Abstract
One of the major toxic effects of exposure to ammonia is the resulting pulmonary acute and chronic effects. This study investigated the acute pulmonary effects of exposure to ammonia lower than the recommended threshold limit value (TLV). This cross-sectional study was conducted in 2021 in four chemical fertilizer production industries using ammonia as the main raw material. A total of 116 workers who were exposed to ammonia were investigated. The level of exposure to ammonia was measured by NMAM 6016, and the evaluation of pulmonary symptoms and function parameters was done using the American Thoracic Society and European Respiratory Society protocols in four sessions. The paired-sample t-test, repeated measures test, Chi-square, and Fisher’s exact test were run to analyze the collected data. The prevalence rates of pulmonary symptoms, including cough, dyspnea, phlegm, and wheezing, were 24.14, 17.24, 14.66, and 16.38%, respectively, after one exposure shift. It was observed that all pulmonary function parameters were reduced after one exposure shift to ammonia. The results revealed that the parameters of vital capacity, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), the FEV1/FVC ratio, and peak expiratory flow significantly decreased (p < 0.05) across four exposure shifts. The findings indicated that exposure to ammonia at concentrations lower than one-fifth of TLV could bring about acute pulmonary effects and reduce pulmonary function parameters, similar to the pattern observed in obstructive pulmonary diseases.
Introduction
Ammonia is used in many chemical processes as the primary chemical substance or intermediate. Ammonia is a widely used compound used to produce fertilizers, chemical materials, explosives, plastics, fiber, and medicine. About 80% of the produced ammonia is used in producing sulfate, ammonium nitrate, ammonium phosphate, and urea for agricultural purposes worldwide (Ouyang et al., 2018; Vecino et al., 2019; Yarandi et al., 2021).
Ammonia is the most important nitrogen-hydrogen compound in nature and is acquired from the decomposition of nitrogenous organic matter. Ammonia is a colorless gas. Ammonia gas is dangerous even at low concentrations; inhaling ammonia or exposing the surface of the skin can cause burns and even death. Exposure to ammonia or its solutions may irritate the skin and cause alkaline burns. The inhalation of ammonia causes rapid symptoms, and its toxic effects are caused by irritation and corrosion. Generally, exposure to considerable amounts of ammonia can generate burning in the depths of the mouth, larynx, and trachea, as well as obstruction of the airways and alveolar edema. Moreover, exposure to high concentrations of ammonia gas may be fatal within minutes (Anjana et al., 2018; Duijm et al., 2005; Yarandi et al., 2021; Zala and Kavishvar, 2012)
Ammonia irritates the respiratory tract, skin, and eyes and can cause death by damaging the lungs due to exposure to considerable volumes of the gas (Yarandi et al., 2021).
Exposure to ammonia can happen in industrial environments, by accident, or by leakage in transportation. It is highly soluble in water and is dissolved in the mucus fluid in the human respiratory system producing ammonium hydroxide, which is a strong base. After a normal inhalation, ammonia can completely stay in the mucus fluid of the upper part of the nose. However, a deep inhalation can result in the complete absorption of ammonia in the lungs (Hou et al., 2007; Neghab et al., 2018). The inhalation of ammonia can cause different pulmonary symptoms via irritation and corrosion. These symptoms include nose, throat, and respiratory tract irritation, causing tears or cough, and increased inhalation and exhalation rates or so-called “pulmonary tension.” High exposure to ammonia can result in irritation in the lowest sections of the oral cavity, pharynx, larynx, and trachea, as well as the congestion of airways and bronchial and alveolar edemas. Generally, the effects of respiratory exposure are limited to the respiratory system and the area of contact with ammonia. A short but high pulmonary exposure to ammonia can irritate and burn the mouth, lungs, and eyes in humans. Moreover, exposures to high concentration levels of ammonia can kill humans in a few minutes (Dasarathy et al., 2017; Waheed and Fuller, 2017).
The American Conference of Governmental Industrial Hygienists (ACGIH) reported that the acceptable time weight average (TWA) for ammonia is 25 ppm. Also, there is not any LD50 for ammonia exposure in humans. The LD50 and LC50 values that were computed for rats are 350 mg/kg and 2000 ppm (4 hr) (Hygienists, 2019). Ammonia gas can create a general discomfort with a concentration between 150 and 200 ppm. At concentrations between 400 and 700 ppm, ammonia gas can generate evident irritation. At 500 ppm, ammonia gas is instantly dangerous to health (Orozco et al., 2019).
