EPA/600/8-89/052F
June 1989
Summary Review of Health Effects
Associated with Ammonia
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
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Preface
The Office of Health and Environmental Assessment has prepared this
health assessment-to serve as a source document for EPA use. The summary
health assessment was developed for use by the Office of Air Quality Planning
and Standards to support decision making regarding possible regulation of
ammonia as a hazardous air pollutant.
In the development of the assessment document, the scientific literature
has been inventoried through January 1989, key studies have been evaluated,
and summary/conclusions have been prepared so that the chemicals' toxicity
and related characteristics are qualitatively identified. Observed effect levels
and other measures of dose-response relationships are discussed, where
appropriate, so that the nature of the adverse health responses is placed in
perspective with observed environmental levels.
Any information regarding sources, emissions, ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air. While
the available information is presented as accurately as possible, it is
acknowledged to be limited and dependent in many instances on assumption
rather than specific data. This information is not intended, nor should it be
used, to support any conclusions regarding risk to public health.
If a review of the health information indicates that the Agency should
consider regulatory action for this substance, considerable effort will be
undertaken to obtain appropriate information regarding sources, emissions,
and ambient air concentrations. Such data will provide additional information
for drawing regulatory conclusions regarding the extent and significance of
public exposure to this substance.
in
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Abstract
Ammonia is a colorless gas with a repellent odor. It is a naturally
occurring compound in the environment; however, it is also released into the
environment from ammonia production facilities and during the manufacture
and use of ammonia-containing products.
Ammonia is a central compound in the environmental cycling of nitrogen
and is involved in major processes such as mineralization, nitrification, and
nitrogen fixation. In the atmosphere, ammonia may undergo many
transformations and is expected to have a relatively short residence time of 5
to 10 days.
Ammonia is a key metabolite in mammals and plays an essential role in
acid-base regulation and biosynthesis of purines, pyrimidines, and non-
essential amino acids. However, ammonia is a toxic gas and in experimental
animals, effects from acute exposure to ammonia gas have ranged from mild
irritation of the respiratory system and mucous membranes to convulsions,
acute pulmonary edema, coma, and death. Continuous or repeated exposure
of animals to sublethal concentrations of ammonia gas have produced adverse
effects on the respiratory tract, liver, kidneys, and spleen.
Quantitative data on the toxic effects of ammonia in humans is limited.
Accidental exposure of humans to unspecified concentrations of ammonia has
resulted in burns of the eyes, skin, and respiratory tract and in death. Chronic
exposure of humans to 40 ppm ammonia has resulted in headache, nausea,
and reduced appetite. A definite conclusion regarding the possible
reproductive/teratogenic, mutagenic, or carcinogenic potential of ammonia
cannot be drawn because of the lack of adequate studies.
IV
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Table of Contents
Preface ijj
Abstract \[\\ jv
Tables '.'.'.'.'.'.'.'.'.'' vi
Figures '.'.'.'.'.'.'.'.'. vi
Authors, Contributors, and Reviewers Vii
1. Summary and Conclusions 1-1
2. Background Information 2-1
2.1 Chemical Characterization and Measurement 2-1
2.2 Sources and Emissions 2-2
2.3 Environmental Release and Exposure '.'.'.'.'.'.'. 2-2
2.4 Environmental Effects 2-6
3. Health Effects 3.!
3.1 Pharmacokinetics and Metabolism '.'.'.'.'.'.'. 3-1
3.2 Biochemical Effects 3.3
3.3 Acute Toxicity 3.7
3.4 Subchronic Toxicity 3-10
3.5 Chronic Toxicity \ . 3-14
3.6 Carcinogenicity '.'.'.'.'.'. 3-14
3.7 Mutagenicity 3-14
3.8 Teratogenicity and Reproductive Effects 3-15
3.9 Neurotoxicity 3_15
3.10 Effects on Humans ' " ^ 3-15
3.10.1 Ocular Toxicity 3-15
3.10.2 Respiratory Toxicity 3-15
3.10.3 Burns of the Skin 3-17
3.10.4 Other Effects 3-17
3.10.5 Experimental Studies '.'.'.'.'.'.'. 3-17
3.10.6 Epidemiology 3-19
4. References 4_1
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List of Tables
No.
2-1
2-2
2-3
3-1
3-2
Occupations with potential exposure to ammonia
Acute lethal concentration values for ammonia in fish . . .
Acute lethal concentration values for unionized ammonia
in aquatic invertebrates
Acute toxicity values for ammonia in laboratory animals ,
Results of subchronic exposures to ammonia gas in
several species
2-7
2-8
2-11
3-8
3-11
List of Figures
2-1
Generalized representation of the nitrogen cycle 2-3
VI
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Authors, Contributors, and Reviewers
The following personnel of Dynamac Corporation were involved in the
preparation of this document: Finis Cavender, Ph.D.' (Department Director);
Nicolas P. Hajjar, Ph.D. (Project Manager/Principal Author); Dana Cazzulino,
Cyrus Hamidi, Y'vonne Jones-Brown, Ph.D., Lawrence Kaufman, Ph.D.,
Leonard Keifer, Ph.D., and Kumar D. Mainigi, Ph.D. (Authors); William
McLellan, Ph.D. (Reviewer); Anne Gardner (Technical Editor); and Gloria Fine
(Information Specialist). This document was prepared under contract with the
Environmental Criteria and Assessment Office, EPA, Research Triangle Park,
NC (Beverly Comfort, Project Manager).
This document has been reviewed for scientific and technical merit by the
following scientists: Professor William J. White, Department of Comparative
Medicine, Milton S. Hershey Medical Center, Pennsylvania State University,
Hershey, PA, 17033; Professor I. W. Waters, Research Institute of
Pharmaceutical Sciences, University of Mississippi, University, MS 38677; Dr.
D. Burrows Schaub, Burrows Associates, Ltd., Fredrick, MD 21701. In addition,
it has been reviewed by members of the Human Health Assessment Group
(HHAG) and the Exposure Assessment Group (EAG) of the Office of Health
and Environmental Assessment (OHEA), EPA, Washington, DC.
VII
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1. Summary and Conclusions
Ammonia (CAS No. 7664-41-7) is a colorless gas with a repellent odor. It
is very soluble in water with a high vapor pressure and a low vapor density.
Ammonia was ranked fourth among the chemicals produced in the United
States in 1987. It is used in the manufacture of fertilizers, fibers and plastics,
and explosives.
Ammonia is released into the environment from ammonia production
facilities via industrial gaseous emissions and aqueous waste streams as well
as during the manufacture and use of ammonia-containing products. It is also
a naturally occurring compound and a product of animal, fish, and microbial
metabolism. Ambient air concentrations range from 0.1 to 9.0 pg/ms, although
higher levels may be found in the vicinity of point sources.
The Occupational Safety and Health Administration has established an 8-
hour TWA permissible exposure limit for ammonia of 50 ppm (35 mg/m3).
Analytical methods used to determine ammonia include colorimetry, titrimetry,
conductimetry, specific ion electrode, ion chromatography,
chemiluminescence, absorption spectroscopy, gas chromatography, and mass
spectrometry.
Ammonia is a central compound in the environmental cycling of nitrogen
and is involved in major processes such as mineralization, nitrification, and
nitrogen fixation. Under most environmental conditions, the ammonium ion
(NH4 + ) is expected to predominate. The ammonium ion is less mobile than
unionized ammonia (NH3) in soil and water. In the atmosphere, ammonia may
undergo many transformations and is expected to have a relatively short
residence time of 5 to 10 days. The most important transformation is its
solution in water droplets together with sulfur dioxide or other gases to form
aerosols, with up to 75 percent removal by rainout.
Ammonia is moderately toxic to aquatic organisms and is more toxic than
the ammonium ion. The acute toxicity of unionized ammonia to fish has been
extensively studied. The 24- and 96-hour acute LDSO values for fish range from
0.07 to 12.7 mg/L, with salmonid species generally being more sensitive.
Aquatic invertebrates have a range of sensitivity comparable to that of fish and
show a varying sensitivity with developmental stages.
Ammonia gas is readily absorbed through the lungs as indicated by
increased ammonia concentrations in the blood following exposure. However,
the increase in blood levels is not exposure-related, so that only modest
increases are noted at higher exposures. Retention of ammonia in the
respiratory tract of dogs exposed to 450 to 1,500 ppm and humans exposed to
up to 500 ppm is >80 percent. Following absorption, ammonia is incorporated
into the amino acid pool and other organic molecules. However, the route of
administration drastically alters the distribution of ammonia between alpha-
amino, amidine, and amide nitrogen of organ proteins. Ammonia is
metabolized largely by pathways involving hepatic glutamic dehydrogenase
and carbamyl synthetase following intragastric and intraperitoneal
administration, whereas the glutamic synthetase route is involved following
subcutaneous and intravenous administration. Approximately 90 percent of
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15N-labeled ammonia administered intravenously to rats was incorporated into
glutamic amide nitrogen (80 percent) and urea (10 percent). Low levels of
labeled 15N (expressed as glutamme and ureas) were found in various tissues
and organs. Ammonia is excreted as urea in mammals, but excretion was also
found to occur via the lungs in expired air of several experimental animals and
human subjects exposed to NH3 vapor or injected intravenously with ammonia
acetate.
Ammonia is a key metabolite in mammals and .plays an essential role in
acid-base regulation and biosynthesis of purines, pyrimidines, and
nonessential amino acids. Elevated levels of endogenous ammonia resulting
from metabolic and genetic disease have caused liver failure, neurologic
disorders, and encephalopathy. There is no information on the potential risk to
humans with genetic or metabolic disorders as a result of exposure to
exogenous ammonia. In experimental ammonia toxicity studies with animals,
alteration in metabolic and functional aspects of the brain, changes in
neurotransmitter levels, involvement of glial cells, and alterations in the blood-
brain barrier have been noted.
Ammonia is a toxic, gaseous compound at relatively moderate
concentrations. In animals, compound- and concentration-related effects of
acute exposure to ammonia gas progress from mild irritation of the respiratory
system and mucous membranes to convulsions, acute pulmonary edema,
coma, and death. The acute inhalation LC50 values for a 60-minute exposure
period are 4,230 ppm in mice and 14,140 and 19,770 ppm in male and female
rats, respectively. The data on acute exposure to low levels of ammonia are
conflicting; however, no signs of irritation or histological changes were seen in
the respiratory tract of rats exposed to 4 ppm ammonia for up to 7 days.
Continuous or repeated exposure of animals to sublethal concentrations of
ammonia has produced adverse effects in the tissues of the respiratory tract,
liver, kidneys, and spleen. It may also increase the tendency towards, and/or
severity of, respiratory tract infections by reducing trachea! ciliary activity and
the phagocytic activity of pulmonary alveolar macrophages and may produce
anorexia. No clinically significant effects were noted in rats, guinea pigs,
rabbits, dogs, or monkeys continuously exposed to ammonia at a
concentration of 57 ppm for 114 days.
No adequate information was found on the effects of chronic exposure to
ammonia in animals. Ammonium hydroxide administered in drinking water to
Swiss mice at levels of 0.1, 0.2, or 0.3 percent or to C3H mice at a level of 0.1
percent was not carcinogenic. In another study a significant increase in lung
tumors was not found in mice after administration of 42 mg/kg ammonia twice
a week for 4 weeks. Limited data suggest that ammonium hydroxide may be
mutagenic to Escherichia coli and Drosophila melanogaster. Ammonium
chloride was also found to reduce multiplication of 3T3 and SV-40 transformed
3T3 mouse fibroblasts. Teratogenicity or reproductive studies in mammals
were not reported for ammonia in the available literature. Additional data are
needed to determine the chronic effects and mutagenic, teratogenic, and
reproductive potential of ammonia.
