Nitrogen dioxide poisoning is a health condition caused by breathing in nitrogen dioxide (NO₂) gas beyond safe levels. This gas is reddish-brown and has a strong, unpleasant smell at high concentrations. At lower concentrations, it may be colorless but still has a harsh odor. The severity of poisoning depends on how long, how often, and how strongly someone is exposed to the gas.
Nitrogen dioxide is a chemical that irritates the lining of the nose, throat, and lungs. It is linked to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and sudden worsening of COPD symptoms. It can also cause serious health problems like heart disease and stroke. Because it does not dissolve easily in water, it can pass through the moist tissues in the respiratory system more easily.
The amount of gas inhaled determines how harmful it is to the respiratory system. People who work in environments with high levels of nitrogen dioxide, such as industrial settings, face the greatest risk. Exposure to low levels over time or high levels briefly can both be deadly. Nitrogen dioxide is a major air pollutant released during fuel burning, such as in car exhaust and power plants. It may also come from non-burning sources, like the breakdown of food grains or biodegradable waste in certain processes.
The World Health Organization (WHO) recommends that long-term exposure to nitrogen dioxide should be below 20 parts per billion (ppb) and that short-term exposure should not exceed 100 ppb for one hour. These limits help monitor pollution from fuel combustion. High indoor nitrogen dioxide levels are connected to more respiratory issues, such as wheezing and chest tightness, especially in children with asthma. In the past, cities like Chicago and Los Angeles in the United States have had nitrogen dioxide levels higher than the U.S. Environmental Protection Agency (EPA) safety standards of 100 ppb for one hour and 53 ppb for long-term exposure.
Signs and symptoms
Nitrogen dioxide poisoning is harmful to all living things, similar to poisoning from chlorine gas or carbon monoxide. It is quickly absorbed through the lungs, and breathing it in can cause heart failure and, in severe cases, death. People may have different levels of tolerance for nitrogen dioxide, and these levels can be influenced by factors such as metabolism, air pressure, and blood-related conditions. However, significant exposure can lead to life-threatening conditions that may shorten a person’s lifespan due to heart failure.
Exposure to high levels of nitrogen dioxide can cause inflammation of the mucous membranes and the upper and lower respiratory tracts. Symptoms of acute nitrogen dioxide poisoning are not unique and may resemble those of poisoning from ammonia gas, chlorine gas, or carbon monoxide. These symptoms can also look like those of pneumonia, viral infections, or other inhalation injuries. Common symptoms include runny nose, wheezing, coughing, eye irritation, headache, throat discomfort, and difficulty breathing. These symptoms may worsen to include cracked skin in the nose, sores, or holes in the nasal area. A person with poisoning often appears very ill, with low oxygen levels in the blood and shallow, rapid breathing. Treatment focuses on removing the person from further exposure to the gas. Systemic symptoms may include fever and loss of appetite. Tests such as electrocardiography and chest X-rays can show widespread changes in both lungs.
Chest X-rays may help diagnose the condition, and baseline lung function tests can be used for comparison. There is no specific lab test for acute nitrogen dioxide poisoning, but tests such as blood gas analysis, methemoglobin levels, blood counts, glucose levels, lactate threshold measurements, and blood smears may provide useful information. Testing for nitrogen dioxide in urine or tissue does not confirm the diagnosis, and these tests have technical and interpretation challenges.
Long-term exposure to high levels of nitrogen dioxide can cause chronic poisoning, which may develop within days or weeks after the safe exposure limit is exceeded. This condition can cause fever, fast breathing, rapid heart rate, labored breathing, and severe shortness of breath. Other effects include sweating, chest pain, and a persistent dry cough. These symptoms may lead to weight loss, loss of appetite, and, in advanced cases, enlargement of the right side of the heart and heart disease. Prolonged exposure to low levels of nitrogen dioxide may cause ongoing headaches and nausea. Like chlorine gas poisoning, symptoms often improve after removing the person from exposure, unless severe poisoning occurred. Treatment depends on the symptoms. If a person shows no initial symptoms, they may be observed for at least 12 hours. Oxygen may be given if low oxygen levels are present. High-dose steroids are recommended for those with lung-related symptoms. Hospitalization for 12 to 24 hours or longer may be needed if gas exchange is impaired. In cases of impaired gas exchange, mechanical ventilation or intubation may be required. If bronchiolitis obliterans develops within 2 to 6 weeks after exposure, corticosteroid therapy or anticholinergic medications may be used for 6 to 12 months to reduce the body’s overreaction to the gas.
