Page 10: Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Ammonia
Part II. Science and Technical Considerations - Continued
Information regarding the health effects of ammonia in humans consists largely of case reports of fatalities or illnesses following massive inhalation and/or dermal exposures resulting from accidental explosions or leakages. Controlled studies on the effects of oral exposure are limited. In general, more data are available on inhalation exposure than on oral or dermal exposure.
Ingestion of concentrated ammonia causes irritation and damage to the mouth, throat and gastrointestinal tract. However, such an exposure scenario is unlikely at the levels of ammonia encountered in the environment. The few case reports of acute oral exposures to ammonia were not conclusive, as no dose information was provided. Poisoning events in humans and related deaths have been reported following accidental or intentional ingestion of household ammonium salts (Klendshoj and Rejent, 1966; Klein et al., 1985), but no quantitative data are available, although levels found in household ammonium salts are expected to be significantly higher than those in drinking water. Qualitative observations reported include oesophageal lesions and oedema, as reported in five persons who ingested household ammonia as ammonium hydroxide, one of whom experienced acute respiratory obstruction (Klein et al., 1985; Christesen, 1995). A 69-year-old woman who ingested an unknown quantity of lemon ammonia (3% ammonium ion) was found semi-conscious and making gurgling respiratory sounds (Klein et al., 1985). Radiographic results were consistent with aspiration pneumonia. The main alterations determined by endoscopic examinations were laryngeal and epiglottic oedema and a friable, erythematous oesophagus with severe corrosive injury. Death occurred several days later following acute respiratory distress syndrome and renal failure (Klein et al., 1985). Klendshoj and Rejent (1966) also reported acute toxicity causing the death of a 57-year-old man who ingested an unknown amount of ammonium hydroxide; autopsy showed haemorrhagic oesophagus, stomach, and duodenum.
Several cases of gastrointestinal disorders have been described among young children (2-3 years old) who bit into ammonia pellets or capsules (Lopez et al., 1988; Rosenbaum et al., 1998). All of the children experienced one or more of the following symptoms: vomiting, drooling, dysphagia, cough, and oral or pharyngeal burns. In the reported cases, none of the children had oesophageal or respiratory burns, and all healed within a few days. In another study, oesophageal lesions, acute respiratory obstruction and oedema were reported following ingestion of household ammonium hydroxide (Klein et al., 1985; Christesen, 1995). These observations were not quantified. Overall, several cases of accidental acute exposure to ammonia gas in humans have resulted in death (Price et al., 1983; Arwood et al., 1985; Burns et al., 1985) or respiratory tract irritation (de la Hoz et al., 1996). The concentrations of ammonia were not clearly quantified in these studies, although the levels of ammonia were higher than those found in drinking water or environmental exposure levels.
No information was available regarding systemic effects (including respiratory, cardiovascular, haematological, hepatic and endocrine effects) of ammonia or ammonium compounds in humans following chronic oral exposure.
The available chronic exposure data are primarily related to inhalation. Several studies of farmers working in enclosed livestock facilities indicate that ammonia may contribute to transient respiratory distress (Vogelzang et al., 1997, 2000; Cormier et al., 2000; Donham et al., 2000; Melbostad and Eduard, 2001). However, it is not clear from these studies what the contribution of ammonia is to the respiratory changes; other factors, including co-exposure to dust, carbon dioxide, endotoxins, fungi, bacteria and/or moulds, complicate the interpretation of these studies.
There are no validated data available regarding carcinogenic effects of ammonia or ammonium compounds in humans following oral exposure. Ammonia has not been classified by the International Agency for Research on Cancer (IARC) according to carcinogenicity.
Neurological symptoms of acute exposure to highly concentrated anhydrous ammonia aerosols include blurred vision, diffuse non-specific encephalopathy, loss of consciousness, muscle weakness and decreased deep tendon reflexes (George et al., 2000).
Ammonia has potentially deleterious effects on the central nervous system. Depending upon the severity and duration of exposure, these effects may include seizures and cerebral palsy (Felipo and Butterworth, 2002).
No information was found regarding neurological effects of ammonia or ammonium compounds in humans following oral exposure.
An increased concentration of ammonia in the blood and brain can occur as a result of hepatic encephalopathy, where liver function is impaired and the organ cannot metabolize ammonia (Felipo and Butterworth, 2002).
