NO_x is a ubiquitous pollutant due to its numerous sources (mainly from stationary and mobile fossil fuel combustion but also from natural causes such as lightning), its potential to be both a primary and secondary pollutant, and its documented impacts on human health.

NO_x occurs primarily in one of two forms: nitric oxide (NO) and nitrogen dioxide (NO₂). NO is generally emitted as a primary pollutant, which photochemically reacts with free radicals in the atmosphere to form NO₂ [4,16]. There are instances where NO₂ is emitted as a primary pollutant, but more often than not, it occurs as a result of pre-existing NO [17]. The rate of secondary oxidation of NO into NO₂ depends on the solar radiation intensity, humidity, concentration, availability of free radicals, and airflow in the region of concern [18]. When no information is not provided, it can be assumed that the NO₂ concentration is essentially equivalent to the NO_x concentration, since any NO in the atmosphere reacts quickly to form NO₂ [4,16].

NO and NO₂ can rapidly cycle back and forth in the atmosphere on a minute-by-minute timescale [19]. NO_x is regarded as a short-lived air pollutant with an atmospheric lifetime on the order of a day [19], although this is typically shorter in the summer (<6 h [20,21]) due to higher ozone concentrations [21]. NO₂ buildup in the atmosphere can be visually seen hanging over many large urban centres as a brown haze on the horizon.

In some instances, nitrous acid (HONO) is also generated [18]. Water molecules in the atmosphere are able to dissolve the ambient NO₂ to form acidic compounds contributing to acid rain, putting ecosystems at risk of acidification. Additionally, NO₂ can be absorbed directly by plants causing damage or death of tissue, which can impact plant growth and yield [7].

NO_x, while a significant environmental pollutant on its own, also acts as a precursor for other air pollutants. NO_x typically resides close to ground level in urban environments and, through a complex set of reactions, can react to form both ground-level ozone (O₃) and fine particulate matter (PM_2.5) in the form of secondary organic and inorganic aerosols (SOAs and SIAs, respectively). This, in turn, contributes to smog formation [22,23,24,25]. These reactions are cyclical in nature and can result in a buildup of NO_x and O₃ at ground level. There is typically a lag time between when the concentration of NO_x increases (during morning and evening rush hours) and when the concentration of O₃ increases (mid-morning and into the afternoon during peak solar intensities) [24].

The main route of NO_x exposure for humans is via inhalation, during which 80–90% is absorbed into the body through the respiratory tract. Nitrogen oxides, both NO and NO₂, are readily absorbed into the bloodstream through the respiratory tract. Once in the bloodstream, NO reacts quite quickly, on the order of three seconds, with O₂ to generate NO₂. NO₂ can further react in the bloodstream, as it is a water-based environment. Highly reactive NO₂ generates superoxide and alloxy radicals, and the ensuing nitrogen anion imbalance contributes to lipid peroxidation [35].

NO occurs naturally in the bloodstream and has essential physiological functions in the human body, including acting as a vasodilator and signalling molecule. Blood concentrations above what is considered normal trigger inflammatory responses [35,36,37,38,39].

Exposure to NO also directly affects the nitric oxide synthase (NOS) activity, generally found in the intercellular fluid or in membranes of blood vessels and can trigger changes to the respiratory system and cellular respiration leading to the formation of reactive oxygen species (ROS). The presence of ROS in the respiratory tract and lung parenchyma result in sensitive tissue damage, such as augmentation of pulmonary permeability, increased mucus secretion, damage to fatty bronchial epithelium, and damage of surfactant properties. Chronic exposure directly causes the inflammation of tracheal mucosa and is often expected to be observed with irritation of the conjunctiva and ulceration of the nasal cavity [35]. Moreover, within the human body, NO can act as a vasodilator of cerebral blood vessels, causing cytotoxic activities in the immune system, as well as acting as neurotransmitter. Within the brain, neurons produce NO during their function and, when the NO and NO-synthase equilibrium is imbalanced, this can disrupt the cerebral blood flow and brain activity connection [36].

Nitrosation is the primary indirect impact of enhanced NO in the bloodstream and leads to the formation of nitrosamines. These byproducts damage DNA leading to carcinogenesis processes as well as chronic inflammation. Another NO reaction byproduct is superoxide nitrates, strong oxidizers responsible for inflammation and lipid peroxidation, with subsequent damage to cells and tissues throughout the body [35,36,37,38,39].

The first signs of NO_x exposure are generally nose and throat irritation. If exposure persists, these symptoms can progress to bronchoconstriction and dyspnea (difficult and laboured breathing), especially in individuals who suffer from asthma [4]. Symptoms can worsen and develop into bronchitis, reduced lung function, and increased susceptibility to other respiratory developments [40]. Continued direct exposure to NO_x can lead to increased sensitivity to respiratory infections, allergic reactions, childhood asthma, lung cancer, cardiovascular and respiratory diseases, and potential reproductive impacts [4,7,41]. These impacts can lead to increased risk for hospital emergency room visits, hospital admissions, and mortality.

Table 1 summarizes the more specific health effects resulting from both acute and chronic NO_x exposure, specifically for NO₂, along with the risk ratio (where available) that represents the increased risk associated with a 10 μg·m⁻³ increase in concentrations of NO₂. It is evident, based on the literature, that exposure to NO₂ has numerous adverse health effects, many of which can be severe in nature if left untreated. In addition, many of these health effects are confounded by the simultaneous exposure to O₃ and PM_2.5, of which NO_x is a precursor gas.