Cause
Workplace exposures are the main cause of harmful effects, and this risk is especially high for farmers who handle food grains. Firefighters, military personnel who work with explosives, arc welders, traffic officers, aerospace workers, miners, and people who work with nitric acid also face high risks. Silo-filler's disease happens when farmers are exposed to nitrogen dioxide gas in silos. This gas is created quickly by certain plants, like corn, millet, alfalfa, and other grasses, because of a process that happens without oxygen. Dangerous levels of nitrogen dioxide often appear within 1 to 2 days and start to decrease after 10 to 14 days. However, if silos are tightly sealed, the gas can stay for weeks. Silage that is heavily fertilized, especially from young plants, produces more of this gas. Nitrogen dioxide is heavier than air and stays near the bottom of silage during storage. Poor ventilation can lead to exposure when workers level the silage.
Pathophysiology
Nitrogen dioxide dissolves slightly in water. When inhaled, it enters the lungs and slowly reacts with water to form nitrous and nitric acids. These acids cause fluid buildup in the lungs (pulmonary edema) and inflammation of the bronchioles and alveoli. This happens because the acids trigger chemical reactions that damage cells and create harmful effects in the lungs. The lining of the airways, type I pneumocytes, and respiratory epithelial cells are mainly affected. Chemical reactions from cell damage produce free radicals, which irritate the bronchioles and alveoli, leading to the breakdown of respiratory epithelial cells. This process causes fluid to leak into the lungs, resulting in pulmonary edema.
Exposure to nitrogen dioxide can change how macrophages (a type of immune cell) function, weakening the body’s ability to fight infections. High levels of the gas may also cause methemoglobinemia, a condition where too much methemoglobin (a form of hemoglobin with iron in the ferric state, Fe³⁺, instead of the normal ferrous state, Fe²⁺) builds up in the blood. Methemoglobin cannot carry oxygen properly, leading to low oxygen levels in the body (hypoxia).
If nitrogen dioxide poisoning is not treated, fibrous tissue may form in the alveolar ducts—tiny tubes that connect respiratory bronchioles to alveolar sacs, which contain clusters of alveoli (small, mucus-lined air sacs made of flat epithelial cells). This can lead to obstructive lung disease. Additionally, nitrogen dioxide poisoning may cause proliferative bronchiolitis, a condition where the bronchioles become inflamed and overgrown.
Epidemiology
The EPA has regulations and guidelines for monitoring nitrogen dioxide levels. In the past, some areas in the United States, including Chicago, the Northeast corridor, and Los Angeles, have had high levels of nitrogen dioxide.
In 2006, the WHO estimated that more than 2 million deaths occur each year due to air pollution, with nitrogen dioxide being one of the pollutants involved. Over 50% of the health problems caused by these pollutants are common in developing countries, but the effects in developed countries are also significant. An EPA survey in the United States found that 16% of housing units are located near airports, highways, or railroads, increasing the exposure risk for about 48 million people.
A study by the WHO on ozone formed from nitrogen dioxide in the air reported that daily deaths increase by 1 to 2% when ozone levels exceed 47.3 ppb. Exposure to ozone levels above 75.7 ppb is linked to a 3 to 5% increase in daily deaths, and levels above 114 ppb are linked to a 5 to 9% increase in daily deaths.
Silo filler’s disease is common during the harvest seasons of food grains.
In May 2015, the National Green Tribunal in India ordered Delhi and other states to ban diesel vehicles older than 10 years to reduce nitrogen dioxide emissions and prevent nitrogen dioxide poisoning. In 2008, a report by the United Kingdom’s Committee on the Medical Effects of Air Pollutants (COMEAP) stated that air pollution causes about 29,000 deaths in the UK each year.
The WHO’s urban air quality database estimated Delhi’s average annual PM10 levels in 2010 as 286 μg/m³, while London’s was 23 μg/m³. In 2014, the database reported Delhi’s annual average PM2.5 levels in 2013 as 156 μg/m³, compared to London’s 8 μg/m³ in 2010. However, nitrogen dioxide levels in London exceeded the European Union’s standard. In 2013, London’s annual average nitrogen dioxide level was estimated at 58 μg/m³, but the safe threshold limit is 40 μg/m³.
