Sources of Exposure

Toxicology refers to the science of poisons. The history of toxicology dates back to the time of cave dwellers. They recognized poisonous animals and plants extracts for warfare and hunting. This branch of science overlaps with chemistry, biology, medicine and nursing. It analyses the relationship between a chemical dose and its adverse effects on a particular organism. Any substance that exhibits immediate adverse effects is termed as a toxin. These toxins can be systemic (affecting the entire body) or organ specific. These toxins can be chemical agents (cyanide), physical agents (radiations) and biological agents (snake venom). Hydrogen cyanide is a potentially deadly and fast acting chemical that prevents oxygen utilization in the body cells. Hydrogen cyanide exists in the form of a colourless gas. Its most toxic effect is the inhibition of enzymes, which contain metals. This report aims to illustrate the different sources of cyanide exposure, the adverse health effects, toxico-kinetics and toxico-dynamics of HCN poisoning.

Hydrogen cyanide mainly affects cellular metabolism. It inhibits aerobic metabolism by acting on cytochrome oxidase. The enzyme is a terminal component of the respiratory chain. Hydrogen cyanide is readily absorbed by the human body through the lungs, Mucous Membrane And Skin.  Exposure of any body part to HCN results in acute intoxication. Occupational exposures occur due to inhalation, skin absorption or oral routes.

Inhalation- Following inhalation, HCN gets rapidly and readily absorbed by the lungs. The symptoms of cyanide poisoning begin a few seconds after the exposure and can cause death in the affected person within a few minutes. Dust particles that contain cyanide components if inhaled produce toxicity in the body. HCN acts as a lung irritant and creates localized damage in the lungs. This damage manifests in the form of dryness, pulmonary congestion and burning sensation in the throat. 0.3mg/l inhalation of HCN is considered lethal. After 10 minutes of exposure to the deadly gas, a dose of 0.2mg/l (181 ppm) is considered as a lethal dose (1). Children generally receive larger doses of the toxic gas when compared to adults who are exposed to the same levels of HCN due to the larger lung surface area and body weight ratio.

Oral routes- Ingestion of solutions that contain cyanide salts or hydrogen cyanide are fatal. These solutions get rapidly absorbed form the alimentary canal when compared to cyanide salts. Higher salt doses produce severe intoxication. Lower doses delay death by an hour or more owing to their exhibition of symptoms at a slower rate. These solutions are strong and corrosive in nature. They lead to inflammation and ulcer formation in the stomach.

Dermal routes- Hydrogen cyanide may be absorbed across uninjured skin primarily and lead to systemic toxicity within the human body. With an increase in pH of the solution containing cyanide, the rate of absorption across the skin increases. This occurs due to the presence of unionized HCN at low pH levels. It can lead to breathing abnormalities like Cheyne Stokes respiration, plasma extravasations and peripheral vasoconstriction (2). The person can also enter a state of coma if parts of skin get immersed in cisterns that contain potassium or copper cyanide solutions.

Health Effects From Exposure

Ocular- Cyanides can also get absorbed through the conjunctiva present in the eyes, in addition to dermal routes.

Some of the most common health effects are:

• Severe hydrogen cyanide poisoning can lead to leads to abnormalities in the heartbeat. The heartbeat may get lowered, blood pressure reduces and the person can even die.
• A victim exposed to systemic cyanide poisoning often reports of breathlessness and tightening of the chest muscles. Pulmonary findings show an increase in respiration depth and rapid breathing. As the effect of poison increases, the respirations become slow and the person gasps for breath. The person may develop a blue color in the skin and on the finger nails. Fluids may get accumulated in the lungs.
• The person may feel dizziness, nausea, anxiety, vomiting, weakness and headache. With progress in poisoning, a person may also develop hallucinations, convulsions, lockjaw, and tetanus spasm and can lose consciousness or enter a state of coma.
• Exposure to liquid hydrogen cyanide leads to skin irritation and skin burns (6).
• Severe poisoning leads to metabolic acidosis and increases the level of lactic acids in the blood.
• Irritation and swelling in eyes are observed.
• Deficiency of oxygen causes brain damage and neurologic sequelae like memory deficit, personality changes and voluntary muscle disturbances.
• Workers who are suffering from chronic HCN exposure report headache, fatigue, eye irritation, discomfort in chest, loss of appetite, palpitation and nose-bleeds.

Maintenance of occupational hygiene practice is essential to prevent the incidence of several diseases among workers. Exposure standards represent the concentrations of airborne chemicals in the breathing zone of workers that can cause undue discomfort or adverse health effects.  The principal aim of these standards is to formulate specific targets that will help to reduce the risk of these adverse health conditions. The exposure standards are given effect under all jurisdictions and are therefore legally enforced. These regulations ensure that a business or workplace must not exceed the minimum standard limits of exposure (5). The ALARP principle is followed while maintaining hygiene standards, which state that though occupational risks cannot be completely avoided, they should be reduced to tolerable levels. It helps to assess the symptoms, potential health effects, toxicity levels and decision formulation regarding the implementation of control measures (3). The stages involved in these standards are described below: 

Elimination	The use is eliminated at all possible workplaces.
Substitution	It is substituted with relatively less hazardous chemicals.
Isolation	Cyanides are removed from incompatible items like oxidizing agents or acids and are enclosed in containers that will prevent exposure (7).
Engineering controls	Local exhaust, particulate air filters or scrubbers are installed to minimize exposure to cyanide fumes.
Administrative controls	Adequate training on safe handling and storage is provided to workers.
Ppe	Rubber boots, impervious gloves, face shields and aprons are provided tom workers (10).
Storage	Cyanides are stored in locked cupboards in fire resistant areas.
Disposal	Non-reusable containers are rinsed in water and disposed in accordance to environmental regulations.