9.1.4 Genotoxicity
Data on the genotoxicity of ammonia in humans are limited to a study of 22 workers exposed to unknown concentrations of ammonia in air at a fertilizer factory compared with 42 control workers (Yadav and Kaushik, 1997). The results of blood sample analyses to detect genotoxic impacts showed a significant increase in the frequency of chromosomal aberrations, sister chromatid exchange and micronuclei induction in exposed workers compared with controls. These results reveal the genotoxic potential of ammonia. The authors clearly demonstrated dose-response correlations, although it is important to be mindful of the possible confounding factors associated with such a study.
Acute studies in animals support the fact that the respiratory tract is a sensitive target of ammonia toxicity (Richard et al., 1978; Kapeghian et al., 1982; Schaerdel et al., 1983). Acute exposures (1 hour to 1 week) to low concentrations of ammonia in air (≤ 1000 ppm) irritate the upper respiratory tract, whereas exposures (3 hours to 2 weeks) to high concentrations (≥ 4000 ppm) result in severe damage to the upper and lower respiratory tract and alveolar capillaries (Coon et al., 1970; Richard et al., 1978; Kapeghian et al., 1982; Schaerdel et al., 1983). Other effects on remote organs (renal, cardiovascular) observed following inhalation exposure were not consistent and may be secondary to the respiratory tract damage.
The syndrome of ammonia intoxication in rats, guinea pigs and cats consists mainly of dyspnoea, muscle fasciculation and convulsions, terminating in an early acute pulmonary oedema (Koenig and Koenig, 1949). However, the results are not consistent through all the studies. A single gavage dose study (Koenig and Koenig, 1949) showed that an ammonium dose of 303 mg/kg bw as ammonium chloride was lethal to guinea pigs (30/40 died) as a result of pulmonary oedema. In contrast, Boyd and Seymour (1946) reported no deaths in cats, rabbits, guinea pigs or rats after administration of a similar dose of ammonium (337 mg/kg bw as ammonium chloride). Other dose-response studies in rats exposed to ammonia for 15, 30 and 60 minutes have been used to establish median lethal concentration (LC50) values of 112, 71.9 and 48.4 mg/L, respectively (ATSDR, 2004). However, the consistency of the database is limited for various reasons, including the use of single exposure data only (Koenig and Koenig, 1949) or too high dosages (Barzel, 1975). In addition, the associated anion in the ammonium salt administered plays an important role. In fact, ammonium chloride is widely used to induce metabolic acidosis in animal studies; it is now known that the metabolic acidosis that can affect the lungs, kidney, nervous system, liver and bone is actually due to the formation of hydrogen chloride. For example, De Sousa et al. (1974) showed that the decrease in plasma bicarbonate induced by the administration of hydrochloric acid to dogs was significantly greater than that induced by the administration of equivalent quantities of hydrogen ion as nitric or sulfuric acid. It is therefore inappropriate to extrapolate findings obtained with ammonium chloride (or any ammonium salt) to equivalent amounts of ammonium derived from a different salt. This is one reason why caution should be exercised in deriving an oral minimal risk level for ammonia.
As with acute exposure, the animal studies that examined the toxicity of short-term intermittent or continuous exposure to ammonia suggest that the respiratory tract is the most sensitive target of toxicity. Symptoms of irritation, nasal lesions, dyspnoea and pulmonary inflammation have been observed in several animal species (Coon et al., 1970; Broderson et al., 1976; Gaafar et al., 1992).
Administration of ammonia in drinking water to rats at a dose of approximately 42 mg/kg bw/day for 8 weeks resulted in accelerated cell migration leading to mucosal atrophy in the stomach antrum and enlargement of the proliferative zone in the atrum (Tsujii et al., 1993).
However, continuous inhalation exposure of groups of rats to ammonia concentrations ranging from 40 to 470 mg/m3 showed no evidence of toxicity in 15 rats exposed to 40 mg/m3 for 114 days or 48 rats exposed to 127 mg/m3 for 90 days (Coon et al., 1970). In the same study, of 49 rats exposed continuously to ammonia at a concentration of 262 mg/m3 in air for 90 days, 25% had mild nasal discharge; 50 of 51 rats died at day 65 of continuous exposure to ammonia at a concentration of 455 mg/m3, whereas 13 of 15 rats exposed to ammonia at a concentration of 470 mg/m3 died before the end of the study. There were no significant haematological differences between experimental and control animals examined following a continuous 90-day exposure of rats to an ammonia concentration of 127 mg/m3.