Although the threshold limit value (TLV) of ammonia is 25 ppm for a long exposure (TLV-TWA for 8 hr) and 35 ppm for a short exposure (TLV-STEL for 15 min) based on AGGIH (2019), Neghab et al. (2019), the results of some studies have demonstrated that exposure to lower concentrations might also cause severe pulmonary effects in humans (Ali et al., 2001; Neghab et al., 2018; Rahman et al., 2007). In a study by Rahman et al. (2007), it was observed that ammonia has reversible, acute pulmonary effects (Rahman et al., 2007). Similarly, Neghab et al. (2018) reported that lower-than-standard exposures to ammonia can reduce the capacity of pulmonary function parameters after 12 h of exposure (Neghab et al., 2018).
Considering the need for annual industrial hygiene exposure assessments and conducting occupational medicine examinations in the work environment, especially in small and medium chemical industries using ammonia on a large scale as raw material, the observation of pulmonary symptoms in the workers of these industries and also the need to be aware of the acute effects of exposure to ammonia in the relevant sectors, this study aimed to investigate the acute pulmonary effects of exposure to ammonia in small and medium chemical industries.
Method
Study design
This cross-sectional study was conducted in 2021 in four chemical fertilizer production industries using ammonia as the main raw material and located in one industrial city in Qom - Iran. The temperature and relative humidity of the study area was 39°C and 41%, respectively. Inclusion criteria included at least 2 years of work experience, absence of chronic and acute respiratory diseases, lack of respiratory exposure to other chemical compounds that can adversely affect the respiratory system, and sufficient willingness to participate in the study. The criterion of 2 years of work experience was considered so that all people were fully familiar with the industrial processes in these industries and also had a good knowledge of the health consequences related to ammonia. Participants could leave the research at any stage of the study. Employees with diagnosed pulmonary disorders like asthma, bronchitis, COPD (Chronic Obstructive Pulmonary Disease), and employees who physically or medically could not perform the spirometry test were excluded. Also, employees with a smoking history were excluded from the study because of the outcomes of smoking on respiratory capacity and developing chronic obstructive pulmonary disease. All participants were working the day shift. All participants in this examination completed the consent form for participation in the study. All participants had similar working conditions, exposure status, and environmental factors. Based on the goals of the study, the acute effects of exposure to ammonia in one workweek covering four work shifts (before and after exposure on the first workday of the week, after exposure at the end of the fifth workday of the week, and before exposure in the first workday of the following week) were investigated. One workday usually consisted of 8 hours in such industries.
In acute exposure, immediately after or shortly after exposure to chemical compounds, symptoms and side effects appear in an individual. Acute side effects often result from exposure to high-levels of chemical compounds concentration over a short period. Chronic exposure occurs over a more extended period than acute; chronic workplace chemical exposure usually involves low levels of exposure over a long period. The effects are not reversible for those who experience this type of exposure. It is often difficult to find the relationship between chemical exposure and related disease owing to the delay between exposure and response onset; however, determining this relationship is not impossible.
Additionally, this study was implemented following the 2014 revision of the Helsinki Declaration (Association, 2014). This study was reviewed by an external ethics review committee and found to be following Helsinki and ethical principles and the national norms and standards for conducting Medical Research in Iran. All industry managers and individuals participating in this study signed the informed consent form.
The population of the study
The study sample included 155 workers working in four ammonia-using chemical industries. The census method was used to estimate the sample size to have valid and reliable results. Thus, all the workers exposed to ammonia were involved in the study. Using a list of personnel exposed to ammonia (based on reports of harmful chemical agents in the workplace), study participants were selected from all four factories. In this list, each person had a profile of occupational exposure to ammonia during different years and the results of occupational medicine examinations.
Then, subjects with a history of smoking cigarettes or chronic pulmonary diseases were removed from the study so that the effects of confounding variables were reduced or obliterated. Eventually, 39 participants were excluded because of pulmonary disorders, smoking, or lack of inclusion criteria, and 116 subjects were included as the study’s final sample. Twenty-nine subjects were selected from each industry. They all consented to participate in the study. All 116 participants were present by the end of the study.