Accidental exposure of humans to unspecified concentrations of ammonia
has resulted in burns of the eyes, skin, and respiratory tract and in death. Both
immediate and long-term effects have been associated with ammonia
exposure. Chronic exposure to 40 ppm ammonia vapor has resulted in
headache, nausea, and reduced appetite. In experimental studies,
hyperventilation, lacrimation, and nasal irritation were noted in subjects
exposed at 500 ppm for 30 minutes, but no changes were noted for blood urea
and nonprotein nitrogen, although increases in nonprotein nitrogen levels were
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observed with longer (4-hour) exposure periods. In another study, exposure at
concentrations of 50 ppm or less did not cause irritation or discomfort. In
repeated exposure studies (25, 50, or 100 ppm for 6-hour sessions once a
week for 6 weeks), no apparent changes were noted in respiratory rate, blood
pressure, pulse, or forced vital capacity. The frequency of mild eye irritation
decreased in the later sessions, suggesting adaptation. No adequate studies
were found on the adverse effects of chronic occupational exposure to
ammonia. Ammonia is classified as group D "not classifiable as to human
carcinogenicity" based on the weight-of-evidence approach in the current EPA
guidelines for carcinogen risk assessment.
1-3
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2. Background Information
This overview provides a brief summary of the data available on the health
effects from exposure to ammonia. Emphasis is placed on determining
whether there is evidence to suggest that ammonia exerts effects on human
health under conditions and at concentrations commonly experienced by the
general public. Both acute and chronic effects are addressed, including
general toxicity, teratogenicity, mutagenicity, and carcinogenicity. To place the
health effects discussion in perspective, this report also reviews certain air
quality aspects of ammonia in the United States, including sources,
distribution, fate, and concentrations associated with rural, urban, and point-
source areas.
2.1. Chemical Characterization and Measurement
Ammonia (CAS No. 7664-41-7) has the empirical and molecular formula
NH3. It is a colorless gas at room temperature with a sharp and repellent odor
and a molecular weight of 17.03. Ammonia is very soluble in water (34 percent
at 20 °C or about 531 g/L at 20 °C) and has a high vapor pressure (8.7 atm at
20°C) and a low vapor density (0.6 g/L) (TDB; Verschueren, 1983).
For determination of ammonia in air, it is first necessary to absorb the
ammonia in a liquid. Sampling air for determination of trace amounts of
ammonia has several inherent problems: minimization of human ammonia
contamination, the propensity of ammonia to adsorb to all surfaces, especially
at low concentrations, differentiation of aerosol ammonia and gaseous
ammonia, and inefficiency of bubbler samplers. After sample collection,
ammonia concentrations are determined by established methods including
colorimetry, titrimetry, conductimetry, specific ion electrode, ion
chromatography, chemiluminescence, absorption spectroscopy, or gas
chromatography and mass spectrometry (National Research Council, 1977).
Ammonia is determined in water or wastewater using one of the standard
methods developed for examination of water and wastewater; i.e., colorimetry,
titrimetry, or the ammonia-selective electrode (Franson, 1981).
Variations of the basic methods have also been instituted in an effort to
overcome difficulties inherent in the established methods. Such variations
include automated colorimetry (Skjemstad and Reeve, 1978; Bos, 1980;
Canelli, 1976), ion chromatography (Bouyoucos and Melcher, 1983), gas
chromatography (Hutchinson et a!., 1982), nonautomated colorimetry (Bower
and Holm-Hansen, 1980; Boo and Ma, 1976; Hampson, 1977), specific ion
electrode (Ferm, 1979), ring oven (Cattell and Du Cros, 1976), automated
distillation-spectrophotometry (Crowther and Evans, 1980),
chemiluminescence (McClenny and Bennett, 1980; Hales and Drewes, 1979),
air sampling techniques (Braman et al., 1982), coated piezoelectric crystals
(Guilbault, 1981; Hlavay and Guilbault, 1978), fluorescence (Abbas and
Tanner, 1981; Aoki et al., 1983; Aoki et al., 1986), teflon beads (Harward et al.,
1982), and harmonic diode laser system (Cappellani et al., 1985).
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2.2. Sources and Emissions
Domestic production capacity of ammonia in 1984 was approximately 18
million tons (Chemical and Engineering News, 1985). As of March 1985,
ammonia was produced domestically by 62 companies at 99 plant sites.
Ammonia was ranked fourth among the chemicals produced in the United
States in 1987 (Reisch, 1988) with a production volume of 16.2 million tons, an
increase of 15.4 percent from 1986 (Reisch, 1988).
Ammonia is manufactured primarily by a modified Haber reduction
method using atmospheric nitrogen and a hydrogen source (TDB). The major
producers of ammonia in the U.S. are CF Industries, Columbia Nitrogen,
Farmland Industries, Union Oil Company, and the Williams Companies
(Agrico). Major end uses for ammonia are in the manufacture of fertilizer (80
percent), fibers and plastics (10 percent), and explosives (5 percent)
(Chemical & Engineering News, 1985).
2.3. Environmental Release and Exposure
Ammonia is released into the environment from ammonia production
facilities via industrial gaseous emissions and aqueous waste streams. It is
also released during direct application of anhydrous ammonia and urea to soil
(National Research Council, 1977; Denmead et al. 1982; Reynolds and Wolf,
1987), the production of urea and ammonium nitrate, application of animal
waste as a fertilizer (National Research Council, 1977) and from animal
feedlots (Hutchinson et al., 1982), vegetation decay (Alkezweeny et al., 1986),
in process gas condensate from coal gasifiers (Hanson et al., 1985), and
automobile exhausts (Pierson and Brachaczek, 1983).
Ammonia is a product of animal metabolism as well as a chemical that is
manufactured and used in commerce. Ammonia is ubiquitous in the
environment, existing in equilibrium in two forms, mostly as a result of the
nitrogen cycle (Figure 2-1).
NH/ +
Ammonium
ion
H2O
NH3 +
Ammonia
Therefore, the fate of anthropomorphic ammonia in the environment should be
considered in the context that the compound is central to the environmental
cycling of nitrogen. A network of active and efficient, natural inorganic and
organic processes has trapped, transformed, produced, and/or used ammonia
before there were contributions from human sources. Consequently, the
ammonia that enters the environment from human sources enters a system
already adapted to the presence of ammonia and would be subject to the
same processes as naturally occurring ammonia. Some of the major
processes of the nitrogen cycle that involve ammonia include, with associated
reactions (unbalanced), the following (National Research Council, 1977):
Mineralization:
RNH2 + O2 -> CO2
Organic Oxygen Carbon
nitrogen dioxide
H2O
Water
+
Ammonia
ion
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Fixation by
Ionizing
Phenomena
(Lightning)
Juvenile (
Addition j
(Volcanoes) I
Atmospheric N2
Biologic Fixation
Industrial
Fixation
Denitrification
Shunt
Symbiotic
y Nonsymbiotic
Soil
Biosphere
I
Ammonium -»- Nitrite —»- Nitrate •
Nitrification Sequence
\ Sediments \
Figure 2-1. Generalized representation of the nitrogen cycle.
Source: National Research Council (1977).
Nitrification:
NH/
Ammonium
+ O2
Oxygen
H2O
Water
Nitrogen fixation:
N2
Nitrogen
gas
+ [HCHO]
Organic
matter
NH4
NO2"
Nitrite
CO2
Ammonium Carbon
ion dioxide
Ammonia is an important intermediate in the assimilation of nitrogen from
the soil by plants. Nitrogen is present in the soil largely in the organic form.
Before being assimilated by plants, it is normally mineralized by microbial
processes. The formation of ammonium ion is the first step in the
mineralization process. Most plants can assimilate ammonium ion, but the
ammonium ion may also be oxidized to the nitrate ion, the most common form
of mineralized nitrogen in soil, which may be assimilated by plants as well
(Andersson and Hooper, 1983; Cullimore and Sims, 1981; Lemon and Van
Houtte, 1980; Kholdebarin and Oertli, 1977; National Research Council, 1977).
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Nitrification is a two-step, energy-yielding process exploited for metabolic
energy by two specific genera of microorganisms. Ammonia is converted to
nitrite by Nitrosomonas, and nitrite is converted to nitrate by Nitrobacter. This
process occurs in soil and water (Andersson and Hooper, 1983; American
Petroleum Institute, 1981; Kholdebarin and Oertli, 1977).
Another source of mineralized nitrogen is from nitrogen fixation, where
gaseous nitrogen is transformed to ammonium ion, usually by metabolic
processes. Nitrogen fixation occurs in blue-green algae and a few genera of
microorganisms, which include aerobic organisms such as Azotobacter spp.,
anaerobic organisms such as Clostridium spp., and organisms in symbiotic
association with higher plants such as Rhizobium spp. (Bailey and Ollis, 1977;
National Research Council, 1977).
Industrial sources of ammonia are also a form of nitrogen fixation and are
included in the nitrogen cycle shown in Figure 2-1. Because the nitrogen cycle
is dynamic, no dramatic buildup of ammonia is expected to occur as a result
of these additional inputs. Also, volatilization, adsorption, and chemical
transformation will affect the fate of ammonia (American Petroleum Institute,
1981; Weiler, 1979; National Research Council, 1977).
In the atmosphere, ammonia may undergo many transformations and is
expected to have a relatively short residence time of 5 to 10 days. Probably
the most important removal mechanism is its solution in water droplets
together with sulfur dioxide or other gases to form aerosols, with up to 75
percent removal by rainout and washout. The principal product formed is
ammonium sulfate, but a number of secondary products can also be formed.
Reactions of ammonia with nitric acid or nitrogen dioxide may yield other
aerosols with the ammonium nitrate as the principal product. Other reactions
of ammonia, such as with OH radical, yield NH2 radical. The products of NH2
radical reaction are not clearly known (Mearns and Ofosu-Asiedu, 1984; Tang,
1980; Doyle et al., 1979; Weiler, 1979; Esmen and Fergus, 1977; National
Research Cancer, 1977).
Nitrification and volatilization are the important and competitive fate
processes in surface waters. Volatilization rates are highest at the sources of
industrial inputs of ammonia, whereas nitrification processes are more
significant in lakes, slow moving rivers, and estuaries. Nitrification is
responsive to high inputs of ammonia, although conditions of high nitrification
may contribute to low levels of dissolved oxygen and the eutrophication of a
body of water. Adsorption to particles may also play a role in the aquatic fate
of ammonia. Once bound to a particle, ammonia may settle to the sediment
where soil-type fate processes will take over (Orhon and Goneng, 1982;
American Petroleum Institute, 1981; Bouwmeester and Vlek, 1981; Weiler,
1979).
In water, the ammonium ion is expected to be predominant; however,
equilibrium is affected by pH and temperature. The fraction of ammonia
increases tenfold with each unit increase in pH and increases to a lesser
degree with increasing temperature (Erickson, 1985; Burkhalter and Kaya,
1977).
The general population may be potentially exposed to ammonia via
inhalation of contaminated air from industrial plants, farms, and numerous
other natural sources, including water supplies from wells. Ammonia has been
detected in emissions from oil refineries at concentrations up to 470 mg/m3
(U. S. Miner, 1969; National Research Council, 1977). Ammonia concentrations
of 1,900 iig/m3 and 42 iig/m3 were measured in emissions from two
pulverized-coal power plants (Bauer and Andren, 1985). Urban ammonia levels
in air as high as 280 jig/m3 have been measured in Italy, while an urban-
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industrial area in Japan had ammonia levels of 7 to 210 pg/mS (National
Research Council, 1977).
