CW agents are frequently called war gases and a war where CW agents are used is usually called a gas war. These incorrect terms are a result of history. During the First World War chlorine and phosgene which are gases at room temperature and normal atmospheric pressure were used. The CW agents used today are only exceptionally gases. Normally they are liquids or solids.
However, a certain amount of the substance is always in volatile form (the amount depending on how rapidly the substance evaporates) and the gas concentration may become poisonous. Both solid substances and liquids can also be dispersed in the air in atomized form, so-called aerosols. An aerosol can penetrate the body through the respiratory organs.
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Some CW agents can also penetrate the skin. Solid substances penetrate the skin slowly unless they happen to be mixed with a suitable solvent.
Classification of War Gases:
CW agents can be classified in many different ways. There are, for example, volatile substances, which mainly contaminate the air, or persistent substances, which are involatile and therefore mainly cover surfaces.
CW agents mainly used against people may also be divided into lethal and incapacitating categories. A substance is classified as incapacitating if less than 1/100 of the lethal dose causes incapacitation, e.g., through nausea or visual problems. The limit between lethal and incapacitating substances is not absolute but refers to a statistical average.
In comparison, it may be mentioned that the ratio for the nerve agents between the incapacitating and lethal dose is approximately 1/10. Chemical warfare agents can also be classified according to their effect on the organism.
In order to achieve good ground coverage when dispersed from a high altitude with persistent CW agents the dispersed droplets must be sufficiently large to ensure that they fall within the target area and do not get transported elsewhere by the wind. This can be achieved by dissolving polymers (e.g. polystyrene or rubber products) in the CW agent to make the product highly-viscous or thickened.
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Although it may appear that a CW agent can be “custom-made” for a certain purpose, this is not the case. Instead, there is always some uncertainty about the persistence time, the dispersal and the effect.
Toxicities of mustard gas, nerve agents, lewisite, phosgene and hydrogen cyanide are discussed below:
Example # 1. Mustard Gas:
Mustard gas is a chemical warfare agent belonging to the blister agent/vesicant class. It is a cytotoxic alkylating compound similar to the other type of vesicants or blister agents such as nitrogen mustard, lewisite, and phosgene oxide. Mustard causes blistering of the skin and mucous membranes.
Actually, mustard gas is not a gas, but a dense, yellow to brown oily liquid with a low vapor pressure and relatively high melting point. Mustard can also be released in the air as a vapor and thus exposure of skin, eyes, and respiratory tract can be to vapor or liquid. If sulfur mustard is released into water supplies, exposure can occur from drinking contaminated water or getting it on the skin. Although it currently has no medical use, it was available for use as a treatment for psoriasis. Mustard may smell like garlic, onions, mustard, or have no odor.
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Toxicokinetics:
Mustard gas is lipophilic and will accumulate in brain and fatty tissue. Mustard gas is soluble in water to less than 0.1% and hydrolyzes in water with a half-life of 3-5 min. It is freely soluble in organic solvents. It has been detected in the blood after dermal or inhalation exposure. Although mustard dis-solves slowly in aqueous solution, it must first dissolve in sweat or extracellular fluid to be absorbed.
Following dissolution, mustard molecules rapidly rearrange to form extremely reactive cyclic ethylene sulfonium ions that immediately bind to intracellular and extracellular enzymes, proteins, and other cellular components. Mustard binds irreversibly to tissues within several minutes after contact. If decontamination is not done immediately after exposure, injury cannot be prevented. However, later decontamination might prevent a more severe lesion.
The biological half-life of the chemical has not been published, but products are excreted in the urine for several days after acute exposure. Traces of the agent are exhaled and excreted in the feces. Several hours can pass before symptoms become manifest but this is attributed to the mechanism of action and not to direct effects of residual levels of the agent. Mustard gas is a greater threat in hot and humid climates.
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Mechanism of Toxicity:
Although the exact mechanism by which mustard produces tissue injury is not known, the mechanism of action has been suggested to be its ability to directly alkylate DNA. This DNA alkylation and cross-linking in rapidly dividing cells such as basal keratinocytes, mucosal epithelium, and bone marrow precursor cells leads to cellular death and inflammatory reactions. Systemic effects with extensive exposures include bone marrow inhibition, with a drop in the white blood cell count, and gastrointestinal tract damage.
