An Evaluation of Risk Ratios on Physical and Mental Health Correlations due to Increases in Ambient Nitrogen Oxide (NO_x) Concentrations

Abstract

Nitrogen oxides (NO_x) are gaseous pollutants contributing to pollution in their primary form and are also involved in reactions forming ground-level ozone and fine particulate matter. Thus, NO_x is of great interest for targeted pollution reduction because of this cascade effect. Primary emissions originate from fossil fuel combustion making NO_x a common outdoor and indoor air pollutant. Numerous studies documenting the observed physical health impacts of NO_x were reviewed and, where available, were summarized using risk ratios. More recently, the literature has shifted to focus on the mental health implications of NO_x exposure, and a review of the current literature found five main categories of mental health-related conditions with respect to NO_x exposure: common mental health disorders, sleep, anxiety, depression, and suicide. All the physical and mental health effects with available risk ratios were organized in order of increasing risk. Mental health concerns emerged as those most influenced by NO_x exposure, with physical health impacts, such as asthma, only beginning to surface as the fourth highest risk. Mental health conditions occupied seven of the top ten highest risk health ailments. The results summarized in this narrative review show that there are clear positive correlations between NO_x and negative physical and mental health manifestations, thus strengthening the argument in support of the reduction in ambient NO_x levels.

1. Introduction

Air pollution has become a global health crisis with no relief in the foreseeable future. In 2015, the World Health Organization (WHO) and the Organisation for Economic Co-operation and Development (OECD) identified air toxins as the form of air pollution that had the greatest impact on health [1]. Outdoor air pollution is now the fourth leading mortality risk worldwide, preceded only by high blood pressure, dietary risk, and smoking [1,2]. Exposure to atmospheric pollution occurs at all hours of the day encompassing where an individual lives and works. It is also exacerbated by the commutes people make in all modes of transportation including walking, biking, public transport, and driving [3].

Air pollutants are defined as those substances in the atmosphere that cause harm to humans, animals, vegetation, or other materials. In the case of humans, this harm occurs primarily in the form of serious illness (morbidity) and/or mortality [4]. There is substantial evidence linking repeated exposure to various air pollutants to significant health effects [5]. In general, air pollution impacts the cardiovascular and respiratory health of humans. Symptoms can range from mild coughing or irritation of airways to more serious illnesses, including lung cancer, heart disease, stroke, acute respiratory infections, and chronic obstructive pulmonary disease (COPD) [6]. The occurrence of these symptoms can also lead to hospital emergency department visits, hospitalization, and/or premature death [7].

Although air quality related health challenges are being encountered worldwide, they are significantly more apparent in urban environments, especially in lower income countries. The total estimations for 2019 point to approximately 99% of the global population living in areas exceeding WHO ambient air quality standards [8]. Low- to middle-income countries see a disproportionately high impact of poor air quality. It is estimated that over 90% of deaths attributed to outdoor air pollution occur in low- and middle- income countries [8].

Premature deaths due to exposure to both indoor and outdoor air pollutants have been estimated to encompass approximately 10% of all deaths worldwide [6]. In 2016, it was estimated that outdoor air pollution resulted in 4.2 million deaths globally, with 58% from stroke and heart disease, 18% from respiratory infections, 18% from COPD, and 6% from lung cancer [8,9]. The effects of exposure to indoor air pollutants are just as significant as exposure to outdoor air pollutants for the overall health of a population. Indoor air exposure was ranked as the ninth largest risk factor for health in the 2015 Global Burden of Disease and, in 2012, the WHO estimated that 54% of the total 8 million premature deaths associated with poor air quality resulted from indoor air exposure [10,11]. Estimates of the combined worldwide health cost related to both outdoor and indoor air pollution were assessed at USD 8.1 trillion in 2019 [12].

Most of the statistics on air pollution and human health are linked only to the impact of fine particulate matter (PM) and do not take into account the contribution from other air pollutants. PM concentrations are readily monitored, and their health effects are well established, providing a foundation for quantifying the impacts of air pollution on human health. The omission of gaseous pollutants, such as nitrogen oxides (NO_x), from air pollution statistics will need to be remedied in future analyses to provide a more comprehensive view of air pollution. The physical health impacts of NO_x and other gaseous air pollutants have become well established over the past two decades and are the grounds for supporting more stringent exposure guidelines [8].

