Reactive nitrogen compounds and their influence on human health: an overview

Introduction

Nitrogen (N), an essential element of life, is the fourth most abundant element in biomass and a participant in environmental redox chemistry. Most N in the atmosphere exists as N₂ gas. In this form it is not available to most biota on earth. When N₂’s bond is broken, N becomes reactive and occurs in various forms. This diverse pool of N is defined as “reactive N” (Nr) which includes all biologically, radiatively, and photochemically active forms of the element [1]. Examples include dissolved NO₃ ⁻ and NH₄ ⁺ which are the major forms taken up by biota, and the gases NH₃, NO _x (NO and NO₂) and N₂O [1]. These forms of N can move readily among the biosphere, the hydrosphere and the atmosphere, and can alter the chemistry of these systems. The rate at which N₂ is transformed into biologically available forms is vital for the functioning of terrestrial, freshwater and marine ecosystems [2]. Nr is a constituent of organic molecules such as amino acids, proteins, chlorophyll, hemoglobin, enzymes, nucleic acids (DNA and RNA), humic acids and others. Therefore, supply of Nr is essential for all life forms. Reactive N can be used by living organisms and provides both beneficial and harmful effects. Adequate amounts of digestible N promote human physiological health throughout the lifetime. The availability of N also has profound implications for the problem of anthropogenic carbon (C), as N is a major factor in determining the amount of atmospheric CO₂ naturally sequestered through production of biomass [3]. In pre-industrial agriculture, N was the most yield-limiting nutrient.

Increases in N supply have been exploited in modern agriculture for yield gains and to produce food for the growing global human population [4]. In absence of human influences, biological N₂ fixation (BNF) and the production of NO _x by lightning are the only sources of new Nr in the environment. A review by [5] provides an estimate of annual pre-industrial BNF in terrestrial ecosystems of 58 Tg N, within a range of 40–100 Tg. Global BNF in croplands is estimated at about 43 Tg N year⁻¹, with a range from 30 to 51 Tg N year⁻¹, based on the ranges of N₂ fixation yields [6]. This estimate includes leguminous crops and N₂ fixation by cyanobacteria associated with the cultivation of rice and sugarcane, but does not include legumes in pasturelands or savannas used for grazing. Lightning fixation of N may amount to additional 5 Tg N year⁻¹ [7].

Humans have dramatically increased the rate of reactive N cycling, in particular via mineral N fertilizer production due to the commercialization of the Haber-Bosch process and cultivation of N₂–fixing crops for increasing crop productivity, as well as by fossil fuel combustion [8]. Synthetic N fertilizer usage since the beginning of the 20th century grew to about 12 Tg N year⁻¹ in 1960, and thereafter it has grown almost tenfold to 110 Tg N year⁻¹ in 2013 [9]. In summary, industrial N fertilizer production and cultivation-induced N₂ fixation sums up to about 150 Tg year⁻¹ [10] indicating that cycling of reactive N due to these activities has more than doubled in the last century [11].

Emissions of NO _x from combustion processes also constitute a source of reactive N. These emissions have increased from about 5.8 Tg N year⁻¹ in 1910 to approximately 38 Tg N year⁻¹ in 2010. Since the 1990s, NO _x emission sources have been subject to pollution controls in the USA and Europe, resulting in substantial emission reductions. However, emissions continue to increase in the developing world and emerging economies, especially in China [12]. The higher use of synthetic fertilizer, increased cultivation of N₂-fixing crops, and elevated emissions of NO _x all contribute to rise in the overall level of Nr in the environment. The total of these three sources for 2014 was 190 Tg N year⁻¹, with a plausible range from 160 to 210 Tg N year⁻¹ [9].

Humans currently produce as much biologically available N as all natural pathways and this may grow by a further 65% by 2050 [13]. Since 1960, global N use efficiency in crop production (portion of N that is converted into harvest products) has declined from ∼68 to ∼47% [14]. Consequently, more than half of the N used for crop production is lost to the environment. Nitrogen efficiency in livestock production is even lower. For example, cattle production per unit area produces 2–10 times less protein in meat and milk compared to cereal grains and 20-fold less compared to legumes such as soybeans [15].

Much of the developed world has easy access to N fertilizers to achieve food security. In contrast, many developing nations still lack access to adequate nitrogen supplies [4]. This disparity is most pronounced in sub-Saharan Africa, parts of Asia and Latin America where nitrogen is mined from diminishing soil pools to grow food [16, 17]. In line with this, the response of agricultural systems to increased N fertilization in different world regions has developed differently. For example, N losses (greatly) exceed 50 kg N ha⁻¹ year⁻¹ in most of Europe, the Middle East, the USA and Central America, India and China, while they remain on average (far) below 25 kg N ha⁻¹ year⁻¹ in most sub-Saharan Africa and some Former Soviet Union countries [14, 18]. Nitrogen is transported and lost to the environment through runoff, leaching to groundwater, and emissions of ammonia (NH₃), nitrogen oxides (NO _x ), and other N compounds [19, 20].