Human Toxicity:
Mustard gas is a powerful irritant and vesicant. Dermal effects range from itching to erythema, blistering, corrosion, and necrosis. Dermal blistering is delayed in onset and slow to heal. Ocular irritation, conjunctivitis, and blindness can occur. Respiratory symptoms include a harsh and painful cough, bronchitis, sneezing, rhinorrhea, and sore throat.
Mustard gas is not acutely lethal; 2-3% of soldiers exposed to mustard gas during World War I died of its direct effects. Death is generally due to respiratory collapse, shock, and secondary infections. Survivors may be susceptible to bronchitis and pneumonia, and may be at an increased risk to develop tumors of the respiratory tract. Mustard gas produces tumors in animal studies.
The International Agency for Research on Cancer has classified sulfur mustard as carcinogenic to humans (Group I). Epidemiological evidence indicates that repeated exposures to sulfur mustard may lead to cancers of the upper airways.
There is limited evidence that repeated exposures to sulfur mustards may cause defective spermatogenesis years after exposure. Sulfur mustard has been implicated as a potential developmental toxicant because of its similarity to nitrogen mustard; however, data are inconclusive.
Chronic Toxicity:
Production workers exposed to mustard gas had increased rates of bronchitis and pneumonia. Increased incidence of tumors of the respiratory tract, lung cancer, bladder cancer, and leukemia were also found. Mustard gas is classified as a human carcmogen.
Clinical Management:
It is important that the agent be washed from the skin with soap and water as soon after exposure as possible. The eyes should be thoroughly flushed. The onset of symptoms typically is delayed and an absence of immediate effect does not rule out toxicity. Although ingestion is unlikely, due to the sources of mustard gas, an emetic should not be administered because of the extreme caustic nature of the chemical.
If the patient is not comatose, dilution of stomach contents with milk or water, prior to gastric lavage, may be attempted. Application of a solution of sodium thiosulfate to the skin and inhalation of a nebulizing mist of sodium thiosulfate may speed inactivation of mustard gas. Animal studies have shown that administration of corticosteroids (e.g., dexamethasone) and antihistamines (e.g., promethazine) may prove beneficial.
Animal Toxicity:
The irritant, vesicant, and respiratory effects of mustard gas are the same in animals and humans, although the hair coat and lack of extensive sweat glands may somewhat protect the animal from the dermal effects of the agent.
Example # 2. Nerve Agents:
Casualties are caused primarily by inhalation; however, they can occur following percutaneous and ocular exposure, as well as by ingestion and injection.
Toxicokinetics:
Nerve agents are absorbed both through the skin and via respiration. Because VX is an oily, nonvolatile liquid it is well absorbed through the skin (persistent nerve agent), although it can also be absorbed by inhalation.
Thus, VX is more of a percutaneous threat than by inhalation, whereas the G agents (nonpersistent), which are also liquids, pose more of an inhalation hazard because of their vapor pressure. Sarin (GB) is the most volatile, but evaporates less readily than water, while cyclosarin (GF) is the least volatile of the G agents.
Nerve agents are hydrolyzed by the enzyme organophosphate (OP) hydrolase. The hydrolysis of GB, soman (GD), tabun (GA), and diisopropyl fluorophosphate occurs at approximately the same rate. The isomers of the asymmetric OPs may differ in overall toxicity, rate of aging, rate of cholinesterase inhibition, and rate of detoxification. The rates of detoxification differ for different animal species and routes of administration.
The onset of effects from nerve agents depends on the route, duration, and amount of exposure. The effects can occur within seconds to several minutes after exposure. There is no latent period following inhalation exposure of high concentrations where loss of consciousness seizures has occurred within 1 min. At low concentrations; however, miosis, rhinorrhea, and other effects may not begin for several minutes. Maximal effects usually occur within minutes after contamination ceases.
Mechanism of Toxicity:
The nerve agents inhibit the enzymes butrylcholi-nesterase in the plasma, acetylcholinesterase on the red blood cell, and acetylcholinesterase at cholinergic receptor sites in tissues. These three enzymes are not identical. Even the two acetylcholinesterases have slightly different properties, although they have a high affinity for acetylcholine.
The blood enzymes reflect tissue enzyme activity. Following acute nerve agent exposure, the red blood cell enzyme activity most closely reflects tissue enzyme activity. However, during recovery, the plasma enzyme activity more closely parallels tissue enzyme activity.
