Nitrogen dioxide poisoning

Nitrogen dioxide poisoning
Nitrogen dioxide, 2D-dimensions
Classification and external resources
Specialty	Emergency medicine
ICD-10	T59.0
ICD-9-CM	987.2

Nitrogen dioxide poisoning is the illness resulting from the toxic effect of nitrogen dioxide. It usually occurs after the inhalation of the gas beyond the threshold limit value. ^[1] Nitrogen dioxide is reddish-brown with a very sharp, harsh smell at high concentrations. It is colourless and odourless at lower concentration, yet remains potentially harmful. Nitrogen dioxide poisoning depends on the duration, frequency, and intensity of exposure. Nitrogen dioxide (NO2) is an irritant of the mucous membrane and is linked with other air pollutants that cause pulmonary diseases such as obstructive lung disease (OLD), asthma, chronic obstructive pulmonary disease (COPD), and sometimes acute exacerbation of COPD and in fatal cases, death.^[2] Its poor solubility in water enhances its passage and its ability to pass through the moist mucosa of the respiratory tract. Like most toxic gases, the dose inhaled determines the toxicity to the respiratory tract. Occupational exposure constitutes the highest risk of toxicity; domestic exposure is uncommon. Prolonged exposure to low concentrations of the gas may have lethal effects, as can short-term exposure to high concentrations, similarly to chlorine gas poisoning. It is one of the major air pollutants capable of causing severe heath hazards such as coronary artery disease as well as stroke.^[3] Nitrogen dioxide is often released into the environment as a byproduct of fuel combustion but is rarely released by spontaneous combustion. Known sources of NO2 poisoning include automobile exhaust and Power stations; toxicity may also result from non-combustible sources such as anaerobic fermentation of food grains and Anaerobic digestion of Biodegradable waste.^[4] Historically, some areas in the U.S, including Chicago and L.A, have high levels of the gas. The EPA has set standard values of less than 100 parts per billion for one hour exposure and less than 53 ppb for chronic exposure.^[5][6] In addition, the WHO (World Health Organization) has developed a global recommendation to limit exposure to less than 20 parts per billion (ppb) for chronic exposure and less than 100ppb for one hour of acute exposure, using the gas as a marker for other pollutants from fuel combustion.^[7] The standard is also based on the particular concentration of NO₂ that has a significant and profound effect on the pulmonary function of asthmatic patients.^[8]

Signs and symptoms

Nitrogen dioxide gas poisoning causes severe damage to the pulmonary artery and respiratory tract only. As is the case with chlorine gas and carbon monoxide, nitrogen dioxide is not harmful to all forms of life. However, in humans, it is easily absorbed through the lungs, and can result in heart failure or even death in severe cases.^[9] Individuals and races may differ in nitrogen dioxide tolerance level; individual tolerance level for the gas can be altered by several factors, such as metabolic rate, barometric pressure, and hematological disorders, though significant exposure may result in fatal conditions that could lead to shorter life span due to heart failure.^[10]

Acute poisoning

Exposure to high level of nitrogen dioxide may lead to inflammation of the mucous membrane and the lower and upper respiratory tracts.^[11] The symptoms of acute poisoning are non-specific and have a semblance with ammonia poisoning, chlorine gas poisoning, and carbon monoxide poisoning. The symptoms also resemble that of pneumonia or viral infection and other inhalational injuries, but common symptoms includes rhinitis, wheezing or coughing, conjunctivitis, headache, throat irritation and dyspnea which may progress to nasal fissures, ulcerations, or perforation.^[12] The patient is usually ill-appearing, and presents with hypoxemia coupled with shallow rapid breathing. Therapy is supportive and includes removal from further exposure. Systemic symptoms include fever and anorexia. Electrocardiography and chest radiography can help in revealing diffuse, bilateral alveolar infiltrates. Chest radiography may be used in diagnosis and the baseline could be established with pulmonary function testing.^[13][14] There is no specific laboratory diagnostic test for acute nitrogen dioxide poisoning, but analysis of arterial blood gas level, methemoglobin level, complete blood count, glucose test, lactate threshold measurement, and peripheral blood smear may be helpful in the diagnosis of nitrogen (II)oxide poisoning.^[15] The determination of NO2 in urine or tissue does not establish the diagnosis, and there are technical and interpretive problems with these tests.^[16]

Chronic poisoning

Prolonged exposure to a very high level of nitrogen dioxide in micro meter-size range may have an inflammatory effect that principally targets the respiratory tracts, leading to chronic nitrogen dioxide poisoning which can occur within days or weeks after the threshold limit value is excessively exceeded.^[17] This condition causes fever, rapid breathing coupled with rapid heart rate, fever and severe seizure of breath. Other effects include diaphoresis, chest pain, and persistent dry cough, all of which may result in weight loss, anorexia, and may also lead to right-side heart enlargement and heart disease in advanced cases. Prolonged exposure to relatively low levels of nitrogen dioxide may cause persistent headaches and nausea.^[18] Like chlorine gas poisoning, symptoms usually resolve themselves upon removal from further nitrogen dioxide exposure unless there has been an episode of severe acute poisoning.^[19] Treatment and management varies with symptoms. Patients are often observed for hypoxemia for a minimum of 12 hours if there are no initial symptoms; if a patient is hypoxemic, oxygen may be administered, but high-dose steroids are recommended for patients with pulmonary manifestations. Patients may also be hospitalized for 12 to 24 hours or longer for observation if gaseous exchange is impaired. In a case where gaseous exchange is impaired, mechanical ventilation and intubation may be necessary. If bronchiolitis obliterans develops within 2 to 6 weeks of nitrogen dioxide exposure, corticosteroid therapy such as anticholinergics may be required for 6 to 12 months to lower the body's overreaction to the gas.^[20]