Reactive N is responsible for various kinds of environmental damages such as eutrophication and oxygen depletion in water bodies, change and loss of biodiversity, acidification of waters and soils, coral reef degradation, contribution to particulate matter (PM) and ozone (O₃) formation (ground level) and depletion (stratosphere), and global warming. All of these processes can cause serious direct or indirect human health effects [21]. For instance, acidification can lead to enhanced mobility of metals in soil [22], which may lead to harmful effects on humans. Lockdown measures due to COVID-19 during the first quarter of 2020 applied in many countries has significantly reduced air pollution [23], but the effect may be only temporary.

Eutrophication, particularly due to enrichment of coastal and inland waters with nitrogen causes fish kills and algal blooms, the latter being potentially toxic to humans [24, 25]. All of these environmental effects are widespread and worsening. Human additions of N to the environment can also drive a range of ecological changes including the dynamics of some human diseases. For example, there is some evidence that abundance and distribution of the mosquito hosts of malaria, West Nile virus, and several types of Vibrio cholerae, causing cholera disease, may be affected by changes in N availability [26]. Several studies also indicate that there is a relationship between the spread of vector-borne diseases and climate change [21].

Human needs and supplies of N

Of all essential nutrients, N is required in the largest amount and is often the limiting nutrient. The element is essential for synthesis of amino acids, proteins, peptides, enzymes, DNA and RNA, growth hormones, neurotransmitters and low-molecular weight substances (e.g. glutathione, creatine, nitric oxide, dopamine, serotonin) [21, 27]. Amino acids are essential for health, growth, development, reproduction, lactation and survival of organisms. On average, amino acids contain 16% N. Dietary glutamate, glutamine and aspartate are major metabolic fuels for the small intestine in the fed state, whereas glutamine is almost the only source of energy in the arterial blood in the post-absorptive state [27]. Glutamine also provides about 50 and 35% of ATP in lymphocytes and macrophages, respectively, to sustain immune responses [27]. The human metabolism is able to synthesize 11 of 20 proteinogenic amino acids. The other nine must be obtained through dietary intake. Essential amino acids include histidine, isoleucine, leucine, lysine, methionine, phenylanaline, threonine, tryptophane and valine. Histidine is essential for the growing children but not for adults. The body needs to replace protein losses caused by breakdown of the compounds, excretions of N in urine, feces and sweat, shedding of skin and cutting of hair and nails [28]. The relative protein demand peaks in infancy when both tissue synthesis and protein breakdown rates are high [29, 30]. The daily protein needs of an adult amount to 0.83 g kg⁻¹ body weight, corresponding to ∼50–70 g protein capita⁻¹ day⁻¹ (Table 1).

Daily adult protein needs change with the degree of physical activity [27]. Dietary intake of 1.0, 1.3 and 1.6 g protein per kg body weight day⁻¹ is recommended for individuals with minimal, moderate, and intense physical activity, respectively [27]. The amino acids or proteins that cannot be synthesized by human body may be either obtained directly from plants or indirectly through consumption of animal products. Currently, plant- and animal-based foods contribute ∼65 and 35% of protein in human diet worldwide (in North America: 32 and 68%, respectively) [31]. However, the production of animal protein has greater environmental footprint as the conversion efficiency for synthesizing human digestible proteins from forages and feedgrains is low, ranging between 5 and 60% [21]. Shifting consumption from animal-based to plant-based proteins can help reduce environmental and the consequential human health impacts. Since the plant sources are generally deficient in some essential amino acids such as lysine, tryptophan, or methionine, it is important to combine different plant protein sources such as cereals and legumes to achieve a balance and avoid deficiencies. A recent study showed that soybean is the most important source of plant-based lysine and can be considered as a substitute for animal-based protein [32]. Though proper combinations of legumes with cereals in the human diet can sufficiently provide most amino acids, yet the availability of legumes for human nutrition is limited in many parts of the world, where these foods are not produced [27]. Despite livestock (meat and milk) production requiring disproportionately high nitrogen, water and land resources, elimination of animal sources from the diet, especially in developing regions where micronutrient (e.g. iron and zinc) and vitamin A and B-complex vitamins deficiency is widespread, is not recommended [33].