Several studies in California indicated measured ammonia levels of 3 to
60 ng/m3. One sample in the vicinity of a dairy farm had an ammonia
concentration of 315 pg/ms. Hutchinson et al. (1982) reported that air samples
taken 1.2 meters above a large cattle feedlot in Colorado contained ammonia
levels ranging from 290 to 1,200 ng/m3. Alkezweeney et al. (1986) reported
ambient ammonia concentrations of 0.04 to 5.6 ng/m3 for the summer of 1983,
in an area surrounded by horse and cattle farms near Lexington, KY. Ambient
ammonia levels ranging from 6,500 to 29,800 n/m3 have been reported in
confinement structures of swine-producing farms (Donham and Popendorf
1985).
Ammonia levels in nonurban air samples in Seattle, WA have ranged from
2.0 to 8.0 iig/m3 and urban air contained 0.8 to 77.0 ng/m3. Ambient ammonia
concentrations in coastal Virginia ranged from 1.4 to 3.5 ng/m3 (Harward et al.,
1982). Analysis of air samples from the Allegheny Mountain Tunnel in
Pennsylvania for ammonia showed mean concentrations of 3.0 yg/mS in the
tunnel and 0.44 ng/m3 outside the tunnel (Pierson and Brachaczek, 1983) and
air samples in a rural area in Pennsylvania have reportedly ranged from 0.01
to 0.137 ng/m3 (Lewin et al., 1986). Analysis of air samples from Commerce
City, CO, Abbeville, LA, and Luray, VA showed average ammonia levels of 2.4,
0.57, and 1.34 jig/ms, respectively. Ambient ammonia levels ranging from 1.4
to 5.6 iig/m3 were reported on a smoggy day in Los Angeles, CA (Hanst et al.,
1982). Hunt et al. (1984) reported ambient ammonia levels ranging from 3.0 to
9.0 ng/m3 in various locations in Texas. In air samples taken from June 1981
to June 1982 in Warren, Ml, average ammonia levels ranged from 0.10 to
0.85 ng/m3. The highest average annual ammonia level was found during the
summer months (Cadle, 1985).
Ammonia may also be present in the atmosphere as particulate
ammonium salts. In 1976 a mean ammonium level of 1.2 ng/m3 was measured
in Washington, D.C. (Kowalczyk et al., 1982). Urban ammonium concentrations
ranging from 0 to 15.1 ng/m3 were reported in 1968 for various air monitoring
stations throughout the United States. Nonurban ammonium concentrations
ranged from 0 to 1.2 iig/m3 (National Research Council, 1977).
Ammonia concentrations in precipitation (the source of surface water)
have averaged from 0.2 to 1.0 ppm in snow in the United States and Canada
(Feth, 1966). Mean ammonium ion concentrations deposited in precipitation at
three sites in Minnesota ranged from 33.6 to 47.9 peq/L (Munger, 1982).
Ammonium ion concentrations in rain ranging from 0.5 to 28.0 ppm were
reported for Israel and average yearly concentrations of 0.17 to 1.5 ppm were
reported in Sweden. High ammonium ion concentrations have been measured
in some natural waters, including levels up to 485 ppm in a group of California
springs and 1,400 ppm in one hotspring.
Determination of the ammonium-nitrogen concentrations in groundwater,
taken from wells located in North Carolina under various soil and crop
conditions, ranged from 0.01 to 8.85 ppm with average quarterly levels of 0.01
to 5.10 ppm (Gilliam et al., 1974). Wells in Michigan contained an average of
0.18 ppm ammonia-nitrogen in a marshy environment and 0.16 ppm in an
agricultural area. A sampling of water from four elementary school sites, each
with a well for its water supply, indicated ammonia-nitrogen concentrations
ranging from 0.01 to 0.57 ppm (Rajagopal, 1978). Ammonia-nitrogen
concentrations as high as 38 ppm were measured in groundwater obtained
from beneath corrals (Stewart et al., 1967).
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Estimates of occupational exposures to ammonia have been reported in
industrial hygiene surveys performed by the National Institute for Occupational
Safety and Health (NIOSH). According to the National Occupational Hazard
Survey (NOHS), 2,524,078 workers were potentially exposed to ammonia in
domestic workplace environments in 1970. Preliminary data for 1980 in the
National Occupational Exposure Survey (NOES) indicate that 417,358 workers,
including 120,599 women, were exposed to the compound. Table 2-1 lists
occupations having potential exposure to ammonia levels higher than that
normally found in the environment.
Atmospheric workplace concentration limits have been established for
ammonia. The Occupational Safety and Health Administration (Code of
Federal Regulations, 1989) established an 8-hour time-weighted average
(TWA) permissible exposure limit of 50 ppm (35 mg/m^) for ammonia, and the
American Conference of Governmental Industrial Hygienists (ACGIH, 1984)
recommended an 8-hour TWA threshold limit value (TLV) of 25 ppm (18
mg/m3) and a 15-minute short-term exposure limit (STEL) of 35 ppm (27
mg/m3).
2.4. Environmental Effects
Ammonia is highly toxic to aquatic organisms, and its concentration in
U.S. waters has been regulated to a maximum of 0.02 mg/L (as unionized
ammonia) (U.S. Environmental Protection Agency, 1977). In aqueous solution,
ammonia is present in unionized (NH3) and ionized (NH4 + ) forms. The
percentage of total ammonia present in the unionized form and its toxicity to
aquatic organisms is highly dependent upon the pH and temperature of the
media (Thurston et al., 1981c). As pH and temperature increases, the
ammonia equilibrium is shifted toward the NH3 chemical species (Emerson et
al.. 1975).
The acute toxicity of ammonia to fish has been studied extensively and is
well summarized in the literature (Thurston et al., 1984; Ruffier et al., 1981;
European Inland Fisheries Advisory Commission, 1973). The reported median
lethal concentrations of unionized ammonia for 22 species of fish are given in
Table 2- 2.
Data on the effect of increasing water pH upon the toxicity of unionized
ammonia are mixed. Thurston et al. (1984) reported increasing acute toxicity
of unionized ammonia to rainbow trout as the pH increased to pH 7.5.
Conversely, Broderius et al. (1985) reported decreasing toxicity of unionized
ammonia to smallmouth bass as water pH increased from 6.55 to 8.71.
Limited data on the subacute and chronic effects of ammonia upon fish
are available. The estimated 32-day no-observed-effect concentrations
(NOEC) for growth effects in smallmouth bass are 17.4, 14.4, 14.6, and 2.4
mg/L total ammonia and 0.0437, 0.148, 0.599, and 0.612 mg/L unionized
ammonia at pH values of 6.60, 7.25, 7.38, and 8.68, respectively (Broderius et
al., 1985). Exposure of carp fry (Cyprinis carpio) to 0.1 mg NH3/L for 3 weeks
resulted in significant (p <0.01) changes in leukocyte, erythrocyte, and
erythroblast counts as well as increases in brain and muscle free amino acid
levels (Dabrowska and Wlasow, 1986).
Aquatic invertebrates are generally less sensitive than fish to exposure to
ammonia. The reported median lethal concentrations of unionized ammonia for
nine species of aquatic invertebrates are given in Table 2-3. Several studies
show varying sensitivity with developmental stage (Watton and Hawkes, 1984;
2-6
-------
Table 2-1. Occupations with Potential Exposure to Ammonia
Acetylene worker
Aluminum worker
Amine worker
Ammonia worker
Ammonium salt maker
Aniline maker
Annealer
Boneblack maker
Brazier
Bronzer
Calcium carbide maker
Case hardener
Chemical-laboratory worker
Chemical manufacturer
Coal-tar worker
Coke maker
Coke-oven byproduct extractor
Compressed-gas worker
Corn grower
Cotton finisher
Cyanide maker
Decorator
Diazo reproducing-machine operator
Drug maker
Dye-intermediate maker
Dye maker
Electroplater
Electrotyper
Explosive maker
Farmer
Fertilizer worker
Galvanizer
Gas purifier
Glass cleaner
Glue maker
Ice cream maker
Ice maker
Illuminating-gas worker
Ink maker
Janitor
Lacquer maker
Latex worker
Manure handler
Metal extractor
Metal-powder processor
Mirror silverer
Nitric acid maker
Organic-chemical synthesizer
Paper maker
Perfume maker
Pesticide maker
Petroleum-refinery worker
Photoengraver
Photographic-film maker
Plastic-cement mixer
Pulp maker
Rayon maker
Refrigeration worker
Resin maker
Rocket-fuel maker
Rubber-cement mixer
Rubber worker
Sewer worker
Shellac maker
Shoe finisher
Soda ash maker
Solvay-process worker
Stableman
Steel maker
Sugar refiner
Sulfuric acid worker
Synthetic-fiber maker
Tannery worker
Transportation worker
Urea maker
Varnish maker
Vulcanizer
Water-base-paint worker
Water treater
Wool scourer
Source: National Research Council (1977).
Armstrong et al., 1978; Jayasankar and Muthu, 1983; Reddy and Menon
1979).
Ammonia can cause various kinds of injury to terrestrial plants including
necrosis, growth reduction, and increased frost sensitivity. Growth reduction
may result from uncoupling photophosphorylation, which lowers carbohydrate
2-7
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production. Necrosis and frost injury may occur from ammonia saturation of
membrane lipids (Van Haut and Prinz, 1979; Van der Eerden, 1982).
Table 2-3. Acute Lethal Concentration Values for Unionized
Ammonia in Aquatic Invertebrates
Organism
LC50 (mg/L)
Exposure conditions
Asellus vacovitzai
(Isopol adult)
Callibaetis skokianus
(Mayfly nymph)
Crangonyx pseudogracilis
(Amphipod adult)
Helisoma trivolvis
(Snail adult)
Musculium transversum
(Fingernail clam adult)
Orconectes immunis
(Crayfish adult)
Philartcus quaeris
(Caddisfly larvae)
Physa gyrina
(Snail adult)
Simocephalus vetulus
(Cladocevan adult)
5.02
3.09
3.12
2.37
1.10
18.3
10.1
1.95
1.71
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 96 h
Flowthrough, 48 h
Source: Arthur et al. (1987)
2-11
-------
-------
3. Health Effects
3.1 Pharmacokinetics and Metabolism
The essential role of ammonia and nitrogen in amino acid, protein, and
nucleic acid metabolism by living organisms has been extensively discussed
in standard textbooks and monographs. This section summarizes the available
information on the metabolism of exogenous ammonia by mammals. The
metabolic activities leading to the production and elimination of endogenous
ammonia, as well as the possible chemical reactions leading to ammonia
toxicity are discussed in the section on biochemical effects
Egle (1973) studied the uptake and retention of ammonia in both the
upper and lower respiratory tract of dogs exposed to ammonia at
concentrations ranging from 346 to 1,076 mg/m3 (459 to 1,522 ppm). He found
that ammonia retention in the lower respiratory tract was slightly less than that
of the upper respiratory tract. Retention ranged from 79.8 to 84.0 percent but
was not concentration-related. Ammonia retention by the respiratory tract of
humans was reported by Landahl and Hermann (1950) and Silverman et al.
(1949). When subjects were exposed to ammonia concentrations varying from
40 to 355 mg/m3 (57 to 502 ppm), approximately 92 percent was retained in
the lungs but without any concentration-related effect (Landahl and Hermann,
1950). Silverman et al. (1949) found that exposure of human subjects to
ammonia vapors at 353 mg/m3 (500 ppm) for a period of 30 minutes resulted
in a steady increase in ammonia concentrations in exhaled air. At equilibrium,
about 80 percent of the inhaled ammonia was released in expired air.