Following nerve agent exposure, inhibition of the tissue enzyme blocks its ability to hydrolyze the neurotransmitter acetylcholine at the cholinergic receptor sites. Thus, acetylcholine accumulates and continues to stimulate the affected organ. The clinical effects of nerve agent exposure are caused by excess acetylcholine.
The binding of nerve agent to the enzyme is considered irreversible unless removed by therapy. The accumulation of acetylcholine in the peripheral and central nervous systems (eNS) leads to depression of the respiratory center in the brain, followed by peripheral neuromuscular blockade causing respiratory depression and death.
The pharmacologic and toxicologic effects of the nerve agents are dependent on their stability, rates of absorption by the various routes of exposure, distribution, ability to cross the blood-brain barrier, rate of reaction and selectivity with the enzyme at specific foci, and behavior at the active site on the enzyme.
Red blood cell enzyme activity returns at the rate of red blood cell turnover, which is ~ 1 % per day. Tissue and plasma activities return with synthesis of new enzymes. The rates of return of these enzymes are not identical. However, the nerve agent can be removed from the enzymes.
This removal is called reactivation, which can be accomplished therapeutically by the use of oximes prior to aging. Aging is the biochemical process by which the agent-enzyme complex becomes refractory to oxime reactivation. The toxicity of nerve agents may include direct action on nicotine acetylcholine receptors (skeletal muscle and ganglia) as well as on muscarinic acetyl-choline receptors and the central nervous system.
These include the effects of nerve agents on y-amino-butyric acid neurons and cyclic nucleotides. In addition, changes in brain neurotransmitters, such as dopamine, serotonin, noradrenaline, as well as acetyl-choline, following inhibition of brain cholinesterase activity, have been reported.
These changes may be due in part to a compensatory mechanism in response to overstimulation of the cholinergic system or could result from direct action of nerve agent on the enzymes responsible for non-cholinergic neurotransmission.
Human Toxicity:
Rhinorrhea may precede miosis as the first indication of exposure to even small amounts of nerve agent vapor. After exposure to high concentrations/doses by any route, rhinorrhea occurs as part of the generalized increase in secretions. Direct ocular contact to nerve agents may cause miosis, conjunctival injection, pain in or around the eyes, and dim or blurred vision.
Acute exposure of 3 mg min m-3 of GB vapor will produce miosis in most of the exposed population. Other routes of exposure may not cause any eye effects or cause a delayed onset of them, but will cause vomiting, sweating, and weakness.
The onset of miosis is within seconds to minutes following aerosol or vapor exposure but may not be maximal for up to 1 h, especially at low concentrations. The duration of miosis varies and is dependent on the extent of exposure. The ability of the pupil to dilate maximally in darkness may not return for up to 6 weeks. There is no correlation between miosis and blood cholinesterase levels.
Respiratory distress also occurs within seconds to minutes following vapor exposure. The symptoms include tightness of the chest, shortness of breath, and gasping and irregular breathing leading to apnea. Bronchoconstriction and bronchial secretions contribute to this. With larger concentrations, cyanosis and audible pulmonary changes occur, which can only be relieved by therapeutic intervention.
Death due to nerve agent intoxication is attributable to respiratory failure resulting from bronchoconstriction, bronchosecretion, paralysis of skeletal muscles, including those responsible for respiration, and failure of the central drive for respiration. Nerve agent intoxication causes skeletal muscles to fasciculate, twitch, and fatigue prior to paralysis.
The cardiovascular effects of nerve agent exposure are variable. Bradycardia may occur via vagal stimulation, but other factors such as fright, hypoxia, and adrenergic stimulation, secondary to ganglionic stimulation may produce tachycardia or hypertension. Following inhalation exposure to large amounts of nerve agent, the CNS effects will cause loss of consciousness, seizure activity, and apnea within 1 min.
Following skin contact with large amounts of liquid, the dermal effects may be delayed up to 30 min. Long-term exposure to an OP, diisopropyl phosphorofluoridate, used in the treatment of myasthenia gravis, caused side effects including nightmares, con-fusion, and hallucinations.
Animal Toxicity:
Small doses of nerve agents can produce tolerance. The cause of death is attributed to anoxia resulting from a combination of central respiratory paralysis, severe bronchoconstriction, and weakness or paralysis of the accessory muscles for respiration.
Signs of nerve agent toxicity vary in rapidity of onset and severity. These are dependent on the specific agent, route of exposure, and dose or concentration. At the higher doses or concentrations, convulsions, apnea, and neuropathies are indications of CNS toxicity. Following nerve agent exposure, animals exhibit hypothermia resulting from the cholinergic activation of the hypothalamic thermoregulatory center.