Ammonia chemical specification (NH3)
NH3 is a colorless gas with a characteristic pungent odor. Its molecular weight is 17.03 g.mol−1, and its density is 0.769 kg.m−3. Most NH3 is utilized in industrial and agricultural applications such as fertilizer, plastics, nitric acid, explosives production, and refrigeration. NH3 is a toxic gas and has high safety risks. The molecular space and interaction energy of ammonia molecules are insignificant. Thus, ammonia is very easy to spread. Ammonia is toxic, and the IDLH-15 min is 50 ppm or 36 mg/m3. Ammonia is kept in liquid form under its vapor pressure in pressurized vessels (Li et al., 2021).
Fertilizer production process in the studied industries
Although nearly 80% of the earth’s atmosphere is comprised of nitrogen, it is chemically unusable in this form. However, using the Haber–Bosch process, nitrogen is captured from the air and converted into a form that growing plants can use. Ammonia in this form is known as anhydrous ammonia. Ammonia is an essential compound in the manufacturing of fertilizers and is one of the largest-volume synthetic chemicals produced in the world. Ammonia (NH3) is the foundation for all nitrogen (N) fertilizers. Eighty-seven percent of anhydrous ammonia is used as fertilizer, and the other 13% is used in industrial sectors. Farmers inject anhydrous ammonia into the subsoil in a liquid form (Lim et al., 2021; Munasinghe-Arachchige and Nirmalakhandan, 2020).
Primary fertilizers include substances derived from nitrogen, phosphorus, and potassium. Various raw materials are used to produce these compounds. Ammonia is used as a nitrogen source in fertilizer (one of the methods of chemical fertilizer production requires using natural gas and air).
In chemical fertilizer production, natural gas and steam are pumped into a large container. The air is pumped into the system and released by burning natural gas and oxygen vapor. First of all, it leaves nitrogen, hydrogen, and carbon dioxide. Carbon dioxide is removed, and ammonia is produced by applying an electric current to the system. Catalysts such as magnetite (Fe3O4) are used to improve the speed and efficiency of ammonia synthesis. Any impurities are removed from the ammonia and stored in tanks until further processing.
While ammonia is sometimes used as a fertilizer, it is often converted to other materials for ease of use. Nitric acid is first produced by mixing ammonia and air in a tank. In the presence of a catalyst, a reaction occurs that converts ammonia to nitric oxide. Nitric oxide reacts more in the presence of water and produces nitric acid.
Nitric acid and ammonia are used to make ammonium nitrate. This material is a good fertilizer because it has a high nitrogen concentration. The two substances are mixed in a tank, and a neutralization reaction occurs, producing ammonium nitrate. Then this material can be stored until it is ready to be granulated and mixed with other fertilizer components.
Measuring exposure to ammonia
The measurement of exposure to ammonia was done based on the NIOSH Manual of Analytical Methods (NMAM) 6016 (Ashley and O’Connor, 2017). During the present study, each person’s respiratory exposure was measured by three samples, indicating the actual exposure of personnel during work shift (one sample at the beginning of the shift, one sample in the middle of the shift, and one sample at the end of the 8-hour work shift). The sampling time was 45 min at each sample, based on the preliminary studies and allowable air volume in the NIOSH 6016 method in order to prevent the phenomenon of break-through. The sampling method for time distribution was chosen according to strategy Number 6 of the National Institute of Occupational Safety and Health. According to this strategy, sampling was done in three 45-minute periods in the work shift. The sampling rate was 0.2 L. min−1. The sampling was carried out by silica gel absorbent smeared with sulfuric acid using an SKC pump. The samples were then analyzed by ion-exchange chromatography.
Assessment of respiratory symptoms
We gathered demographics and respiratory symptom histories (such as chronic cough, wheezing, phlegm, bronchitis, etc.) utilizing a modified version of the American Thoracic Society (ATS) respiratory symptom questionnaire. Participants self-completed the questionnaire. Furthermore, participants were given adequate explanations during the training courses before completing the questionnaire (Sadeghi-Yarandi et al., 2020).