Another challenge associated with air pollution statistics and messages communicated to the public is that they are solely based on the physical health impacts of air pollution and do not account for mental health effects [13]. The number of people impacted by mental health disorders globally is on the rise. In 2016, these disorders were prevalent in over one billion people, or 16% of the world’s population (Ref. [14] citing data in [15]). Given that approximately one in seven individuals around the world are impacted by mental illnesses, there is a need for a better understanding of how air pollution impacts mental health.

Historically, the repercussions of gaseous pollutant exposure have been perceived through a single lens of physical health effects, but research into the mental health implications of NO_x exposure has begun to gain traction in the last decade. To achieve a holistic understanding of the correlation between NO_x and human health, both the physical and mental health implications must be accounted for. As a result, the aim of this paper is to provide an overview of the health risks due to NO_x exposure, by means of a risk ratio comparison, with a particular focus on the recent developments in mental wellness and how mental health risks compare to physical ailments.

2. Nitrogen Oxides (NO_x) as a Targeted Pollutant

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].

It can be quite difficult to attribute the amount of PM_2.5 or O₃ in the atmosphere to either primary or secondary sources. Source attribution is influenced by geographic location, season, meteorological conditions, wind directions, and surrounding air pollution releases, as these, among other conditions, influence the equilibrium for secondary reactions. Several studies from China [26,27] estimated that between 14% and 27% of the measured secondary PM_2.5 was generated from nitrates, thus illustrating that the NO_x secondary aerosol pathway is significant in PM_2.5 generation. The authors highlight that the significant contribution of secondary PM to the atmosphere necessitates a reduction in the precursor pollutants, such as NO_x, as the focal point for air pollution reduction measures. By reducing NO_x in the atmosphere, not only are the direct negative effects associated with NO_x minimized, but the subsequent health impacts associated with exposure to O₃, PM_2.5, and smog will similarly be reduced.

3. Methodology, Considerations and Contribution of Research

3.1. Methodology

3.1.1. Overview

As stated above, the intention of this work is to provide an illustrative overview of the extensive health research conducted with respect to NO_x exposure, with emphasis on the newly emerging research into mental health. As a result, this work should be considered in a narrative context and not as an exhaustive or comprehensive literature review. Both original epidemiological studies and review papers were collected. Studies covered primarily single pollutant analyses, with some containing multi-pollutant regressions. A multitude of countries are represented with studies including both region-specific and multi-city study locations.

There has been an abundance of research, covering a range of NO_x concentrations for both indoor and outdoor exposure, that has examined the negative physical human health impacts associated with NO_x exposure. The results presented herein do not provide an exhaustive list of the physical health literature but, rather, offer an extensive effort to illustrate the findings in this field, particularly studies presenting risk ratios. Both individual longitudinal studies and also review articles on the association between NO_x exposure, physical health impacts, and risk ratios were collected. One such example is Atkinson et al. [28] which analysed the results from 48 articles on the association between NO₂ exposure and human mortality.

Similar to the physical health research, both individual longitudinal studies and review articles were collected and reviewed herein for associations between mental health and NO_x exposure. With the novelty of the mental health research, limited literature reviews have been completed in this field. Of those available, Łopuszańska and Makara-Studzińska [29], Gładka et al. [30], Zeng et al. [31], and Borroni et al. [32] focus only on depression and, in the case of Gładka et al. [30], suicide. Buoli et al. [33] provides an encompassing view of many different mental health disorders. The challenge with these literature reviews is that they are now outdated, as significant research has been published on the topic since 2019. Additionally, the reviews do not provide a succinct review specifically of NO_x and its impacts on mental health. Over thirty-five longitudinal studies and reviews, published between 2007 and the beginning of 2022, were found concerning NO_x air pollution and mental health disorders.