Causes of regional malnutrition

Mineral fertilizers have led to a tremendous increase in world food production from the 1960s to the 2000s [8, 26]. Despite large population increases over the same time period, starvation and malnutrition have declined in many regions [30], though these are still widespread in some regions, especially in sub-Saharan Africa, parts of Asia and Latin America. In poor countries with substantial malnutrition problems, increased N fertilizer use can considerably reduce malnutrition [34]. However, synthetic N fertilizer use is unevenly distributed over the globe with low consumption in Africa compared to countries in Asia (Table 2).

In Africa, the N fertilizer use increased slowly during the past two decades, although cropland expansion widely occurred. In sub-Saharan (Eastern, Middle, Western) Africa most areas still received less than 15 kg N ha⁻¹ in 2018. In most of Europe, agricultural N fertilizer use rate peaked in the 1970s and decreased slightly during the last 2 decades, while the USA still demonstrate a slight increase of agricultural N input. Large areas of cropland in China stand out due to extremely high N fertilizer input (on average ∼200 kg N ha⁻¹ per crop in 2018; in eastern and southern China even >300 kg N ha⁻¹ in 2018), with still increasing trend [36]. There is also a strongly increasing trend in N fertilizer use in India up to now. Parts of South America also experienced a rapid increase in N fertilizer use rate during the past 20 years, particularly agricultural areas of Brazil, with N input reaching levels close to those of the USA. Australia demonstrates a relatively low level of agricultural N input (less than 50 kg N ha⁻¹ in 2018). N fertilizer use in Russia is still low due to the breakup of the Soviet Union and conversion to market economies [36].

Distinct relationships exist between N fertilizer availability and protein supply for the population of different world regions [16]. Affluent countries (Europe, North America) currently consume about 35% of all N fertilizers. Some countries use more than 60% of all N fertilizers (China alone about 33%) [37]. In these countries, N application could be reduced significantly and adequate nutrition would still be available. Despite excessive N application in agriculture, the supply of dietary protein remains inadequate in countries such as India, Bangladesh, and parts of China. On the other hand, protein deficiencies in these countries would not occur with egalitarian access to food, while countries with stagnating or falling food production due to low soil fertility and limited or no access to N fertilizers (sub-Saharan Africa; several countries in Central Asia and Latin America) would not be able to secure adequate protein nutrition [16].

Health effects of inadequate dietary N intake

Currently, the number of people with chronic inadequate protein intake amounts to ∼1 billion [35] including ∼165 million children under five years of age. In Central Africa and South Asia about 30% of children suffer from malnutrition [27]. Protein deficiency is also common in sections of population in developed countries (e.g. elderly people; home-delivered meals, patients in long-term care facilities, cancer patients) [27]. The global distribution of protein supply to humans reveals that most countries across Europe, Oceania and North America have per capita protein supplies greater than 100 g day⁻¹ (Figure 1). Countries across South Asia, sub-Saharan Africa and South America tend to be close to or below the critical range of 50–70 g capita⁻¹ day⁻¹. Protein deficiency in humans can cause various health problems such as kwashiorkor (caused by severe protein deficiency), marasmus (caused by severe deficiency of protein and energy), impaired mental health, edema, organ failure, wasting and shrinkage of muscle tissue, and weakness of immune system, particularly in children of developing countries [38].

Figure 1:

Daily per capita protein supply [39]. Map derived based on data from FAO: http://www.fao.org/faostat/en/#data/FBS.

Protein-energy malnutrition (PEM) is the most widespread form of malnutrition in the world today and accounts for ∼6 million deaths annually [31]. The number is expected to rise with increasing world population (9.4–10.1 billion by 2050) [40]. PEM includes the classifications of oedematous kwashiorkor (protein deficiency disease), non-oedematous marasmus (energy deficiency disease) and the intermediate form marasmic kwashiorkor [41]. Clinical symptoms of kwashiorkor include weight loss, decrease of muscle mass, swollen abdomen, ascites caused by increase of capillary permeability, enlarged (fatty) liver, anemia, and hair and skin changes; those of marasmus include weight loss (“skin and bones”), growth retardation, chronic diarrhoea, muscle atrophy, skin folds and “old man” face (Figure 2).

Figure 2:

Clinical signs of kwashiorkor and marasmus.

In kwashiorkor, a greater suppression of protein breakdown creates shortages of essential and conditionally essential amino acids, and these insufficiencies impair protein metabolism, while the reduced availability of lipid impairs energy metabolism [42, 43]. Complications of PEM include hypoglycemia, hypothermia, electrolyte imbalance, micronutrient deficiencies and infections, the latter being one of the major complications of PEM. Malaria, bronchopneumonia and measles are the most frequently associated infections with PEM in African children [44]. In sub-Saharan Africa as well as in India, an additional concern is that a number of patients with severe malnutrition are also infected with HIV [45].

