Ammonia toxicity

When ammonia enters the body, it is converted to urea and excreted by the kidneys. The capacity for detoxification via urea is sufficient to eliminate the ammonium ion when ammonia is inhaled in non-irritating concentrations. Repeated inhalation can cause a higher tolerance because the mucous membranes become increasingly resistant. Ammonia is not considered to be carcinogenic nor is it mutagenic. The effects of different ammonia concentrations are summarized in Table 8.374. 

250 to 500 Difficulty in Breathing and Eye Irritation Rapid Heart Beating 

700 Comeal Opacities Immediate Onset of Burning Sensation in the Eyes 

Within the liver, elimination of ammonia occurs via urea synthesis (Chapter 17). Since urea is uncharged, it does not disturb the acid-base balance. Many interorgan relationships in protein and nitrogen homeostasis arose because of the role that the liver plays in excess nitrogen excretion. 

For birds, insects, and reptiles, which have an egg stage during development, so that water availability is severely restricted, the synthesis of a highly soluble excretory product would have serious osmotic consequences therefore most of the ammonia is converted to the virtually insoluble uric acid (urate). This product can be safely retained in the egg or excreted as a slurry of fine crystals by the adult. In birds that nest colonially this can accumulate in massive amounts on islands off the coast of Peru cormorants have deposited so much that this guano (hence the name guanine) is collected for use as a fertiliser. Uric acid is less effective as an excretory product, since it has a lower nitrogen content than urea (33%) and is more expensive to synthesise (2.25 molecules ATP per atom of nitrogen). Mammals do produce uric acid but as a product of purine catabolism (see above). 

The low solubility of uric acid has unfortunate consequences since at higher than normal concentrations it can crystallise in the body. For example, when the urine is unusually acid, calcium urate stones can form in the kidney and bladder. High levels of uric acid in the blood can result in the formation of urate crystals in the joints, which causes a very painful condition, since it results in inflammation in these joints. Gout is unlikely to develop if the urate concentration remains low ( 0.4 mmol/L) but any factor that increases the rate of production or decreases that of elimination by the 

The presence of sodium urate in the amorphous deposits in a jug found in 1903, but dating back to the Middle Ages, suggests that it was used to store urine, from which the urate precipitated as the urine evaporated. But why was urine stored in a jug in the Middle Ages Perhaps because drinking urine was highly recommended at this time for treatment of bubonic plague and other diseases Lancet, July 11, 1942). 

A marked increase in the plasma concentration of urate has been linked to a neurological disorder. Lesch-nyhan syndrome which is characterise by mental retardation and a compulsive form of self-mutilation (Chapter 20). 

The toxicity of ammonia was dramatically demonstrated by experiments carried out as early as 1931 injection of the enzyme urease, which catalyses the conversion of urea to ammonia, into rabbits rapidly caused their death. The normal concentration of ammonia in blood is about 0.02 mmol/L toxicity becomes apparent at a concentration of abont 0.2 mmol/L or above (see Table 10.1). Ammonia toxicity in very young children is usually associated with vomiting and eventually coma. It is almost invariably due to the deficiency of an enzyme of the urea cycle (see below). In adults, ammonia accnmulation, and hence toxicity, usually results from damage to the liver caused by poisons, alcohol or viral infection. 

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The third potentially most hazardous kind of projects is trunk pipelines. There are trunk pipelines in Ukraine that are tens, hundreds, and even thousands of kilometers long, through which hundreds of thousand and million cubic meters of oil, gas condensate, gas, ammonia, toxic chemical waste, mineral ore-dressing waste, including radio-active one, are pumped over long distances. 

TThe catabolic production of ammonia poses a serious biochemical problem, because ammonia is very toxic. The molecular basis for this toxicity is not entirely understood. The terminal stages of ammonia intoxication in humans are characterized by onset of a comatose state accompanied by cerebral edema (an increase in the brain s water content) and increased cranial pressure, so research and speculation on ammonia toxicity have focused on this tissue. Speculation centers on a potential depletion of ATP in brain cells. 