In addition, plasma levels of pituitary, gonadal, thyroid, and adrenal hormones are increased during OP intoxication. The nerve agents are anticholinesterases and as such inhibit the cholinesterase enzymes in the tissues resulting in the accumulation of acetylcholine at its various sites of action in both the autonomic nervous system and the CNS.
These include the endings of the parasympathetic nerves to the smooth muscles of the iris, ciliary body, bronchial tree, gastrointestinal tract, bladder, blood vessels, the secretory glands of the respiratory tract, the cardiac muscles, and the endings of sympathetic nerves to the sweat glands.
Accumulation of acetylcholine at these sites results in characteristic muscarinic signs and symptoms, while the accumulation at the endings of the motor nerves to voluntary muscles and in the autonomic ganglia results in nicotinic signs and symptoms. The accumulation of acetylcholine in the brain and spinal cord results in the characteristic CNS signs and symptoms.
Nerve agents inhibit the activity of acetyl cholinesterase by attaching to its active sites so that it cannot hydrolyze the neurotransmitter acetylcholine into choline, acetic acid, and regenerated enzyme. Thus, acetylcholine cannot attach to the enzyme, is not hydrolyzed, and continues to produce action potentials until the mechanism is fatigued. The biological effects of the nerve agents result from the excess of acetylcholine.
Although there is a lack of information on the general toxicological effects of low- level, and sublethal repeated exposures, there are studies on the behavioral effects of such exposures to nerve agents in animals free of observed signs of intoxication. These were conducted in an effort to determine whether behavioral studies can provide markers of early neurotoxicity that are more sensitive than neurochemical and neuropathological changes.
Clinical Management:
Following exposure the victim should be removed from the area to avoid further contamination and decontaminated (water/hypochlorite) by adequately protected (protective clothing and gas mask) and trained attendants. Contaminated clothing should be removed carefully so as to avoid further contamination. Respiration should be maintained and drug and supportive therapy instituted. If exposure is anticipated, pretreatment with carbamates (pyridostigmine bromide) may protect the cholinesterase enzymes before GD and possibly GA exposures, but not for GB and VX exposures.
The three types of therapeutic drugs to be administered following nerve agent exposure are:
(1) A cholinergic blocker, anticholinergic or cholinolytic drug such as atropine;
(2) A re-activator drug to reactivate the inhibited enzyme, such as the oxime pralidoxime chloride; and
(3) An anticonvulsant drug such as diazepam or benzodiazepine. Oxygen may be indicated in respiratory failure.
Example # 3. Lewisite:
Lewisite was synthesized in 1918 by Dr. Wilford Lee Lewis as a vesicant for chemical warfare. Its production was too late to use in World War 1. It can be used with mustard to lower the freezing point of the mixture for ground dispersal and spraying.
Other organic arsenical chemical warfare agents are methyldichlorarsine (MD), phenyldichloroarsine (PD), and ethyldichloroarsine (ED). These plus lewisite (L), mustard agents and phosgene oxime make up the vesicant chemical warfare agents.
Exposure Routes and Pathways:
Lewisite is an oily, colorless liquid that can appear amber to black in its impure form. It has the odor of geraniums. It is more volatile than the mustard agents. Lewisite in the air can cause damage to the eyes, skin, and airways by direct contact. Lewisite in water can lead to exposures from drinking water or from skin contact, and lewisite- contaminated food can be ingested. Lewisite remains as a liquid under a wide range of environmental conditions, from below freezing to very hot temperatures.
Toxicokinetics:
Although the exact mechanism of biological activity is unknown, the trivalent arsenic in lewisite combines with the thiol groups in many enzymes.
Mechanism of Toxicity:
Lewisite is readily absorbed from the skin, eyes, and respiratory tract, as well as after ingestion and through wounds. It causes blistering on the skin and mucous membranes on contact. After absorption, it causes an increase in capillary permeability, which produces hypovolemia, shock, and organ damage. Unlike the mustard agents, lewisite vapor or liquid causes immediate pain or irritation although lesions require up to 12 h to become full-blown cases.