The other end of the nutrition spectrum is over-consumption of dietary protein from meals and excessive supplementation in many of the world’s wealthier nations [26]. A prominent example is the doubling of per capita meat consumption in the developed world since 1960. Chronic high protein intake (>2 g kg⁻¹ day⁻¹) may result in diabetes, cancer, intestinal, hepatic, renal or cardiovascular abnormalities [27, 46]. Another important aspect is that much of the world’s grain production is used for animal feed. Feed crops like corn are fertilized at high N levels, which means that increased meat production and consumption has been a significant driver of rising N fertilizer use. In addition, the environmental and health consequences of meat production and consumption vary with the way livestock is raised [26]. Beef, pork, chicken, and turkey are increasingly produced in concentrated animal feeding operations (CAFOs), where the livestock is fed with intensely fertilized grain products [47]. CAFOs lead to a cascade of environmental problems, including high N losses, that can have human health implications [47]. In particular poor manure management practices and decoupling of geographical regions specialized in intensive livestock farming and intensive crop production contribute to high anthropogenic N emissions [48]. Consequently, without high N fertilizer input, the growing use of CAFOs in meat production would not be possible.

Direct health effects of exposure to mobile forms of Nr

Increased circulation of Nr in the environment is also responsible for serious human health effects via different pathways [33]. Nitrate (NO₃ ⁻) is the most common chemical contaminant in the world’s aquifers. Ammonia (NH₃), NO _x and N₂O are classified as primary air pollutants which are emitted directly from a source. Secondary air pollutants result from primary pollutants interactions (e.g. secondary particulate matter formation from NH₃ and NO _x ; ozone formation from NO _x ) and are difficult to control, as they are not emitted directly.

Water polluted with NO₃ ⁻

Sources of NO₃ ⁻

Almost half of the drinking water in the world is sourced from groundwater (GW), and in many parts of the world GW is the most important source of drinking water [49, 50]. In many world regions high levels of nitrate (NO₃ ⁻) are present in GW (Figure 3). In 15 European countries, nearly 10 million people (0.5–10% of population) are exposed to high NO₃ ⁻ levels (above the threshold value of 50 ppm NO₃ ⁻ or ∼11.3 ppm NO₃ ⁻–N) in drinking-water [51, 52]. In China, 28% of the groundwater samples tested during 1980–2008 exceeded the WHO threshold value with 1.5 fold increase in N movement to the groundwater during the period [53]. Major anthropogenic sources of NO₃ ⁻ contamination include cropland (60%), domestic wastewater and septic tanks (20%), industrial waste (13%) and deforestation (7%) [54]. Besides drinking water, vegetables are an important source of dietary nitrate. Green leafy vegetables such as spinach, parsley, lettuce accumulate higher amounts of nitrate (1,000–6,000 mg kg⁻¹ fresh weight) compared to cabbage, cauliflower, celery, artichoke, kale, leek etc. (a few hundred to 1,000 mg kg⁻¹) [21]. Presence of high amounts of free nitrate and nitrite in vegetables can be a health risk to humans. Depending on dietary habits the nitrate consumption through vegetables can reach up to 85% of the total intake.

Figure 3:

Global map with the presence of zones with high nitrate in groundwater.

In global waterways, levels of NO₃ ⁻ have risen by ∼36% since 1990 [55]. Excessive additions of anthropogenic N (and P) from fertilizer runoff have promoted widespread eutrophication of fresh and coastal water bodies [25]. Typical effects include blooms of harmful algae species, the development of O₂-depleted dead zones due to draw down of O₂ levels by aerobic bacteria during their degradation of algal biomass, associated fish kills, as well as acidification as a result of CO₂ formation by vigorous decomposition [56].

Map based on a literature study with information about the percentage of high nitrate concentration in groundwater [57].