3.1.2. Data Collection

In an effort to document and effectively evaluate the literature gathered from the search for the physical and mental health correlation with NO_x exposure, various information was collected from the articles. The information of interest, although not always available, from each study included: initial NO_x exposure level, type of health ailment, acute or chronic exposure, metric for assessing health implication (e.g., medication use, hospital admission, etc.), geographic location and context (e.g., some studies looked at multi-city analyses), exposure duration, both categorial and continuous demographic variables (e.g., age or pre-existing medical considerations), seasonality, lag-time to response, single and multi-pollutant considerations, and, ultimately, risk or odds ratio. Once the data were collected, the sheer volume of the experimental conditions used became apparent. In effort to consolidate the information into a format to allow for initial comparisons to be made, type of health ailment, acute vs. chronic exposure, metric, and exposure level were the primary pieces of information extracted from each study, along with the risk or odds ratio result.

3.1.3. Risk Ratio Conversion

Where available, researchers presented results in one of two fashions, either as the risk ratio (RR) or the odds ratio (OR). The risk ratio is the incidence of a health ailment (number with the symptom divided by the total number in group) observed in the group exposed to NO_x air pollution divided by the incidence of the same health effect in the unexposed group, otherwise known as the probability. When this ratio is greater than one, it indicates that there is a higher risk of developing a defined health effect when exposed to air pollution [34]. Odds ratios, on the other hand, provide a ratio of the odds (number with the symptom divided by the number without) of the health impact for the exposed and unexposed study groups [34]. It is possible to calculate RR from OR, and vice versa, based on the following Equation (1) adapted from Viera [34].

$$RR=\left(\frac{OR}{OR+1}\right)+1$$

(1)

3.2. Considerations

This research evaluation was subject to numerous variables that may have influenced the results and findings presented herein. It should be understood that the evaluation was limited by the studies included, the quality of research and results produced in each study, the types of health ailments documented, the participant groups utilized, and the exposure conditions the participants were subject to, among other variables. No manipulation of the original study data, outside of a conversion from OR to RR where applicable, was performed on the data to account for any influencing factors outside of the analysis performed by the original authors.

One of the most prevalent limitations was the ability to isolate and attribute direct causation of health ailments to NO_x exposure. As previously mentioned, NO_x exists in the atmosphere alongside many other air pollutants; therefore, it is difficult to definitively link an observed health ailment solely to NO_x exposure. Research methodologies are advancing in the field to include multi-pollutant models that may point to causation, but the evaluations presented herein should be viewed as correlational in nature between NO_x exposure and health maladies and not as direct causation.

Finally, this review provides a snapshot in time of physical and mental health correlations with NO_x exposure based on the research gathered to date. The results and comparative rankings will evolve as more research is published and included in the evaluation.

3.3. Research Contribution

The breadth of literature available under both physical and mental health studies also covered an expansive set of study variables. Due to the breadth of the research documented herein, the evaluation presented in this work is an initial effort to explore the relationship between physical and mental health, NO_x exposure, and the correlated relative risk associations.

The contribution being offered through this work is to provide insight into the increased likelihood of observing significant health outcomes if ambient NO_x concentrations increase throughout the world or the potential benefit that may be realized as NO_x levels fall. The novel side-by-side comparison of both mental and physical health correlations will provide a unique lens for air pollution and human health discussions. The unique lens presented by this paper can be then used to educate future work into the more extensive and detailed modelling and analysis.

4. Physical Health Impacts of NO_x

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. Human physical health effects linked to NO₂ exposure.