Although no short-term dermal exposure studies were identified, based on the irritant properties of ammonia, it is reasonable to assume that direct contact of the skin with ammonia for a prolonged time will produce irritation.
The available information does not suggest that ammonia is carcinogenic. However, well-designed studies in animals have not been conducted, and the relevance of the available data to assess the cancer risk of oral exposure to ammonia is uncertain (ATSDR, 2004).
Exposure of 50 randomly bred 5-week-old Swiss C3H mice to ammonium at a dose of 193 mg/kg bw/day as ammonium hydroxide in drinking water for 2 years did not produce carcinogenic effects, nor did it affect spontaneous development of breast adenocarcinomas, which are characteristic of these animals (Toth, 1972). In another study, mice treated by gavage with ammonia dissolved in water at a dose of 42 mg/kg bw/day as ammonium ion for 4 weeks did not show any evidence of a carcinogenic effect (Uzvölgyi and Bojan, 1980). However, the authors demonstrated that, in the presence of ammonia, a non-carcinogenic precursor can initiate the development of lung tumours. For example, in the study above, when mice were treated with diethyl pyrocarbonate (a widely used antimicrobial agent for the preservation of beverages and food) prior to the administration of ammonia, lung tumours were observed in 9 of 16 mice; thereaction of diethyl pyrocarbonate or its by-products with ammonia may have formed urethane, a known carcinogen. In addition, Tsujii et al. (1995) demonstrated that gastric cancer metastasis significantly increased in rats pretreated with the initiator N-methyl-N-nitro-N-nitrosoguanidine in drinking water 24 weeks before receiving ammonia solution (estimated dose 200 mg/day), compared with control rats receiving ammonia only.
Very limited in vivo and in vitro studies pertaining to the genotoxicity of ammonia are available.
Early studies suggesting that ammonia may be mutagenic have been reviewed in other work (U.S. EPA, 1989). In vitro studies demonstrated that ammonia was able to induce back-mutations from dependence on streptomycin in E. coli (Demerec et al., 1951). The authors suggested that the mutagenic effect observed may not be specific, but that treatment with ammonia may increase the mutation rate of the whole genome. The addition of ammonia solution to mouse 3T3 cells resulted in a dramatic decrease in cellular multiplication (p < 0.001) and changes in morphology (Visek et al., 1972).
The effect of exposure of larvae of Drosophilia melanogaster to ammonia was examined by Lobashev and Smirnov (1934). A 95% mortality rate was reported when the flies were exposed to fumes of 10 000 ppm ammonia hydroxide solution. The offspring of the survivors displayed a mutation rate of 0.54%, which was statistically significant in comparison with controls, which showed a rate of 0.05%.
Several in vivo studies in D. melanogaster resulted in a positive response for mutagenic lethality, but negative responses for sex-linked recessive lethal mutations and dominant lethality (Auerbach and Robson, 1947).
There are no adequate studies for assessing the potential reproductive toxicity of ammonia. Very limited data were found regarding developmental effects of ammonia in animals. The most relevant study available was conducted on female Wistar rats (Miñana et al., 1995). Rats exposed to ammonium ion through their mother's diet (estimated dose 4293 mg/kg bw/day for the mothers) both in utero from gestational day 1 and through lactation, followed by a normal diet after lactation, had offspring with a marked decrease in growth rate. The authors suggested that the reduced growth of ammonia-exposed rats could be a consequence of the impaired function of N-methyl-D-aspartate receptors.
Neurological effects of acute exposure to low levels of ammonia (100 ppm) via inhalation include depression of free-access wheel running behaviour in rodents (Tepper et al., 1985). Data concerning the oral route of exposure were not available.
The mode of action for ammonia varies with the route of exposure. Many reported effects of ammonia are due to its alkalinity, which results in tissue damage (ATSDR, 2004). Toxicological information considered appropriate for the inhalation route of exposure appears different from the oral route of exposure; however, little information is available for oral exposure. There are no overt data on the pharmacokinetics of ammonia in the available literature, and no health-based endpoint that occurs from ingestion of ammonia at current exposure levels has been identified.
In general, ammonia is thought to alter the acid-base balance in the body, which in turn can result in physiological effects such as an alteration in glucose tolerance and a decreased sensitivity to insulin (U.S. EPA, 1989; WHO, 2003).