Health effects of NO₃ ⁻

Nitrate per se is generally considered non-toxic for humans. Adverse effects on human health are due to conversion of NO₃ ⁻ to nitrite (NO₂ ⁻). WHO (10 ppm), USA (10 ppm) and EU (11 ppm) have adopted NO₃ ⁻–N maximum standards in drinking water. Mainly rural domestic water wells and shallow wells beneath farmlands exceed the standards. Major health issues include infant methemoglobinemia (MHG: “cyanosis” or “blue baby syndrome”) and cancers of the digestive tract. MHG is potentially fatal, usually in infants under 6 months. Nitrite ions in the blood can change hemoglobin (Hb) to methemoglobin (MetHb), thereby inactivating hemoglobin by oxidizing iron from Fe²⁺ to Fe³⁺ and lowering the ability of blood to carry O₂ [58]. Neonates <3 months of age are particularly prone to adverse effects of NO₃ ⁻ exposure [59]. Compared to adults, the gastric pH is higher which enhances conversion of NO₃ ⁻ to NO₂ ⁻. Moreover, babies drink three times more water for their size than older people. In addition, MHG reductase (enzyme that converts MetHb back to Hb) activity is reduced by half in infants. Normal methemoglobin levels do not exceed 1–3%. Clinical symptoms of increased levels include cyanosis (at MetHb concentrations between 10 and 20%), hypoxia (MetHb levels at 20–35%), coma, arrhythmias, shock (MetHb levels at 35–55%), and are lethal at >70% MetHb [21]. However, there exists only limited evidence on the relationship between NO₃ ⁻ and MHG. Infantile MHG directly associated with higher NO₃ ⁻ intake has been demonstrated only in a few studies and NO₃ ⁻ as a cause of MHG is still being debated [60]. A complex co-factor relationship exists; for example, gastroenteritis from bacteria also stimulates NO₂ ⁻ production and MHG. Association of MHG also exists with inflammation, acidosis, exposure to drugs, nitrates from cured meats, fruits and vegetables, and exogenous NO₂.

High nitrate ingestion has also been associated with acute respiratory tract infection, increased risk of spontaneous abortion or certain birth defects in infants, reproductive problems and cancer [59, 61, 62]. N-nitroso compounds, formed from reaction of nitrites with amines and amides in the alimentary canal, have been linked with the risk of different cancers [63]. Nitrate has been associated with ovarian and liver cancers [64], [65], [66]. In England, an ecological study found an increased incidence of adult brain and central nervous system tumours in areas with high drinking water nitrate levels, but a number of case-control studies did not find any relationship [67]. Contrary or mixed results have also been found for other types of cancer. For example, about 50 epidemiological studies conducted since 1975 did not find a convincing link between NO₃ ⁻ and stomach cancer [60]. Analysis of the relationship between different concentrations of nitrate in drinking water and cancer of the stomach, bladder, prostate, and colon among 258 citizens of the province of Valencia (Spain) showed that mortality from gastric cancer in males and females had increased with increasing exposure to nitrate [68]. In populations that had been exposed to high concentrations of nitrates of 50 mg per liter, the relative risk for gastric cancer in the age group of 55–75 years for males and females was 1.91 and 1.81 times, respectively [69]. According to the latter study, deaths from prostate cancer in males have also increased and relative risk for the age group of 55–75 years was higher by a factor 1.86 and for patients older than 75 years this was 1.8 times. Similarly, high dietary intakes of dairy products and meat also increase prostate cancer risk [70]. Consumption of red and processed meat is positively associated with prostate cancer via mechanisms involving heme iron, grilling/barbecuing, benzo[a]pyrene and nitrite/nitrate [71].

In a study conducted in Slovakia, Hodgkin’s Lymphoma and colorectal cancer incidence was observed among males and females who were exposed to water containing concentrations of 4.5–11.3 mg of NO₃ ⁻–N L⁻¹ [72]. In other studies, no association was found between high concentrations of NO₃ ⁻ in drinking water and bladder or kidney cancer [73, 74]. The effect of NO₃ ⁻ concentrations in drinking water on the prevalence of urinary tract cancer in Germany in two groups that were exposed to NO₃ ⁻ concentrations ranging from 10 to 60 mg L⁻¹ was evaluated [75]. In the groups that had greater exposure, a positive correlation was found between urinary tract cancer in both genders, and a negative correlation was found with testicular tumor, but no association with kidney cancer. Negative relationships between NO₃ ⁻ concentration in drinking water and the incidence of Hodgkin’s Lymphoma were found in the UK [76] and Iowa, USA [66]. In Sardinia (Italy), there was limited evidence for prevalence of Hodgkin’s Lymphoma among males but not in females [77].

Different results were obtained from case-control studies on both males and females [78] in the USA. There was a dose-response relationship and the risk of Hodgkin’s Lymphoma doubled with exposure to the highest NO₃ ⁻ concentrations in drinking water. In the same study, the concentration of NO₃ ⁻ in private wells with Hodgkin’s Lymphoma risk was considered irrelevant when intervening pesticides, and vitamin C and carotene were taken into account. In general, most studies have shown that NO₃ ⁻ concentrations in drinking water have either no association with Hodgkin’s Lymphoma or reduced it.