The TLV (threshold limit value) of a particular chemical is the level to which a worker can get exposed for many days in a workplace without manifestation of any adverse effects like irritation, tissue damage and narcosis. The term was coined by the   ACGIH (American Conference of Governmental Industrial Hygienists). The time weighted average (TWA) is generally considered for a workday of 8 hours, for 5 days per week. The short term exposure limits (STEL) are bound to remain within the TWA levels. The levels can exceed TWA by 3 times only for a maximum time period of 30 minutes in a workday. Rates of exposure 5 times beyond the permissible limits are not allowed. Section 59 (10) of the Factories Act cites some permissible exposure levels for toxic substances. PEL refers to the maximum TWA concentration of a hazardous substance to which a person can get exposed (15). Long term PEL considers 8 hour working day for 40 hours per week as the permissible limit. On the other hand, for short term PEL, 15 minutes during a workday are regarded as the exposure level.  Short term PEL for hydrogen cyanide are 4.7 ppm and 5 mg/m³. Accoridng to the Safe Work Australia standards, HCN exposure limits are 10 peak for TWA/ppm and 11 peak for TWA/mg/m³.

Following inhalation, dermal exposure or entry through oral routes, hydrogen cyanide gets rapidly absorbed by the cells. Cyanide exists in an equilibrium state as undissociated HCN and as an anion. Hydrogen cyanide exists in ionised form at the physiological pH of 7.4 owing to its pKa value of 9.21.  The distribution of cyanide ions is limited across biological membranes. On the other hand, non-ionised hydrogen cyanide is readily able to cross the membranes.  On crossing the membrane, it gets distributed through the body cells rapidly. The highest concentration of cyanide is found in the liver upon oral administration. Maximum concentration of cyanide is found in the brain and the heart irrespective of any routes of exposure (12). These two organs are most affected by the toxic levels. Whole blood levels with minimum lethality have been found to be near the range of 250-300 µg/dl. The major pathway for hydrogen cyanide metabolism is the by the process of detoxification that occurs on the liver in the presence of 2 mitochondrial sulfur transferase enzyme: thiosulfate cyanide sulfurtransferase (rhodanese) and β-mercaptopyruvate cyanide  sulfurtransferase (4). These enzymes catalyse the transfer of sulfane sulfur present in thiosulphate to cyanide ions that forms thiocyanate. Rhodanese is the primary pathway that is responsible for 80% detoxification of cyanide. The concentration of this enzyme is highest in the liver. Sulfur donor availability acts as the limiting factor in detoxification by this pathway during events of acute cyanide intoxication. Cyanide metabolism slows down when the reserves of sulfur donor ions get depleted. Thus, it can be stated that sodium thiosulphate accelerate the inactivation of cyanideby acting as an antidote (16).

Standards and Codes of Practice

Exhalation from the lungs (1-2%) ids one route of cyanide elimination forms the body. There are several minor pathways that help in its elimination (<15%). These pathways involve conversion of cyanide to 2-aminothiazoline-4-carboxylicn acid, formation of cyanocobalamine by combining cyanide with hydroxycobalamine and incorporating into 1-C metabolic pool (14). Cyanide metabolites are also eliminated in the form of thiocyanate by urination. Urine thiocyanate levels are used as markers for cyanide poisoning.

HCN shows high affinity for sulfur compounds like sulfanes that contain 2 covalently bonded sulfur atoms that carry unequal charge. It also shows affinity for cobalt and ferric ions containing metallic compounds. Cyanide forms a combination with ferric ions in cytochrome oxidase, located in the mitochondria and prevents electron transport system in the cytoplasm. This stops oxidative phosphorylation and ATP synthesis. Due to prevention of oxidative metabolism mechanism, an increased demand is created on anerobic glycolysis, which leads to lactic acid accumulation in the muscles and produces severe disbalance in the composition of acids and base (11). HCN leads to activation of voltage sensitive and receptor operated calcium channels, inhibition of antioxidants enzymes like catalase and superoxide dismutase and reactive oxygen species generation. It also leads to failure in utilization of oxygen and causes histotoxic anoxia. There occurs a shift to anaerobic respiration that elevates plasma lactate concentrations. An initial increase in cardiac output is observed that is soon followed by a decrease. This leads to a fall in blood pressure and causes vasodilation. It also creates visual disturbances by impairing the capacity to focus on an object and mydriasis (dilation of the pupil). Stimulation of the chemoreceptors that are situated near aortic bifurcation leads to respiratory problems and the person gaps for breath (13). This is followed by hyperventilation. Cyanide poisoning leads to an increase in enkephalin release, that manifests in the form of reduced awareness, convulsions and loss of consciousness. Cyanide also affects the cardiac cells and produces negative inotropy and arrthymia. MRI and PET scans reveal lesions in the cerebellum, globus pallidus and substantia nigra following acute cyanide poisoning. It also reduces metabolism of glucose in the cerebrum. Chronic exposure has been associated with tobacco amblyopia, neuropathy and Leber’s hereditary optic atrophy.

Conclusion

Thus, it can be concluded that toxicology is the branch of science that studies the harmful effects of chemical or biological compounds on the living body. Hydrogen cyanide is a deadly poison that acts rapidly on the cells and inhibits the enzyme cytochrome oxidase. The possible routes of exposure include inhalation of smoke, workplaces like metal polishing industries and exposure to insecticides and liquid cyanide solutions. Several laws have been formulated by the governments to regulate the permissible exposure limits in order to prevent impairment of cellular respiration. Thus, it can be concluded that the probable sources of exposure should be identified and legislations should be imposed to prevent cyanide contamination among people. 

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