By Dr. Mohd. Isa Abdul Majid
The Sun, March 22, 1997
A NERVE GAS ATTACK IN A JAPANESE subway station by the followers of Shoko Asahara represents the lethal action of a chemical warfare agent. The compound, sarin, chemically known as isopropyl-methylphosphonofluoridate, is a volatile liquid.
When absorbed into the human body, it will react irreversibly with the enzymes responsible for inactivating neurotransmitters involved in the transmission of nerve impulses, leading to their being accumulated in the body.
This in turn will lead to the overdischarge of the nerve signals along the nervous system to create a condition known as cholinergic overdrive. On exposure to these compounds, death would result almost instantaneously. As an example, 12 people died and more than 5,000 were injured in the Japanese subway incident.
Other chemicals in the same group as sarin include tabun (ethylphosphoro-dimethylamido-cyanidate), soman (plnacolyl methylphospphonerfluoridate) and VX (ethyl S-2diisopropyl aminoethyl methylphosphorothioate). The characteristics and relative toxicity of these compounds are as follows:
- Tabun
Dark amber liquid, no odour in pure state, emits rotting fruits odour as it oxidises, mean lethal dose is 14 mcg/kg. - Sarin
Colourless liquid, no odour in pure state, evaporates at the same rate as water, mean lethal dose is 0.01 mg/kg. - Soman
Colourless liquid, emits rotting fruit odour as it oxidises, impurities may impart a camphor-like odour, mean lethal dose is 1500 mg/kg. - VX
Pale amber liquid, colourless vapour, odorless, mean lethal dose is 1500 mg/kg.
In addition to these compounds, which are normally used as chemical warfare agents, there are less harmful compounds of the same group which are used to kill insects. Although their permanent disability effect on the enzymes take a longer time to occur, the poisoning symptoms observed with the insecticides resemble those of nerve gases. The compounds widely used in the agricultural sector are known as the organophosphates and the lesser active form, the carbamates.
Both organophosphates and carbamates are classified as insecticides, used to eradicate insects and undesirable pests.
Organophosphates are esters, amides or thiol derivatives of phosphoric, phosphonic, phosphorothionic or phosphonothioc acids. They can be classified into two groups: aryl phosphate which must be activated by liver microsomal enzymes before becoming toxic and alkyl phosphates which do not require activation for toxicity.
Most organophosphates are polar, water-soluble chemicals but a few lipophilic compounds exist and are thus formulated in petroleum distillate vehicles. On the other hand, carbamates are mainly esters of carmabic acid and therefore commonly formulated in petroleum distillates.
Exposed subjects to both compounds who are not treated usually die within 24 hours. Death occurs as a result of respiratory muscular weakness, central nervous system depression and excessive bronchial secretions.
In addition, organophosphates and carbamates usually contain solvents such as petroleum distillates which may be listed as inert ingredients but which can produce toxic effects in any accidental ingestion. When such poisonings occur, there may be persistent effects to the central and peripheral nervous systems lasting from several weeks to months. The effects include peripheral neuropathies, memory impairment, personality changes, depression, confusion and thought disorders.
Mechanism of toxicity
Organophosphates are rapidly absorbed by inhalation, ingestion and through the skin. The absorbed chemical as well as the active metabolite formed then binds to the cholinesterase enzymes found in the red blood cell and plasma The binding to these enzymes will lead to their inactivation and hence render them incapable of degrading an important neurotransmitter, acetycholine.
The excessive acetylcholine then accumulates at nerve junctions in the skeletal muscle system and in the autonomic and central nervous systems. With time, this inactivation becomes progressively irreversible after 24 to 36 hours.
However, the toxic effects of carbamates are typically short-lived. Spontaneous hydrolysis of the carbamylated cholinestrase enzyme will regenerate the enzyme again and normal activity resumes within 24 hours.
Signs and symptoms of poisoning
In carbamate poisoning, the signs and symptoms are transient in nature and the chemicals classified under this group do not penetrate the central nervous system. Thus central nervous system toxicity is limited for the carbamates. With respect to all other chemical manifestations, there is a little difference between organophosphates and carbamates. In organophosphate and carbamate poisoning, the signs and symptoms may be classified into three groups.
Stimulation of receptors in the bronchus, gastrointestinal system, sweat and lacrimal systems, heart, pupil, ciliary body and bladder may occur. The major symptoms can be best remembered by DUMBELS (defaecation, urination, miosis, bradycardia, bronchospasm, emesis, lacrimation, salivation).
Stimulation of a second set of receptors which control the muscle and a specific area in the brain may also take place.
Major symptoms include muscle weakness and fasciculation, increase in the secretion of a gland found in the kidney, increase in heart rate, cramps and hypertension.
In addition, the central nervous system can be affected too, resulting in restlessness, anxiety, lethargy, confusion, coma, seizures and depression of the respiratory and cardiovascular centres.
Management and treatment
If a confined space has been contaminated with nervous system altering agents, emergency personnel should wear protective clothing to prevent absorption of these compounds. The protective assembly includes protective mask and hood, charcoal-impregnated suits and butyl rubber gloves and boots.
For decontamination of these agents from any surfaces, caustic soda or bleaches are recommended to break down these compounds. In cases of any exposure, the emergency rescue or medical team should also be well protected to prevent absorption. Pre-treatment with a drug called pyridostigmine, a reversible cholinestrase inhibitor, every eight hours provides protection by preventing the attachment of the nerve gas agent to the receptor sites.
It there is any absorption of the nerve agents or the organophosphate into the body, the symptoms of poisoning usually occur. In the presence of symptoms, atropine is given to block the receptors on the nerve endings from the continual increase of acetylcholine which tends to cause the excessive discharge of electrical impulse along the body's nervous system.
Besides atropine, an antidote, pralidoxime mesylate (2-PAM) is given. This will specifically regenerate the cholinesterase and thus allow the enzyme to break down the circulating acetylcholine. it should be given in cases of nerve gas poisoning provided there is no irreversible binding between the chemical warfare agent to the acetylcholinesterase. The irreversible binding of the chemical warfare agent to the enzyme is also known as ageing. If ageing has occurred, 2-PAM will be ineffective in reversing the effects of nerve gas or the insecticide toxicity.
In inhalation exposure, the patient should be brought to a place that is well ventilated with fresh air and any respiratory distress should be monitored by medical personnel. In dermal exposure, the contaminated clothing should be removed from the patient. The skin should also be decontaminated by washing with copious amounts of tap water and soap. Emergency care personnel should wear gloves and avoid contamination.
In eye exposure, decontamination can be carried out by irrigating the exposed eye with copious amounts of tepid water for at least 15 minutes. It irritation, pain, swelling, lacrimation or photophobia persist, the patient should be referred to a healthcare facility.
As a conclusion, extreme precaution should be instituted to prevent any untoward incident when using insecticides from this group. In addition, proper storage and personal protection when dealing with these chemicals are equally important if we want to prevent any poisoning.
The writer is a pharmacist and head of the Toxicology Laboratory at the National Poison Centre, Universiti Sains Malaysia, Penang.