Schaerdel et al. (1983) studied the pulmonary absorption of ammonia gas
by male rats by exposing the rats from 11 to 818 mg/m3 (15 to 1,157 ppm)
ammonia for 1 day. They found a significant increase in blood ammonia levels
with an increase in the ammonia exposure level, but blood levels decreased
with time, suggesting that the body in some way compensates for the increase
in blood ammonia. There were no significant effects noted on pH, pCO2, pO2,
liver cytochrome P-450 concentration, or ethylmorphine-N-demethylase
activity. In another study, blood and brain ammonia levels, blood glutamate,
glutamine, creatinine, and urea nitrogen levels, and alkaline phosphatase
activity were not affected in male rats exposed to 3.1 ± 0.21, 0.35 ± 0 07 or
0.14 ± 0.21 mg/m3 (4.4 ± 0.3, 0.5 ± 0.1, or 0.2 ± 0.3 ppm) of ammonia
generated from decomposing urine and feces in animal rooms (White and
Mans, 1984).
Cooper and Lai (1987) studied the metabolism \n vivo of ammonia by rat
brain. Male Wistar rats (normal, acutely hyperammonemic, or chronically
hyperammonemic) were treated with 13N-ammonia via a carotid artery
cannula. In both normal and hyperammonemic rats, the major portion of the
13N-ammonia nitrogen was present as the amide nitrogen of glutamine. The
rate of conversion of blood-denied ammonia to glutamine was rapid in normal
rats (t1/2 s3 seconds only) and slower in hyperammonemic rats (t1/2 £10
seconds only). Hyperammonemia did not induce increased glutamine
synthetase activity in rat brain.
3-1
-------
Manninen et al. (1988) exposed groups of five female Wistar rats 6
hours/day for 5, 10, or 15 days to each of the following ammonia
concentrations in air: 0, 18, or 212 mg/ms (0, 25, or 300 ppm). On day 5 of
exposure, a concentration-dependent increase in blood ammonia and an
increase of blood and brain glutamine were observed in rats exposed at 212
mg/m3 compared with controls. By day 10, blood ammonia and blood and
brain glutamine levels were similar to those of controls.
The initial biochemical reactions involved in the incorporation of ammonia
into organic molecules in mammals involve the following: (1) the biosynthesis
of glutamic acid from ammonia and alpha-ketoglutarate; (2) the biosynthesis of
glutamine; (3) the formation of carbamyl phosphate; (4) the biosynthesis of
asparagine; and (5) some other relatively rare processes. However, it appears
that the route of administration drastically alters the distribution of ammonia
(15NH4+) between alpha-amino, amidine, and amide nitrogen of organ
proteins. Vitti et al. (1964) found that when 15N-ammonium citrate was given
intragastrically or intraperitoneally to untreated and growth-hormone-treated
hypophysectomized female Sprague-Dawley rats, extensive labeling of
alanine, arginine, glutamic acid, and other amino acids of liver protein
occurred. In contrast, subcutaneous injection resulted in extensive labeling of
the amide nitrogen of glutamine. In addition, various levels of N label were
found in proteins of the heart, kidneys, and spleen, although the distribution
varied among the various amino acids analyzed. The relative rate of
incorporation of 15N was highest in the liver and lowest in the heart and varied
with the route of administration (subcutaneous intraperitoneal intragastric). The
authors suggested that ammonia administered intragastrically or
intraperitoneally was metabolized largely by pathways involving hepatic
glutamic dehydrogenase and carbamyl synthetase, whereas subcutaneously
administered ammonia is metabolized, to a great extent, by the glutamine
synthetase route.
Following intravenous administration of 15N-ammonia in male rats,
ammonia was incorporated mainly into the amide position of glutamine (Duda
and Handler, 1958). Approximately 90 percent of the isotope was incorporated
into glutamine and urea 30 minutes after administration of 52.2 micromoles
(mol) of i5N-ammonia, with 80 percent being glutamine amide nitrogen. Urea
synthesis represented a fixed percentage of available ammonia over a large
concentration range. Incorporation into glutamine, urea, and glutamic acid
reached a maximum at 20 minutes, but the specific activity of glutamine was
approximately seven times that of either urea or glutamic acid. The distribution
of labeled glutamine and urea in the tissues of rats following intravenous
administration of 47.5 mol of 15N-ammonium lactate was also determined by
these investigators. The residue levels in glutamine and urea in various
organs, expressed as nmol of glutamine and urea, respectively, were as
follows: carcass (25.85, 5.60); liver (1.37, 0.39); heart (0.30, 0.03); kidneys
(0.11, 0.15); spleen (0.10, 0.023); brain (0.08, 0.01); and testes (0.051, 0.028).
A fraction of exogenous ammonia is excreted via the lungs in expired air.
Measurable amounts (about 269 g/m3; 377 ppb) of free ammonia were found
in the expired air of dogs injected intravenously with ammonium acetate
(Robin et al., 1959). Exposure of human subjects to ammonia vapor at 353
mg/m3 (494 ppm) for a period of 30 minutes also resulted in a steady increase
in ammonia concentrations in exhaled air. At equilibrium, about 80 percent of
the inhaled ammonia was released in expired air (Silverman et al., 1949).
Like exogenous ammonia, endogenous ammonia is also excreted via the
lungs in expired air. For instance, Barrow and Steinhagen (1980) found
endogenous ammonia in the expired air of rats at concentrations ranging from
3-2
-------
7 to 250 ug/m3 (10 to 353 ppb) in nose-breathing animals and 24 to 526 ng/m3
(34 to 744 ppb) in tracheal-cannulated animals. They attributed these
differences to the absorptive effect of moisture in the respiratory tract of nose
breathers.
Ammonia is also excreted in the urine as urea. A study by Minana et al.
(1988) indicated that in groups of 18 male Wistar rats given a diet containing
20 percent (w/v) ammonium acetate for 15 days and then a single
intraperitoneal injection of 7 mmol ammonium acetate/kg, ammonia was
initially sequestered and finally eliminated in the urine as urea. Saul and
Archer (1984) also showed that repeated oral administration of 15N-ammonium
chloride to male Sprague-Dawley rats resulted in low but significant amounts
of excess 15N-nitrate in the urine. Rats were gavaged with 1,000 iimol of 15N-
ammonium chloride daily for 5 days. Nitrate was detected in the urine during
the exposure period and on 5 subsequent days; approximately 0.008 percent
of the dose was converted to nitrate. The authors suggested that
hydroxylamine was a possible intermediate in the ammonia oxidation process,
and postulated that ammonia is oxidized in vivo by a nonenzymatic process
that involves active oxygen species such as the hydroxyl radical. Similar
results were reported by Wagner et al. (1985) after continuous intravenous
infusion of 15NH3 to male Sprague-Dawley rats over a 96-hour period.
3.2 Biochemical Effects
Ammonia is a key metabolite in mammals and plays an essential
biochemical role in acid-base regulation and in the biosynthesis of purines,
pyrimidines, and nonessential amino acids (Kvamme, 1983; Visek, 1984;
Stryer, 1981). A high concentration of endogenous ammonia, however, is quite
toxic to mammals and may lead to life-threatening conditions.
The gastrointestinal (Gl) tract is a major site of ammonia production.
Amino acid deaminases and ureases of bacterial flora in the colon liberate
ammonia from dietary amino acids and urea. Newly generated ammonia is
transported to the liver through the portal circulation, where it is converted to
urea. The urea is then transported by the blood to the kidneys for excretion:
a-ketoglutarate + NH3 + NADH + H* ^ glutamate + NAD* + H2O
NH3 + CO2 + 2ATP + H2O ^ carbamoylphosphate + 2ADP + Pi
Carbamoylphosphate ^ urea
The kidneys produce ammonia from the deamination of glutamine (Good
and DuBose, 1987; Dass and Welbourne, 1986; Eriksson et al., 1985;
Windmueller and Spaeth, 1978; Visek, 1984). The ammonia produced by the
kidneys acts as an urinary buffer (Windmueller and Spaeth, 1978). The
metabolic activity of skeletal muscle also generates ammonia (Eriksson et al.,
1985). In the central nervous system, the purine nucleotide cycle appears to
be the main generator of ammonia, which under normal conditions is
incorporated into glutamine (Kvamme, 1983).
NH3 + a-ketoglutarate + NADH + H+ ^ gfutamate + NAD* + H2O
ATP + glutamate + NH3 ^ glutamine + ADP + Pi
3-3
-------
The liver is the only organ that has a complete urea cycle that converts
ammonia to urea. In other organs, ammonia is incorporated into glutamine.
Muscle tissue comprises the largest glutamine pool in humans (Lund, 1980;
Windmueller and Spaeth, 1978).
The importance of the urea cycle is not restricted to detoxifying ammonia;
it also exchanges substrates with the citric acid cycle and provides substrates
for the synthesis of pyrimidines and polyamines that regulate RNA and protein
synthesis. For this reason, deficient or abnormal operation of the urea cycle
may have serious metabolic consequences (Grisolia et al., 1976).
In humans, excretory mechanisms for detoxification and removal of
ammonia are very rapid. For instance, under normal conditions, the hepatic
portal circulation assures that all of the ammonia from the Gl tract is
transported to the liver for detoxification. Fifty percent of the arterial blood
ammonia is detoxified by the skeletal muscle in healthy individuals (Freed and
Gelbard, 1982; Lockwood et al., 1979). At the same time, the urea cycle
normally operates at about 60 percent capacity (Hems et al., 1966); thus it is
the availability of the substrate that may limit the rate of urea production. Fico
et al. (1986) studied the rate of urea synthesis in human liver samples
obtained by biopsy. They found that increasing the ammonia concentration in
the incubation medium from 0 to 5.0 mM produced a 200 percent increase in
urea synthesis.
Inherited conditions in children have been reported in which all or some of
the enzymes participating in the urea cycle were defective (Hjelm et al., 1986;
Brusilow, 1985; Shambaugh, 1978; Zimmermann et al., 1985). Such subjects
exhibited various neurologic disorders, hyperammonemia, inhibited growth,
and protein intolerance. Several acquired diseases can also affect the urea
cycle enzymes (Zimmerman et al., 1985; Glasglow, 1983; Boutros et al.,
1980), causing severe hyperammonemia, hyperaminoaciduria (Hilty et al.,
1974), hepatic failure, and encephalopathy. In pathologic conditions such as
alcoholic hepatitis, uremia, and liver cirrhosis, defective urea-cycle enzymes
are also present (Muting et al., 1986; Swendseid et al., 1975; Maier et al.,
1974; Brown et al., 1967).
It is possible that exogenous ammonia may cause a potential health risk
under certain conditions to man (e.g., genetic or metabolic disorder). However,
since ammonia is severely irritating to sensitive areas such as the eyes, skin,
lungs, and throat, it is likely that humans will avoid exposure to quantities of
"environmental" ammonia that can produce metabolic toxicity.
Acute exposure of mice for 2 days to ammonia vapors (50,000 ppm)
increased the activity of sodium ion (Na+) and potassium ion (K*)-activated
ATPase of the brain, resulting in an increased concentration of adenine
derivatives (Sadasivudu et al., 1979, 1977), and decreased the activity of
adenosine deaminase, thus reducing the degradation of adenosine
(Sadasivudu et al., 1981). Since adenosine has been implicated both as a
cerebral depressant as well as a sleep-inducing agent (Haulica et al., 1973), its
accumulation could be a major factor in the depression of brain function.
Alternatively, a rise in ATPase activity may lead to stabilization of neuronal
membranes and increased transport of NH4+ into glial cells, exceeding the
detoxifying ability of the cells. Increased transport of NH4* into glial cells may
possibly be due to its similarity to hydrated K+, whose concentration is
normally maintained by these cells (Lewis, 1976). Hence, this could produce a
gross disturbance in ionic fluxes possibly leading to depression of neuronal
transmission, the degree of which would depend on the extent of damage to
the glial cells (Sadasivudu et al., 1979).