Human Toxicity:
Nasal irritation by lewisite begins at ∼ 8 mg min m-3 and its odor is detected at ∼ 20 mg min m-3. Vesication and death from lewisite inhalation is caused at the same concentration as mustard, which is 1500 mg min m-3. The immediately dangerous to life health (IDLH) value of lewisite is 0.003 mg m-3. Lewisite causes vesication at ∼ 14 mg and the LD50 is 2.8 g on the skin.
Within 5 min after contact with liquid lewisite, a grayish area of dead epithelium is produced. Erythema and blister formation follows more rapidly that it does with mustard even though the full-blown lesion does not develop for 12-18 h. The lesion has more tissue necrosis and tissue sloughing than does a mustard agent lesion.
On the eyes, lewisite causes pain, tearing, and blepharospasm on contact. Edema of the conjunctiva and lids follows and the eyes may be swollen shut within an hour. Iritis and corneal damage may also occur. Within minutes, liquid lewisite causes severe eye damage on contact. Upon inhalation, the airway mucosa is the primary target and the damage progresses down the airways with pseudo-membrane formation.
Pulmonary edema may complicate exposure to lewisite. Runny nose, sneezing, hoarseness, bloody nose, sinus pain, shortness of breath, and cough also occur on inhalation. Lewisite causes an increase in permeability of systemic capillaries resulting in intravascular fluid loss, hypovolemia, shock, and organ congestion. This has been termed ‘Lewisite shock’ or hypotension. This also leads to hepatitis or renal necrosis with more prominent gastrointestinal effects of diarrhea, nausea, and vomiting.
The long-term effects of lewisite exposure do not include extensive skin burning as is seen with the mustard agents, but chronic respiratory disease may occur. Also, unlike the mustard agents, suppression of the immune systems does not occur, but extensive eye exposure may cause permanent blindness.
Clinical Management:
To prevent or lessen lewisite damage, early decontamination within minutes after exposure must be instituted. Unlike mustard, lewisite does not cause damage to the hematopoietic organs, but fluid loss from increased capillary permeability necessitates careful attention to fluid balance.
British anti lewisite (BAL) or dimercaprol was developed as an antidote for lewisite. It is used in medicine as a chelating agent for heavy metals. Although BAL can cause toxicity itself, evidence suggests that BAL in oil administered intramuscularly will reduce the systemic effects of lewisite. BAL skin and ophthalmic ointment decrease the severity of skin and eye lesions when applied immediately after early decontamination, but neither of these ointments is currently manufactured.
Example # 4. Phosgene Oxime:
Phosgene oxime was originally developed as a chemical warfare agent. It is sometimes grouped with the vesicant agents, but it is not a true vesicant in that it does not induce blisters. Phosgene oxime is an urticant or nettle agent that causes corrosive- type injuries. There is no evidence that this agent has ever been used as a chemical warfare agent.
Exposure Routes and Pathways:
Phosgene oxime is a colorless solid or yellowish-brown liquid that can vaporize at room temperature. Due to its ability to rapidly change physical state, phosgene oxime can be absorbed through inhalation, dermal/ocular contact, or oral ingestion.
Toxicokinetics:
Phosgene oxime appears to act directly and there have been no reported studies that have determined if any metabolism of phosgene in vivo.
Mechanism of Toxicity:
The molecular mechanism of phosgene oxime toxicity is unknown.
Acute and Short-Term Toxicity:
Most studies on the action of phosgene oxime have utilized animal studies. Human information has been obtained from accidental exposure to the chemical. Health effects following phosgene oxime exposure are dependent on the route of exposure.
Since phosgene oxime is an urticant/nettle agent, common physical effects include erythema, wheals, and urticaria. Phosgene oxime is a highly corrosive agent and the response resembles wounds caused by strong acids. Ocular contact results in severe pain, conjunctivitis, and keratitis.
Direct dermal exposure to phosgene oxime causes immediate pain and blanching with an erythematous ring. In – 0.5 h a wheal will form followed by tissue necrosis. Extreme pain can persist for days. Absorption of phosgene oxime through the skin can result in pulmonary edema. Inhalation of phosgene oxime vapor will produce immediate irritation to the airways.
Pulmonary edema, necrotizing bronchiolitis, and pulmonary thrombosis can also occur following inhalation or systemic absorption of phosgene oxime. There has been no human data on effects of phosgene oxime following ingestion, but animal studies suggest that hemorrhagic inflammatory lesions may occur throughout the gastrointestinal tract.
Chronic Toxicity:
There have been no studies on chronic exposure to phosgene oxime. Thus, there is no data regarding the carcinogenicity or teratogenicity of phosgene oxime.