The evaluation of pulmonary function parameters
The pulmonary symptoms were evaluated based on the American Thoracic Society (ATS) questionnaire (Wedzicha et al., 2017). This evaluation consisted of vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) in line with the ATS and European Respiratory Society (ERS) protocols (Graham et al., 2019) and was conducted by the portable calibrated spirometer device (Vitalograph ALPHA made in England) and a disposable mouthpiece filter and nose clip during the test on-site. Participants were informed about the pulmonary function test before the measurement. Furthermore, information about the participants, like height, weight, and age, was recorded to calculate the predicted PF parameter before the measurement.
The PF test was applied as follows: 1. Normal inhalation and exhalation 2–3 times. 2. Taking the deepest breath. 3. Exhale as much as possible.
Each participant repeated the spirometry test at least three times for test reliability, and the best of the three was chosen. It should be noted that the evaluation of pulmonary function parameters for four work shifts (before and after exposure in the first workday of the week, after exposure at the end of the fifth workday of the week, and before exposure in the first workday of the following week) was made after 64 h of non-exposure.
Data analysis
The data were analyzed by the IBM SPSS v. 22 software, and the significance level was set at p < 0.05. First, the Kolmogorov-Smirnov test of normality was run, and it was observed that the data were normally distributed. The following statistical tests conducted the analyses of the effects of acute pulmonary effects of ammonia: Chi-square, paired-samples t test, Fisher exact test, McNemar test, and repeated measures ANOVA.
Results
A total of 116 workers were exposed to ammonia in four work shifts (i.e., before and after exposure in the first workday of the week, after exposure at the end of the fifth workday of the week, and before exposure in the first workday of the next week). The results of the measurements revealed that exposure levels on five workdays of the week were 4.75 ± 2.11, 4.90 ± 1.45, 4.80 ± 1.54, 4.77 ± 1.60, and 4.78 ± 2.18 ppm, respectively. The repeated measures test results showed no significant differences among these exposures in the four work shifts (p > 0.05).
Individual characteristics of the studied subjects (n = 116).
Individual characteristics have been presented in Table 1 were including mean and standard deviation of age, work experience and body mass index (BMI), and frequency of marital status and education level of the studied subjects.
The clinical evaluation results of acute, adverse symptoms among the subjects revealed pulmonary issues such as cough, dyspnea, phlegm, and wheezing in 28, 20, 17, and 19 subjects, respectively. The incidence rate of these symptoms in the two work shifts after exposure at the end of the first and fifth days of the workweek was significantly different from before exposure on the first day of the workweek (Figure 1). Frequency of pulmonary symptoms in studied subjects (n = 116).
Results of pulmonary function parameters of the study subjects in four exposure shifts (n = 116).
These Findings are related to mean, standard deviation and comparative evaluation of pulmonary function parameters (including VC, FVC, FEV1, FEV1 /FVC and PEF) of the study subjects in four exposure shifts (including before 1st shift on workweek and next workweek and after the 1st & 5th shift on the first workweek). The comparative evaluation of these parameters was performed by analysis of variance for repeated measure test.
Note. VC: Vital capacity; FVC: Forced vital capacity; FEV1: Forced Expiratory Volume in the first second; PEF: Peak Expiratory Flow.
The evaluation of the acute effects of exposure to ammonia using the changing trend in the mean of pulmonary function parameters in 1 week is depicted in Figure 2. As can be seen, the results revealed that the changing trend of pulmonary function parameters was almost U-shaped for all parameters, unless for the FVC parameter. Changing trend of pulmonary function parameters of the study subjects in 1 week.
Discussion
Pulmonary exposure to chemicals is one of the critical types of occupational exposure. Therefore, pulmonary injuries, such as different chronic and acute pulmonary diseases, are among the most frequent complaints made by industrial workers who are exposed to such chemicals (Heidari et al., 2019; Neghab et al., 2012a, 2012b, 2013). The findings of this study showed that the average exposure of small and medium industries’ workers to ammonia was lower than 1/5 (20%) of the standard limit for a long exposure (TLV-TWA = 25 ppm) and lower than 1/7 (14.3%) of the standard limit for a short exposure (TLV-STEL = 35 ppm) (Neghab et al., 2019). Based on the findings, the acute effects of exposure to such low levels of ammonia are expected to be zero or very slight.
