organs affected
after mustard exposure are skin, eyes, and lungs. Sulfur mustard has
also been reported to be a potent carcinogen. Burns caused by mustard
are severe and require long healing periods. Depending on the type and
time of exposure, mustard renders persons disabled temporarily or
permanently. Various antidotes such as sodium thiosulfate,
dexamethasone, promethazine, heparin, vitamin E and atropine have been
recommended for combating mustard poisoning. Protective clothing can
substantially reduce the toxic effects of mustard exposure. The best
possible way of eliminating mustard hazard is to ban its use
completely


Suzuki, J., Kohno, T., Tsukagosi, M., Furuhata, T., and Yamazaki, K.
(1997). Eighteen cases exposed to sarin in Matsumoto, Japan (see
comments) Intern Med 36, 466-70. Forty-six patients who were exposed
to sarin consulted our hospital because of darkness of vision, and
ocular pain, vomiting, dyspnea and headaches on June 27 and 28, 1994.
Eighteen patients were admitted and 4 of them were in the critical
state. There were 6 features: 1) depression of plasma cholinesterase
activity (17 of 18 patients, 94%), 2) hypokalemia (4/18, 22%), 3)
depression of triglyceride (12/18, 67%), 4) hypocapnia (5/17, 29%), 5)
partial pressure of oxygen (Pa02) <80 mmHg, or requirement of 02
inhalation (15/18, 83%), 6) white blood cells (WBQ >9,000 per mm3
(13/18, 72%). Seventeen patients were discharged from hospital, but
one patient is still suffering from akinetic mutism after two years


Tokuoka, S. (1985). (Early cancer and related changes in the bronchial
epithelium of former mustard gas workers) Gan To Kagaku Ryoho 12,
708-13. The bronchial epithelium taken in stepwise transverse sections
was examined histologically in 66 autopsy cases, composed of groups
consisting of 19 mustard gas (MG) ex-workers with lung cancer, 17 MG
ex-workers with non-lung cancer, 10 nonMG lung cancer cases, and 20
non-MG non-lung cancer cases. An additional 5 surgical lung cancer
specimens removed from MG ex-workers were also examined. From these
groups, foci of moderate or severe atypia including cellular atypia,
dysplasia and carcinoma in situ (CIS), detected in the total number of
slides for each autopsy group, were counted as 146 out of 3,485, 72
out of 2,226, 70 out of 3,797, and 18 out of 4,611, respectively.
Seven CIS lesions were detected from among all MGexposed cases and 1
CIS lesion was found in a non-MG lung cancer case. Six of these
occurred with dysplasia and 4 were associated with early invasion.
Among 62 autopsy cases with known smoking histories, multivariate
analysis revealed a significant correlation between the incidence rate
of atypia and MG exposure only in non-lung cancer cases: the incidence
rate of atypia was also influenced significantly by smoking and age.
Among lung cancer cases, the incidence rate of atypia was
significantly higher (p less than 0.01) in cases of squamous cell
carcinoma than those of small cell carcinoma


Weiss, A., and Weiss, B. (1975). (Carcinogenesis due to mustard gas
exposure in man, important sign for therapy with alkylating agents)
Duch Med Wochenschr 100, 919-23. Sulphur-mustard and nitrogen-mustard
are known to act as carcinogens in animal experiments. A similar
effect in humans was demonstrated in 245 workers previously exposed
occupationally to mustard gas and followed for over 20 years. There
was a statistically significant increase in malignant tumours,
especially bronchial carcinoma, bladder carcinoma and leukaemia. These
findings underline the need for using alkylating agents of the mustard
type exclusively in the treatment of malignant neoplasms.
Immunosuppression with alkylating agents in the treatment of chronic
inflammatory diseases associated with a long life expectancy is no
longer justified


Willems, J., Nicaise, M., and De, B., HC (1984). Delayed neuropathy by
the organophosphorus nerve agents soman and tabun Arch Toxicol 55,
76-7. The organophosphorus nerve agents soman and tabun were tested in
the hen at doses 120-150 times higher than their acute LD50, as it was
assumed that these doses would produce delayed neuropathy. The animals
were protected against the acute lethal effect of these agents by
pretreatment with atropine, physostigmine, diazepam, and the oxime
HI-6 or obidoxime. The surviving animals were followed for 30 days and
the occurrence of delayed neuropathy was clinically diagnosed. Soman
produced severe delayed neuropathy at a dose of 1.5 mg/kg, a dose
which produced acute lethality in five animals out of six. Tabun
elicited very mild neuropathic symptoms in one animal out of two at a
dose of 6 mg/kg given on 2 consecutive days. Delayed neuropathy was
not seen in the hens that survived the acute toxicity of a single dose
of tabun , 12 mg/kg (three out of six) or 15 mg/kg (two out of six)


Yanagida, J., Hozawa, S., Ishioka, S., Maeda, H., Takahashi, K.,
Oyama, T., Takaishi, M., Hakoda, M., Akiyama, M., and Yamakido, M.
(1988).Somatic mutation in peripheral lymphocytes of former workers at
the Okunojima poison gas factory Jpn J Cancer Res 79, 1276-83. The
former workers at the Okunojima poison gas factory comprise a high
risk group for malignant tumors such as respiratory tract cancer.
Demonstration of injury to somatic cell genes in this group may
provide important data for evaluating the association between mustard
gas and malignant tumors. So we measured the frequency of T
lymphocytes lacking the hypoxanthine guanine phosphoribosy1
transferase (HGPRT) activity, by cloning with interleukin 2 (IL2). In
this study, we performed cloning of T lymphocytes lacking the HGPRT
activity using recombinant IL2 (rIL2) and observed an increased
frequency of somatic mutation in poison gas workers who had had more
chances to be exposed to mustard gas and those who had worked for a
longer period. This result suggested that inhalation of small amounts
of mustard gas damaged somatic cell genes, resulting in carcinogenesis




(End text)