3.2.1.1. Death

There are many reports in the literature of human deaths resulting from inhalation of ammonia (Arwood et al. 1985; Burns et al. 1985; Close et al. 1980; Couturier et al. 1971; George et al. 2000; Heifer 1971; Price et al. 1983; Sobonya 1977; Walton 1973; Weiser and Mackenroth 1989; Yang et al. 1987). Most of these reports are of acute accidental exposure to ammonia gas. A review of the early literature on ammonia toxicity cites acute exposure to 5,000–10,000 ppm as being rapidly fatal in humans (Henderson and Haggard 1927; Mulder and Van der Zalm 1967) and exposure to 2,500–4,500 ppm as being fatal in about 30 minutes (Helmers et al. 1971; Millea et al. 1989). Immediate deaths resulting from acute exposure to ammonia appear to be caused by airway obstruction while infections and other secondary complications are lethal factors among those who survive for several days or weeks. Chemical burns and edema of exposed tissues, including the respiratory tract, eyes, and exposed skin, are often observed after exposure to lethal levels. Post-mortem findings in the fatal case described by Walton (1973) included extensive edema and burns affecting the mouth, faces, trunk, arms, and upper part of the trunk. The airway at the larynx was almost blocked and the lungs were greatly distended and congested. Histological examination of the lungs showed acute congestion and edema. The bronchial walls were stripped of their epithelial lining, and some smaller bronchi contained plugs of debris, which included epithelial cells, red blood cells, and dust cells. No reports of human death due to intermediate or chronic exposure to ammonia were located.

Studies in animals indicate that the acutely lethal exposure concentration depends on the exposure duration. The lethal concentration in rats and mice increases 5–10 times as the exposure duration decreases from 16 hours to several minutes (Hilado et al. 1977, 1978; Kapeghian et al. 1982; Morgan 1997; Prokop'eva et al. 1973; Weedon et al. 1940). Exposure frequency also appears to be an important factor in determining lethality. Continuous exposure to 653 ppm for 25 days resulted in nearly 64% lethality in rats, whereas intermittent exposure (5 days/week, 8 hours/day) to nearly twice this concentration was tolerated for 42 days (Coon et al. 1970). It appears that male rats are more sensitive than female rats to the lethal effects of ammonia (Appelman et al. 1982; Stupfel et al. 1971). Animals exposed to acutely lethal concentrations show severe lesions in the respiratory tract that are similar to those observed in humans. Less severe lesions of the liver, heart, and kidney have been observed following continuous long-term exposure to lethal concentrations in rats, guinea pigs, rabbits, and dogs (Coon et al. 1970). However, these may represent secondary complications from chronic respiratory tract injury.

3.2.1.2. Systemic Effects

Respiratory Effects. Ammonia is an upper respiratory irritant in humans. Exposures to levels exceeding 30 ppm result in immediate irritation to the nose and throat (Industrial Bio-Test Laboratories 1973; MacEwen et al. 1970; Sekizawa and Tsubone 1994; Verberk 1977). Four out of six human subjects described moderate irritation of the nose and eyes when exposed to 50, but not 30, ppm ammonia gas for 10 minutes (MacEwen et al. 1970). Twenty to 30% of subjects exposed to 72, but not 50, ppm ammonia gas for 5 minutes experienced eye, nasal, and throat irritation (Industrial Bio-Test Laboratories 1973). However, tolerance appears to develop with repeated exposure (Sekizawa and Tsubone 1994; Verberk 1977). Thus, subjects exposed to 50 ppm ammonia 6 hours/day, 5 days/week for 6 weeks experienced nose and throat irritation only during the first week (Ferguson et al. 1977). Acute exposure to higher levels (500 ppm) has been shown to alter respiratory minute volume (Cole et al. 1977; Silverman et al. 1949). Buff and Koller (1974) suggest that this is due to an effect on "irritant receptors" in the lungs resulting in increased activity of reflex respiratory muscles. This mechanism is also suggested by Cole et al. (1977), who exposed men to 100–331 ppm ammonia gas for 8–11 minutes while they were exercising on a stationary bicycle. Respiratory minute volume was decreased at concentrations of 150–331 ppm (but not at 100 ppm), and tidal volume was increased at 100 ppm ammonia, but decreased at higher concentrations (Cole et al. 1977). Accidental exposures to concentrated aerosols of ammonium solutions, high concentrations of ammonia gas, or anhydrous ammonia fumes have resulted in nasopharyngeal and tracheal burns, airway obstruction and respiratory distress, and bronchiolar and alveolar edema (Burns et al. 1985; Close et al. 1980; Couturier et al. 1971; de la Hoz et al. 1996; George et al. 2000; Hatton et al. 1979; Heifer 1971; Kass et al. 1972; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Millea et al. 1989; Morgan 1997; O’Kane 1983; Price et al. 1983; Sobonya 1977; Taplin et al. 1976; Walton 1973; Weiser and Mackenroth 1989). Chronic occupational exposure (about 14 years) to low levels of airborne ammonia (12.5 ppm) had no significant effect on pulmonary function or odor sensitivity in a group of workers at a soda ash factory compared to a control group from the same factory that was not exposed to ammonia (Holness et al. 1989). An acute-duration inhalation MRL of 1.7 ppm was derived from the Verberk (1977) study, and a chronic inhalation MRL of 0.1 ppm was derived from the Holness et al. (1989) study; MRLs are presented in Table 3-1 and Figure 3-1 and are discussed in Section 2.3.

Table 3-1

Levels of Significant Exposure to Ammonia And Ammonium Compounds - Inhalation.

One human study with somewhat controlled exposure to ammonia showed that pulmonary function was not affected by low levels (25–100 ppm) of ammonia (Ferguson et al. 1977). Transient nose and throat irritation was noted the first week of exposure in male and female volunteers exposed to 50 ppm, but not 25 ppm ammonia 5 days/week, for 6 weeks. No significant differences were noted between exposed and control groups for pulmonary function tests, physical examinations, or performance of normal job duties (Ferguson et al. 1977).

Figure 3-1

Levels of Significant Exposure to Ammonia And Ammonium Compounds - Inhalation.

A number of occupational cohort studies that examined farmers who worked in enclosed livestock buildings have been conducted. These studies all included measurements of ammonia in the livestock confinement buildings, as well as measurements of one or more of the following: total dust, respirable dust, carbon dioxide, total endotoxins, respirable endotoxins, fungi, bacteria, and molds (Choudat et al. 1994; Cormier et al. 2000; Donham et al. 1995, 2000; Heederik et al. 1990, 1991; Melbostad and Eduard 2001; Reynolds et al. 1996; Vogelzang et al. 1997, 2000). Of the pollutants measured, ammonia and dust were most frequently associated with respiratory effects, many of which were temporary and disappeared with cessation of exposure. Ammonia levels ranged from 2.3 to 20.7 ppm and total dust levels from 0.04 to 5.64 mg/m³. Most of these studies reported an association between exposure to pollutants, including ammonia, in livestock confinement buildings and an increase in respiratory symptoms (such as bronchial reactivity/hyperresponsiveness, inflammation, cough, wheezing, or shortness of breath) and/or a decrease in pulmonary function (such as forced expiratory volume in the first second [FEV_1.0], maximum expiratory flow rates [MEF₅₀ and MEF₇₅], and maximal mid-expiratory flow rate [MMEF]) (Choudat et al. 1994; Cormier et al. 2000; Donham et al. 1995, 2000; Heederik et al. 1990; Reynolds et al. 1996; Vogelzang et al. 1997, 2000). One study, however, reported correlations only between total dust, fungal spore, and endotoxin mean exposure levels and task-specific prevalences (Melbostad and Eduard 2001). Another study reported no significant correlations between lung function or chronic respiratory symptoms and dust or ammonia levels, but suggested that endotoxins and bacteria levels may play a role (Heederik et al. 1991). Most studies adjusted for confounding factors, such as smoking and number of years worked on a farm, in their statistical analyses. All of the studies concluded that prevalence of respiratory symptoms of some type was higher in the farmer cohort than in the respective control group. It is not clear from these studies what the contribution of ammonia is to the respiratory changes, but the cumulative data indicate that ammonia may contribute to transient respiratory distress in farmers working in enclosed livestock facilities.

A cross-sectional study of male workers at two fertilizer factories in Saudi Arabia showed a significant association between exposure to ammonia gas and respiratory symptoms including bronchial asthma (Ballal et al. 1998). Workers in factory one were exposed to air ammonia levels of 2.82–183.86 ppm (2.0–130.4 mg/m³), and workers in factory two were exposed to 0.03–9.87 ppm (0.02–7.0 mg/m³).

However, continuous exposure levels for workers could not be calculated because the number of days worked per week was not provided by the study authors. Logistic regression analysis showed that ammonia concentration was significantly related to cough, phlegm, wheezing (with and without shortness of breath), and asthma, whereas smoking was only a factor for wheezing and phlegm. Additionally, those workers exposed to ammonia levels above the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) of 25.4 ppm (18 mg/m³) had significantly higher relative risks for cough, phlegm, wheezing, dyspnea, and asthma than workers exposed to levels below the TLV. Incidence of wheezing was also elevated in workers exposed to ammonia levels below the TLV. Cumulative ammonia concentration (CAC) of >50 mg/m³-years also showed a significantly increased relative risk for all of the above symptoms compared to workers with a CAC of ≤50 mg/m³-years. None of the relative risks for workers in the second factory (ammonia levels <25.4 ppm) were significant.

Other occupational studies also evaluated the effects of ammonia exposure and pulmonary function. Firefighters who reported exposure to ammonia while working had a rate of decline of FEV₁ of 1.7 times that of nonexposed firefighters over a period of 6–10 years (Tepper et al. 1991).

