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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 22nd 1998 at 2:30 pm
216 Hart Senate Building


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.

Chemical Weapons, Their Effects, and Treatment for Exposure to Them Table 1

After lethal or near lethal exposures to nerve agents, the time to onset of symptoms and to maximal severity of symptoms is shorter; it may be extremely brief after overwhelming exposure. Following exposure to lethal concentrations, the time interval to death depends upon the degree, the route of exposure, and the agent. If untreated, exposure to lethal concentrations of nerve agent can result in death 5 minutes after appearance of symptoms.

Adapted from Army FM8-285, Navy NAVMED P-5041, Air Force AFM 160-11 Field Manual. The Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries, Washington, DC: Departments of the Army, The Navy, and the Air Force, February 28, 1990.

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 Neededp>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.

Decontaminate

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 commmercially 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.


a Adapted from Shalit 1. In: Reis ND, Doley E, eds. Manual of disaster medicine. Civilian and military. Berlin: Spinger-Verlag, 1989; p. 1:4.



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 photogrpahs 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/dl, free testosterone 35.5 +/- 11.2 pg/ml and DS 207 +/- 37 micrograms/dl. 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 lc-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)sulfide] 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 chromatography-mass 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 hemi-diaphragm 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 HPLC 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 central-type 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 posttraumatic 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 (PaO2)<80 mmhg, or requirement of o2 inhalation (15/hite blood cells (wbc)>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 non-MG 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 MG-exposed 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] Dtsch 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 phosphoribosyl 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