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The toxicokinetics of cyanide are based on its physico-chemical properties. As HCN is a relatively weak acid, with a pKa value of 9.11 at 30°C, at the physiological pH of about 7, HCN is distributed in the body as such and is not present as CN ion. Hence, the form of cyanide, to which exposure takes place, i.e. a simple salt or the free acid, does not influence the distribution, metabolism or excretion from the body.

 

Absorption of gaseous HCN is related to the water solubility of HCN and the ease of absorption in the moist respiratory tract. On the basis of experimental observations, the retention of HCN in the nasal passages was reported to be between 13 and 23% (average 19%) and the retention in the lung from mouth breathing between 39 to 77% (average 61%). From this an average retention in the respiratory tract of 50% might be estimated. Probably the majority of the HCN retained in the respiratory tract is absorbed into the blood as it is likely to diffuse readily due to its water solubility, low molecular mass (size) and the fact that it is undissociated at cellular pH.

 

The capacity of the lungs to metabolise HCN is assumed to be low. HCN absorbed in the lungs is distributed to the tissues including the brain, which is extremely sensitive. The free HCN in plasma is distributed to the body tissues. In the body tissues cyanide binds intracellularly to cytochrome oxidase, inactivating the enzyme and resulting in termination of cellular respiration.

 

HCN is not equally distributed through the body. In Beagle bitches HCN had an apparent distribution volume of 0.209 l/kgbw. A complete analysis of the body distribution in humans (3 fatally poisoned persons) showed that 50% of the absorbed cyanide was present in the blood, about 25% in the muscles and the remaining 25% in all the organs together. The apparent distribution volume was 0.075 l/kgbw. 

 

Cyanides are metabolised via various pathways. The following pathways have been reported:

 

1. Trans-sulphuration via the enzymes rhodanese or 3-mercaptopyruvate sulphotransferase, in which cyanide receives an atom of sulphur from thiosulphate and is converted into the less toxic thiocyanate (major pathway);

2. Reaction with hydroxocobalamin into cyanocobalamin (vitamin B12);

3. Oxidation to cyanate and carbon dioxide;

4. Hydrolysis into formate;

5. Reaction with cysteine into 2-imino-4-thiazolidine carboxylic acid.

 

Thiocyanate, cobalamin, formates and 2-imino-4-thiazolidine carboxylic acid are excreted via the urine. HCN and CO2 are exhaled.

 

The main pathway of transformation of cyanide into thiocyanate is catalysed by the enzyme rhodanese, a mitochondrial enzyme that occurs in many tissues. The other enzyme capable of converting CN ion to thiocyanate has been identified as 3-mercaptopyruvate sulphotransferase in liver and erythrocytes of different species. 

 

The detoxifying enzyme rhodanese is not only found in the liver but also in muscles and other tissues. Rhodanese in muscles contributes considerably to the detoxification of cyanide in the body to thiocyanate. In the absence of sulphur donating agents in the human body, the maximum detoxification rate was up to 3.0 μg CN ion/kgbw/min (80 min mean infusion duration), based on the dose rate at which no clinical symptoms occurred. Inter-individual variation in serum rhodanese activity can vary by a factor of 3 to 8. However, rhodanese is present in all body tissues in considerable excess and not rate-limiting. No major polymorphisms have been identified to date. Protein deficient populations are more susceptible to cyanide intoxication as thioamino acid levels are reduced.

Discussion on absorption rate:

Cyanide is readily absorbed through the skin from aqueous solutions, as well as from gaseous sources. The permeation of cyanide from aqueous solutions of cyanide through human skin has not been specifically quantified from dermal toxicity studies; effects of cyanide absorption are rapid and severe. Time to onset of clinical symptoms in acute dermal toxicity studies is 15 - 60 minutes, and to onset of death 15 minutes to 4 hours. Absorption in vitro was strongly influenced by the pH of the solution. HCN appeared to permeate 30 times faster than CN ion. At a pH of 9.11 (= pKa) about 50% is present as undissociated HCN. The ratio of HCN and CN ion at a certain pH follows from the Henderson-Hasselbach equation.

 

Dermal absorption from airborne HCN must take into account the concentration in the air at the skin surface, transfer from the air layer to water layer on the skin, and transfer from the water layer into the skin. Using an overall permeation coefficient (Kp skin-air-air) for HCN is 6.25 cm/h, it has been calculated that the ratio of absorption by skin compared to lung for HCN is 0.18 or 18%.