Children (8–9 years old) who attended two schools in the vicinity of a fertilizer plant had higher incidences of acute respiratory diseases than children of the same age who attended a school 20 kilometers away (Gomzi and Šarić 1997). Incidence was related to levels of measured pollutants (ammonia, hydrogen fluoride, nitrogen dioxide, total suspended particulate matter, and smoke) in the inside and outside air. Forced expiratory volumes were not statistically different between the three schools. These results indicate that exposure to low levels of ammonia (0.04–0.23 ppm) and other airborne pollutants may not cause functional respiratory deficits, but may lower the resistance to respiratory pathogens in children. These effects may be due in part or in whole to toxicants other than ammonia, such as nitrogen dioxide.

Case reports of individuals acutely exposed to anhydrous or aqueous ammonia reported respiratory effects including nasal irritation; epiglottic, laryngeal, pharyngeal, tracheal, and pulmonary edema; dyspnea; wheezing; coughing; rhonchi; pneumonia; and cardio-respiratory arrest (de la Hoz et al. 1996; George et al. 2000; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Lee et al. 1993; Millea et al. 1989; Morgan 1997; Prudhomme et al. 1998; Weiser and Mackenroth 1989). de la Hoz et al. (1996) described the initial and residual effects of three adult males who had been acutely exposed to ammonia gas in separate incidents. All three men complained of burning eyes, throat, and skin, cough, and wheezing, and all had been treated at hospitals shortly after exposure. Follow-up examinations 2–2½ years later showed persistent dyspnea, cough, and wheezing at rest and/or on exertion, which is consistent with restrictive lung disease secondary to acute ammonia inhalation injury. Another man exposed to anhydrous ammonia gas experienced pharyngeal and laryngeal edema, dyspnea, chest tightness, copious bronchial secretions, and wheezing (Leduc et al. 1992); 12 years postexposure, he continued to have cough, exertional dyspnea, and recurrent bronchial infections. Similar cases were reported by Kerstein et al. (2001) and Latenser and Lucktong (2000); no follow-up reports were available.

A more severe exposure was reported by George et al. (2000). An adult male was found unconscious next to a burst pipe carrying liquefied ammonia. He had ocular and cutaneous burns and severe difficulty breathing. Over the next 27 days, he suffered many medical setbacks, including attacks of bradycardia, a complete circulatory collapse from which he was resuscitated, and finally, a fatal cardiac arrest from severe bleeding. Another similar severe exposure resulted in the death of the patient 13 days postexposure due to treatment-resistant bronchopneumonia; histological examination showed massive, hemorrhagic pulmonary edema, regions of emphysema, and edema of the epiglottis and glottis (Weiser and Mackenroth 1989).

Reports of apparently rare effects have been found. A man exposed occupationally for 5 months to low levels of ammonia gas (8–15 ppm) from ammonia-containing silver polish developed asthma-like symptoms (Lee et al. 1993). Separate specific bronchial provocation tests to the silver polish and to 12 ppm ammonia produced asthmatic reactions, implicating the ammonia in the silver polish as the cause. Another study reported hyposmia (loss of the sense of smell) in a man following acute inhalation exposure (for several hours) to an unknown concentration of ammonia gas; the hyposmia had not resolved 30 months after exposure (Prudhomme et al. 1998).

Studies in animals have demonstrated similar dose-effect and duration-effect patterns for the respiratory tract. Acute exposures (1 hour to 1 week) to low concentrations of ammonia (≤1,000 ppm) irritate the upper respiratory tract whereas exposures (3 hours to 2 weeks) to high concentrations (≥4,000 ppm) result in severe damage to the upper and lower respiratory tract and alveolar capillaries (Coon et al. 1970; Kapeghian et al. 1982; Mayan and Merilan 1972; Richard et al. 1978a, 1978b; Schaerdel et al. 1983; Stombaugh et al. 1969). Prolonged or repeated exposures to lower levels (≥150 ppm) produce inflammation and lesions of the upper respiratory tract (Broderson et al. 1976; Coon et al. 1970).

Clinical and histological effects have been seen in the lungs of animals following exposure to ammonia gas (Dodd and Gross 1980; Gaafar et al. 1992; Sjöblom et al. 1999). Cats exposed to 1,000 ppm ammonia gas for 10 minutes and observed for up to 35 days showed a biphasic course of respiratory pathology (Dodd and Gross 1980). Effects seen at 24 hours post-exposure included severe dyspnea, anorexia, and dehydration, with rhonchi and coarse rales evident upon auscultation. Microscopy of lung samples on day 1 showed necrotizing bronchitis in the large conducting airways, and necrosis and sloughing of the epithelium and acute inflammatory reaction in the bronchi. On day 7, the mucosal lesions had resolved, but on day 35, varying degrees of bronchitis and early bronchopneumonia with areas of bulbous emphysema were seen. Gross pathology revealed varying degrees of congestion, hemorrhage, edema, interstitial emphysema, and collapse of the lungs at all time points. Pulmonary resistance was increased throughout the study (Dodd and Gross 1980). Swiss mice exposed to 909 ppm, but not 303 ppm, ammonia gas 6 hours/day, 5 days/week for 4–14 days had histological lesions in the respiratory epithelium in the nasal cavity (Zissu 1995); no lesions were observed in the trachea or lungs. Nasal mucosa was adversely affected in adult male mice exposed to vapor of 12% ammonia solution for 15 minutes/day, 6 days/week for 4, 5, 6, 7, or 8 weeks (Gaafar et al. 1992). Histological changes progressed from weeks 4–8 from crowding of cells forming crypts and irregular arrangements to epithelial hyperplasia, patches of squamous metaplasia, loss of cilia, and dysplasia of the nasal epithelium. One animal that had loss of polarity of the epithelium, hyperchromatism, and mitotic figures with an intact basement membrane also had a carcinoma in situ in one nostril. At week 8, one mouse had an invasive adenocarcinoma of the nasal mucosa. Histochemical results were also abnormal. The levels and cell locations of succinic dehydrogenase, acid phosphatase, alkaline phosphatase, and nonspecific esterase activities were altered, indicating altered cell metabolism and energy production, cell injury, proliferation, and possibly chronic inflammation and neoplastic transformation (Gaafar et al. 1992).

Anesthetized, mechanically ventilated rabbits exposed to high levels of nebulized ammonia (2 mL of 23–27% ammonia solution; estimated by the study authors as peak ammonia concentrations of 35,000–39,000 ppm) for 4 minutes had a decrease in blood oxygen saturation and an increase in airway pressure (a measure of changes in airway resistance) (Sjöblom et al. 1999). Arterial oxygen tension decreased from 23.3 (±3.6) to 11.0 (±3.6) kPa and peak airway pressure increased from 13 (±2) to 17 (±2) cm H₂O. At baseline and 5 and 15 minutes after ammonia administration, measurements were taken via a catheter in the left auricular artery, which monitored pressure and sampled for arterial blood gases, and via transducers in the ventilator. Thirty and 150 minutes after ammonia exposure, rabbits received inhalation therapy of either 0.5 mg budesonide (a steroid) or a placebo, and airway pressure, hemodynamics, and gas exchange were measured every 30 minutes for 6 hours. Slight, gradual improvement of blood gas parameters was noted over the 6-hour observation period in all rabbits, with or without steroid treatment; however, no parameters approached normal during that time period.

Other studies examined pigs in normal swine production facilities (Donham 1991) or in environmentally regulated enclosures (Diekman et al. 1993; Gustin et al. 1994; Urbain et al. 1994). Donham (1991) investigated the correlation of housing air environment (in the finishing barn) to swine diseases and productivity over 12 months on 28 swine farms. Total dust, respirable dust, endotoxin activity of the dust, and hydrogen sulfide levels were determined, and area dust and microbial counts were monitored at 1.2 meters above the floor (the human breathing zone). Ammonia and carbon dioxide levels were determined 1.2 meters and 20 cm (swine breathing zone) above the floor. The average ammonia concentration in the human breathing zone for all farms was 9.1 ppm; the mean concentration in the swine breathing zone was 14.5 ppm. The mean concentrations of environmental contaminants were calculated for the most productive farrowing operations and the least productive ones and compared with lower production variables (Donham 1991). Ammonia concentration was related to number of pigs weaned per litter, and total and respirable dust concentrations were related to prolonged age to reach a weight of 25 kg. Another comparison involved the stratification of the finishing farms into quartiles according to percentage of pigs with specified disease conditions and comparison of mean concentrations of various environmental contaminants for each farm in each strata (Donham 1991). Levels of ammonia (in the animal breathing zone) greater than 25, 29, and 23 ppm were associated with buildings in which pneumonia, pleuritis, and arthritis, respectively, were greater than the mean value for the group. Overall, respirable dust (>0.8 mg/m³), ammonia (>23 ppm in the animal breathing zone), and carbon dioxide (>2,000 ppm) levels were most often associated with increased disease. Possible study shortcomings noted by the study author were that pre-existing conditions could have been present in the pigs (before they entered the finishing barns) and that nasal turbinates were not routinely examined for abnormalities. These data suggest that ammonia may contribute to respiratory and other pathological conditions in pigs raised in crowded, enclosed conditions, but the exact contribution of ammonia is difficult to assess.

The lungs of young pigs exposed continuously to 0, 25, 50, or 100 ppm ammonia gas for 6 days in air-pollutant exposure chambers were removed, ventilated, and perfused, and the pulmonary vascular hemodynamics and permeability and the endotoxin-induced vascular response were assessed (Gustin et al. 1994). In lungs from pigs exposed to 100 ppm, but not 25 or 50 ppm ammonia, the endotoxin-induced vascular response seen in lungs from control pigs was abolished. The study authors suggested that this is due to a modification of the balance between vasodilators (such as cyclooxygenase products and platelet activating factor) and vasoconstrictors (such as prostacyclin). Since vasoconstriction, as induced by endotoxin, may serve as a protective mechanism in the lungs and attenuate edema formation, the effective abolishment of this effect by ammonia may be detrimental.