An investigation of the previous research shows that few studies have been conducted on the acute effects of exposure to lower-than-standard ammonia concentrations. Nevertheless, some research has reported that low concentrations of ammonia can still cause acute pulmonary effects (Neghab et al., 2018; Rahman et al., 2007), but no study has investigated the acute effects of ammonia after several exposures across different work shifts. The findings of this study demonstrated that low concentrations of ammonia could also result in pulmonary symptoms such as cough, dyspnea, phlegm, and wheezing, even after short exposures. Additionally, the results depicted in Table 1 indicated that these symptoms resulted from acute effects of exposure to ammonia, and after 2–3 days of non-exposure, the symptoms started to fade away. In agreement with this finding, Rahman et al.’s (2007) study found that one of the acute effects of exposure to ammonia is pulmonary symptoms such as cough and wheezing (Rahman et al., 2007).
In addition to the results mentioned above, it was also observed that the mean of pulmonary function parameters (VC, FEV1, FEV1/FVC, and PEF) significantly reduced after exposure to low ammonia concentrations. Neghab et al. (2018) also reported that short exposure to ammonia could decrease pulmonary function parameters such as VC, FVC, FEV1, and PEF (Neghab et al., 2018). Moreover, Rahman et al. (2007) also observed that exposure to ammonia could reduce some pulmonary function parameters, such as FVC and FEV1 (Rahman et al., 2007). What differentiates this study from previous ones is that the results of this study demonstrated that the pulmonary effect of exposure to ammonia follows the pattern observed in obstructive pulmonary diseases. In such diseases, the FEV1 and FEV1/FVC parameters usually start to diminish, and the FVC stays the same or decreases (Bhatt et al., 2019; Quanjer et al., 2016).
Similarly, it was observed in this study that the acute effects of exposure to ammonia significantly decreased FEV1 and FEV1/FVC parameters and slightly reduced/maintained the FVC parameter. Furthermore, the significant symptoms of pulmonary disease found in this study were wheezing, cough, and phlegm, which are also reported in other studies (Antus et al., 2010; Eduard et al., 2009).
The key finding of this study was the changing trend of acute effects of exposure to ammonia in the studied population. As observed in Figure 2, although the reduction trend of the pulmonary function parameters was reversible, it was not completely reversible. Therefore, this is a very important finding showing that the accumulation of such a reduction, in the long run, can lead to irreversible chronic effects. In general, the results of this study demonstrated that exposure to concentrations of ammonia one-seventh lower than the short-term exposure limit can also result in acute pulmonary effects such as the incidence of pulmonary symptoms and the reduction of pulmonary function parameters similar to obstructive pulmonary diseases. Therefore, it can be said that the acute pulmonary effects caused by exposure to ammonia can occur at concentrations much lower than the permitted limits, which requires more detailed laboratory, interventional and cohort studies with a larger statistical sample.
Therefore, carrying out control measures such as engineering changes (removing emission sources if possible, employing dilution and local ventilation systems, using chemical compounds with less toxicity, regular and continuous determination of emission values, etc.), management measures (such as regular measurement of harmful factors in the work environment and occupational medicine examinations of personnel, job rotation, regulation of work-rest cycles, non-employment of workers with pulmonary disorders in tasks with exposure to stimulating chemical compounds such as ammonia, etc.), and finally personal protective equipment (such as using a variety of protective masks with cartridges) are recommended.
Pointing to the inadequacy of the ACGIH TLV index for the exposures in work environments during the present study may not be ideal because its most significant limitation can be the study’s cross-sectional nature. But its findings can create new scientific insights into the field of acute effects of exposure to ammonia in work environments and a motivation to conduct cohort and intervention studies in the future.
Conclusion
The findings indicated that exposure to ammonia at concentrations lower than one-fifth of TLV could bring about acute pulmonary effects and reduce pulmonary function parameters, similar to the pattern observed in obstructive pulmonary diseases. The present study’s findings provide new insights into the acute effects of exposure to ammonia and support the implementation of suitable control measures in work environments.
Footnotes
Acknowledgments
The authors would like to express their gratitude to Vice-Chancellor for Research and Technology of Qom University of Medical Sciences and management and study subjects of the four chemical industries.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Vice-Chancellor for Research and Technology of Qom University of Medical Sciences and Health (project number 991307 and ethical code IR.MUQ.REC.1399.264).