3-4
-------
Chronic exposure to 50,000 ppm ammonia also alters the metabolism of
amino acids belonging to the glutamic acid family (gamma-aminobutyric acid,
alanine, glutamic acid, aspartic acid, glutamine) by increasing the activities of
aspartate aminotransferase, glutamate dehydrogenase, and glutamine
synthetase. This change facilitates greater removal of ammonia ultimately in
the form of glutamine, thus compensating for a rise in the level of ammonia
(Sadasivudu et al., 1979). The process occurs in the astroglial cells, which are
known to possess most of glutamine synthetase activity in the brain (Martinez-
Hernandez et al., 1977).
Hepatic encephalopathy has been linked with a derangement in the
metabolism of a number of neurotransmitters like catecholamines, serotonin,
gamma-aminobutyric acid (GABA), and acetylcholine (Fischer and
Baldessarini, 1976; Biebuyck et al., 1975; Walker et al., 1971). Increased
ATPase and decreased monoamine oxidase (MAO) and glutamate
decarboxylase (GD) activities in all three regions of the brain were observed in
mice intraperitoneally injected with 200 mg/kg ammonium chloride
(Sadasivudu and Murthy, 1978). Glutamate decarboxylase (GD) and GABA-
aminotransferase (GABA-T) are involved in the production and metabolism of
GABA, whereas MAO degrades catecholamines and serotonin. While an
increase in ATPase activity leads to membrane stabilization, GABA is known
to bring about hyperpolarization (Krnjevic et al., 1966). Decreased GD and
GABA-T activities may be regarded as compensatory because they reduce
the GABA level. A decrease in MAO activity would tend to raise the levels of
catecholamines and serotonin. An increase in catecholamine concentration, in
particular, would promote consciousness in the animal. However, following
exposure to 50,000 ppm ammonia vapors for 2 and 5 days, increased MAO
levels in the cerebellum were observed. A greater destruction of biogenic
amines may lead to a state of unconsciousness (Sadasivudu and Murthv
1978).
During the last three decades, several mechanisms have been proposed
to explain the biochemical basis for ammonia neurotoxicity. Because the brain
is highly vulnerable to decreases in the ATP level, these hypotheses postulate
an eventual decrease in available cerebral energy due either to reduced
production or enhanced utilization of ATP during ammonia detoxification
and/or due to ammonia-induced stimulation of ATPase activity (McCandles
and Schenker, 1981; Walker and Schenker, 1970). Other theories include the
formation or accumulation of GABA, an inhibitory neurotransmitter (Goetcheus
and Webster, 1965), and depletion of acetylcholine (Braganca et al., 1953).
However, none of these hypotheses has been conclusively proven. It is
possible that ammonia intoxication produces a multiplicity of biochemical
injuries. The following theories are briefly discussed.
McKhann and Tower (1961) suggested that ammonia reduces the
incorporation of pyruvate into the tricarboxylic acid (TCA) cycle, thus slowing
the oxidative metabolism. This conclusion was drawn from an in vitro
observation that high concentrations of ammonium chloride (15 mM) inhibit
oxygen consumption in cat cortex mitochondria, indicating impaired pyruvate
decarboxylation. However, tests conducted on the brain of ammonia-
intoxicated rats and from brains incubated with ammonium chloride or
ammonium acetate (2 to 18 mM) failed to reveal any alteration in pyruvate
decarboxylation (Walker and Schenker, 1970; Ratnakumari et al., 1986).
Based on in vitro studies with high ammonia concentrations, Worcel and
Erecinska (1962) suggested that cerebral detoxification of ammonia to
glutamate depletes the NADH pool, resulting in decreased amounts of NADH
available for ATP formation in the mitochondria. However, results from in vivo
3-5
-------
studies indicated that the cerebral cytoplasmic NADH:NAD+ ratios increased
during acute ammonia intoxication due to a marked increase in the
lactate:pyruvate ratio (Hawkins et al., 1973; Hindfelt, 1973). Moreover, there
was an apparent decrease in NADH:NAD+ ratio in the mitochondria,
suggesting a failure to transport reduced equivalents from the cytoplasm to
the mitochondria (Hindfelt et al., 1977).
The "Energy Depletion Hypothesis" was suggested by Bessman and
Bessman (1955). According to this hypothesis, ammonia entering the brain
reacts with alpha-ketoglutarate (alpha-KG) and NADH, forming glutamate.
Glutamate would deplete the TCA cycle of one of its dicarboxylic acids,
resulting in a drop in the cerebral oxygen utilization observed in hepatic coma.
This reduction in oxidative metabolism would also result in a drop in ATP
formation in the brain, eventually leading to coma. It has been observed that
the brains of hepatic coma patients often exhibit ammonia uptake (Bessman
and Bessman, 1955) and decreased oxygen consumption (Fazekas et al.,
1956). Further, after ammonia injections, the concentrations of alpha-KG were
decreased in the cerebral cortex and whole brain of dogs and mice,
respectively (Bessman, 1961; Clark and Eiseman, 1958). However, other
studies with animals have failed to detect any significant change in the
concentrations of alpha-KG or ATP in the brain during the induced ammonia
intoxication (Ratnakumari et al., 1986; Raabe and Lin, 1984; Hawkins et al.,
1973; Hindfelt and Siesjo, 1970, 1971). Bessman and Pal (1982) suggested
that the major problem with the acceptance of this hypothesis in the past was
the lack of exact correlation between levels of ammonia concentration in the
blood and the mental state of the patient. In fact, correlation between cerebral
symptoms and CSF glutamine content was somewhat better than the
correlation with ammonia concentration. However, they have now
demonstrated the presence of a relation between ammonia concentration in
the blood and the state of consciousness.
Another theory explains the depletion of cerebral ATP through enhanced
synthesis of glutamine (Nakazawa and Quastel, 1968). A fourfold increase in
cerebral glutamine was found within 15 minutes after administration of an
acute dose of ammonium acetate to rats (du Ruisseau et al., 1957). Other
investigators have reported similar findings (Berl et al., 1968). However, it has
been suggested that glutamine synthesis alone cannot utilize enough ATP to
affect cerebral function, unless a "vital" ATP pool is involved (Bessman, 1961).
Administration of methionine sulfoximine, a potent inhibitor of glutamine
synthetase, caused a marked decrease in ammonia toxicity in mice. It was
concluded that ammonia intoxication does not depend on the mere presence
of high cerebral ammonia content, but is related to a metabolic process that
occurs directly or indirectly through the major known pathway of cerebral
ammonia detoxication, i.e., synthesis of glutamine (Warren and Schenker,
1964). Hindfelt (1973) failed to support the sparing mechanism of methionine
sulfoximine through ATP-saving inhibition of glutamine synthesis. In addition,
Hawkins et al. (1973) found no significant arteriovenous difference in glutamate
or glutamine concentration in acutely intoxicated mice. Although a
considerable amount of ammonia was incorporated into glutamine, it was not
rapidly released from the brain into the circulatory system.
Hawkins et al. (1973) suggest that the general increase in nerve cell
excitability and activity that results in convulsions, as well as the increased
metabolic rate of the brain, may be due to Na* and K* stimulation of ATPase
activity produced by ammonia. After an injection of ammonium acetate, the
plasma K* concentration increased from 3.3 to 5.4 mol/L, with no significant
increase in Na* concentration. A possible decrease of 15 mV in the resting
3-6
-------
transmembrane potential was calculated. Accordingly, the likely mechanism
for pharmacologic action of ammonia is the effect on the electric properties of
nerve cells. Extracellular ammonia-like K* decreases the resting
transmembrane potential, and, therefore, the resting potential is closer to the
threshold for nerve conduction. This could then cause a general increase in
nerve-cell excitability leading to convulsions.
Ulshafer (1958) suggested that the depletion of ATP may cause a
decrease in cerebral acetylcholine, which requires ATP for its synthesis.
Administration of sufficient ammonium carbonate to produce convulsions in
rats caused a decrease in the brain content of acetylcholine. Ammonia also
inhibits the synthesis of acetylcholine in brain cortex slices, which can be
relieved by the addition of glutamine synthetase inhibitors (Braganca et al
1953). However, Walker et al. (1971) failed to detect any change in
acetylcholine, serotonin, or norepinephrine during the development of acute
ammonia-induced coma.
Raabe and Lin (1983:1984) found that systemic ammonia toxicity
inactivates the extrusion of the chloride ion (CI') from the neurons and thus
decreases the hyperpolarizing action of postsynaptic inhibition, producing the
first signs of ammonia neurotoxicity. The decrease in the hyperpolarizing
action of postsynaptic inhibition was without a concurrent decrease in energy
metabolism (decrease of pyruvate, a-ketoglutarate, glutamate, or ATP) as had
been suggested by Bessman and Bessman (1955). Similar results were also
reported by lies and Jack (1980).
3.3 Acute Toxicity
Several studies have been conducted with laboratory animals to
determine the effects of acute exposure to ammonia. Acute toxicity values,
presented in Table 3-1, suggest that ammonia is very toxic at high exposure
levels.
In animals, compound- and concentration-related effects resulting from
exposure to ammonia progress from mild irritation of the respiratory system
and mucous membranes to convulsions, acute pulmonary edema, coma, and
death. Typical signs of toxicity associated with exposure to ammonia include
initial excitation, closed eyes, labored respiration, mouth breathing, nose
pawing, scratching, ocular and nasal discharge, and coughing (Kapeghian et
al., 1982; Silver and McGrath, 1948; Appelman et al., 1982; Boyd et al 1944-
Weedon et al., 1940; Dodd and Gross, 1980; Cralley, 1942; Dalhamn, 1956;
Dalhamn and Sjoholm, 1963; Drummond et al., 1978).
Exposure to sublethal and lethal concentrations of ammonia has produced
adverse effects in the respiratory tract and liver in some species. Kapeghian et
al. (1982) studied the effect of inhalation of ammonia gas in mice exposed to
ammonia levels ranging from 0 to 3,436 mg/ms (0 to 4,860 ppm) for 1 hour
followed by an observation period of 14 days. Exposed animals exhibited
irritant effects (excitation, rapid, vigorous tail revolutions, eye blinking, nose
scratching, and dyspnea) immediately following exposure. At exposure levels
of 2,793, 2,984, 3,188, and 3,450 mg/m3 (3,950, 4,220, 4,490, and 4,860 ppm)
there was 25, 42, 67, and 100 percent mortality, respectively. Diffusely
hemorrhagic lungs were noted in animals that died during exposure. No
deaths were noted at exposure levels lower than 2,792 mg/mS. Appelman et al.
(1982) found that exposure to ammonia levels ranging from 21,353 to 38,547
mg/m3 (30,075 to 54,292 ppm) for 10 minutes; 18,642 to 23,641 mg/m3
(26,256 to 33,305 ppm) for 20 minutes; 12,862 to 17,164 mg/m3 (18,116 to
24,175 ppm) for 40 minutes; and 10,059 to 13,491 mg/m3 (14,169 to 19,002
3-7
-------
Table 3-1. Acute Toxicity Values for Ammonia in Laboratory Animals
Route/species,
sex
Inhalation
Mouse, M
Mouse
Rat,M
Rat,F
Rat,M
Rat,F
Cat
Rabbit
Acute
toxicity value
LC50 = 2,991 mg/m3
(4,230 ppm)
LC50 = 6,988 mg/m3
(9,884 ppm)
LC50 = 26,327 mg/m3
(37,238 ppm)
LC50 = 31,899 mg/m3
(45,119 ppm)
LC50 = 9,997 mg/m3
(14,1 40 ppm)
LC50 = 13,977 mg/m3
(19,770 ppm)
LC50 = 7,1 27 mg/m3
(10,080 ppm)
LC50 = 7,1 27 mg/m3
(10,080 ppm)
Exposure
duration,
min
60
10
10
10
60
60
60
60
Reference
Kapeghian et al. (1982)
Silver and McGrath
(1948)
Appelman et al. (1982)
Appelman etal. (1982)
Appelman et al. (1982)
Appelman et al. (1982)
Boydetal. (1944)
Boyd etal. (1944)
Oral
Guinea piga LD7s = 900-1,200 mg/kg
Intravenous
Chicken
Mouse
Intraperitoneal
Rat"
Chicken0
Mouse0
LDSO = 46.3 mg/kg
LD50 = 95.9 mg/kg
LD100 = 400 mg/kg
LD50 = 177.5 mg/kg
LDSO = 184.3 mg/kg
NA" Koenig and Koenig
(1949)
NA Wilson et al. (1968)
NA Wilson et al. (1968)
NA Koenig and Koenig
(1949)
NA Wilson etal. (1968)
NA Wilson etal. (1968)
aAmmonium chloride used.
bNA = Not applicable.