Young pigs exposed continuously to ammonia vapors (0, 25, 50, or 100 ppm) for 6 days in air-pollutant exposure chambers had increased numbers of neutrophils in nasal lavage fluid in all exposure groups (Urbain et al. 1994) and increased porcine serum albumin at 100 ppm.

Not all studies have shown adverse respiratory effects from intermediate exposure to ammonia vapors. Groups of gilts (virgin female pigs) were raised from the age of 2–4.5 months in a conventional grower unit where they were naturally exposed to mycoplasmal and bacterial pathogens that cause enzootic pneumonia and atrophic rhinitis (Diekman et al. 1993). The pigs were then transferred to environmentally regulated rooms, where they were exposed continuously to low (mean 7 ppm) or moderate (mean 35 ppm) levels of ammonia for 6 weeks. No statistically significant differences were seen in the percent of lung tissue containing lesions or in snout grade (Diekman et al. 1993). Ninety-five percent of all gilts had lung lesions, with a wide range of degree of severity. Snouts were graded at the level of the second deciduous premolar as having normal turbinates (grade of 0), slight to moderate degeneration (grade of 1–3), or severe degeneration to complete loss of turbinates (grade of 4 or 5). Some of the gilts were continuously exposed through puberty and breeding (around 205 days of age) and the lungs and turbinates were examined at 30 days of gestation. No statistically significant differences were observed in percent of lung tissue containing lesions or in snout grade (Diekman et al. 1993).

A number of cattle were acutely exposed to anhydrous ammonia when a pipeline running through their pasture ruptured and leaked 1,800 barrels of ammonia in a short period of time (Morgan 1997). The ammonia combined with moisture and formed a white cloud (ammonia aerosol), which drifted south across two additional fields containing cattle. In the field where the rupture occurred, four head of cattle were found dead and two others were euthanized because of blindness and respiratory distress. Cattle in the adjacent pasture had runny eyes and noses and were coughing and wheezing. Eight days after the pipeline rupture, the cloud of ammona aerosol, which had apparently settled in a low-lying protected area, blew back up the valley and exposed the remaining cattle again and also exposed a horse in the same pasture. All animals had respiratory distress, elevated body temperatures, and one cow and the horse had swollen tongues and enlarged lymph glands. All cattle were given antibiotics and some were treated specifically for respiratory problems. No measurements or estimations of ammonia concentrations were provided and no follow-up examinations were available to assess long-term effects from the exposures.

All reliable LOAELs and highest NOAELs are presented in Table 3-1 and Figure 3-1.

Cardiovascular Effects. Acute exposure to highly concentrated aerosols of ammonium compounds may cause elevated pulse and blood pressure, bradycardia, and cardiac arrest in humans (George et al. 2000; Hatton et al. 1979; Montague and Macneil 1980; White 1971). These effects did not occur after acute exposure to 500 ppm ammonia or repeated exposure to 100 ppm ammonia (Ferguson et al. 1977; Silverman et al. 1949).

Cardiovascular changes that may be analogous to those observed in humans have been observed in rabbits exposed to high concentrations of ammonia (Richard et al. 1978b). Bradycardia was seen at 2,500 ppm, and hypertension and cardiac arrhythmias leading to cardiovascular collapse followed acute exposures to concentrations exceeding 5,000 ppm. Pathological correlates for these effects have not been demonstrated. Atrophy of pericardial fat has been observed in mice exposed to 4,000 ppm ammonia (Kapeghian et al. 1982). Myocardial fibrosis has been observed in rats, guinea pigs, rabbits, dogs, and monkeys after prolonged (90 days) continuous exposure to 653 ppm (Coon et al. 1970). The contribution of these lesions to the morbidity and mortality of affected animals has not been determined.

Exposure of pigs in vivo to up to 100 ppm ammonia for 6 days did not alter the baseline values of any hemodynamic or permeability parameters (arterial, pre- or postcapillary, or venous blood flow resistance, or total pulmonary blood flow resistance), but did eliminate the hemodynamic response to Escherichia coli endotoxins in the lungs (Gustin et al. 1994). This may affect the ability of the lungs to resist bacterial infection. The pulmonary blood flow resistance measurements were taken in vitro in ventilated and perfused lungs from pigs exposed to ammonia in vivo (Gustin et al. 1994). Reliable LOAELs and highest NOAELs for cardiovascular effects are presented in Table 3-1 and Figure 3-1.

Gastrointestinal Effects. Exposure to highly concentrated aerosols of ammonium compounds can produce burns of the lips, oral cavity, and pharynx, along with edema of these areas (Hatton et al. 1979; Kass et al. 1972; Leduc et al. 1992; Levy et al. 1964; Price et al. 1983; Stroud 1981; Ward et al. 1983; Yang et al. 1987). Gastrointestinal effects of ammonia in animals have not been reported. As shown in Table 3-1, pathological changes in the gastrointestinal tract were not observed in guinea pigs exposed repeatedly to 170 ppm ammonia (Weatherby 1952).

Hematological Effects. Cyanosis, elevated white blood cell count, and pulmonary artery thrombosis have been observed in humans exposed to highly concentrated aerosols of ammonium compounds (Sobonya 1977; Taplin et al. 1976; Voisin et al. 1970; Ward et al. 1983; White 1971).

Standard hematological measurements, including blood hemoglobin and differential cell counts, have been reported for a few animal species. As shown in Table 3-1 and Figure 3-1, acute hematological effects of ammonia have not been demonstrated (Doig and Willoughby 1971; Gustin et al. 1994). Pigs exposed to up to 100 ppm ammonia for 6 days had no statistically significant differences from controls in total leukocytes or percent lymphocytes, neutrophils, or eosinophils (Gustin et al. 1994). Repeated exposure to 1,100 ppm had no effect on hematological parameters in guinea pigs, rats, and rabbits (Coon et al. 1970). Weatherby (1952) reported increased concentrations of hemosiderin in the spleen of guinea pigs exposed to 170 ppm ammonia for 18 weeks. This suggests the possibility of increased turnover of red blood cells; however, this has not been corroborated.

Musculoskeletal Effects. Spasms of muscles of the extremities have resulted from an acute exposure of a man to anhydrous ammonia gas (White 1971), but this was probably caused by an effect of ammonia on the nervous system.

Hepatic Effects. Hemorrhagic necrosis of the liver was observed in an individual exposed to a lethal concentration of ammonia gas and liquid for a short period of time (<45 minutes) (Heifer 1971). No other cases of hepatic effects have been reported in humans. Hepatic effects are usually not seen in animals exposed to ammonia gas. As shown in Table 3-1, liver necrosis has been observed following acute lethal exposure of mice to 3,440 ppm ammonia for 1 hour (Kapeghian et al. 1982). Fatty changes of liver plate cells were seen in rats following continuous long-term exposure to 642 ppm ammonia for 90 days, but no such changes were seen in rats, squirrel monkeys, and guinea pigs exposed to 1,086 ppm ammonia 8 hours/day, 5 days/week for 6 weeks (Coon et al. 1970).

Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to ammonia. In animals, renal effects do not appear to be an important feature of the toxicity of inhaled ammonia. Effects reported have not been corroborated or cannot be interpreted. Mild abnormalities in the renal tubules have been described in guinea pigs exposed to 170 ppm for 12 weeks, 5 days/week, 6 hours/day; however, renal effects at this relatively low level have not been corroborated (Weatherby 1952). Exposure to more than 6 times this concentration for 6 weeks, 5 days/week, 8 hours/day did not result in pathological changes to the kidney (Coon et al. 1970). Renal tubular calcification (severity not reported) has been reported in rats continuously exposed to near lethal levels (Coon et al. 1970).

Endocrine Effects. Adrenaline levels in urine, 17-oxycorticosteroids in the urine, and 11-oxycortico-steroid levels in blood were increased in humans exposed to 3.0 ppm ammonia for 37 days (Kalandarov et al. 1984). Exposure to 7.2 ppm for 17 days also increased adrenaline levels in urine and 17-oxycortico-steroids in the urine, and increased free, but not total, 11-oxycorticosteroid levels in blood (Kalandarov et al. 1984). Experimental details were lacking in this study; additionally, no clinical or histological data were provided for this or other end points in this study and no supporting data are available in the literature. Therefore, the significance of these effects is unclear. Exposure of pigs to up to 100 ppm ammonia for 6 days did not significantly alter the plasma cortisol concentration (Gustin et al. 1994). No statistically significant difference was seen in adrenal gland weight of female pigs exposed to about 35 ppm ammonia for 6 weeks or for 6 weeks plus through day 30 of gestation compared to pigs exposed for similar time frames to about 7 ppm ammonia (Diekman et al. 1993). No unexposed controls were included in that study. The endocrine system does not appear to be a primary target of inhaled ammonia.

Dermal Effects. Ammonia gas and aerosols of ammonium compounds derived from anhydrous ammonia are dermal irritants in humans and animals. These effects are described in the discussion of dermal effects associated with dermal exposure (Section 3.2.3.2).

Ocular Effects. Ammonia gas and aerosols of ammonium compounds derived from anhydrous ammonia are ocular irritants in humans and animals. These effects are described in the discussion of ocular effects associated with dermal exposure (Section 3.2.3.2).

Body Weight Effects. Reduced body weight has been observed in rats exposed via inhalation to 500 ppm (Richard et al. 1978a) and in pigs exposed to 50 ppm or more ammonia for 6 days (Gustin et al. 1994; Urbain et al. 1994). Pigs gained less weight and showed decreased food consumption when exposed to 100 ppm ammonia for 4 or 5 weeks (Drummond et al. 1980; Stombaugh et al. 1969). Female pigs exposed to about 35 ppm for 6 weeks gained less weight than those exposed to only about 7 ppm (Diekman et al. 1993). However, females that were continuously exposed to about 7 or 35 ppm ammonia from 6 weeks before breeding until day 30 of gestation had no statistically significant difference in body weight (Diekman et al. 1993); however, no controls were included in this study.