In March 2015, Brussels took the United Kingdom to court for exceeding nitrogen dioxide emissions limits at the coal-fired Aberthaw power station in Wales. The plant operated under a permit allowing emissions of 1200 mg/Nm³, which is more than twice the 5 mg/Nm³ limit set by the EU’s large combustion plant directive.
Prognosis
Long-term outlook for survival after initial exposure to nitrogen dioxide is often influenced by the body's ability to recover. In some cases, nitrogen dioxide poisoning may not cause noticeable symptoms, and lung function tests can confirm if the lungs are working normally. If long-term exposure causes lung damage, it may take days or months for lung function to improve. However, some people may experience lasting mild lung issues, such as bronchiolitis obliterans, which can reduce airflow to 50 to 70 percent of normal lung capacity. This condition may also cause mild inflammation, blocked airways, and require treatment with steroids to address weakened lung function. Long-term exposure can lead to serious health problems, including bronchiolitis obliterans and infections like pneumonia, caused by damage to the lungs' lining from fluid buildup and a weakened immune system. Nitrogen dioxide inhalation can cause short-term or long-term illness or death, depending on the amount inhaled, the concentration of the gas, and the length of exposure. Illness from sudden exposure is usually not deadly, but it can cause bronchiolitis obliterans, fluid buildup in the lungs, or rapid breathing failure. If the gas concentration is extremely high, it may replace oxygen in the air, leading to fatal breathing failure.
Doctors and healthcare workers should teach patients and workers how to recognize signs of nitrogen dioxide poisoning. Farmers and other workers should be taught proper methods for storing food grain to prevent silo filler's disease.
Biochemical effects
Long-term exposure to high amounts of nitrogen dioxide can stop important enzymes called glutathione peroxidase and glutathione S-transferase from working properly. These enzymes are part of the body’s defense system in the mucous membranes and help protect cells by using a substance called reduced glutathione (GSH) to attack harmful non-polar compounds with electrophilic carbon and nitrogen. When these enzymes are blocked, free radicals are created. These free radicals damage lipids in the mucous membranes, causing a reaction that spreads quickly and leads to oxidative stress. This stress weakens the mucous membranes and causes the GSTp-JNK complex to break apart, leading to the formation of GSTP clusters and activation of the JNK pathway. These changes can cause cell death or inflammation in the bronchioles and pulmonary alveoli in mild cases. When nitrogen dioxide enters the bloodstream, it permanently stops an enzyme called acetylcholinesterase in red blood cells from working. This can lead to muscle weakness, seizures, narrowed airways, and breathing difficulties that may result in death. It also lowers the activity of glucose-6-phosphate dehydrogenase, which can cause favism, a condition that makes red blood cells more likely to break down. Both short-term and long-term exposure to nitrogen dioxide also reduces glutathione reductase, an enzyme that helps convert glutathione disulfide (GSSG) back into its active form, glutathione (GSH), which is essential for fighting oxidative stress and keeping cells healthy.
Reproductive effects
Exposure to nitrogen dioxide can harm the male reproductive system by reducing the production of Sertoli cells, which are special cells in the testicles that support the creation of sperm. These cells are located in the seminiferous tubules, which are the tubes in the testicles where sperm develop. When Sertoli cells are affected, the production of sperm cells slows down.
In females, nitrogen dioxide exposure may harm reproduction by increasing oxidative stress, which is a condition caused by an imbalance of reactive oxygen species (ROS). ROS are chemicals that play important roles in the body, including the development of egg cells, fertilization, embryo growth, and pregnancy. However, too much ROS can cause damage. Exposure to nitrogen dioxide can lead to oxidative damage to the DNA of cells in the ovaries during ovulation.
Research shows that ROS can contribute to health problems in females, such as birth defects, miscarriages, hydatidiform moles, and pre-eclampsia. ROS also play a role in the development of endometriosis, a condition where tissue similar to the lining of the uterus grows outside the uterus. Oxidative stress can harm the placenta, reducing oxygen supply to the placenta and causing damage during blood flow restoration after a blockage, which may harm the cells lining blood vessels.
High levels of oxidative stress from nitrogen dioxide exposure can cause inflammation in the cells of the ovaries. In severe cases, this may increase the risk of ovarian cancer.