°Ammonium acetate used.
ppm) for 60 minutes produced excitability and nasal and eye irritation in rats.
Macroscopic examination revealed hemorrhagic lungs in all exposed animals.
Exposure-related deaths occurred in all exposure groups except those animals
exposed to 21,353 mg/mS ammonia for 10 minutes. Exposure to ammonia gas
levels of 6,063 to 8,946 mg/m3 (8,540 to 12,600 ppm) for 10 minutes resulted
in 25 to 80 percent mortality. Of 180 mice tested, 100 died within the 10
minute exposure period (Silver and McGrath, 1948). An increase in the
hexobarbital sleeping time was reported by Kapeghian et al. (1985) after
exposing mice to 3,110 mg/ms (4,380 ppm) ammonia for 4 hours; however,
this exposure level was lethal to 4 of the 12 animals. No effect was noted on
the hexobarbital-induced sleeping time in animals exposed to 958 mg/m3
(1,350 ppm) ammonia for 4 hours; however, the latent periods were
significantly reduced in both exposure groups.
The results of acute exposure to lower levels of ammonia are conflicting.
Schaerdal et al. (1983) saw no signs of irritancy or histological changes in the
3-8
-------
respiratory tract of rats exposed to ammonia levels of 11 to 818 mg/m3 (15 to
1,157 ppm) for 1 day or 3 to 507 mg/m3 (4 to 714 ppm) for 3 or 7 days. The
National Research Council (1977) reported no signs of ill effects in 4 mice and
7 rats exposed to 707 mg/m3 (1,000 ppm) ammonia for 16 hours; however, 1
rat died during the exposure period. Gross examination revealed congestion,
hemorrhage, and edema of the lungs. Slight irritation was reported in rats
exposed to from 339 to 403 mg/m3 (480 to 570 ppm) ammonia for 4 hours
(Carson et al., 1981). Exposure to 71 to 212 mg/m3 (110 and 300 ppm)
ammonia for 6 hour intervals reduced free access wheel running in rats and
mice. Reductions in wheel running during exposure to irritants may be
interpreted to reflect sensory irritation (Tepper et al., 1985). Wood (1981)
calculated the aversive concentration at which 50 percent (AC50) of the
ammonia exposures were terminated using an operant conditioning procedure.
His calculations indicate that ammonia produces irritant effects in mice at
levels <243 mg/m3 (344 ppm). In a later work, Tepper and Wood (1985) using
a similar operant conditioning procedure, calculated an AC50 value for mice of
303 ± 92 mg/m3 (428 ± 130 ppm). After repeated exposures to high levels of
ozone prior to ammonia exposure, the AC50 value decreased from 303 to 165
mg/m3 (428 to 233 ppm). Exposure to 198 mg/m3 (280 ppm) ammonia for 36
hours resulted in frothing of the mouth and excessive secretions from the
noses of pigs. After the exposure period, convulsions occurred and respiration
was short and irregular (Stombaugh et al., 1969). Merilan (1973) saw a
significant decrease in respiratory rates in calves exposed to 35 to 71 mg/m3
(50 and 100 ppm) ammonia for 7.5 hours. Exposure to 35 to 71 mg/m3 for 2.5
hours did not produce this effect (Mayan and Merilan, 1976). Vesell et al.
(1973) reported that the ammonia produced from fecal matter in animal cages
could produce hepatic microsomal enzyme inhibition (ethylmorphine N-
demethylase and aniline hydroxylase activity) in rats. This finding was not
confirmed by Schaerdal et al. (1983) and Kapeghian et al. (1985) after
exposing rats to 505 mg/m3 (714 ppm) ammonia for 7 days and mice to 248
mg/m3 (350 ppm) ammonia for 4 days. Dodd and Gross (1980) detected
necrosis and sloughing of the airway mucosal surface in cats exposed to 707
mg/m3 (1,000 ppm) ammonia for 10 minutes. A cessation of tracheal ciliary
activity was seen in rats 7 to 8 minutes after exposure to 2 mg/m3 (3 ppm)
ammonia, 150 seconds after exposure to 4 to 5 mg/m3 (6 to 7 ppm), 20
seconds after exposure to 14 mg/m3 (20 ppm), 10 seconds after exposure to
32 mg/m3 (45 ppm), and 5 seconds after exposure to 64 mg/m3 (90 ppm)
(Dalhamn, 1956). A reduction in ability to clear pulmonary bacteria (scherice in
cats exposed to 707 mg/m3 (1,000 ppm) ammonia for 10 minutes. A cessation
of tracheal ciliary activity was seen in rats 7 to 8 minutes after exposure to 2
mg/m3 (3 ppm) ammonia, 150 seconds after exposure to 4 to 5 mg/m3 (6 to 7
ppm), 20 seconds after exposure to 14 mg/m3 (20 ppm), 10 seconds after
exposure to 32 mg/m3 (45 ppm), and 5 seconds after exposure to 64 mg/m3
(90 ppm) (Dalhamn, 1956). A reduction in ability to clear pulmonary bacteria
(Escherichia coli) was found in pigs exposed to 35 to 53 mg/m3 (50 to 75
ppm) ammonia for 2 hours (Drummond et al., 1978). While ammonia had little
effect on performance or respiratory tract structure, the authors suggested that
exposure to ammonia could be a contributing factor in pulmonary tract
infection.
Buckley et al. (1984) exposed via inhalation groups of 16 to 24 male
Swiss-Webster mice to ammonia at the RD50 concentration of 214 mg/m3 (303
ppm) 6 hours/day, for 5 days. An evaluation of the ammonia-induced
histopathological lesions of the respiratory tract indicated mild to moderate
epithelial exfoliation, erosion, ulceration, necrosis, inflammation, and squamous
3-9
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metaplasia in the nasal cavity. No lesions were observed in the olfactory
epithelium.
Rothenberg et al. (1986) exposed five male and three female beagle dogs
(nose only) to 1 mg/m3 ammonium sulfite mixed with sulfate for 1 hour. The
levels of sulfur dioxide and ammonia were <0.5 ppm and <5.0 ppm,
respectively. No statistically significant differences were observed in the
tracheal mucosal clearance rate between preexposure and postexposure. In a
separate experiment, inhalation exposure (nose only) of 12 male and 12
female guinea pigs to aerosol concentrations of 50, 250, or 450 mg/m3 of
ammonium sulfite (60 to 80 percent) for 1 hour produced no deaths at any
level.
Minana et al. (1988) investigated the protective effect of long-term
ammonium ingestion against acute ammonium intoxication in
hyperammonemic rats. Groups of 18 male Wistar rats were fed either a control
diet or a diet containing 20 percent (w/v) ammonium acetate for 15 days. Both
the control and the treated rats were then given a single intraperitoneal
injection of 7 mmol ammonium acetate/kg. Blood ammonia, blood urea, and
glutamine levels were determined at various intervals (1 to 8 hours
postinjection). Survival was higher (nine survivors) for hyperammonemic rats
than for control rats (one survivor). In addition, of the nonsurvivors,
hyperammonemic rats died within 31 ± 10 minutes, and the control rats died
within 18 ± 5 minutes postexposure. Ingestion of ammonium-containing diet
for 15 days had a protective effect against a single high dose of ammonia.
Blood ammonia levels were the same (2 mM) for both groups; the maximum
was reached after 15 and 30 minutes for hyperammonemic and control rats,
respectively, suggesting a more rapid detoxification in hyperammonemic rats.
3.4 Subchronic Toxicity
Subchronic exposure to ammonia levels higher than those encountered in
ambient air produces adverse effects on the tissues of the respiratory tract
and impairs the pulmonary defense system. It may also produce anorexia;
increase the tendency towards, or severity of, respiratory tract infections;
and/or produce degenerative changes in the lungs, liver, kidneys, and spleen.
Coon et al. (1970) in four experiments studied the effects of repeated or
continuous exposure to varying concentrations of ammonia gas in several
species. Table 3-2 gives the results of those experiments. In summary, nasal
and ocular effects were associated with repeated exposure to ammonia at 778
mg/m3 (1,100 ppm) in dogs and rabbits; however, these signs disappeared
during the second week of exposure. No clinically significant effects were
detected in guinea pigs, rabbits, dogs, and monkeys continuously exposed to
ammonia at a concentration of 40 mg/m3 (57 ppm) for 114 days. There were
inflammatory changes noted in the lungs and kidneys of rats exposed to 127
mg/m3 (181 ppm) ammonia continuously for 90 days. However, these changes
were reported in 50 percent of the control and exposed animals. In rats
exposed to 262 mg/m3 (374 ppm) ammonia there were nonspecific circulatory
and degenerative changes in the lungs and kidneys that, according to the
authors, were difficult to specifically relate to ammonia exposure. Deaths
occurred at concentrations of 460 and 455 mg/m3 (650 and 672 ppm).
Numerous other subchronic toxicity studies have also been reported.
Weatherby (1952) found that exposure of male guinea pigs to 120 mg/m3 (170
ppm) (range 99 to 141 mg/m3; 140 to 200 ppm) ammonia for 6 hours/day, 5
days/week for up to 18 weeks resulted in congestion of the spleen, liver, and
kidneys and early degenerative changes in the suprarenal gland. No
3-10
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significant effects were detected following exposure of guinea pigs and mice
to an ammonia concentration of 14 mg/m3 (20 ppm) for 28 days. When the
exposure duration was increased to 42 days or when the ammonia
concentration was increased to 35 mg/m3 for guinea pigs, pulmonary edema,
congestion, and hemorrhage were seen in both species (Anderson et al.,
1964). Richard et al. (1978) found nasal irritation and severe inflammatory
lesions in rats exposed to 353 mg/m3 ammonia for 3 weeks which were not
present after 8 weeks of exposure. The authors believed this finding
suggested the occurrence of an adaptive process. Mayan and Merilan (1972)
found no pathologic" changes in the liver, lungs, spleen, or kidneys after
exposing female white rabbits to 35 mg/m3 ammonia for 2.5 to 3 hours (22
exposures) or 71 mg/m3 for. 16 exposures (duration of each exposure not
indicated). Examination of guinea pig alveolar macrophages after
subcutaneous inoculation with Mycobacterium bovis BCG and intradermal
injection of 2.5 g of tuberculin-purified protein derivative (PPD) and exposure
to 35 or 64 mg/m3 (50 or 90 ppm) ammonia for 3 weeks resulted in no
significant alterations in bactericidal or phagocytic activities. However, the
addition of ammonia to cultures of alveolar macrophages from normal animals
significantly inhibited the bactericidal activity of those cells (Targowski et al.,
1984). An increase in the severity of rhinitis, otitis media, tracheitis, and
pneumonia was seen by Broderson et al. (1976) after inoculating rats with
Mycoplasma pulmonis and exposing them for 4 to 6 weeks to ammonia levels
routinely found in animal cages 18 to 177 mg/m3 (25 to 250 ppm). The authors
also found pathologic changes in the nasal passages of animals exposed to
106 mg/m3 (150 ppm) ammonia for 75 days and 177 mg/m3 for 35 days.