Pathophysiology

Nitrogen dioxide is sparingly soluble in water. On inhalation, it diffuses into the lung and slowly hydrolyzes to nitrous acid and nitric acid, which causes pulmonary edema and pneumonitis; this leads to inflation of the bronchioles and pulmonary alveolus via lipid peroxidation as well as oxidative stress.^[21] Mucous membranes are primarily affected, along with type I pneumocytes and the respiratory epithelium. The generation of free radicals from lipid peroxidation results in irritation of the bronchioles and alveoli, causing rapid destruction of the respiratory epithelial cells. The reaction's net result is the release of fluids, leading to pulmonary edema.^[22] Nitrogen dioxide poisoning may alter macrophage activity and immune function, leading to susceptibility of the body to a wide range of infections. Overexposure to the gas may also lead to methemoglobinemia, a disorder characterized by a higher-than-normal level of methemoglobin (metHb, i.e., ferric [Fe³⁺] rather than ferrous [Fe²⁺] hemoglobin) in the blood. Methemoglobinemia prevents the binding of oxygen to hemoglobin, causing oxygen depletion which can potentially lead to severe hypoxia.^[23] If poisoning goes untreated, fibrous granulation tissue is likely to develop within the alveolar ducts, tiny ducts that connect the respiratory bronchioles to alveolar sacs, each of which contains a collection of alveoli (small mucus-lined pouches made of flattened epithelial cells). The overall reaction may cause obstructive lung disease. Meanwhile, proliferative bronchiolitis is a secondary effect of nitrogen dioxide poisoning.^[24]

Etiology

Occupational exposure constitutes the highest risk of toxicity.This risk is often high for farmers, especially those dealing with food grains. It is equally high for firefighters and military personnel(especially those dealing with explosives). The risk is also high for arc welders, traffic officers, aerospace staff, and miners, as well as people whose occupation is connected with nitric acid.^[25] Silo-filler's disease is a consequence of nitrogen dioxide exposure to farmers dealing with silos. Food grains such as corn and millet, grasses such as alfalfa, and some other plant materials produce nitrogen dioxide within hours due to anaerobic fermentation.^[26] Threshold concentrations of nitrogen (II)oxide are often attained within 1 to 2 days, and begin to decline gradually after 10 to 14 days; however, if a silo is well sealed, the gas may remain there for weeks. Heavily fertilized silage, particularly if produced from immature plants, generates a higher concentration of the gas within the silo.^[27] Nitrogen dioxide is about 1.5 times heavier than air; thus during storage of silage, it may remain in the silage material. Improper ventilation may result in exposure during leveling of the silage.^[28]

Epidemiology

Nitrogen dioxide 2011 tropospheric column density.

The EPA have some regulations and guidelines for monitoring nitrogen dioxide levels, although historically, some areas in the U.S including Chicago, the Northeast Corridor and L.A have high levels of nitrogen dioxide. In 2006, the WHO estimated that over 2 million deaths result annually from air pollution in which nitrogen dioxide constitutes one of the pollutants. While over 50% of the disease that results from these pollutants are common in developing countries, the effects in developed countries is not insignificant.^[29] An EPA survey in the U.S suggests that 16 percent of the country's housing units are sited close to airports, highway, and railroads, increasing the exposure risk of approximately 48 million Americans. A feasibility study of the ozone formed from the oxidation of nitrogen dioxide in ambient air reported by the WHO suggested that daily deaths of 1 to 2% are attributed to exposure to ozone at a concentration above 47.3 ppb and that exposure above 75.7 ppb is attributed to a 3 to 5% increase in daily mortality. Levels above 114 ppb were attributed to a 5 to 9% increase daily mortality. Silo filler's disease in particular is pervasive during the harvest seasons of food grains.^[30]

In May 2015, the National Green Tribunal directed Delhi and other states in India to ban diesel vehicles that are over 10 years old as a measure to reduce nitrogen dioxide emission that result in poisoning.^[31] In 2008, the report of United Kingdom committee on the medical effects of air pollutants (COMEAP) suggested that air pollution is the cause of about 29, 000 deaths in the UK.^[32] The WHO urban air quality database estimated Delhi's mean annual PM 10 levels(that is, the average level of particles up to 10 micrometers in size present in the air^[33]) in 2010 as 286 μg /m³ and London as 23 μg /m³. In 2014, the database estimated Delhi's annual mean PM 2.5 particulate matter levels in 2013 as 156 μg /m³ whereas, London have only 8 μg /m³ in 2010 but the Nitrogen dioxide in London breach the European Union's standard.^[34] In 2013, the annual mean Nitrogen dioxide levels in London was estimated as 58 μg /m³ but the save and "threshold limit value" is 40 μg /m³.^[35] In March 2015, Brussels brought suit against the United Kingdom for the breaching of emissions limits of nitrogen dioxide at its coal-fired Aberthaw Power Stations in Wales. The plant operated under a permit allowing emissions of 0.0012 μg /m³ which is more than twice the 0.000 5μg /m³ limit set out in the EU’s large combustion plant directive.^[36]