Health Effect Resulting from NOx Exposure		Exposure Duration	Risk Ratios (Per 10 μg·m−3 Increase in NO2 Exposure)	References
General	Diabetes	Chronic	1.23	[42]
	High Blood Pressure	Chronic	1.01	[42]
	Headache	Chronic	1.13	[42]
	Stroke	Chronic	1.01	[42]
	Nose and Throat Irritation	Acute		[4]
	Increased sensitivity and susceptibility to respiratory illness and disease	Chronic		[4,7,17,40,41,43]
	Respiratory Illness	Chronic		[39]
	Chest Colds, Chronic Cough and Wheezing, Chest Cough	Acute and Chronic		[7,11,37,39,44,45]
	Dyspnea	Chronic		[4]
	Reduced Lung Function	Acute and Chronic		[7,37,40,44]
	Bronchitis and Bronchitis Symptoms	Chronic	1.021	[4,16,39,40,46,47,48,49]
	Allergic Reactions	Chronic		[4,7,41]
	Inflammatory Responses	Chronic		[11,16,35,36,37,38,39,47]
	Potential Reproductive Impacts	Chronic		[4,7,41]
	Cell Damage	Chronic		[11,16,35,36,37,38,39,47]
	Cardiovascular Disease (CVD)	Chronic	1.04–1.22	[4,7,17,41,43,50,51,52,53,54]
	Respiratory Disease	Chronic		[4,7,16,17,41]
	Asthma	Chronic	1.05–1.5	[4,7,11,41,42,45,55,56,57]
Hospital Admissions	General	Acute and Chronic	1.01	[46,48,49,58,59]
	Emergency Room	Chronic	1.1	[17,60]
	Stroke	Chronic	1.14	[61]
	Asthma	Acute and Chronic	1.001–1.27	[35,59,61]
	Respiratory Ailments	Chronic	1.009–1.05	[9,59,61,62]
	Respiratory Disease	Acute	1.018	[46,49]
	Chronic Obstructive Pulmonary Disease (COPD)	Acute		[35]
	Blood Poisoning	Acute		[35]
	Cardiovascular-Circulatory System Disease	Chronic	1.05	[61]
	Cardiovascular-Myocardial Infraction	Chronic	1.15	[61]
	Cancer-Lung	Chronic	1.2	[61]
	Cancer-Kidney	Chronic	1.2	[61]
	Cancer-Other	Chronic	1.06	[61]
Cancer	Lung	Chronic	1.12	[3,4,7,41,55,63,64,65,66,67]
	Brain	Chronic		[55,68]
	Cervical	Chronic		[55,68]
	Breast	Chronic		[55,63,68]
	Prostate	Chronic		[63]
Premature Mortality	All-Cause	Acute	1.003–1.016	[41,49,69]
	All-Cause	Chronic	1.003–1.06	[16,17,28,46,48,49,69,70,71,72,73]
	Cardiovascular	Chronic	1.004–1.03	[28,52,69]
	Respiratory	Chronic	1.004–1.03	[16,28,69,74,75,76]
	Lung Cancer	Chronic	1.05	[28,41]
	Coronary Heart Disease	Chronic	1.05	[28]
	COPD	Chronic	1.03	[28]
	Pneumonia	Chronic	1.08	[28]
	Diabetes	Chronic	1.04	[28]

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].

5. Mental Health Impacts of NO_x

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. Human mental health effects linked to NO₂ exposure.