3.2.1.3. Immunological and Lymphoreticular Effects

Several case reports describe occupational asthma that developed due to exposure to aerosols that contained ammonium compounds (Ballal et al. 1998; Lee et al. 1993; Weir et al. 1989).

Secondary infections often complicate the clinical outcome of burns and respiratory lesions related to exposure to highly concentrated aerosols derived from anhydrous ammonia (Sobonya 1977; Taplin et al. 1976). However, there is no evidence that the decreased immunological resistance represents a primary impairment of the immune system in humans following exposure to ammonia. Nevertheless, as shown in Table 3-1 and Figure 3-1, studies in animals have shown that acute and long-term exposure to ammonia can decrease the resistance to bacterial infection and decrease immune response to infection. A significant increase in mortality was observed in mice exposed to ammonia for 168 hours followed by exposure to the LD₅₀ of Pasteurella multocida (Richard et al. 1978a). Exposure of rats to ammonia at ≥25 ppm for 4–6 weeks following inoculation with Mycoplasma pulmonis intranasally significantly increased the severity of respiratory signs characteristic of murine respiratory mycoplasmosis (Broderson et al. 1976). Guinea pigs exposed to 90 ppm ammonia for 3 weeks developed a significant decrease in the cell-mediated immune response to challenge with a derivative of tuberculin (Targowski et al. 1984). Furthermore, the response of blood and bronchial lymphocytes to mitogens (phytohemagglutinin, concanavalin A, purified protein derivative of tuberculin) was markedly reduced. The hemodynamic response (increased total pulmonary blood flow resistance) to E. coli endotoxins in the lungs of pigs was eliminated by exposure to up to 100 ppm ammonia for 6 days, which may affect the ability of the lungs to resist bacterial infection (Gustin et al. 1994). Also, a reduction in gamma globulin concentration was reported in pigs exposed to 100 ppm ammonia for 31–45 days (Neumann et al. 1987).

3.2.1.4. Neurological Effects

Case reports of accident victims exposed to highly concentrated aerosols derived from anhydrous ammonia describe blurred vision, diffuse nonspecific encephalopathy, loss of consciousness, muscle weakness, and decreased deep tendon reflexes (George et al. 2000; Hatton et al. 1979; Latenser and Lucktong 2000; White 1971). Acute exposure to low levels of ammonia (100 ppm) has been shown to depress free-access wheel running behavior in rodents (Tepper et al. 1985). No overt symptoms of neurological disorders were reported in guinea pigs or monkeys that were exposed to up to 1,105 ppm ammonia for 6 weeks (Coon et al. 1970). Exposure of the nasal mucosa to ammonia-saturated air elicited vasodilatation and corresponding increased blood flow and reflex hypertension in the lower lip of cats (Izumi and Karita 1993). Stimulation of the nasal mucosa by chemical irritants has been shown to elicit changes in the respiratory system, such as apnea, laryngeal spasm, and bronchoconstriction, and in the cardiovascular system, such as bradycardia and variable blood pressure changes (Izumi and Karita 1993). Brain glutamine levels have also been shown to increase in rats that inhaled 25 or 300 ppm ammonia vapor for 6 hours/day for 5 days, which is likely a result of ammonia metabolism by the astrocytic glutamate-glutamine cycle (Manninen and Savolainen 1989; Manninen et al. 1988).

3.2.1.5. Reproductive Effects

No studies were located regarding reproductive effects in humans after inhalation exposure to ammonia. No statistically significant differences were noted in ovarian or uterine weights of pigs exposed to about 7 or 35 ppm ammonia for 6 weeks (Diekman et al. 1993). Female pigs that were continuously exposed to about 35 ppm ammonia from 6 weeks before breeding until day 30 of gestation had no statistically significant differences in age at puberty, number of live fetuses, or fetus-to-corpus luteum ratio compared to pigs exposed to only about 7 ppm (Diekman et al. 1993). No unexposed controls were included in that study.

3.2.1.6. Developmental Effects

No information was located regarding developmental effects of ammonia in humans following inhalation exposure. No statistically significant difference in fetal length was evident at 30 days of gestation in offspring of pig dams that were continuously exposed to about 7 or 35 ppm ammonia from 6 weeks before breeding until day 30 of gestation (Diekman et al. 1993).

3.2.1.7. Cancer

Carcinogenic potential of ammonia by the inhalation route has not been assessed in humans or animals. One case report was found of an individual who developed epidermal carcinoma of the nasal septum 6 months after being badly burned by accidental contact with a refrigeration ammonia-oil mixture (Shimkin et al. 1954). However, the role of ammonia is impossible to ascertain and no conclusion can be drawn from this study. Shimkin et al. (1954) indicated that “no single case can prove a general principle, and it is only by the publication of additional reports of similar cases that enough data can become available for critical analysis.” No other such reports were located, although other cases of inhalation exposure to ammonia from spills have been followed for more than 6 months after exposure. One of 10 adult male mice exposed to ammonia gas for 15 minutes/day 6 days/week for 8 weeks had mitotic figures with an intact basement membrane and a carcinoma in situ in one nostril and one mouse had an invasive adenocarcinoma of the nasal mucosa (Gaafar et al. 1992). Again, there is no conclusive evidence that ammonia played a role in the induction of the carcinoma. Gaafar et al. (1992) provided an alternate explanation by stating that “prolonged exposure to ammonia may interfere with the normal protective reflexes of the respiratory nasal mucosa resulting in the accumulation of particulate matter initiating or promoting a neoplastic process.” However, the plausibility of tumor formation in only 8 weeks by a weak carcinogen such as particulate matter is debatable.

3.2.2.1. Death

Human deaths due to ingestion of household ammonium salts have been reported (Klein et al. 1985; Klendshoj and Rejent 1966), but no quantitative data for oral exposure in humans were located. 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, and endoscopy showed laryngeal and epiglottic edema and a friable, erythematous esophagus with severe corrosive injury. The woman died several days later after developing acute respiratory distress syndrome and renal failure (Klein et al. 1985). A 57-year-old man was found dead with a glass containing dilute ammonium hydroxide (2.4% ammonium ion) nearby (Klendshoj and Rejent 1966); autopsy showed hemorrhagic esophagus, stomach, and duodenum. As shown in Table 3-2 and Figure 3-2, 303 mg ammonium/kg as ammonium chloride is a lethal dose in guinea pigs when given as single gavage dose (30/40 died) (Koenig and Koenig 1949). Death, in this study, resulted from pulmonary edema. No deaths were seen in cats, rabbits, guinea pigs, or rats after a similar dose of ammonium (337 mg ammonium/kg given as ammonium chloride) (Boyd and Seymour 1946).

Table 3-2

Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral.

3.2.2.2. Systemic Effects

No information was located regarding dermal or ocular effects of ammonia or ammonium compounds in humans or animals following oral exposure.

Respiratory Effects. No information was located regarding respiratory effects of ammonia or ammonium compounds in humans following oral exposure. Guinea pigs that received a single gavage dose of ammonium chloride developed serious respiratory effects including increased rate and depth of respiration, pulmonary edema, and death by respiratory failure (Koenig and Koenig 1949). Because the blood pH of the guinea pigs decreased after administration of ammonium chloride, adjustments in respiratory rate and depth may have been a compensatory mechanism for acidosis. Similarly, administration of ammonium chloride in doses of approximately 100 mg of NH₄⁺/kg/day (as ammonium chloride) or higher for up to a year to rabbits resulted in metabolic acidosis and compensatory changes in respiratory rate and tidal volume (Seegal 1927). The low blood pH results in increased lung ventilation, which increases the elimination of carbon dioxide from the blood, and therefore, can be considered a compensatory response to acidosis rather than a direct effect of ammonium ion on the lungs or respiratory system.

Cardiovascular Effects. No information was located regarding cardiovascular effects of ammonia or ammonium compounds in humans following oral exposure. No pathological abnormalities were noted in the hearts of adult and weanling rats fed doses of up to 79 mg ammonium/kg/day as ammonium sulfamate for 90 days in drinking water (Gupta et al. 1979). These data are presented in Table 3-2 and Figure 3-2.

Figure 3-2

Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral.

Gastrointestinal Effects. Several cases have been described of young children (2–3 years old) who bit into ammonia pellets/capsules (Lopez et al. 1988; Rosenbaum et al. 1998). Two of the children drooled and had ulcerative lesions on the tongue and/or on the buccal mucosa; one child had superficial ulcerations on the posterior esophageal wall and the other child had edematous, erythematous upper and lower lips with areas of desquamation, eschar of the hard palate, and edema and erythema of the supraglottic structures and upper trachea (Rosenbaum et al. 1998). All of the children experienced one or more of the following symptoms: vomiting, drooling, dysphagia, cough, or oral or pharyngeal burns (Lopez et al. 1988; Rosenbaum et al. 1998). None of the children had esophageal or respiratory burns and all healed within a few days. Esophageal lesions and edema were reported in five persons who ingested household ammonia (ammonium hydroxide), one of whom experienced acute respiratory obstruction (Christesen 1995; Klein et al. 1985). These observations were not quantified. The effects are probably due to the alkaline nature of ammonium hydroxide. A single case report described a self-administered ammonia solution enema that resulted clinically in anal pain, diffuse abdominal colic, and tenesmus (da Fonseca et al. 1998). Sigmoidoscopy showed diffuse erythematous friable mucosa with large ulcerations covered by yellowish exudate that receded in a few days, but chronic inflammation and fibrosis of the rectum and sigmoid colon was noted 3 months postexposure (da Fonseca et al. 1998).