Prognosis

Generally, long-term prognosis is optimistic for survival of initial exposure to nitrogen dioxide. Some cases of poisoning resolve with no observable symptoms, in which case patient status may be determined with pulmonary function testing.^[37] However, if chronic exposure causes lung damage, it could take several days or months for pulmonary function to improve. Meanwhile, permanent mild dysfunction may result from bronchiolitis obliterans and could manifest as abnormal flow at 50 to 70 percent of vital capacity. It may also manifest as mild hyperinflation and/or airway obstruction, in which case the patient may be subject to steroid treatment to treat deconditioning.^[38] Complications from prolonged exposure include bronchiolitis obliterans and other secondary infections such as pneumonia due to injuries of the mucous membrane by pulmonary edema, and inhibition of the immune system by nitrogen dioxide.^[39] Nitrogen dioxide results in short and long-term morbidity or death depending on the extent and length of exposure and concentration of NO2 inhaled. Illness resulting from acute exposure is usually not fatal, although some exposure may cause bronchiolitis obliterans or pulmonary edema as well as rapid asphyxiation.^[40] If the concentration of exposure is excessively high, the gas may displace oxygen resulting in fatal asphyxiation.^[41]

Generally, patients and workers should be educated by medical personnel on how to identify the signs and symptoms of nitrogen dioxide poisoning. Farmers and other farm workers specifically should be educated on proper methods of food grain storage to prevent silo filler's disease.^[42]

Biochemical effects

Mechanism of Inhibitors of AChE

Chronic exposure to high levels of nitrogen dioxide results in the allosteric inhibition of glutathione peroxidase and glutathione S-transferase, both of which are important enzymes found in the mucous membrane antioxidant defense system, that catalyse nucleophilic attack by reduced glutathione (GSH) on non-polar compounds that contain an electrophillic carbon and nitrogen. This inhibition mechanism generates free radicals that cause peroxidation of lipids in the mucous membrane, leading to increased peroxidized eyrthrocyte lipids, a reaction which initiates a free radical chain reaction mechanism that results in oxidative stress.^[43] This oxidative stress on the mucous membrane causes the dissociation of the GSTp-JNK complex, oligomerization of GSTP and induction of the JNK pathway, resulting in apoptosis or inflammation of the bronchioles and pulmonary alveolus in mild cases.^[44] On migrating to the bloodstream, nitrogen dioxide causes an irreversible inhibition of erythrocite membrane acetylcholinesterase, which may lead to muscular paralysis, convulsions, bronchoconstriction, narrowing of the airways in the lungs (bronchi and bronchioles), and death by asphyxiation.^[45][46][47] It also causes a decrease in Glucose-6-phosphate dehydrogenase which may result in Glucose-6-phosphate dehydrogenase deficiency, also known as Favism, which predisposes the affected to hemolysis (spontaneous destruction of red blood cells).^[48] Acute and chronic exposure also reduces Glutathione reductase, an enzyme that catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell.^[49][50][51]

Reproductive effects

Exposure to nitrogen dioxide has significant effects on the male reproductive system by inhibiting the production of Sertoli cells, a "nurse" cell of the testicles that is part of a seminiferous tubule and aids in the process of spermatogenesis.^[52] These effects consequently retard the production of sperm cells.

The effects of nitrogen dioxide poisoning of female reproduction may be linked with the effects of oxidative stress in female reproduction.^[53]

Nitrogen dioxide poisoning disrupts the balance of Reactive oxygen species, ROS, which results in OS and this have a significant effects on female reproductive life span. ROS play a significant role in body physiology, from Oocite production, development and maturation, to fertilization, development of embryo, and pregnancy. Exposure to nitrogen dioxide causes ovulation-induced oxidative damage to the DNA of ovarian epithelium.^[54]

There is a growing amount of literature on the pathological effects of ROS on female reproduction in relation to free radical-induced birth defects, abortion, hydatidiform mole, and pathophysiogy of pre-eclampsia. ROS also play a significant role in etiopathogenesis of endometriosis, a disease in which tissue that normally grows inside the uterus grows outside the uterus.^[55] Oxidative stress causes defective placentation which is likely to lead to placental hypoxia (a shortage of oxygen in the placenta), as well as reperfusion injury due to ischemia, which may in turn lead to endothelial cell dysfunction.^[56]

Over-expression of oxidative stress caused by nitrogen dioxide poisoning may result in ovarian epithelium inflammation, and sometime leads to cancer in severe cases.^[57]

References