Schoeb et al. (1982) found that ammonia had a direct growth-promoting effect
on Mycoplasma pulmonis which was responsible for respiratory disease
syndromes in rats.
In commercial animal species, Deaton et al. (1982; 1984) showed that
exposure of laying hens to ammonia at a concentration of 141 mg/m3 (200
ppm) for 17 days resulted in a significant reduction in egg production. Deaton
et al. (1982), Oyetunde et al. (1978), and Reece et al. (1981) found that
exposure of chickens to sublethal concentrations of ammonia (18 to 141
mg/m3) for up to 28 days significantly reduced body weight gain. Mild to
moderate macroscopic and microscopic changes in the lungs and air sac were
seen in chickens exposed to 71 mg/m3 (100 ppm) ammonia for 4 weeks
(Oyetunde et al., 1978). No significant effects were detected following the
exposure of chickens to ammonia at a concentration of 14 mg/m3 (20 ppm) for
up to 28 days and turkeys for up to 6 days; however, pulmonary edema,
congestion, and hemorrhage were detected in chickens exposed at 141
mg/m3 for 17 to 21 days or 707 mg/m3 (990 ppm) for 14 days, and in turkeys
exposed at 35 mg/m3 for 10 to 14 days. Also, chickens maintained in
environments containing 14 mg/m3 ammonia for 72 hours or 35 mg/m3 (50
ppm) for 48 hours were found to be more susceptible to Newcastle disease
virus (Anderson et al., 1964). Like Dalhamn (1956), Nagaraja et al. (1983)
found that exposure to ammonia produced a reduction in tracheal ciliary
activity. After exposure to 7 to 28 mg/m3 (10 to 40 ppm) ammonia for 1 to 7
weeks, turkeys exhibited deterioration of the mucociliary apparatus which is
thought to reflect a breakdown in the defense mechanism of the respiratory
tract against an accumulation of pathogenic bacteria and viruses. With the
exception of mild conjunctivitis and blepharitis in one pig, Curtis et al. (1975),
found no evidence of structural aberrations in any organ or tissue of pigs'
exposed to ammonia levels of 35 to 53 mg/m3 for up to 75 days. The National
Research Council (1977) reported an increased thickness of tracheal
3-13
-------
epithelium and goblet cells in pigs after exposure to 75 mg/m3 (106 ppm)
ammonia for 2 weeks.
3.5 Chronic Toxicity
No adequate information was found on the effects of chronic exposure to
ammonia in animals.
3.6 Carcinogenicity
No information was found on the carcinogenic potential of inhaled
ammonia in animals. However, oral administration of ammonium hydroxide
and ammonia was not carcinogenic in mice. Toth (1972) investigated the
carcinogenic potential of ammonium hydroxide in Swiss and C3H mice.
Ammonium hydroxide was administered daily in the drinking water of Swiss
mice at levels of 0.1, 0.2, or 0.3 percent (1,000, 2,000, or 3,000 ppm) and to
C3H mice at a level of 0.1. percent over the normal life span of the animals.
Ammonium hydroxide was not carcinogenic in either species, and did not
affect the development of breast adenomas in C3H females. The incidences of
breast adenomas in the treated and control groups were 60 and 76 percent,
respectively. In another study, no significant increase in lung tumors was
found in mice with a high sensitivity to lung tumorigenesis after the
administration of 42 mg/kg ammonia twice a week by stomach tubes for 4
weeks (UzvSlgyi and Bojan, 1980).
3.7 Mutagenicity
Limited data suggest that ammonia may be mutagenic. Demerec et al.
(1951) tested ammonia for its ability to induce back-mutations from
streptomycin dependence (Sd-4) to nondependence in Escherichia coli.
Bacterial suspensions were added to ammonia solutions ranging from 0.025 to
0.500 percent (250 to 5,000 ppm) in distilled water, and incubated at 37°C for
3 hours. Control cultures were incubated in distilled water only. A definite
mutagenic activity was observed at concentrations of 0.25 and 0.50 percent
(2,500 and 5,000 ppm); however, the proportion of survivors was lower than 2
percent.
Lobashev and Smirnov (1934) reported that 95 percent mortality occurred
in larvae of Drosophilia melanogaster (100-120 hr old) exposed to the fumes
of 1 percent (10,000 ppm) ammonium hydroxide solutions. The offspring of
the survivors showed a mutation rate of 0.54 percent while control cultures
showed only 0.05 percent, which was a statistically significant effect.
Visek et al. (1972) examined the effect of ammonia in cultures of normal
and transformed 3T3 cells. Normal 3T3 and SV-40 transformed 3T3 mouse
fibroblasts were cultured in media with serum and antibiotics plus ammonia
added as ammonium chloride. The amount of ammonia added was 0, 10, 20,
or 35 ug/mL (0, 10, 20 or 35 ppm) of culturing medium. Normal morphology
and cell multiplications were seen in both cell lines when ammonia was not
added. However, when ammonia was added both cell lines showed distinct
changes in the morphology and highly significant (p < 0.001) reductions in cell
multiplications. These changes increased progressively as the concentration of
ammonia increased. Control 3T3 cultures released significantly (p < 0.001)
greater quantities of ammonia per cell than control cultures of transformed
cells, but their multiplication was more adversely affected with the addition of
3-14
-------
ammonia. The affect of ammonia on cell multiplication was independent of the
pH of the medium.
3.8 Teratogenicity and Reproductive Effects
No information was found on the teratologic or reproductive effects of
ammonia in animals.
3.9 Neurotoxicity
Elevated levels of ammonia in the blood of animals and humans have
been known to cause neurologic disorders and encephalopathy.
Hyperammonemia may result from liver failure or metabolic and genetic
diseases that affect the synthesis of urea and/or removal of ammonia. The
biochemical basis for ammonia neurotoxicity is discussed in Section 3.2.
3.10 Effects on Humans
Most of the available literature on the effects of ammonia on humans
consisted of case reports following accidental exposure via inhalation;
consequently, exposures were not well quantified. The major effects of acute
exposure to ammonia are burns of the eyes, skin, and respiratory tract. Since
ammonia is highly water soluble, these effects are likely the result of the
formation of ammonium hydroxide in situ.
3.10.1
Ocular Toxicity
Eye injuries are the most common cause of permanent disability due to
accidental acute exposure to ammonia (Helmers et al., 1971; Jarudi and
Golden, 1973). Ammonia, in the form of ammonium hydroxide, forms soaps as
it reacts with the fatty epithelial layer of the cornea, after which it traverses the
stroma and disrupts the endothelium. Edema of the cornea can appear a few
minutes after exposure. In a severe exposure, ammonia may reach the iris and
start cataractous changes in the lens. The trabecular meshwork may become
edematous and plugged with iris pigment and inflammatory cells. Following
these changes, an increase in intraocular pressure can be detected a few
hours after exposure. Weeks after exposure, infiltration of the cornea may
result in fibrosis and neovascularization. Ulceration of the conjunctiva! surfaces
may cause adhesion of the lids to the globe. The inflammatory progression
may continue until the cornea, iris, and lens are fused into a mass of vascular
granulation tissue.
Gaseous ammonia is slightly irritating to the human eye at a concentration
of 99 mg/m3 (140 ppm) and immediately irritating at 495 mg/ms (700 ppm)
(National Research Council, 1977; Griffiths and Megson, 1984). Reported
ocular effects following exposure to ammonia are inflamed eyes, lacrimation,
swelling of the eyelids (O'Kane, 1983; Ward et al., 1983; Hoeffler et al., 1982;
Close et al., 1980; Montague and Macneil, 1980; Ferguson et al., 1977;
Verberk, 1977; Helmers et al., 1971; Silverman et al., 1949; Caplin, 1941),
hyperemic conjunctiva (Hatton et al., 1979; Sobonya, 1977; Helmers et al.,
1971; Levy et al., 1964; Caplin, 1941; Slot, 1938), and sustained corneal
damage (Birken et al., 1981; Kass et al., 1972; Osmond and Tallents, 1968;
Caplin, 1941). Highman (1969) described two cases in which ammonia was
squirted in the face and eyes. The presenting signs mimicked those of acute
angle closure glaucoma; i.e., oval, semidilated, nonreacting pupils; corneal
edema; and a rapid rise in intraocular pressure (to 60 mmHg in the damaged
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eye of one patient and 36 mmHg in the damaged eye of the other patient).
(The normal range for intraocular pressure is 10 to 30 mmHg.) Continued
medication was necessary to decrease and maintain intraocular pressure.
Other signs observed in the two patients were burns of the eyelids, chemosis,
and corneal ulcers.
Moeller (1974) examined ophthaimologic changes due to chronic
exposure in 109 persons working in an ammonia plant. The average exposure
time was 7.6 years. The following examinations were carried out: vision
determination, slit lamp examination, ophthalmoscopy, examination of the
central and peripheral visual fields, and anomaloscope examination. No ocular
effects due to chronic ammonia exposure were noted.
3.10.2
Respiratory Toxicity
The range of odor threshold concentrations for ammonia in humans was
reported to be from 0.5 to 35.0 mg/m3 (0.7 to 50 ppm), with the average
threshold concentration estimated at 4.0 mg/m3 (5 ppm) (National Research
Council, 1977). Many case report studies of accidental ammonia inhalation
have classified the exposures as mild, moderate, or severe. Mild exposure
usually results in temporary, irritating respiratory symptoms; moderate
exposure, in more insidious and prolonged effects; and severe exposure, in
death and long- term irreversible respiratory changes. Close et al. (1980)
reported that in moderately exposed persons, initial chest findings may be
normal but may worsen with time due to insidious penetration of ammonia into
the lower airways.
Immediate signs of accidental ammonia inhalation are dyspnea (Flury et
al., 1983; O'Kane, 1983; Hoeffler et al., 1982; Close et al., 1980; Montague and
Macneil, 1980; Dalton and Bricker, 1978; Sobonya, 1977; Walton, 1973; Kass
et al., 1972; Levy et al., 1964; Caplin, 1941), wheezing, rhonchi, and rales
(Flury et al., 1983; O'Kane, 1983; Montague and Macneil, 1980; Helmers et al.,
1971; Sobonya, 1977; Levy et al., 1964; Caplin, 1941), chest pain (Montague
and Macneil, 1980; Walton, 1973), nonproductive cough (O'Kane, 1983;
Hoeffler et al., 1982; Montague and Macneil, 1980; Walton, 1973), productive
cough (Price et al., 1983; Hoeffler et al., 1982; Caplin, 1941), nasal discharge
and bronchial secretions (O'Kane, 1983; Helmers et al., 1971; Levy et al.,
1964), acute upper airway obstruction (Close et al., 1980), aphonia (Montague
and Macneil, 1980), laryngopharyngeal edema (Griffiths and Megson, 1984;
Flury et al., 1983; O'Kane, 1983; Montague and Macneil, 1980; Dalton and
Bricker, 1978; Osmond and Tallents, 1968; Levy et al., 1964), cyanosis
(O'Kane, 1983; Dalton and Bricker, 1978; Walton, 1973; Caplin, 1941),
hypoxemia and hypercapnia (Price et al., 1983; Flury et al., 1983; Hoeffler et
al., 1982), decreased blood gas levels (O'Kane, 1983; Close et al., 1980;
Montague and Macneil, 1980), pulmonary edema (Hoeffler et al., 1982; Chu,
1982; Griffiths and Megson, 1984; Birken et al., 1981; Sobonya, 1977; Helmers
et al., 1971; Capiin, 1941), bronchospasm (O'Kane, 1983; Sobonya, 1977;
Walton, 1973; Levy et al., 1964), and pseudomembranous covering of the
pharynx wall (Flury et al., 1983).