Category	Symptom	Exposure Duration	Risk Ratio (95% CI) per 10 μg·m−3 Increase in NO2 (Unless Otherwise Specified) *-Calculated from OR	Mean NO2 Exposureug μg·m−3	Reference
Common Mental Disorders (CMD)	CMD	Chronic	1.35 (1.26, 1.35)* for NO2 1.23 (1.19, 1.27)* for NOx		[81]
	CMD	Chronic	1.28 (1.05, 1.46)* for NO2 1.27 (1.04, 1.45)* for NOx	35.8–39.6 (NO2) 57.0–67.4 (NOx)	[13]
	Physical Symptoms	Chronic	1.23 (1.02, 1.39)* for NO2 1.22 (1.02, 1.38)* for NOx
	Self-Rated Health	Chronic	1.15 (0.94, 1.32)* for NO2 1.13 (0.93, 1.30)* for NOx
		Chronic	1.07 (1.05, 1.10)* per IQR	23.4	[82]
		Chronic	0.95 (0.39, 1.31)* highest vs. lowest tertile range	34.64	[83]
	Psychological Distress	Chronic	Positive, statistically significant relationship with NOx		[84]
	Mental Health Service Use	Chronic	1.32 (1.25, 1.38) per IQR for NO2 1.31 (1.24, 1.37) per IQR for NOx	40.2 (NO2) 71.1 (NOx)	[85]
	Hospital Admissions	Acute	1.17 (1.00, 1.36)	56.75	[86]
	Hospital Admissions	Acute	1.0188 (−0.40,4.16) for 1-day lag, moving average concentration	46	[87]
	Hospital Admissions	Chronic	1.18 (1.05, 1.34) per IQR for NO2 1.18 (1.05, 1.34) per IQR for NOx	40.2 (NO2) 71.1 (NOx)	[85]
	Emergency Room Visits	Chronic	1.02 (−0.6, 4.6)		[88]
		Acute	1.0494 (1.0203, 1.0792) per IQR	39.8	[89]
		Acute	1.0377 (1.0278, 1.0478)	32.79–53.23	[90]
		Acute	0.9966 (0.9873, 1.0061) per IQR	23.57	[91]
		Acute	1.0445 (1.0290, 1.0604)	24.69	[92]
		Acute	1.0794 (1.0628, 1.0962)	30.13	[92]
		Acute	1.0219 (0.0051, 1.0389)	33.35	[92]
	Psychosis Mortality	Acute	1.0010 (0.9999, 1.0021)	18.7	[93]
Sleep	Low Sleep Efficiency	Chronic	1.16 (1.07, 1.25)*	27.82	[94]
	Sleep Apnea	Chronic	1.28 (1.03, 1.47)*	27.82	[94]
	Sleep Disorder	Chronic	1.11 (1.02, 1.19)* per IQR	36.78	[95]
	Sleep Disorder	Chronic	1.17 (0.77, 1.44)* highest vs. lowest tertile range	34.64	[83]
Anxiety	Anxiety Disorder	Chronic	1.09 (0.90, 1.25)*	27.5	[43]
		Chronic	1.34 (0.85, 1.62)* highest vs. lowest tertile range	34.64	[83]
	Medication Use	Chronic	1.21 (0.90, 1.44)* for NO2 1.13 (0.89, 1.32)* for NOx	57.3	[96]
	Hospital Admissions	Acute	2.23 (1.02, 4.91)	56.75	[86]
	Emergency Room Visits	Acute	1.0342 (1.0210, 1.0475)	32.79–53.23	[90]
		Acute	1.0506 (1.0233, 1.0786)	24.69	[92]
		Acute	1.0740 (1.0545, 1.0938)	30.13	[92]
		Acute	1.0429 (1.0217, 1.0645)	33.35	[92]
Depression	Depressive Symptoms	Chronic	1.50 (1.27, 1.67)* per 10 μg·m−3 increase NO2 1.38 (1.18, 1.53)* per 20 μg·m−3 increase NOx	57.3 (NO2) 92.8 (NOx)	[96]
		Chronic	1.33 (1.27, 1.39)* for highest quartile exposure		[97]
		Acute	1.25 (1.11, 1.36)*	36.2	[98]
		Acute	1.24 (0.99, 1.43)* per IQR	31.4	[99]
		Chronic	1.24 (1.06, 1.39)*	11.7–18.8	[100]
		Chronic	1.35 (1.07, 1.52)* for NO2 1.27 (0.94, 1.50)* for NOx	25.9 (NO2) 39.6 (NOx)	[101]
		Chronic	1.05 (0.98, 1.11)* for NO2 1.05 (0.99, 1.09)* for NOx		[81]
	Medication Use	Chronic	1.03 (1.00, 1.05)* per IQR	23.4	[82]
	Depressive Disorder	Chronic	1.13 (0.95, 1.28)*	27.5	[43]
		Chronic	1.05 (0.86, 1.20)* per 188 μg·m−3-30 days before indexing date	46	[102]
		Chronic	1.05 (0.78, 1.21)* per 188 μg·m−3-365 days before indexing date	46.1	[102]
		Acute	1.04 (0.99, 1.08)* per IQR	34.78	[103]
		Chronic	1.37 (0.99, 1.60)* highest vs. lowest tertile range	34.64	[83]
	Major Depressive Disorder	Chronic	1.14 (0.72, 1.41)* highest IQR for NO2 1.30 (0.96, 1.53)* highest IQR for NOx	26.04 (NO2), 35.19 (NOx)–mean 39.85 (NO2), 59.71 (NOx)–Q4	[104]
	Emergency Room Visits	Acute	1.039 (1.013, 1.066)-Cold Season 1.066 (1.012, 1.124)-Warm Season	41.17	[105]
		Acute	1.10 (1.066, 1.136) per 20.1 ppb NO2-All Season 1.20 (1.133, 1.272) per 20.1 ppb NO2-Warm Season 1.064 (1.021, 1.108) per 20.1 ppb NO2-Cold Season	37.79	[105]
		Acute	1.03 (0.98, 1.04)*-Warm Season, Male 1.03 (1.00, 1.05)*-Warm Season, Female	22.18	[106]
		Acute	1.0369 (1.0224, 1.052)	32.79–53.23	[90]
		Acute	1.08 (1.03, 1.12)*		[107]
		Acute	0.9875 (0.9704, 1.0049) per IQR	23.57	[91]
		Acute	1.36 (0.44, 2.28)	48.5	[108]
		Acute	1.0494 (1.0270, 1.0723)	24.69	[92]
		Acute	1.0802 (1.0623, 1.0984)	30.13	[92]
	Hospital Admissions	Acute	1.18 (0.55, 2.53)	56.75	[86]
		Acute	1.0178 (1.0073, 1.0283)-1-day Lag	34.6	[109]
Suicide	Emergency Room Visits	Acute	1.112 (1.006, 1.228) All Seasons, Male, 1-day Lag 1.239 (1.078, 1.424)-Cold Season, Male, 1-day Lag	36.47	[110]
		Acute	0.9990 (0.9730, 1.0258) per IQR	23.57	[91]
	Risk of Death by Suicide	Chronic	1.33 (1.09, 1.64)	48.20	[111]
			1.39 (1.03, 1.87)-for individuals with pre-existing physical or mental disease	48.20	[111]
		Acute	1.06 (1.01, 1.12)*-All Gender, Under 30 years old, 0-day Lag 1.04 (1.00, 1.08)*-All Age, Warm Season, 0-day Lag	68.94	[112]
		Acute	1.019 (0.999, 1.039)-0–1 day Lag		[113]
		Acute	1.0057 (1.0023, 1.0081)	18.7	[93]
	Completed Suicide	Acute	1.17 (1.04, 1.29)*-all 1.26 (1.09, 1.40)*-Spring and Fall Transitions		[114]
Alzheimer’s Disease	Hospital Admissions	Chronic	1.06 (0.96, 1.17)	26.2	[61]
Parkinson’s Disease	Parkinson’s Disease	Chronic	1.08 (0.94, 1.24)	26.2	[61]