Though there is no clear association between NO₃ ⁻ in drinking water and the adverse human health effects, evidence is emerging of possible benefits in cardiovascular health and providing protection against infections. Nitrate is considered to have a role in protecting the gastrointestinal tract against a variety of pathogens, as nitrous oxide and acidified nitrite have antibacterial properties. It is particularly effective in the stomach against Salmonella, Escherichia coli and other organisms that cause gastroenteritis [21]. It also acts against dental caries and even against fungal skin pathogens such as Tinea pedis (athlete’s foot). Recent research indicates that NO₂ ⁻ participates in host defence because of antimicrobial activity and it protects against a number of problems including ischemia-reperfusion injury (e.g. in heart attack and stroke), kidney injuries and hypertension [79]. Other NO₃ ⁻ metabolites, e.g. nitric oxide, have important physiological roles such as vasoregulation [80]. It is generally suspected that animals lick their wounds because of antimicrobial salivary NO and other compounds. The presence of NO has been shown to increase both mucosal blood flow and mucus generation in the gastrointestinal tract [81]. Nitrite and its conversion to NO in the stomach also have an important role in promoting neonatal health [82]. Human breast milk is known to contain NO₃ ⁻ and NO₂ ⁻, but the breast milk during the first three days (colostrum) contains more NO₂ ⁻ than NO₃ ⁻, which presumably provides more NO in the baby’s stomach because of lack of nitrate reducing bacteria in its mouth and stomach. This ensures protection against infection to the newborn. Finally, it is important to note that increased consumption of vegetables is widely recommended because of their beneficial effects for health notwithstanding that these are a major source of NO₃ ⁻ [80]. There may, therefore, be some benefit from exogenous NO₃ ⁻ uptake, but there is a need to balance the potential risks and benefits.

Air polluted with NH₃

Sources of NH₃

Ammonia (NH₃) as a primary air pollutant is emitted to the atmosphere mainly from agriculture. Farming and animal husbandry (∼80% of total global emissions) are main sources of atmospheric NH₃. Results from a study using recently available retrievals from the Atmospheric Infrared Sounder aboard NASA’s Aqua satellite provide evidence of substantial increases in atmospheric NH₃ concentrations over 14 years in several of the global hotspots represented by major agricultural regions ([83]; Figure 4). The values presented in Figure 4 are integrated over large areas; the local concentrations might be much higher as the transport distance of NH₃ from source to deposition is usually small. Significant increasing trends can be identified over the USA (2.61% year⁻¹), Western Europe (1.83% year⁻¹) and China (2.27% year⁻¹). Over the USA, increases in NH₃ were explained by control of SO₂ and NO _x , resulting in reduced binding of NH₃ in fine aerosols, and by regionally increasing temperatures. Over Western Europe, NH₃ concentrations have increased despite reduced fertilizer use, again due to improved control of SO₂ and NO _x . Over China, a combination of increased agricultural activities, nascent SO₂ control and increasing temperatures caused the observed increases in NH₃ [83].

Figure 4:

Atmospheric NH₃ trends over the world’s major agricultural areas detected from space; volume mixing ratio computed for 1° × 1° latitude-longitude grid cell [83] (with kind permission from John Wiley and Sons).

Health effects of NH₃

Atmospheric NH₃ is highly water-soluble and causes wet tissue (i.e. mucosa, eyes, and sinuses) and skin irritation and damage [21]. Long-term inhalation can be responsible for chronic lung disease. At concentrations >17 ppm, NH₃ can be detected by odor (smell of drying urine). At increased concentration (e.g. 50 ppm for 2 h), irritation of eyes, nose and throat occurs [84]. Clinical symptoms at even greater levels cause rapid eye and respiratory tract irritation and skin burns (100 ppm), immediate irritation of eyes and throat (700 ppm) pulmonary edema and coughing (>1,500 ppm), and extremely high concentrations are fatal (2,500–5,500 ppm for 30 min) or rapidly fatal (5,000–10,000 ppm) [84].

Secondary particulate matter formation from NH₃ and NO _x

Sources of particulate matter

Secondary particulate matter (PM) is a complex mixture of extremely small particles and liquid droplets. Commonly used indicators describing PM that are relevant to health refer to the mass concentration of particles with a diameter of less than 10 μm (PM₁₀) and of particles with a diameter of less than 2.5 μm (PM_2.5) [88]. The effect of PM_2.5 is 4–5 times as severe as PM₁₀. Gases are major contributors to PM. Formation of secondary PM is influenced by emission source profiles and climate/temperature. NH₃ can form ammonium nitrate (NH₄NO₃) mainly in winter and ammonium sulfate ((NH₄)₂SO₄) in summer. NH₄NO₃ has been identified as an important contributor to PM_2.5 in many polluted regions [89, 90]. NO _x and SO _x require oxidants and water vapor; they contribute to PM formation mainly in summer.

Health effects of particulate matter

The WHO estimated that in 2016 globally ambient air pollution was responsible for 4.2 million premature deaths and approximately 3% of cardiopulmonary and 5% of lung cancer deaths were attributable to PM [91]. In 2010 annual PM_2.5 alone accounted for 3.1 million deaths and around 3.1% of global disability-adjusted life years, [88]. In 2012 (with no change since 2000), roughly 75% of humans were exposed to PM concentrations exceeding the WHO guideline value of 20 μg m⁻³ [92]. Figure 5 presents PM_2.5 concentration in different world regions during 2014.