No histopathological abnormalities of the gastrointestinal tract were observed in adult or weanling rats administered doses of up to 79 mg ammonium/kg/day as ammonium sulfamate for 90 days via drinking water (Gupta et al. 1979). Likewise, a 3% solution of ammonium chloride administered to rats via gastric tube produced no gastric mucosal damage in 1 hour and a 10% solution produced only a minimum of hemorrhagic lesions (about 9 mm²) (Takeuchi et al. 1995). However, similar administration of 1 or 3% ammonium hydroxide in rats produced severe hemorrhagic lesions (about 26.6 or 97.7 mm², respectively) (Takeuchi et al. 1995). Gavage administration in rats of 0.3% ammonia (33.3 mg/kg) produced gastric mucosal lesions within 5 minutes with corresponding decreases in gastric wall immunoreactive endothelin-1 (ET-1) and immunoreactive thyrotropin-releasing hormone (TRH) concentrations and increases in gastric juice ET-1 and TRH concentrations (Mori et al. 1998). In situ gastric exposure has also shown ammonia-induced gastric mucosal damage (Murakami et al. 1995; Nagy et al. 1996). These lesions are exacerbated by neutrophil products, especially hypochlorous acid (Murakami et al. 1995) and cysteine proteases, such as some of the cathepsins (Nagy et al. 1996). Administration of 0.01% ammonia in drinking water to rats (approximately 42 mg/kg/day) for 8 weeks resulted in acceleration of cell migration leading to mucosal atrophy in the stomach antrum, increased labeling indices, and enlargement of the proliferative zone in the antral and body mucosa (Tsujii et al. 1993).

Hematological Effects. No information was located regarding the hematological effects of ammonia or ammonium compounds in humans following oral exposure. Repeated exposure to ammonium chloride in animals resulted in metabolic acidosis with related changes in bone metabolism and serum calcium. For example, rats fed diets containing high levels of ammonium chloride had increased serum calcium (Barzel 1975). The increased serum calcium resulted from enhanced demineralization of bone in response to chronic acidosis. This effect was not found to be a specific effect of ammonium and was reported to occur in states of chronic metabolic acidosis produced from repeated doses of acidifying agents (e.g., hydrochloric acid, sulfuric acid). Decreased blood pH was seen in cats fed an acidifying diet containing ammonium chloride for several weeks (Kienzle and Wilms-Eilers 1994). As shown in Table 3-2 and Figure 3-2, no effects on blood hemoglobin or blood cell counts were observed in adult or weanling rats that received doses of up to 79 mg ammonium/kg/day administered as ammonium sulfamate in drinking water (Gupta et al. 1979).

Musculoskeletal Effects. No information was located regarding musculoskeletal effects of ammonia or ammonium compounds in humans following oral exposure. Guinea pigs and rats that received lethal gavage doses of ammonium chloride developed muscle weakness, fasciculation, and incoordination (Koenig and Koenig 1949). In other animal studies, repeated ingestion of ammonium salts resulted in metabolic acidosis, which stimulated bone demineralization. As is shown in Table 3-2 and Figure 3-2, repeated ingestion of ammonium chloride in drinking water resulted in net bone resorption in rats and bone deformities in dogs (Barzel and Jowsey 1969; Bodansky et al. 1932). This effect can be anticipated with repeated exposure to any acidifying agent.

Hepatic Effects. No information was located regarding hepatic effects of ammonia or ammonium compounds in humans following oral exposure. As shown in Table 3-2 and Figure 3-2, no toxic effects were noted in livers of adult or weanling rats fed doses of up to 79 mg ammonium/kg/day as ammonium sulfamate for 90 days in drinking water (Gupta et al. 1979).

Renal Effects. Renal failure was identified as the cause of death in humans after ingestion of an unknown amount of household ammonia (ammonium hydroxide) (Klein et al. 1985). It is not certain if this represents a primary effect of ammonium or is secondary to massive burns to the gastrointestinal tract.

Renal effects have been observed in animals following repeated oral doses of ammonium chloride. These effects may be secondary to chronic acidosis produced from the interaction of ammonium chloride with water (which results in an increased H⁺ concentration) rather than from a direct effect of ammonium ion on the kidney. Renal enlargement, increased blood ammonia content, and increased urinary ammonia have been reported in rats exposed to 180–433 mg/kg/day for 3–7 days (Benyajati and Goldstein 1975; Janicki 1970; Lotspeich 1965;), but are unlikely to be indicative of renal pathology. The highest NOAELs and LOAELs are presented in Table 3-2 and Figure 3-2.

Endocrine Effects. No information was located regarding endocrine effects of ammonia or ammonium compounds in humans following oral exposure. Enlarged adrenal glands were observed in rabbits that received 124 mg ammonium/kg/day as ammonium hydroxide by gavage in water for 17 months (Fazikas 1939). These limited data suggest that the endocrine system is not a primary target for ammonia or ammonium compounds.

Body Weight Effects. Decreased body weight or weight gain has been observed in animals following oral exposure to ammonium ion (Barzel and Jowsey 1969; Bodega et al. 1993; Boyano-Adánez et al. 1996; Gupta et al. 1979; Noda and Chikamori 1976). Rats exposed to ammonium ion in utero and during lactation (dams received 4,293 mg ammonium/kg/day in the diet from gestational day 1 through lactation day 21) and then received a normal diet had showed reduced body weight gain (Miñana et al. 1995); body weight gain was reduced by 25 and 16% in male and female offspring, respectively, at 120 days of age. Rats that were continued on the same ammonia diet as their dams had an even greater reduction in body weight gain (27 and 26% for males and females, respectively) (Miñana et al. 1995). Birth weights were not reported in the Miñana et al. (1995) study. Gupta et al. (1979) noted increased water intake and reduced food intake in weanling rats, and decreased body weight in adults but not weanlings fed 79 mg ammonium/kg/day in drinking water for 90 days as ammonium sulfamate. This represents the LOAEL for this effect. A NOAEL of 39.5 mg ammonium/kg/day was also identified in this study (see Table 3-2 and Figure 3-2).

3.2.2.3. Immunological and Lymphoreticular Effects

No information was located regarding immunological effects of ammonia or ammonium compounds in humans or animals after oral exposure.

3.2.2.4. Neurological Effects

No information was located regarding neurological effects of ammonia or ammonium compounds in humans after oral exposure.

Guinea pigs that received lethal gavage doses of ammonium chloride (303.5–404.7 mg NH₄⁺/kg) developed neuromuscular effects including fasciculation; incoordination; hyperexcitability to tactile, auditory, and painful stimuli; and tonic convulsions (Koenig and Koenig 1949).

A number of studies have indicated that increased ammonium ion levels in the brain may disrupt energy production and modify the availability of some receptors that are involved in neurotransmission. Administration of 20% ammonium acetate in the diet of rats for 20 days resulted in statistically significant increases in brain ammonium ion (12.8-fold), glutamine (37%), and alanine (93%) and in some TCA cycle-associated components in the brain including glucose, lactate, and pyruvate, and decreases in brain cytosolic NAD⁺/NADH ratio, β-hydroxybutarate, and ATP content (Kosenko et al. 1993). Rats with high NH₄⁺ intake from administration of 20% ammonium acetate in the diet and 5 mM ammonium acetate in the water for up to 15 days had a decreased number of available somatostatin receptors in the frontoparietal cortex and hippocampus (Boyano-Adánez et al. 1996). Since somatostatin hyperpolarizes neurons in the cerebral cortex, the study authors speculated that this reduction in available receptors may contribute to the alteration of electrophysiological properties of neural tissue caused by excess NH₄⁺ (Boyano-Adánez et al. 1996). Binding of [H³]MK-801 (an NMDA receptor antagonist) to NMDA receptors was reduced by approximately 60% in cerebellar cell cultures from 8-day-old rats exposed to NH₄⁺ in utero and during lactation (dams received 4,293 mg ammonium/kg/day in the diet from gestational day 1 through lactation day 8) (Miñana et al. 1995). Additionally, aspartate aminotransferase (AST) induction was absent in treated neurons (occurred in neurons from control rats), which also indicates impairment of NMDA receptors. Treated neurons were much more resistant to the toxic effects of glutamate than control neurons; since glutamate toxicity is mediated by NMDA receptors, attenuation of glutamate toxicity is indicative of impaired NMDA receptor function (Miñana et al. 1995). Loss of glial fibrillary acidic protein (GFAP) has been shown to occur in human spontaneous hyperammonemia (Kimura and Budka 1986; Kretzschmar et al. 1985; Sobel et al. 1981) and in other hyperammonemia models, such as portacaval shunt rats (Bodega et al. 1991; Suárez et al. 1992), but was not evident after exposure of rats to ammonium acetate (20% ammonium acetate in the diet and 5 mM ammonium acetate in the water for up to 90 days) (Bodega et al. 1993). Rats fed 19.5% ammonium acetate in the diet had increased NH₄⁺ levels in the brain and altered assembly and disassembly of tubulin, an essential component of the axonal transport system in the brain (Miñana et al. 1989a). The amount of polymerized tubulin increased but the amount of free tubulin was not affected. In vitro experiments using brains of rats fed a diet high in NH₄⁺ indicated that the cause of the alteration might be a modification of the tubulin (and not the microtubule-associated proteins [MAPs], which modulate polymerization of the tubulin), which may result in a disruption in neurotransmission (Miñana et al. 1989a). Additional studies in rats brain showed that tubulin was significantly increased specifically in the septum, ventral hippocampus, dorsal hippocampus, hypothalamus, reticular formation, and frontal cortex, but not in the temporal amigdala, mammillary nucleus, locus coeruleus, caudate nucleus, or cingulate cortex after 2 months on the high ammonia diet (Miñana et al. 1989b).

3.2.2.5. Reproductive Effects

No information was located regarding reproductive effects of ammonia or ammonium compounds in humans or animals following oral exposure.