found that, in all cases, air pollution was mapped to NO₂ exposure (NO_x levels were sometimes also included). For the purposes of this review, 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 reviewed 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 (2)), as well subcategories with five or more data points (Equations (3)–(6)):

$$R{R}_{mental health}=0.0064 C+0.9228 {\mathrm{R}}^2=0.1436$$

(2)

$$R{R}_{CMD}=0.0048 C+0.9281 {\mathrm{R}}^2=0.1621$$

(3)

$$R{R}_{Anxiety}=0.021 C+0.4455 {\mathrm{R}}^2=0.3888$$

(4)

$$R{R}_{Depression}=0.0037 C+1.0197 {\mathrm{R}}^2=0.084$$

(5)

$$R{R}_{Suicide}=0.0026 C+1.0656 {\mathrm{R}}^2=0.0793$$

(6)

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.

6. Physical and Mental Health with NO₂ Exposure Relative Risk

With the collected literature on the relative health risk associated with NO₂ exposure, Figure 3 presents the information in a visual form that has been organized from the lowest to the highest RR. The top three highest-ranked health risks fall under the mental health category, spanning anxiety, suicide, and CMDs, with RRs ranging from 1.32 to 2.23. Seven of the top ten highest risk health ailments correlated with NO_x exposure fall under the mental health category. Asthma (ranked fourth (general symptoms) and sixth (hospital admissions)) and diabetes (general symptoms, ranked eighth) are the only physical health conditions in the top ten.

Of the 21 health impacts with an RR of 1.10 or higher, 12 were related to mental health, and the remaining nine were physical health manifestations. The implication of this finding suggests that NO₂ exposure has a significant correlation with the mental wellbeing of the global population, with a risk on par or even greater than the physical health impacts that have been extensively studied. Physical health effects have long been the basis for establishing air pollution exposure guidelines. These results advocate that, for NO_x, it is essential to incorporate mental health into the discussion for setting appropriate exposure guidelines to ensure a healthy population, and solely examining physical ailments is not sufficient.