Detection of hidden toxicants (those that do not express their toxicity because of the presence of a second toxicant) can be one of the most difficult aspects of TIE testing and can be difficult to identify when ammonia is the main toxicant (U.S. EPA, 1993b). Ammonia toxicity is attributable to the free or un-ionized (NH3, N) form as opposed to the ionized (NHfy, N) species (Thurston et al., 1981). The relative concentration of un-ionized ammonia increases proportionately with pH and water temperature. Although toxicity due to ammonia can be observed in a variety of effluents, it is commonly observed in effluent associated with metal mining and municipal discharges (Novak et al., 2002 U.S. EPA, 1999). Because of its ability to mask the presence of other toxicants, it may be more effective to address toxicity due to ammonia before proceeding with a full Phase I TIE. The approach would include the use of multiple species with differing sensitivities to ammonia (e.g., fish... 

Burgess, R.M., Pelletier, M.C., Ho, K.T., Serbst, J.R., Ryba, S.A., Kuhn, A., Perron, M.M., Raczelowski, P. and Cantwell, M.G. (2003) Removal of ammonia toxicity in marine sediment TIEs a comparison of Ulva lactuca, zeolite and aeration methods, Marine Pollution Bulletin 46, 607-618. 

D5. Du Ruisseau, J. P., Greenstein, J. P., Winitz, M., and Birnbaum, S., Free amino acid levels in the tissues of rats protected against ammonia toxicity. Arch. Biochem. Biophys. 68, 161 (1957). 

The fine roots of plants are killed by the urea treatment, presumably due to ammonia toxicity, but recover vigorously and abundantly during the LP (Sagara 1975). This recovery of roots is accompanied by colonization of the hyphae of LP fungi and by formation of ectomycorrhizas if the associated plants are ectomycorrhizal (Sagara 1995). 

Adverse effects Toxicities include a range of hypersensitivity reactions (since it is a foreign protein), a decrease in clotting factors, and liver abnormalities, as well as pancreatitis, seizures, and coma due to ammonia toxicity. 

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase, which catalyzes the reaction in which ammonia is condensed with 2-oxoglutarate to form glutamate (Sec. 15.1). Small amounts of ammonia are produced from important amine metabolites such as epinephrine, norepinephrine, and histamine via amine oxidase reactions. It is also produced in the degradation of purines and pyrimidines (Sec. 15.6) and in the small intestine from the hydrolysis of glutamine. The concentration of ammonia is regulated within narrow limits the upper limit of normal in the blood in humans is 70/tmol L-1. It is toxic to most cells at quite low concentrations hence there are specific chemical mechanisms for its removal. The reasons for ammonia toxicity are still not understood. The activity of the urea cycle in the liver maintains the concentration of ammonia in peripheral blood at 20/ molL. ... 

Persons who suffer from hepatic or renal insufficiency can become susceptible to ammonia toxicity. Toxicity from ammonia in these cases, however, results from endogenously produced ammonia. The limited systemic absorption of ammonia following inhalation exposure would be insignificant when compared with concentrations produced within the body (WHO 1986). Persons with hyperactive airway disease or other conditions that alter airway function (colds, cough, nasal congestion) are expected to be more susceptible to irritant effects of ammonia. 

Warren, K.S., and S.Schenker. 1964. Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J. Lab. Clin. Med. 64(3) 442-449. 

Greenstein, J.R, Winitz, M., GnUino, P, Birnbanm, S.M., Otey, MC. Studies on the metabolism of amino acids and related compounds in vivo. III. Prevention of ammonia toxicity by arginine and related compounds. Arch. Biochem. 1956 64 342—354... 

Zieve, L., Lyftogt, C., Raphael, D. Ammonia toxicity comparative protective effect of various arginine and ornithine derivatives, aspartate, benzoate, and carbamyl glutamate. Metab. Brain Dis. 1986 1 25-35... 

The dose of ammonium chloride can be calculated on the basis of the chloride deficit using the same method as for HCl, using the conversion of 20 g ammonium chloride providing 374 mEq of H . However, only half of the calculated dose of ammonium chloride should be administered so as to avoid ammonia toxicity. Ammonium chloride is available as a 26.75% solution containing 100 mEq in 20 mL, which should be further diluted prior to administration. A dilute solution may be prepared by adding 100 mEq of ammonium chloride to 500 mL of normal saline and infusing the solution at a rate of no more than 1 mEq/min. Improvement in metabolic stams is usually seen within 24 hours. CNS toxicity, marked by confusion, irritability, seizures, and coma, has been associated with more rapid rates of administration. Ammonium chloride must be administered cautiously to patients with renal or hepatic impairment. In patients with hepatic dysfunction, impaired conversion of ammonia to urea may result in increased ammonia levels and worsened encephalopathy. In patients with renal failure, the increased urea synthesis may exacerbate uremic symptoms. ... 

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