Figure 5:

PM_2.5 concentration in different regions during 2014. Line bars represent standard errors. Emr: Eastern Mediterranean; LMI: Low- and middle income; HI: High-income (based on WHO data [92]).

In 2014, except for Americas (e.g. Canada, USA, Chile, Latin America, Brazil, Mexico), and high-income regions of Europe (e.g. countries in European Union, UK, Switzerland) and Western Pacific (e.g. Australia, New Zealand, Japan, Republic of Korea) all other regions exceeded the threshold value for PM_2.5 (Figure 5). High-income Eastern Mediterranean region (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE) exhibited the highest PM_2.5 followed by low- and middle-income region of Western Pacific (China, Malaysia, Philippines) and South East Asian region (Bangladesh, India, Myanmar, Thailand). These differences in level of pollution point towards regions that need maximum attention.

On a global scale, a 10% reduction of NO _x and NH _y (NH₃ + NH₄ ⁺) would each prevent 22,000 premature deaths per year [93]. A complete removal of agricultural emissions (in particular NH₃) may prevent as many as 800,000 deaths annually [94]. While PM concentrations in the USA and in Europe are moderate and decreasing, there is still an increasing trend of the high levels in East and SE Asia [92]. In recent years, developing countries in Asia such as India and China have embarked on major urbanization and industrialization and consequently have been struggling immensely with severe air pollution. In China, chronic respiratory diseases due to air pollution remained in the top five leading causes of mortality, accounting for 870,000 deaths in 2016 [95]. Approximately one million people died in 2015 due to ambient particulate matter pollution in India [96].

Clinical signs of PM_2.5 exposure are manifold [97]. They include short-term effects such as decreased lung function, increased respiratory symptoms, cardiac arrhythmias, heart attacks and premature death. Long-term effects include decreased lung function, chronic bronchitis, lung cancer and premature death. According to [98] there is an 8% increase in lung cancer development for every 10 μg m⁻³ increase in PM_2.5. The adverse effects of air pollution reveal substantial need for more stringent control policies on the emission of air pollutants worldwide.

Tropospheric O₃ formation from NO _x

Sources of O₃

In addition to PM formation, NO _x also enhances production of tropospheric ozone (O₃), which is a colorless, highly reactive and water-soluble gas with unpleasant odor. As a strong oxidant, O₃ is used as disinfectant for water treatment. Two very different impact categories exist (Figure 6). The first and negative is tropospheric (ground-level) O₃, a local air pollutant that has direct human health impacts. Tropospheric O₃ is also known as a strong greenhouse gas, which over the short term contributes to warming [99]. The second and positive is stratospheric O₃ which is essential in reflecting UV radiation and protecting humans from dangerous levels of UV exposure.

Figure 6:

Concentration profiles of O₃ in the atmosphere [100].

Ground-level O₃ is formed from reaction of NO₂ with O₂ [33]. Requirements for forming ground-level O₃ are solar radiation, NO _x (released from soils or combustion products) and reactive volatile organic compounds (VOCs) which are released as natural VOCs from forests or produced during combustion. VOCs play a key role in O₃ formation. In absence of VOCs, reaction reaches equilibrium, because most O₃ oxidizes NO back into NO₂, creating a cycle. VOCs shift the photochemical reaction towards O₃ build-up. Peak O₃ concentrations occur when high O₃ precursor emissions coincide with appropriate meteorological conditions (sunshine, temperature), resulting in highest O₃ levels during the afternoon hours. The stratospheric O₃ layer is vulnerable to depletion, mainly by N₂O.

Health effects of increased tropospheric O₃

Increased O₃ levels are known to cause serious respiratory diseases. In the EU about 20,000 premature deaths each year are associated with O₃ [101]. Acute health effects of increased O₃ levels include severe ear/nose/throat irritation, eye irritation (at 100 ppb O₃), damages to cells lining the respiratory system, interference with lung functions (O₃ reaches terminal bronchioles and alveoli) and coughing (at 2 ppm O₃). Chronic health effects include irreversible accelerated lung damage, including asthma [102].