It is essential to note a few points regarding this comparison between mental and physical health implications correlated with NO_x exposure. First, the evaluation presented herein is not exhaustive of all longitudinal studies conducted in either the physical or mental health realms but has primarily focused on studies that have determined a risk or odds ratio for the particular health impact. This means that there may be factors presented in other studies, which could influence the RR and ranking position. Additionally, mental health research is continuing to emerge; therefore, new studies published following the research conducted for this current work may again influence the RR and ranking for mental health manifestations. Finally, the studies and risk results collected have not been manipulated, outside of the work performed by the original authors, to account for socioeconomic status, living conditions, or other variables that may influence the correlations.

The associations drawn between NO_x exposure and human health were correlations primarily based on single pollutant models and did not examine NO_x pollution impacts independent from other air pollutants, such as PM, black carbon, or SO_x. Causal relationships are difficult to determine as human participants are ubiquitously subject to exposure from a mixture of air pollutants. Advances in modelling and analysis are allowing for complex multi-pollutant assessments to be made. For example, Gu et al. [109] performed two-pollutant assessments and found that the impact of NO₂ exposure on hospital admissions for depression remained significant even after controlling for other pollutants. Another study by Kim et al. [113] looked at the impact of single and two-pollutant models on correlations between air pollutants and suicide in citizens from ten Northeast Asian cities. Single pollutant models showed positive associations for NO₂ exposure, as well as SO₂ and PM₁₀. When considering the two-pollutant models, it was found that there was a reduced RR, when NO₂ was adjusted for the impacts of SO₂ and PM₁₀. A similar finding was shown by Bakolis et al. [13], where single pollutant models were positive between CMD and exposure to each of NO₂, NO_x, and PM_2.5, though the risk was attenuated for all pollutants in two-pollutant sensitivity analyses. As more multi-pollutant studies are conducted a clearer causal association between individual air pollutants and human health may arise, though the significant correlation between air pollutants [13,113] will continue to make isolating these causal relationships difficult.

7. Conclusions

NO_x is a ubiquitous primary air pollutant that contributes to the formation of additional harmful secondary pollutants. As a result, understanding how NO_x impacts human health is critical for use in developing legislation and reduction strategies that may subsequently reduce the excessive exposure experienced by the global population.

The physical health impacts of the exposure to NO_x have been well established over decades of research. A narrative review of some of these studies has been completed and summarized in this paper with a focus on reporting the risk ratio. In support of other bodies of knowledge on the topic, there are clear correlations between NO₂ and NO_x exposure and the development of health problems in the global population.

Since 2015, there has been a shift in air pollution research to examine and quantify the relationships between exposure and the mental health of the global population, but a review of the mental health research has not been completed with up-to-date research. Longitudinal research, published up to the beginning of 2022, into the impacts of NO_x on mental health was collected, and the literature review completed herein found that there were positive and statistically significant correlations between NO₂ exposure and the occurrence of mental health disorders. Significant gaps exist in gaining a geographically holistic understanding, as there is no current research from South America, Africa, Australia, and little in Asia and Eastern Europe on this topic.

Combining the understanding of both the physical and mental health effects of NO₂ exposure into one review has allowed for the ordering of risk ratios. The results illustrated that mental health ailments correlated with the most significant risk from increasing NO₂ exposure. Mental health conditions spanning anxiety, suicide, and CMDs hold the top three RR rank positions. Following these conditions, asthma was the physical health condition most impacted by NO₂ exposure, and it holds the fourth and sixth rank positions. With mental health conditions presiding in the top RR positions, this signals the incredible impact that NO₂ can have on mental health. Therefore, there is an imperative need for mental health to be further studied and accounted for when presenting the impact of air pollution on human health.

The evaluation of NO_x exposure and correlations with both physical and mental health through a side-by-side comparison of risk ratios offers a unique lens for viewing the air pollution and human health dialogue. An initial understanding was presented of the likelihood of significant human health ailments arising with increased levels of NO_x concentrations and emphasizes the need for a global reduction in NO_x pollution. This preliminary exploration is not intended to be static in nature but instead provides a basis for future research to further expand and enhance the concepts presented herein.