Clinical Management:
Individuals who come in contact with phosgene oxime liquid or solid can contaminate those around them by release of vapor. Individuals who have been exposed to the vapor will not be able to contaminate others. Patients who come in contact with phosgene oxime will experience immediate pain and develop necrotic lesions. Since there is no antidote for phosgene oxime exposure, only supportive measures can be given.
Patients arriving to the triage area must first be decontaminated to prevent cross- contamination. For inhalation exposures, the individual should be removed from the source of exposure. Oxygen must be administered to patients with significant respiratory symptoms. Artificial respiration should be given if necessary. For ocular treatment, eyes should be flushed with copious amounts of water.
Topical antibiotics should be applied to reduce the risk of infections and adhesions. Topical anticholinergic should be applied to reduce the risk of future synechiae formation. Skin contact will require decontamination with large amounts of water. Treatment should be in the same fashion as with a chemical burn. If phosgene oxime has been ingested, emesis should not be induced. Parental analgesics such as morphine or meperidine may be administered to reduce pain.
Environmental Fate:
Phosgene oxime does not accumulate in the soil. Small amounts that may be present can vaporize into the air or be degraded by soil bacteria. Once in vapor form, phosgene oxime remains in vapor form and will be inactivated by compounds in the atmosphere or broken down by bacteria. There is no evidence that phosgene oxime will accumulate in ground-water.
Example # 5. Cyanide:
Cyanide compounds are widely used in industry. Sodium cyanide and potassium cyanide are used extensively in the extraction of gold and silver from low-grade ores. The cyanide ion can form a wide range of complex ions with metals. These complex metal cyanide ions are extensively used in electroplating.
Cyanide compounds are also used in case-hardening of iron and steel, metal polishing, photography, and the fumigation of ships and ware-houses. Organic cyanide compounds are used in synthetic rubber, plastics, and synthetic fibers; they are also used in chemical synthesis. Cyanides are used in rodenticide and fertilizer production.
In addition, cyanides can be found in the seeds of the apple, peach, plum, apricot, cherry, and almond in the form of amygdalin, a cyanogenic glycoside. Amygdalin (Laetrile) has been used as an antineoplastic drug, but such beneficial effects have not been scientifically proven.
Background Information:
Cyanide poisoning causes a high incidence of severe symptomatology and fatality. Between 1926 and 1947, death rates from cyanide poisoning in America ranged between 79 and 416 per 10 million population and gradually declined thereafter. The availability of the antidote kit may have contributed to this decreasing death rate.
There are numerous sources of potential cyanide exposure. With the increased use of plastic building materials, the potential hazards of cyanide poisoning as a component of smoke inhalation in closed space fires still exist.
Exposure Routes and Pathways:
Humans may be exposed to cyanide in a number of different forms. These include solids, liquids, and gases. Sources include industrial chemicals, natural products, medications, and combustion products.
Inhalation of toxic fumes and ingestion of cyanide salts, cyanide-containing fruit seeds, and cyanide waste-contaminated drinking water are the most common exposure pathways. The respiratory route represents a potentially rapidly fatal type of expo-sure. Exposure to cyanides may also occur via the dermal route in industrial workers.
Toxicokinetics:
Cyanide is rapidly absorbed from the skin and all mucosal surfaces; it is most dangerous when inhaled because toxic amounts are absorbed with great rapidity through the bronchial mucosa and alveoli. Once absorbed, distribution of cyanide through the body is rapid. Within a few minutes, cyanide is distributed through the body and its conversion to thiocyanate starts.
The majority of cyanide in the body is protein-bound (60%). In sublethal doses, cyanide reacts with sulfane sulfur to form nontoxic thiocyanate through an enzymatic reaction involving rhodanase and mercaptopyruvate sulfur transferase. Within 3h, 90% of the dose of cyanide is converted to thiocyanate appearing in blood.
Cyanide is also trapped as cyano of vitamin B12, oxidized to formate and carbon dioxide, and incorporated into cysteine. In nonfatal cases, metabolized cyanide (thiocyanate) is excreted in the urine. Although cyanide is volatile, excretion through the lungs is not a significant route of elimination of cyanide.
Mechanism of Toxicity:
Cyanide is described as a cellular toxin because it inhibits aerobic metabolism. It reversibly binds with ferric (Fe3+) iron-containing cytochrome oxidase and inhibits the last step of mitochondrial oxidative phosphorylation.