3.2.2.6. Developmental Effects

No information was located regarding the developmental effects of ammonia or ammonium compounds in humans. Rats exposed to NH₄⁺ in utero and during lactation (dams received 4,293 mg ammonium/kg/day in the diet from gestational day 1 through lactation day 21), which then received a normal diet, had a statistically significant reduction in body weight gain (Miñana et al. 1995); body weight was reduced by 25 and 16% in male and female offspring, respectively, at 120 days of age. Rats that were continued on the same ammonia diet as their dams had an even greater decrease in body weight gain (27 and 26% for males and females, respectively) at 120 days of age (Miñana et al. 1995). No information was provided in the study regarding the health of the dams, but it is likely that the high ammonium dietary concentration made them hyperammonemic. Body weights and food consumption by the dams throughout the study were not reported.

3.2.2.7. Cancer

No information was located regarding carcinogenic effects of ammonia or ammonium compounds in humans following oral exposure. Exposure of mice to 193 mg ammonium/kg/day as ammonium hydroxide in drinking water for 2 years did not produce carcinogenic effects, nor did it affect spontaneous development of breast cancer, which is common to C3H female mice (Toth 1972). No evidence of a carcinogenic effect was found in mice treated by gavage with ammonia dissolved in water alone at a dose of 42 mg NH₄⁺/kg/day for 4 weeks or with diethyl pyrocarbonate alone, but 9 of 16 mice treated with a combination of ammonium and pyrocarbonate developed lung tumors (Uzvolgyi and Bojan 1980). The ammonia and pyrocarbonate may have reacted in vivo to form the carcinogen, urethane. In a group of mice treated with urethane, the incidence of lung tumors was 9 of 9. Data from studies in vitro cited by Uzvolgyi and Bojan (1980) demonstrated the formation of urethane from diethyl pyrocarbonate added to beverages containing ammonia. No lung tumors were observed in the offspring of mice exposed similarly to NH₄⁺ and diethyl pyrocarbonate during pregnancy or during lactation (Uzvolgyi and Bojan 1985). In another study, Tsujii et al. (1992a, 1995) tested the hypothesis that ammonia produced in the stomach in humans infected with Helicobacter pylori may play a role in the development of gastric cancer. Rats pretreated with the initiator N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) in the drinking water for 24 weeks before receiving 0.01% ammonia solution in the drinking water for 24 weeks had a statistically significantly greater incidence of gastric cancer (70% of rats) and number of tumors per tumor-bearing rat (2.1) than rats receiving only MNNG and tap water (31% and 1.3 tumors/rat) (Tsujii et al. 1992a). Additionally, the size, depth, and metastasis of the MNNG-initiated tumors were enhanced in the rats treated with ammonia (Tjusii et al. 1995). It can be estimated that the dose of ammonia received by the rats was approximately 42 mg/kg/day (the daily intake from food and water for the general population is approximately 0.3 mg/kg/day [WHO 1986]). The relevance of these studies to assess the cancer risk of oral exposure to ammonia is uncertain.

3.2.3.1. Death

Human and animal deaths involving dermal exposure to ammonia and ammonium have been reported (Prokop'eva et al. 1973; Slot 1938; Sobonya 1977), but the extent of exposure is not known, and effects were probably due to inhalation exposure as well. A 25-year-old woman exposed to ammonia gas from a broken pipe had burns on her face, arms, and torso, and had difficulty breathing and swallowing (Slot 1938). She was treated symptomatically and with supportive treatment, but died about a month after exposure (Slot 1938). Autopsy showed edematous, inflamed, hemorrhagic epiglottis, trachea, and lungs. Petechial hemorrhages were found on the heart and the kidneys were congested with hemorrhagic nephritis. A 25-year-old man died after a tank of anhydrous ammonia exploded near him while he was farming (Sobonya 1977). Immediately after exposure he had mild bilateral conjunctival edema, burns over about 30% of his body surface, bilateral pulmonary edema, and severe respiratory distress. He developed pneumonia and died on the sixtieth day post-exposure. In rats, LC₅₀ values of 112, 71.9, and 48.4 mg ammonia/L were determined for exposures of 15, 30, and 60 minutes, respectively (Prokop’eva et al. 1973). These data are presented in Table 3-3.

Table 3-3

Levels of Significant Exposure to Ammonia And Ammonium Compounds - Dermal.

3.2.3.2. Systemic Effects

No information was located on hematological, musculoskeletal, hepatic, endocrine, or body weight effects in humans or animals after dermal exposure to ammonia or ammonium.

Dermal or multiple route exposure to ammonia or ammonium has produced respiratory, cardiovascular, gastrointestinal, renal, dermal, and ocular effects.

Respiratory Effects. Respiratory effects have been reported in humans from exposure to massive amounts of ammonia gas, but no quantitative data were located. It is also unclear as to what extent the effects were a result of inhalation and dermal exposure. Tracheitis, bronchitis, edema, and bronchopneumonia were reported by Slot (1938). Lung infection and respiratory distress were reported in one case (Sobonya 1977). Dyspnea, rales, rhonchi, and blocked airways were found by Levy et al. (1964). The effects probably resulted from concurrent inhalation and dermal exposure. No information was located regarding respiratory effects of ammonia or ammonium in animals following dermal or ocular exposure.

Cardiovascular Effects. Elevated pulse, shock, and cardiac failure were reported in humans from accidental exposures to massive amounts of ammonia gas, but the extent of exposure was not quantified (Slot 1938). No information was located regarding cardiovascular effects of ammonia or ammonium in animals following dermal or ocular exposure.

Gastrointestinal Effects. Persistent vomiting was noted by Slot (1938) in human accidental massive exposure cases, but the extent of exposure was not quantified. Oral and pharyngeal burns and edema were reported by Levy et al. (1964) in four human males accidentally exposed to an unknown quantity of anhydrous ammonia. Inhalation exposure may have contributed to these effects also.

Renal Effects. Renal congestion and hemorrhagic nephritis were reported by Slot (1938) in six cases of accidental human exposures to highly concentrated aerosols of ammonium derived from anhydrous ammonia. The exposure level cannot be determined from the available data.

Dermal Effects. Skin and eyes are extremely sensitive to airborne ammonia or ammonium in water. The topical damage caused by ammonia is probably due mainly to its alkaline properties. Its high water solubility allows it to dissolve in moisture on these surfaces, react with fatty substances in the corneal layer, be absorbed into deeper layers, and inflict extensive damage (Jarudi and Golden 1973). Reports of skin damage in humans are numerous, but good quantitative data are lacking. The severity of the damage is proportional to concentration and duration of exposure; flushing with water immediately after contact alleviates or prevents effects. Burns, blisters, and lesions of the skin have been reported (Close et al. 1980; Flury et al. 1983; Shimkin et al. 1954; Slot 1938; Taplin et al. 1976; Walton 1973). Exposure levels associated with dermal effects are presented in Table 3-3.

Several case reports described exposure of individuals to ammonia liquid and/or gas that resulted in cutaneous burns (Amshel et al. 2000; da Fonseca et al. 1998; George et al. 2000; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Rosenbaum et al. 1998; Weiser and Mackenroth 1989). All exposures were occupationally related. Total body surface area burned ranged from 14 to 45% and most had at least small areas of full-thickness burns that required skin grafting. A summary of 12 case reports of liquid anhydrous ammonia injuries reported a range of percent body surface area burned of 3–22%, with 25% of the patients having full-thickness burn injuries (Millea et al. 1989). One case report included a skin litmus paper test that showed the pH of the skin to be 10 at the time of hospital admission (Amshel et al. 2000). Infection of the burn wounds was not uncommon, with most of the patients responding to antibiotic treatment. One person had facial and neck hyperemia, erythematous petechiae on one ear, and edematous and peeling lips (Latenser and Lucktong 2000). The individual with 45% total body surface area burned had additional severe injuries, including respiratory and ocular, and developed circulatory and hematological problems, which led to his death (George et al. 2000).

Rosenbaum et al. (1998) described two cases of young children (2–3 years old) who bit into ammonia pellets/capsules. Both children drooled and had ulcerative lesions on the tongue and/or on the buccal mucosa. One child had superficial ulcerations on the posterior esophageal wall and the other child had edematous, erythematous upper and lower lips with areas of desquamation, eschar of the hard palate, and edema and erythema of the supraglottic structures and upper trachea. Both children recovered without incident.

A single case report described a self-administered ammonium solution enema that resulted in anal pain, diffuse abdominal colic, and tenesmus (da Fonseca et al. 1998). Sigmoidoscopy showed diffuse erythematous friable mucosa with large ulcerations covered by yellowish exudate. Six days later, the ulcers had receded, but the colon was still erythematous. Three months postexposure, biopsies showed chronic inflammation and fibrosis of the rectum and sigmoid colon, but no stenosis.

Animal data regarding dermal and ocular effects of exposure to ammonia support the findings in humans. A number of cattle were acutely exposed to anhydrous ammonia fumes when a pipeline running through their pasture ruptured and leaked 1,800 barrels of ammonia in a short period of time (Morgan 1997). The ammonia combined with moisture in the air and formed a white cloud, which drifted south across two additional fields containing cattle. The noses of the cattle in the field with the pipeline turned black and peeled and the horns of cattle in an adjacent field turned black and peeled. Hair coats on all livestock within a 2-mile radius of the rupture were singed.

Ocular Effects. Reported ocular effects in humans following ammonia or ammonium exposure increase in severity with dose and duration. Good quantitative data are lacking, but symptoms progress as follows: inflamed eyes, lacrimation, swelling of the eyelids (Beare et al. 1988; Caplin 1941; Close et al. 1980; Ferguson et al. 1977; Jarudi and Golden 1973; Legters et al. 1981; Montague and Macneil 1980; O’Kane 1983; Price et al. 1983; Silverman et al. 1949; Stombaugh 1969; Verberk 1977; Ward et al. 1983), hyperemic conjunctiva (Caplin 1941; Hatton et al. 1979; Levy et al. 1964; Slot 1938; Sobonya 1977), transient blindness, blurred vision, and corneal abrasions (Latenser and Lucktong 2000), and sustained corneal damage (Caplin 1941; Grant 1974: Kass et al. 1972; McGuinness 1969; Stroud 1981; Yang et al. 1987). Ammonia is slightly irritating to human eyes at concentrations of 100 ppm (Ferguson et al. 1977), and immediately irritating to the eyes and throat at 698 ppm (Henderson and Haggard 1927). Exposure to an air concentration of 250 ppm is bearable for most persons for 30–60 minutes (Withers et al. 1986). Exposure levels associated with ocular effects are presented in Table 3-3.