While NO_x, O₃, and PM_2.5 have individual health impacts [77], they coexist in the ambient atmosphere; hence, it is not possible to allocate the health impacts, or portions of the impacts, to one specific pollutant outside of a controlled laboratory setting. Based on the medical evidence to date, the WHO has established annual and 24-h mean NO₂ exposure limits of 10 μg·m⁻³ and 25 μg·m⁻³, respectively [8]. Prior to 2021, the annual limit was set at 40 μg·m⁻³. These limits are guidelines, and many countries impose their own regulations, having not yet adopted the new WHO guidelines. In Canada, for example, the current annual and 1-h NO_x exposure levels are 35 μg·m⁻³ and 123 μg·m⁻³, respectively. These limits are scheduled to be reduced to 25 μg·m⁻³ and 86 μg·m⁻³, respectively, in 2025 [7].

The mental health impacts of NO_x are not as established as the physical health effects of NO_x and appear to have become a major focus of research after approximately 2015. This date coincides with the emergence of a worldwide societal focus on the mental health of the population and has been a focus over the past decade [14]. Mental health has been identified in the UN Sustainable Development Goals and focuses on promoting wellbeing among global citizens [78].

Mental health is an integral part to the overall wellness of an individual and, when not cared for properly, can also contribute to detrimental physical health impacts. A recent study at the University of Washington [79] found that the prevalence of mental health disorders increased at a rate of approximately 9,876,000 cases per annum between 2000 and 2019. This means that in 2020 there were be over 976 million people, 12.6% of the world’s population, with a mental health disorder. With the high ever-increasing prevalence of mental health disorders and with air pollution being a ubiquitous challenge significantly impacting physical health, the question becomes how does air pollution, specifically NO_x, impact mental health?

The evaluation of the over thirty five longitudinal studies and reviews presented herein in Table 2 found that, in all cases, air pollution was mapped to NO₂ exposure (NO_x levels were sometimes also included). Any OR from studies were converted to RR, and the data converted from ORs are clearly indicated. The mental health concerns investigated included common mental disorders (CMD), sleep apnea, anxiety, depression, and suicide. Sleep apnea was included in the research because of its strong association with the occurrence of many psychopathological conditions, including psychological distress, anxiety, depression, and suicidal ideation [80]. Most commonly, researchers collected data based on emergency room visits, though other metrics were used to quantify mental health impacts including self-reported assessments, medication use, hospital admissions, and number of deaths. The work was primarily collected on adults of all sexes, over numerous years, and spanning multiple seasons.

All studies found positive relationships between NO₂ exposure and mental health disorders, and all but twelve of the 66 relationships were statistically significant to at least the p < 0.05 significance level. Depending on the length of the study and the data set available, some of the studies made adjustments for the sex, season, and the lag after the exposure event. There were no distinguishable trends across the literature as to whether sex or season posed any greater risk to mental health disorders due to NO₂ exposure. Studies that examined the time separation between exposure event and mental health disorder manifestation did, in general, find that there was increased risk associated with shorter time scales (i.e., a mental health disorder generally had greater risk of manifestation in a zero to one day lag from the exposure event with the risk diminishing with more time passing from the exposure event). An overall observation from the body of literature points to a positive statistically significant correlation between NO₂ exposure and the mental health of the global population.

A comparison between the RR for each mental health disorder and for NO₂ exposure level is presented in Figure 1. For reference, the WHO 24-h and annual mean exposure guidelines for NO₂ are included on the plot. All studies had NO₂ exposure concentrations that surpassed the 2021 WHO annual mean exposure guideline for NO₂, and all but four exceeded the 24-h guideline. Data points are grouped based on the type of mental health disorder, and the metric used to quantify the disorder (i.e., emergency room visits, medication use, etc.) is not distinguished. The scattered nature of both data sets does not lead to any significant correlation for linking mean exposure to the level of risk of the presence of a mental health disorder. Linear trend lines were fit to the entire data set (mental health) (Equation (1)), as well subcategories with five or more data points (Equations (2)–(5)): with RR being the risk ratio for all types of mental health disorders due to NO₂ exposure, and C is the NO₂ concentration (µg·m⁻³).

In all instances, there were positive correlations between NO₂ exposure and mental health disorders, though with low correlation coefficients. Based on the trend line slopes, anxiety carries the most risk with increased NO₂ exposure levels. The subcategory of ‘sleep’ only had four data points, and ‘other’ included only Alzheimer’s and Parkinson’s diseases; thus, no trend lines were generated given the limited data. Additionally, the correlation coefficients for all the linear trend lines were very low ranging from a minimum of R² = 0.0793 to a maximum of R² = 0.3888. One primary reason for the large degree of scatter in the plot is that the exposure duration and concentration for each study was varied. The length of exposure and fluctuations of NO₂ about the mean were not well communicated in the research and, thus, not accounted for. This makes it difficult to definitively correlate the risk ratio back to a single NO₂ concentration value. While the scatter of the data may not lead to a strong fit, there is a distinct trend that increasing concentration enhances the risk of an individual manifesting a mental health disorder. This positive association, coupled with the fact all studies examined exceed the WHO annual mean NO₂ guideline, leads to the observation that NO₂ levels in urban areas must be reduced in order to help protect the mental health of global citizens.

Figure 2 provides a geographical representation for where the studies on mental health have been conducted, in regard to NO₂ exposure, on a world map by highlighting countries in blue. There is significant representation in North America, North and Western Europe, and some in Asia (mainly from China). Study gaps exist for Australia, South America, Africa, most of Asia, and Eastern Europe. Many of these regions are known to be heavy emitters of anthropogenic air pollution and are also highly populated. For example, ambient air quality in India (home to 1.4 billion people) can be extremely poor, with the capital city, Delhi, having the worst air quality in the world in 2020 [115]. Without mental health study data in these regions, any regional nuances and ramifications of NO₂ exposure on mental health cannot be ascertained.