Page 9: Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Ammonia
Part II. Science and Technical Considerations - Continued
There is evidence of absorption of ammonia by the inhalation and oral routes of exposure. Most ammonia, either ingested from exogenous sources or produced endogenously in the intestinal tract, is absorbed. Very little is known about the distribution of ammonia through inhalation and dermal exposures. A substantial part of ammonia is metabolized in the liver, where it is transformed into urea and glutamine. Ammonia or ammonium ion reaching the tissues is taken up by glutamic acid, which is an intermediate in other reactions. The principal means of excretion of ammonia that reaches the circulation in mammals is as urinary urea; minimal amounts are excreted in the faeces and in exhaled air. Although some data exist on distribution of ammonia from the oral exposure, there are no quantitative data published on distribution of ammonia from the inhalation and dermal exposure (U.S. EPA, 1989; ATSDR, 2004).
Most of the ammonium ion in humans is endogenously produced in the digestive tract (4200 mg/day on average), much of it arising from the bacterial degradation of nitrogenous compounds from ingested food. More than 70% is synthesized or liberated within the colon and its faecal contents (Summerskill and Wolpert, 1970). About 99% of the ammonium ion endogenously produced is absorbed. Although the ammonium ion is a normal constituent of plasma at low levels, human and animal data show that little of the ammonium ion absorbed from the gastrointestinal tract reaches the systemic circulation as ammonia or ammonium compounds. Rather, it is absorbed via the hepatic portal vein directly to the liver, where most of it is converted to urea and glutamine in healthy individuals (Brown et al., 1957; Salvatore et al., 1963; Summerskill and Wolpert, 1970; Pitts, 1971). Analysis of plasma drawn from 10 healthy young male subjects yielded a mean endogenously derived ammonium ion concentration of 39 µg/100 mL (Brown et al., 1957). Analysis of urinary urea from subjects following oral administration of 15N-labelled ammonium chloride solution indicated that 30-65% of the radioactive nitrogen administered was absorbed and metabolized (Richards et al., 1975; Metges et al., 1999).
Information on exposure to exogenous ammonia by the oral route predominantly involves case reports of people who have swallowed household ammonia. Studies provide evidence of ammonia absorption by the oral route, few provide quantitative data. For example, ammonium ion concentrations of 153 and 33 ppm were detected in the stomach and blood, respectively, of a man who died following the ingestion of an unknown amount of ammonium hydroxide solution (Klendshoj and Rejent, 1966). In a study conducted in volunteers who ingested approximately 15 mg NH4+/kg bw/day as a single dose, 11 out of 20 subjects showed a 33% increase in arterial blood concentrations of ammonium above fasting levels, whereas cirrhotic patients showed increases of about 150% of arterial blood concentrations of ammonium, followed by a slow return to normal levels (Conn, 1972).
Inhalation studies conducted in humans (Silverman et al., 1949; Landahl and Hermann, 1950) and animals (Boyd et al., 1944; Dalhamn, 1963; Egle, 1973) suggest that ammonia is mainly retained in the upper respiratory tract and that only a small proportion is absorbed into the blood. Animal studies also suggested that an adaptive response mechanism may be activated with long-term exposure (Schaerdel et al., 1983).
No relevant quantitative data on the dermal absorption of ammonia were found in available literature.
No quantitative data on the distribution and metabolism of exogenously introduced ammonia in humans were located in the available literature. Ammonia plays a part in maintaining the acid-base balance in tissues of mammals. The dynamic equilibrium of the ammonium ion with ammonia in an aqueous solution is dependent on pH. For example, at physiological pH (~7.4), ammonium hydroxide is 99% in the ammonium ion form, but only 50% would be ionized at pH 9.25 (ATSDR, 2004). It is known that non-ionized ammonia (NH3) is freely diffusible, whereas the ammonium ion is less so, and it is mostly confined to the extracellular compartment (Stabenau et al., 1958).
Human oral exposure data clearly indicate that ammonia readily enters the portal circulation and is delivered to the liver. The most substantial first-pass metabolites of ammonia are urea and glutamine (Fürst et al., 1969; Pitts, 1971; Conn, 1972), as has been demonstrated for endogenously produced ammonia (Summerskill and Wolpert, 1970; Pitts, 1971). Ammonia and the ammonium ion can be rapidly converted to glutamine in the brain and other tissues (Takagaki et al., 1961; Warren and Schenker, 1964). The nitrogen is released from glutamine within tissues and used for protein synthesis as needed (Duda and Handler, 1958; Vitti et al., 1964; Fürst et al., 1969; Richards et al., 1975). In hypophysectomized rats that were administered [15N]ammonium citrate orally by gavage, labelled protein was found in liver, kidney, spleen, heart and skeletal muscle 6-72 hours after administration (Vitti et al., 1964). The administration of ammonium salt to humans by gavage resulted in a corresponding increase in blood urea concentration transported out of the liver (Fürst et al., 1969). Information on the distribution of endogenously produced ammonia suggests that the proportion of ammonia absorbed through inhalation would be distributed to all body compartments via the blood, where it would be used in protein synthesis or as a buffer, and that excess levels would be reduced to normal levels by urinary excretion or converted by the liver to glutamine and urea. If present in quantities that overtax these organs, ammonia is distributed to other tissues and is known to be detoxified in the brain (Takagaki et al., 1961; Warren and Schenker, 1964).
No quantitative data on the distribution of ammonia following dermal exposure were found in the available literature.
There is no published information on the transfer of ammonia from pregnant women to the feotus through the placenta or from nursing women to their offspring through breast milk. However, umbilical uptake of ammonia has been demonstrated in the lamb (Marconi et al., 1989).
In healthy people, ammonia is efficiently metabolized via the urea cycle, primarily in the liver, and eliminated in the urine and faeces (Fürst et al., 1969; Richards et al., 1975). A limited study on human exposure to 15N-labelled ammonia in drinking water showed that 25% of the initial dose was excreted in the urine within the first 6 hours after exposure, and approximately 72% within 3 days (Fürst et al., 1969). Small amounts of labelled nitrogen were also excreted as urea in faeces (Richards et al., 1975). These data are in agreement with data on the excretion of endogenously produced ammonia (Summerskill and Wolpert, 1970).