Animal data regarding ocular effects of exposure to ammonium support the findings in humans. Corneal opacity has been observed in rabbits following brief exposures (2 seconds) to a solution of 28.5% ammonium hydroxide (Grant 1974). Volume administered was not reported. Cattle in an adjacent field to a pipeline that ruptured and released 1,800 barrels of ammonia had runny eyes; two cows in the same field with the ruptured pipeline were euthanized because of blindness and respiratory distress (Morgan 1997).

3.2.3.3. Immunological and Lymphoreticular Effects

Secondary infections often complicate the clinical outcome of burns and respiratory lesions related to exposures to highly concentrated aerosols derived from anhydrous ammonia in which dermal and ocular exposure accompanies inhalation exposure (Sobonya 1977; Taplin et al. 1976). However, there is no evidence that the decreased immunological resistance represents a primary impairment of the immune system in humans. No information was located regarding the immunological effects of ammonia or ammonium in animals following dermal or ocular exposure.

No information was located regarding the following effects of ammonia or ammonium compounds in humans or animals following dermal or ocular exposure:

3.2.3.4.

Neurological Effects

3.2.3.5.

Reproductive Effects

3.2.3.6.

Developmental Effects

3.2.3.7. Cancer

Carcinogenic potential of ammonia has not been established in humans or animals by the dermal route of exposure. One case report was found of a person who developed epidermal carcinoma of the nasal septum 6 months after being badly burned by accidental contact with a refrigeration ammonia-oil mixture (Shimkin et al. 1954). It is unclear whether ammonia played a role in this tumor development. No other reports were located, although many cases of contact with ammonia from spills have been followed for more than 6 months after exposure.

3.4.1.1. Inhalation Exposure

Experiments with volunteers show that ammonia, regardless of its tested concentration in air (range, 57–500 ppm), is almost completely retained in the nasal mucosa (83–92%) during short-term exposure, i.e., up to 120 seconds (Landahl and Herrmann 1950). However, longer-term exposure (10–27 minutes) to a concentration of 500 ppm resulted in lower retention (4–30%), with 350–400 ppm eliminated in expired air by the end of the exposure period (Silverman et al. 1949), suggesting an adaptive capability or saturation of the absorptive process. Nasal and pharyngeal irritation, but not tracheal irritation, suggests that ammonia is retained in the upper respiratory tract. Unchanged levels of blood-urea-nitrogen (BUN), non-protein nitrogen, urinary-urea, and urinary-ammonia are evidence of low absorption into the blood. Exposure to common occupational limits of ammonia in air (25 ppm) with 30% retention (and assuming this quantity is absorbed into the blood stream) would yield an increase in blood ammonium concentration of 0.09 mg/L (calculated by WHO 1986). This calculated rise is only 10% above fasting levels, as reported by Conn (1972).

Animal data provide supporting evidence for high-percentage nasal retention, thus protecting the lower respiratory tract from exposure (Dalhamn [1963] and Boyd et al. [1944], rabbit; Egle [1973], dog). Continuous exposure of rats for 24 hours to concentrations up to 32 ppm resulted in significant increase in blood ammonia levels (Schaerdel et al. 1983). Exposures to 310–1,157 ppm led to significantly increased blood concentrations of ammonia within 8 hours of exposure initiation, but blood ammonia returned to pre-exposure values within 12 hours of continuous exposure and remained so over the remaining of the 24-hour exposure period. This suggests an adaptive response mechanism may be activated with longer-term exposure (Schaerdel et al. 1983).

3.4.1.2. Oral Exposure

Case reports of human ingestion of household ammonia (ammonium hydroxide) provide evidence of its absorption by this route, but few provide quantitative data. For example, in a fatal case of a man who drank an unknown amount of a 2.4% solution of ammonium hydroxide, analysis of the contents of the stomach and blood showed ammonium ion concentrations of 153 and 33 ppm, respectively (Klendshoj and Rejent 1966). In a study of volunteers, ingestion of a single ammonium chloride tablet (approximately 15 mg NH₄⁺/kg/day) led to a small transient increase (33% above fasting levels) in arterial blood concentrations of ammonium ion in 11 out of 20 subjects (Conn 1972); no change was noted in the remaining nine subjects in this group. Among 50 cirrhotic patients, increases of about 150% were noted in arterial blood concentrations of ammonium ion and return to normal levels was slow (Conn 1972). These data indicate that ingested ammonia is readily absorbed from the digestive tract and that the liver plays a large role in removing it from the blood (Conn 1972). Analysis of urine samples from subjects on high and low protein diets and given ¹⁵N-ammonium chloride, showed that 30–65% of labeled nitrogen from ¹⁵N-ammonium chloride is absorbed and metabolized (Richards et al. 1975). Oral administration of ¹⁵NH₄Cl to a group of six subjects for six days resulted in absorption of at least 38.7% of the administered radioactivity as determined by the amount of ¹⁵N that appeared in urinary urea within 24 hours of the last ¹⁵NH₄Cl ingestion (Metges et al. 1999).

Ammonium ion is endogenously produced in the human digestive tract, much of it arising from the bacterial degradation of nitrogenous compounds from ingested food. About 4,200 mg/day are produced, greater than 70% of which is synthesized or liberated within the colon and its fecal contents. The total amount absorbed is about 4,150 mg/day, or 99% of the amount produced (Summerskill and Wolpert 1970); absorption after oral loading of NH₄⁺ is similarly complete (Fürst et al. 1969). Evidence from Castell and Moore (1971) and Mossberg and Ross (1967) suggests that absorption of NH₄⁺ increases as the pH of the contents of the lumen increases, and that the ammonium ion is actively transported at the lower pH levels (pH 5 was lowest detected absorption). Ammonium ion absorbed from the gastrointestinal tract travels via the hepatic portal vein directly to the liver, where in healthy individuals, most of it is converted to urea and glutamine. Human and animal data show that little of it reaches the systemic circulation as ammonia or ammonium compounds, but that it is a normal constituent of plasma at low levels (Brown et al. 1957; Pitts 1971; Salvatore et al. 1963; Summerskill and Wolpert 1970). Analysis of plasma drawn from 10 healthy young male subjects yielded endogenously derived NH₄⁺ concentrations ranging from 30 to 55 μg NH₃/100 mL, with a mean of 39 μg/100 mL (Brown et al. 1957).

3.4.1.3. Dermal Exposure

Quantitative data on absorption from exposure by the dermal route were not located in the available literature. Human case reports of dermal exposure describe local damage (burns, irritations). One report of case histories of five persons exposed to an exploding, bursting anhydrous ammonia gas pipe indicated there was systemic toxicity (vomiting, renal congestion, delirium), but exposure was by inhalation as well as dermal route, and it is impossible to delineate a systemic dermal exposure contribution (Slot 1938). WHO (1986) concluded that systemic effects from skin and eye exposure are not quantitatively important. Ammonia is readily absorbed into the eye; it was found to diffuse within seconds into cornea, lens, drainage system, and retina (Beare et al. 1988; Jarudi and Golden 1973). However, amounts absorbed were not quantified, and absorption into systemic circulation was not investigated.

3.4.2.1. Inhalation Exposure

No quantitative reports of distribution of ammonia from inhalation exposure were found in the available literature. Absorption data from human inhalation exposure suggest that only small amounts of ammonia are absorbed into the systemic circulation (Silverman et al. 1949; WHO 1986). Initial retention of inhaled ammonia in the mucus of the upper respiratory tract may be 80% or more, but after equilibrium is established (within 30 minutes) 70–80% of inspired ammonia is expired in exhaled air (Silverman et al. 1949). The lack of change in blood nitrogen compounds and urinary-ammonia compounds lends further support to a limited absorption into the systemic circulation (Silverman et al. 1949). Toxic effects reported from inhalation exposure suggest local damage, or changes resulting from necrotic tissue degradation, rather than the presence of elevated levels of NH₄⁺, per se, in tissues other than the respiratory/pharyngeal tissues. Information on the distribution of endogenously-produced ammonia suggests that any NH₄⁺ 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 by urinary excretion, or converted by the liver to glutamine and urea. If present in quantities that overtax these organs, NH₄⁺ is distributed to other tissues and is known to be detoxified in the brain (Takagaki et al. 1961; Warren and Schenker 1964).

3.4.2.2. Oral Exposure

Human oral exposure data for NH₄⁺ clearly indicate that it readily enters the portal circulation and is delivered to the liver (Conn 1972; Fürst et al. 1969), as has been shown to be the case for endogenously produced NH₄⁺ (Pitts 1971; Summerskill and Wolpert 1970). In nitrogen-deficient persons, NH₄⁺ (as ammonium acetate) administered orally was absorbed and carried directly to the liver where most of it was converted to urea and excreted in the urine; little change in the negative nitrogen balance was observed (Fürst et al. 1969). Output of urea from the liver corresponded to the amount of NH₄⁺ ingested (Fürst et al. 1969).