Long-term effects of accidental ammonia inhalation are hypoxemia
(Sobonya, 1977; Kass et al., 1972), pulmonary edema (Price et al., 1983;
O'Kane, 1983), emphysema (Kass et al., 1972), bronchiectasis (Price et al.,
1983; Kass et al., 1972), mucopurulent exudate arising from the
tracheobronchial tree (Flury et al., 1983; Sobonya, 1977; Kass et al., 1972),
infection with Nocardia asteroides (Sobonya, 1977), pneumonia or pneumonia
infiltrate (Flury et al, 1983; O'Kane, 1983; Hoeffler et al., 1982; Kass et al.,
3-16
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1972; Osmond and Tallents, 1968; Caplin, 1941; Slot, 1938), chronic infectious
lung disease (O'Kane, 1983), and a prolonged decrease in pulmonary function
(Price et al., 1983; Birken et al., 1981; Close et al., 1980; Kass et al., 1972).
Reported pathologic findings in deceased victims 2 to 120 days following
excessive ammonia inhalation have been loss of cartilage in both lungs (Birken
et al., 1981); cystic bronchiectasis (Hoeffler et al., 1982; Birken et al., 1981;
Sobonya, 1977); distended, congested lungs (Arwood et al., 1985; Birken et
al., 1981; Sobonya, 1977; Walton, 1973; Caplin, 1941; Slot, 1938); denudation
of epithelium from bronchial walls (Arwood et al., 1985; Burns et al., 1983;
Sobonya, 1977; Walton, 1973; Caplin, 1941); edema (Burns et al., 1983;
Walton, 1973; Caplin, 1941; Slot, 1938); bronchopleural fistula, thickened
bronchial wails, fibrous tissue growths (Sobonya, 1977), and hemorrhage
(Burns et al., 1983).
3.70.3
Burns of the Skin
Chemical burns of the skin constitute the remaining major consequence of
accidental exposure to high concentrations of ammonia. Upon contact with the
skin, ammonia forms ammonium hydroxide, which causes burns similar to
those caused by other alkalies. A concentration of 7,070 mg/m3 (10,000 ppm)
is sufficient to evoke skin damage (Birken et al., 1981). The maximal
concentration of vapor tolerated by the skin for more than a few seconds is
14,140 mg/m3 (20,000 ppm), whereas 21,210 mg/m3 (30,000 ppm) may
produce blisters in a few minutes (National Research Council, 1977). Several
case reports of chemical burns as a result of acute exposure have been
reported (Flury et al., 1983; Close et al., 1980; Hatton et al., 1979; Walton,
1973; Kass et al., 1972; Helmers et al., 1971; Osmond and Tallents 1968-
Levy et al., 1964; Slot, 1938).
3.10.4
Other Effects
Chronic exposure to 28 mg/m3 (40 ppm) ammonia vapor has resulted in
headache, nausea, and reduced appetite (National Research Council, 1977).
Other reported effects of exposure to ammonia vapor are convulsions (Kass et
al., 1972), shock (Osmond and Tallents, 1968; Slot, 1938), gastritis (Dupuy et
al., 1968; Slot, 1938), urticaria (Morris, 1956), leukocytosis (Ward et al., 1983),
and inflammatory bronchoconstriction (Bernstein, 1982). Herrick and Herrick
(1983) described a case of allergic reaction in a female weight lifter who
inhaled an aromatic ammonia inhalant. Shortly after inhalation, the woman
presented with rhinitis, rhinorrhea, conjunctivitis, dizziness, headache,
dyspnea, wheezing, periorbital swelling, and urticaria. Ingestion of ammonia
(usually in the form of household ammonia, a 15 M solution of 28 percent
ammonia) has resulted in acute corrosive esophagitis and gastritis followed by
esophageal and gastric stenosis (Ernst et al., 1963; Norton, 1960).
Shimkin et al. (1954) reported a case in which epidermoid carcinoma of
the upper lip was diagnosed 2 months after the patient spilled an oil-ammonia
mixture on the area. The authors suggested that the case was "acceptable as
an instance of a single-exposure, chemical-trauma exteriorization of a latent
cutaneous carcinoma in man." However, no similar reports were found in the
available literature.
3.70.5 Experimental Studies
Several studies have been carried out in human subjects exposed to low
levels of ammonia. Schmidt and Vallencourt (1948) exposed one subject
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(Schmidt) to 375 to 396 mg/m3 (530 to 560 ppm) of ammonia for 4 hours and
found no significant changes in the pulse, pH, urea and creatinine levels, or
CO2-binding power (the amount of CO2 that can exist in serum or plasma as
HCO ' at a PCO2 of 40 mm/Hg) of the blood over the exposure period. The
systolic blood pressure stayed constant for the first 35 minutes of exposure,
then decreased from 127 mmHg at 35 minutes to 102 mmHg at 180 minutes.
There was a marked linear increase in nonprotein nitrogen from 27 to 57 mg%
at 4 hours when exposure was ended. After termination of exposure,
nonprotein nitrogen levels decreased linearly, approaching the preexposure
level 3 hours after exposure cessation. However, later studies disputed these
findings; i.e., the reported blood nitrogen levels reached 36.4 mg% after 4
hours, exceeded maximum theoretical retention levels (Silverman et al., 1949)
and were inordinately higher than levels sufficient to induce death in rats and
rabbits (Ting, 1950).
In a study by Silverman et al. (1949), all exposed persons (7) experienced
hyperventilation ranging from 150 to 250 percent above normal values after
being exposed to 354 mg/m3 (500 ppm) ammonia for 30 minutes. Lacrimation
and nasal irritation were noted in two subjects. No changes were observed in
blood urea, nonprotein nitrogen, or CO2-binding power in two subjects tested.
In one of the two subjects, a slight elevation in pulse and blood pressure was
noted.
Verberk (1977) exposed 16 volunteers to 42, 57, 78, and 99 mg/m3 (60,
80, 110, and 140 ppm) ammonia for 2 hours at each exposure level over a 4-
week period. The subjects consisted of eight "experts," persons familiar with
the effects of ammonia, and eight "students," persons who were not. No
changes in vital capacity, forced expiratory volume, or forced inspiratory
volume were noted. The "students" were more responsive than the "experts"
for subjective effects; e.g., smell; irritation of the eyes, throat, or nose; urge to
cough; and general discomfort. The effect of ammonia exposure on "students"
seemed to be concentration-dependent.
In another study with six volunteers, two subjects were exposed to 18, 35
or 71 mg/m3 (25, 50, or 100 ppm) ammonia for 6-hour sessions once a week
for 6 weeks (Ferguson et al., 1977). No apparent changes in respiration rate,
blood pressure, pulse, or forced vital capacity were noted. An increase in the
1-second forced expiratory volume occurred with increasing concentrations.
The frequency of mild eye irritation decreased in the later sessions,
suggesting an adaptation to the exposure. However, the authors stated that the
exposure concentrations were not constant, with excursions to 106 to 141
mg/m3 (150 to 200 ppm) occurring, which produced lacrimation and transient
discomfort.
Cole et al. (1977) examined minute volume, tidal volume, and heart rate
during submaximal exercise in 18 male volunteers exposed to ammonia. The
exposure took place in two periods during which the volunteers exercised at
20 to 120 W for 8 minutes and 20 to 180 W for 11 minutes. The exposure
level was 50 to 79 mg/m3 (71 to 113 ppm) ammonia gas for the first period
and 115 to 158 mg/m3 (165 to 226 ppm) for the second period. Reported
subjective responses consisted of a prickling sensation in the nose and a
slight dryness of the mouth but no real discomfort. There was no significant
difference in heart rate, but there were significant decreases (p <0.05) in
minute volume (from 25 to 22.5 liters/minute), tidal volume (from 1.57 to 1.43
liters), and an increase in mean respiratory frequency (from 19.1 to 21.0
breaths/minute) with exposure at the higher level. There were no significant
changes in these parameters with exposure at the lower level (50 to 79
mg/m3). The authors suggested that the ventilatory responses to ammonia
3-18
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occurred a few minutes after exposure onset and were reversible, indicating a
reflex rather than a structural reaction.
Eleven of 23 subjects complained of nasal irritation after exposure to 71
mg/m3 ammonia for up to 30 seconds in each nostril (McLean et al., 1979). All
of the subjects showed increased nasal airway resistance, which was
suspected to be due to vascular dilation in the nasal mucosa, and/or edema
resulting from increased vessel permeability.
In a study by an independent testing laboratory reported in Johnston et
al., (1979), 10 subjects were sequentially exposed for 5-minute intervals to 23,
35, 51, and 95 mg/ms (32, 50, 72, and 134 ppm) ammonia. At 23 and 35
mg/m3, 1 of 10 and 2 of 10, respectively, noted dryness of the nose. At 51
mg/m3 eye irritation (3 of 20), nasal irritation (2 of 10), and throat irritation (3 of
10) were experienced. At 95 mg/ms, lacrimation accompanied by eye irritation
(5 of 10), nasal irritation (7 of 10), throat irritation (8 of 10), and chest
discomfort (1 of 10) were reported by the subjects. These subjective
symptoms were the only effects investigated. The laboratory workers
concluded that concentrations of 35 mg/m3 or less did not cause irritation or
discomfort.
Increased incidences of upper respiratory tract disease, skin changes, and
alterations in lipoprotein and protein metabolism were reported in 140
adolescents exposed to ammonia and nitrogen oxides for 3 hours/day for 2 to
3 years while enrolled in a vocational training program, when compared to a
control group. However, the exposure concentrations were reported as "not
exceeding maximal permissible concentrations," and it was not stated whether
these increased incidences were statistically significant (National Research
Council, 1977).
Donham et al. (1984) evaluated the acute respiratory effects of the work
environment in swine confinement workers. Workers were selected from 21
swine confinement operations with a history of spending at least 5 hours/day
in the buildings. Controls were nonsmoking office workers and students with
no previous occupational exposure to swine confinement and no history of
chronic respiratory disease. Both groups were subjected to a 4-hour exposure
period inside a swine confinement building for two separate exposures.
Pulmonary function tests were taken immediately before and after exposure A
decrease in FEV1; FVC, FEV^FVC, and FEF25.75 was seen in all exposed
subjects. However, a greater decrease in the pulmonary function parameters
was seen in the swine confinement workers. Further, these effects were more
significant in workers that had been employed in the swine confinement
operation for >6 years compared to workers employed for <6 years. The
levels of respiratory irritants found in the swine confinement building were not
given; however, levels of ammonia ranging from 14 to 30 mg/m3 (20.3 to 42.2
ppm) in addition to high levels of other, respiratory irritants in swine
confinement buildings have recently been reported by Donham and Popendorf
(1985).
3.70.6 Epidemiology
The earlier data on the adverse effects associated with chronic
occupational exposure to ammonia have been discussed by the National
Research Council (1977) and Carson et al. (1981). Most of these studies
involve chronic exposure to a mixture of substances and lack adequate
experimental design to abstract any meaningful information. More recently, in
a case control study of renal cancer mortality at a Texas chemical plant,'an
increased incidence of renal cancer mortality from exposure to a variety of
3-19
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physical agent exposures for 26 former employees deceased of renal cancer
and two matched control groups. There was however, an elevated risk for
"chlorine" workers but those workers were exposed to other compounds as
well (Bond et al., 1985).
There are no adequate epidemiology studies or animal carcinogenicity
studies for ammonia in the present data base. However, since ammonia is a
key metabolite in mammals and plays an essential role in acid-base regulation
and in the biosynthesis of purines, pyrimidines and nonessential amino acids,
it is unlikely that ammonia is a human carcinogen. Comprehensive assays
however, have not been done and therefore, ammonia should be classified as
group D "not classifiable as to human carcinogenicity" based on the weight-
of-evidence approach in the current EPA guidelines for carcinogen risk
assessment.
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