Effect of restricted emissions during COVID-19 on air quality

In the first quarter of 2020, coronavirus disease 2019 (COVID-19) spread worldwide and resulted in a global crisis. A relationship between the number of infected people and the lethality of COVID-19 increased exponentially between February and March of 2020, forcing most countries around the world to be under some form of lockdown [23]. Transport was one of the most affected sectors, but also industrial, commercial, and entertainment activities were closed. Several studies have reported decrease in the concentrations of atmospheric pollutants due to the lockdown. Changes of PM_2.5 (monthly averages) during lockdowns in selected cities in Asia, the USA and Europe were reported by [115]. In Delhi and Mumbai (India), a decline of 35 and 14%, respectively, compared to March 2019 was observed. Significant changes were also observed in Beijing and Shanghai cities of China. In Beijing, a decline of 50% was observed from February to March, whereas in Shanghai PM_2.5 declined by more than 50% in the same time period. In Zaragoza (Spain) significant decline (58%) in PM_2.5 was observed during March 2020 compared to February 2020. In New York city, a reduction in PM_2.5 by 32% was recorded during March 2020 compared with March 2019, and by 20% compared to February 2020. In Los Angeles, 4% reduction in PM_2.5 was observed during March 2020 with reference to March 2019, and by about 30% compared with February 2020. In Rome, the average value of PM_2.5 in the month of March 2020 was 24% lower compared with February and 159% compared to the month of January 2020 [115]. After two weeks of lockdown in Barcelona (Spain), the urban air pollution markedly decreased [116]. A lower reduction was observed for PM₁₀ (∼30%). The most significant reduction was observed for NO₂ (51%) which was mainly related to reduction of traffic emissions. In China, several European countries (Spain, France, Italy) and in the USA, NO₂ was reduced by up to 20–30% due to lockdown [23]. In India (mean of 22 cities), around 43, 31 and 8% decreases in PM_2.5, PM₁₀ and NO₂ were observed during the lockdown period compared to previous years [117]. The positive impact on air quality may be temporary. However, the changes in air pollution in the COVID-19 lockdown period provide an insight into the achievability of long-term air quality improvement under significant restrictions in emissions from different sources.

Indirect ecological feedback effects to human health

Conclusions

Reactive nitrogen (Nr) has a wide range of beneficial and detrimental effects on ecosystems and humans. Humans consume N as protein that is indispensable for the development, upkeep and repair of all body cells. In contrast to the developed world with widespread access to commercial mineral N fertilizers, large areas of Africa and smaller but significant regions of Asia and Latin America continue to experience constraints in access to N fertilizers. These regional disparities in N availability contribute to food insecurity, famine, economic insecurity and social unrest. Universal access to mineral N fertilizers combined with improving agricultural practices is critical for reducing malnutrition and promoting resilience. Solving this problem will require inter-governmental cooperation and policies that incentivize the private sector, local NGOs, and citizens to make fertilizers accessible to all.

Human activity creates more reactive N forms (NO₃ ⁻, NH₄ ⁺, NH₃, NO _x (NO + NO₂) and N₂O) than all terrestrial natural processes together. The resulting effects on the environment are widespread but there are also serious human health effects due to the ingestion of N‐containing compounds in air or water, or compounds and particulates produced because of excess reactive N in those reservoirs. Improved agricultural management practices and mitigation technologies can help to reduce direct N emissions as well as secondary particulate matter formation from NH₃ and NO _x . Since atmospheric NO _x also arises from combustion processes, it is important to reduce emissions from traffic, industry and biomass burning. The positive impact of restricted emissions during COVID-19 pandemic on air quality (e.g. NO _x emission reduction) may be only temporary. However, governments should learn from the lockdown on how to reduce air pollution.

Increases in N availability can lead to a cascade of ecological responses at multiple levels. It’s a fact that increased N is not only a main cause of lowered biodiversity but also a driver of vector-borne disease dynamics. Changes in the epidemiology of human diseases due to increased N are variable and complex. They depend on the life histories of disease-causing organisms and their vectors, the structure and composition of food webs controlling their abundance, and the overall sensitivity to increased N shown by the ecosystems in which they reside. Enrichment of surface waters with N and P contributes to eutrophication leading to harmful algal blooms, causing neurological, amnesic, paralytic, and/or diarrheic shellfish poisoning as well as production of human-toxic substances by cyanobacteria and estuarine dinoflagellates. An effective counteractive measure is the protection of groundwater and surface water quality by reducing input of N and P in agricultural systems.

To reduce N emissions from agriculture, optimized management based on the 4-R concept (right type, rate, timing and method of application of N fertilizer) is required. Improvements in animal production systems include efforts to reduce unwanted N release to the environment via inadequate animal nutrition and waste management, as well as reducing excessively high densities of livestock towards appropriate stocking rates. Sharing these approaches to improve N management among developed and developing countries could be a solution to avoid problems with N excess in developing regions. Optimized ways of N use and minimizing stress to natural resources and humans presents a major multinational challenge across the fields of agriculture, ecology and public health. Dealing with all these cross-border challenges, interdisciplinary dialog and collaboration are the key prerequisite.