This inhibition halts carbohydrate metabolism from citric acid cycle, and intracellular concentrations of adenosine triphosphate are rapidly depleted. When absorbed in high enough doses, respiratory arrest quickly ensues, which is probably caused by respiratory muscle failure. Cardiac arrest and death inevitably follow.
For this reason, cyanide action has been described as ‘internal asphyxia’. Although some cyanide com-bines with hemoglobin to form a stable non oxygen-bearing compound, cyanhemoglobin, this substance is formed only slowly and in a small amount. Therefore, death is not due to cyanhemoglobin but to inhibition of tissue cell respiration.
Recent studies have shown that cyanide also inhibits the antioxidant defense enzymes (such as catalase, superoxide dismutase, and glutathione peroxidase) and stimulates neurotransmitter release. These effects of cyanide may also contribute to its acute toxicity. The prolonged energy deficit and the consequent loss of ionic homeostasis, which may result in activation of calcium signaling cascade and eventually cell injury, contribute to cyanide toxicity resulting from subacute exposure or in the post-intoxication sequela.
Acute and Short-Term Toxicity:
Animal:
Cyanide toxicity varies with the animal species, type of cyanide compound, route of uptake, metabolic state, and other factors. The LDS0 for cyanide has been ported in various species. Potassium cyanide, if injected, has a 24 h LDS0 of 6.7-7.9 mg kg I in mice. The lethal dose of potassium cyanide infused at a rate 0.1 mgkg I min I is 2.4mgkg- I in dogs breathing room air. When hydrogen cyanide is inhaled by mice.
The LD50 is 177 ppm with a lethal time of 29 min. The time to death is greater than 17 min for exposure to less than 266 ppm, but falls to 40 s at 873 ppm. The LD50 for sodium cyanide is 4.6-15mgkg I in rats.
Male gerbils are 50-fold more sensitive to methacrylonitrile, which is metabolized to cyanide in rodents, than Sprague-Dawley rats, and about fivefold more sensitive than albino Swiss mice. Single and repeated low- dose cyanide intoxication can result in demyelinating lesions of the cerebral white matter in monkeys, but high doses of cyanide are required to produce similar brain lesions in rat.
Human:
Cyanide is a chemical asphyxiant, which renders the body incapable of utilizing an adequate supply of oxygen. Exposure to high dose of cyanide is often lethal. The lethal dose of cyanide in humans is 0.5-1.0 mg kg-1. The lethal dose of hydrocyanic acid is ∼ 50 mg for an adult and the lethal dose of the potassium or sodium salt is 200-500 mg. The threshold limit value (TLV) of HCN for inhalation is 4.7 ppm.
This is defined as the maximum safe average exposure limit for a 15 min period by the Occupational Safety and Health Administration. Exposure to 20 ppm of HC in air causes slight warning symptoms after several hours; 50 ppm causes disturbances within an hour; 100 ppm is dangerous for exposures of 30-60 min; and 300 ppm can be rapidly fatal unless prompt, effective first aid is administered. The median lethal dose for skin contamination is ∼ 100 mg kg-1.
Following the inhalation of toxic amounts of cyanide, symptoms usually appear within a few seconds, whereas it may take a few minutes for symptoms to appear following oral ingestion or skin contamination by the salts. The symptoms include a flushed skin, tachypnea, and tachycardia. Stupor, coma, and seizure immediately precede respiratory arrest and cardiovascular collapse. Death shortly occurs.
If large amounts have been absorbed, collapse is usually instantaneous-the patient falling unconscious and dying almost immediately. With smaller doses, weakness, giddiness, headache, nausea, vomiting, and palpitation usually occur. With the rise of the blood cyanide level, ataxia develops and is followed by lactic acidosis, convulsive seizures, coma, and death. At higher cyanide doses, cardiac irregularities are often noted, but heart activity always outlasts the respiration.
Chronic Toxicity:
Animal:
Ingestion of cyanogenic plants, such as cassava and sorghum, has been associated with development of goiter and tropical pancreatic diabetes in both human and animals. However, results from animal studies indicate this association in animals is controversial. Chronic cyanide exposure has been reported to reduce memory along with reduction in the levels of dopamine and 5-hydroxytryptamine in the rat brain.