Un-ionized ammonia is freely diffusible, whereas the ammonium ion is less so and is relatively confined to the extracellular compartment (Stabenau et al. 1958). However, ammonium ion is in dynamic equilibrium with dissolved ammonia. Therefore, ammonium compounds that enter the circulatory system or other body fluids can thus freely penetrate tissue cells as ammonia. In hypophysectomized rats that were administered ¹⁵N-ammonium citrate orally by gavage, labeled protein was found in liver, kidney, spleen, heart, and skeletal muscle 6–72 hours after ¹⁵N-ammonium citrate administration (Vitti et al. 1964). The percentages of ingested label absorbed and then excreted as urea in the urine were not provided (Vitti et al. 1964).

3.4.2.3. Dermal Exposure

No quantitative data on distribution of ammonia from dermal exposure were located in the available literature. Toxic effects from dermal exposure suggest that little or no ammonia gains entry into the systemic circulation by this route.

3.4.2.4. Other Routes of Exposure

Intravenous administration of NH₄⁺ (as ammonium salts) to people with a nitrogen deficiency (in negative nitrogen balance) resulted in an increase in the peripheral blood NH₄⁺ level and a shift in the nitrogen balance from negative to positive; no increase in urinary urea was seen (Fürst et al. 1969). The nitrogen from NH₄⁺, which gains entry into the general circulation, is distributed to cells throughout the body and incorporated into tissues (Fürst et al. 1969; Vitti et al. 1964). After intraperitoneal injection of ammonium chloride in mice, ammonia distributes to brain tissues within 20 seconds (Warren and Schenker 1964), and in rats, brain concentrations increase dramatically within 5 minutes (Salvatore et al. 1963). Tissues other than blood and brain were not analyzed by these researchers. Comparative patterns of distribution of ¹⁵N-labeled ammonium citrate indicate that the amount of NH₄⁺ taken up by tissues other than the liver is greatest by subcutaneous injection, less by intraperitoneal injection, and least following intragastric administration. Intravenous administration of ¹⁵N-labeled ammonium salts leads to rapid distribution of ¹⁵N-labeled metabolites throughout the body, with the highest levels of labeled urea appearing in the kidney and liver, and lesser amounts in heart, spleen, brain, testes, and carcass. Highest levels of labeled glutamine were found in heart and liver, with lesser amounts in brain, spleen, carcass, kidney, and testes (Duda and Handler 1958).

3.4.4.1. Inhalation Exposure

Studies using low levels of ammonia show that inhaled ammonia is temporarily dissolved in the mucus of the upper respiratory tract, and then a high percentage of it is released back into the expired air. Following exposure to 500 ppm ammonia for 10–27 minutes, healthy male subjects eliminated 70–80% of the inspired ammonia by this route (Silverman et al. 1949). Analysis of endogenous ammonia levels in the expired air of rats showed concentrations ranging from 10–353 ppb (mean=78 ppb) in nose-breathing animals (Barrow and Steinhagen 1980).

The quantitative difference between inspired and expired ammonia suggests that small amounts are absorbed across the nasopharyngeal membranes into the systemic circulation. Absorbed ammonia is excreted by the kidneys as urea and urinary ammonium compounds (Gay et al. 1969; Pitts 1971; Richards et al. 1975; Summerskill and Wolpert 1970), as urea in feces (Richards et al. 1975), and as components of sweat (Guyton 1981; Wands 1981), but quantitative data are lacking. Toxic levels do not develop as a result of chronic inhalation exposure because the body has multiple effective mechanisms for detoxifying and excreting it.

3.4.4.2. Oral Exposure

Excretion data for humans orally exposed to ammonia have been quantified with respect to excretion of isotope from ¹⁵N-labeled ammonium salts, thus providing an indication of the turnover rate of the compound within the body and excretion route of its metabolites. Approximately 72% of a dose of ¹⁵N was excreted in the urine of three subjects within 3 days of ingestion of ammonium salts in drinking water; 25% (24% urinary urea and 1% urinary NH₄⁺) was eliminated within the first 6 hours after exposure. Ammonium salt administered by gavage to humans led to a corresponding increase in blood urea concentration transported out of the liver, leading the authors (Fürst et al. 1969) to conclude that orally ingested ammonium salt is quickly and almost completely converted in the liver and eliminated from the body as urinary urea. Analysis of urine samples from subjects on high and low protein diets showed higher cumulative excretion of ¹⁵N (percent of dose) in the urine of the high protein group (approximately 70%) than that of the low protein group (35%). Small amounts of labeled nitrogen were also excreted as urea in feces (Richards et al. 1975).

These data correspond to that for excretion of endogenously produced ammonia (Davies and Yudkin 1952; Muntwyler et al. 1956; Summerskill and Wolpert 1970; Van Slyke et al. 1943). Ammonia is also known to be excreted via sweat (Guyton 1981; Wands 1981) and expired air (Barrow and Steinhagen 1980; Larson et al. 1980; Robin et al. 1959; Utell et al. 1989); quantitative data are unavailable for excretion via sweat.

3.4.4.3. Dermal Exposure

Data regarding excretion of ammonia absorbed following dermal exposure were not located in the available literature.

3.4.4.4. Other Routes of Exposure

Data are available on exposure of humans and dogs to ammonium salts by intravenous injection. Excretion of isotope after ¹⁵N-ammonium lactate injection in three human subjects yielded 5–7% of isotope excreted as urinary NH₄⁺ in the first 6 hours postexposure, and another 2% within 3 days. Approximately 6% of the isotope was excreted as urea in urine in the first 6 hours. An average of approximately 60% of the dose of label was excreted in urine within 3 days. These data are considerably different from that resulting from oral loading (as described in Section 3.4.4.2). Intravenous loading led to decreased labeling of urinary urea and grossly increased labeling of urinary ammonia; the differences are attributed by the authors to a "first pass" effect from oral loading (Gay et al. 1969). The hepatic transformation of ammonium ion to urea is so efficient that relatively little unconverted ammonium salt is released to the general circulation.

Intravenous exposure of seven dogs to 107 mg/kg ammonium acetate led to amounts ranging from 0.044 to 0.073 mg ammonia excreted in expired air. No measurable amount of ammonia was present in expired air during the pre-exposure control period (Robin et al. 1959).

Biomarkers of Exposure and Effect

Exposure. There are no known specific biomarkers of exposure for ammonia in humans or animals. Furthermore, no evidence for alterations in clinical indices of body ammonia or nitrogen levels after exposure to exogenous ammonia has been reported. It does not seem useful at this time to develop biomarkers of exposure for ammonia because after exposure to low levels, ammonia is either rapidly cleared from the body or metabolized to compounds found endogenously at appreciable levels. Exposure to high concentrations is immediately and overtly toxic, which eliminates the need for a more subtle biomarker.

Effect. There are no known specific biomarkers of effect for ammonia in humans or animals. Lesions produced by exposure to high concentrations of ammonia are similar to those produced by other caustic substances.

Absorption, Distribution, Metabolism, and Excretion. Measurement of ammonia absorption is complicated by the appreciable levels of endogenously produced ammonia. Although, most of the inhaled ammonia is retained in the tissues of the upper respiratory tract, inhalation exposure to low levels of ammonia can result in a small amount of absorption (Silverman et al. 1949). As the ammonia concentration increases, the ability of the upper respiratory tract to retain ammonia is saturated, and a larger percentage is absorbed into the blood stream (Silverman et al. 1949). Absorption into the systemic circulation after oral exposure is limited (Metges et al. 1999). Ammonium ions absorbed from the gastrointestinal tract travels via the hepatic portal vein directly to the liver where, in healthy individuals, most of it is converted to urea and glutamine. Although it has not been extensively studied, dermal absorption of ammonia does not occur to a great extent; WHO (1986) concluded that systemic effects from skin and eye exposure to ammonia are not quantitatively important. Data are not available to assess the distribution of ammonia in humans or animals. Studies examining the distribution of ammonia would be useful for identifying potential targets of toxicity. Studies on endogenously produced ammonia, however, indicate that it is distributed to most of the organs and tissues of the body. Extensive work has been completed on the metabolism of ammonia and its participation in the glutamine cycle and the urea cycle (Duda and Handler 1958; Fürst et al. 1969; Richards et al. 1975; Vitti et al. 1964). Data regarding excretion are limited but it is known that ammonia inhaled at low levels is excreted primarily unchanged in the expired breath (Silverman et al. 1949); NH₄⁺ absorbed from the gastrointestinal tract is excreted primarily in the urine as urea and other urinary nitrogen compounds (Gay et al. 1969; Pitts 1971; Richards et al. 1975; Summerskill and Wolpert 1970). No information regarding excretion after dermal exposure was located.

Comparative Toxicokinetics. Available data indicate that ammonia has similar targets of toxicity in humans and animals. Ammonia is most hazardous as a site-of-contact toxicant; therefore, the respiratory system is most vulnerable after inhalation exposure, the gastrointestinal tract is most vulnerable after oral exposure, and the skin and eyes are most vulnerable after dermal/ocular exposure. Limited human and animal data are available for toxicokinetics; however, these data indicate that humans and animals are probably very similar regarding the toxicokinetic disposition of ammonia. Furthermore, it is reasonable to expect, especially given the biochemical importance of ammonia, that humans and animals would handle this compound similarly.

Methods for Reducing Toxic Effects. There are limited specific data on reducing the toxic effects of ammonia. Many of the methods are generic approaches, such as getting to an area with fresh air and removal of contaminated clothing. No methods were identified for reducing the body burden or interfering with the mechanisms of toxicity. Studies designed to identify methods for interfering with the damage associated with direct contact with ammonia would be useful.

Children’s Susceptibility. There are limited data on the toxicity of ammonia in children and no information on effects in adults who were exposed as children. A higher incidence of respiratory diseases was found in school children exposed to airborne ammonia and other chemicals (Gomzi 1999; Gomzi and Šarić 1997). There is no indication that children are more susceptible to the effects of ammonia than adults; studies of children and adults exposed to ammonia would be useful for assessing potential age-related differences in ammonia toxicity.

Child health data needs relating to exposure are discussed in Section 6.8.1 Identification of Data Needs: Exposures of Children.