Human:
Chronic low-level exposure to cyanide produces various signs and symptoms. Exposure to small amounts of cyanide compounds over long-term periods of time is reported to cause loss of appetite, headache, weakness, nausea, dizziness, and symptoms of irritation of the upper respiratory tract and eyes. The most widespread pathologic condition attributed to cyanide is tropical ataxic neuropathy associated with chronic cassava consumption.
This is a diffuse degenerative neurological disease with peripheral and central signs. Cassava is the major staple food in various tropical areas; the plant has a high content of cyanogenic glycoside (linamarin). With continued ingestion over a period of time, tropical neuropathy gradually develops. The syndrome is characterized by optic atrophy, nerve deafness, and ataxia due to sensory spinal nerve involvement.
Other signs include scrotal dermatitis, stomatitis, and glossitis. Chronic low-level exposure to cyanide may also lead to ultra-structural changes of heart muscle. In addition, with chronic cyanide ingestion, the thyroid may be affected due to enhanced formation of thiocyanate. Thiocyanate can block uptake of iodide by the thyroid gland, and myxedema, thyroid goiter, and cretinism may occur. This chronic effect of cyanide may pass to the fetus through maternal exposure.
Clinical Management:
To be of any value, treatment of cyanide poisoning must be rapid and efficient. The rapid and early recognition of cyanide poisoning is usually difficult because most of the clinical manifestations are non-specific. Potentially valuable cyanide blood levels are usually available for confirmation of diagnosis. Arterialization of venous blood has been used as a significant symptom of cyanide poisoning.
If cyanide was ingested, removing the unabsorbed poison by ravaging the stomach with copious amounts of water through a gastric tube is necessary. This should be comminuted until all odor of cyanide is gone from the lavage fluid. Artificial respiration with 100% oxygen is often used in the treatment of cyanide poisoning, although oxygen is not a specific antidote.
It is theorized that oxygen therapy increases the rate of displacement of cyanide from cytochrome oxidase, and the increased intracellular oxygen tension non-enzymatically converts the reduced cytochrome to the oxidized species, enabling the electron trans-port system to function again. The nitrite-thiosulfate antidotal combination is still one of the most effective treatments of cyanide poisoning.
If the victim is conscious and speaking, no treatment is necessary. If the victim is unconscious but breathing, an open ampoule of amyl nitrite can be placed under the victim’s nose for 15 s and it can be repeated 5 to 6 times. A fresh ampoule should be used every 3 min until the victim regains consciousness. Amyl nitrite is a powerful cardiac stimulant and should not be used more than necessary.
If the patient is not breathing, 0.3 g (10 ml of a 3% solution, adults) of sodium nitrite should be administered intravenously at the rate of 2.5 ml min – I followed by 12.5 g (50 ml of a 25% solution) of sodium thiosulfate at the same rate. Inhalation of amyl nitrite should also be performed. Nitrite will convert hemoglobin to methemoglobin, which has higher affinity for cyanide than hemoglobin.
A methemoglobin level of ∼ 25% is desired for maintaining normal hemoglobin function and detoxification. Thiosulfate is a sulfur donor for converting cyanide to nontoxic thiocyanate. For children weighing less than 25 kg, sodium nitrite should be dosed on the basis of their hemoglobin level and weight. The patient should be observed for the next 24-48 h and if the signs of intoxication persist or reappear, injection of nitrite thiosulfate at one-half of the recommended dose should be repeated.
Hydro-xocobalamine has been effectively used in France as an antidote for acute cyanide poisoning. Hydro-xocobalamine (vitamin B12a) is currently approved by Food and Drug Administration, but is not popularly used in the United States as an antidote for cyanide poisoning. Because of its extremely low adverse effect, hydroxocobalamine is ideal for out of-hospital use in suspected cyanide intoxication. It is actively proposed to be used in the United States.
Ecotoxicology:
The toxicity of cyanide in the aquatic environment or natural waters is a result of free cyanide, that is, as HCN and C -. Fish are extremely sensitive to cyanide. Most fish can tolerate a free cyanide stream concentration of 0.05 mg 1-, but some species are even more sensitive.
Exposure Standards and Guidelines:
a. Occupational Safety and Health Administration permissible exposure limit- time-weighted average (TWA) 5mg (CN) m-3.
b. American Conference of Governmental Industrial Hygienists TLV- CL 5 mg m-3 (skin)
c. DFG MAK- 5mgm-3.
d. National Institute of Occupational Safety and Health recommended exposure limit (cyanide) TWA CL 5mgm-3 per 10 min.